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Flashcards in Pharmacy Deck (261):

LO 1.1 Be aware of the major underlying causes of poor prescribing and see how these causes relate to each other

Deaths relating to prescribing rate is five times higher than it was ten years ago, perhaps due to increased reporting.

Prescribing Problems
o Prescribing errors are complex and multi factorial.
o poor communication in particular has been shown to be a major factor in both causing and compounding prescription error.

Patient and Population Related Problems
o Rapid patient turnover
o Sicker and older patients, more vulnerable to adverse effects
o Increased use of medicines generally (Multiple drugs)
o Increasing complexity of medical care (Co-morbidity)

Pharmaceutical Problems
o Vast numbers of new drugs
o Clinical evidence for new drugs is usually from selected, relatively healthier patients and/or young volunteers
o Some side effects only come to light after the drug comes to market
o Blind adherence to guidelines can lead to prescription where contraindications or serious interactions exists

Doctor related problems
o No room for error and expected to be perfect from day 1 after qualification
o Experience from medical school (level of teaching/examining)
o On call medicine (Sleep deprivation, exhaustion)
o Shift work (Lack of continuity of care, working alone more often)


LO 1.2 Recognise how problems in prescribing can compound prescription error giving the two models of error, and the types of error

Reason’s Model of Error Causation is a model of the general factors underlying error and accident causation in human systems. It is broken down into three components, Latent Conditions, Error Producing Conditions and Active Failures.

Swiss Cheese Model
In the Swiss cheese model, the layers represent defences on the path from hazard to accident. If weaknesses in the defences, either from inadequate design or error line up (‘holes in the cheese’), hazards may pass completely through all the layers to cause an adverse event.

Types of Error
Skill based errors
o Slips – Action based errors
o Lapses – Memory based errors
o Knowledge based mistakes
o Violations - Knowingly disregard rules


LO 1.3 What are the requirements for a prescription. What should you confirm, legal requirements and a basic checklist.

Before writing a prescription confirm
o Name of Drug(s)
o Dose
o Strength
o Frequency
o Duration of treatment
o Allergies/adverse effects
o Indication
o Adherence

Legal Requirements
o Written in indelible ink
o Patient identification (name, address, hospital number)
o Date of birth (if under 12)
o Signed
o Dated
o Name and address of practitioner

Basic Check List for safe prescribing
o The right drug
o Drug distribution/elimination
o Alternatives - Non prescription medications
o Route
o Dose
o Frequency
o Duration
o Monitoring
o Information
o Special requirements


`What is the yellow card scheme

In Black Triangle Drugs (one being monitored, e.g. newly released, changed indication or formulation) and unlicensed herbal preparations you should report all suspected reactions, however trivial

In Established products and vaccines, report all suspected serious reactions, even if the reaction is well known and recognised, a serious reaction is any that results in or prolongs hospitalisation. Also ones that are fatal, life threatening, disabling or incapacitating. Also report paediatric cases


LO 1.6 Be familiar with a modern day formulary and give examples of formularies in everyday use

The British National Formulary is a comprehensive listing of all the drugs currently licensed in the UK. It is in widespread use throughout the NHS. It also includes some drugs that have traditionally been used but have now been identified as less suitable for prescribing, either because of lack of efficacy or increased toxicity.


LO 1.9 Identify the most important characteristics of a drug relevant to therapeutic use

Efficacy - How effective it is compared with similar drugs or a placebo

Safety - Major and minor adverse effects

Cost - But only if efficacy and safety of two drugs are equivalent


LO 1.10 Recognise the central role of the pharmacist in overviewing prescription and minimising the risk and consequences of prescription error to both patient and doctor

The pharmacist often has a deeper and broader understanding of pharmacology than most medics. They also occupy a pivotal position in the healthcare system in overseeing that prescriptions are correctly made out.

However, the primary role they play in detecting prescription error does not mean they take the responsibility for what is written on the prescription. This always lies with the prescribing medic, the legal responsibility of the pharmacist is to dispense according to prescription.


Deifne Pharmacokinetics, Pharmacodynamics and Pharmacogenetics

Pharmacokinetics – What the body does to the drug
Pharmacodynamics – What the drug does to the body
Pharmacogenetics – The effect of genetic variations on pharmacokinetics/dynamics


What are the Key Pharmacokinetic Factors and understand the importance of pharmacokinetics applied to clinical practice

Absorption, Distribution, Metabolism, Elimination

Bio availability - leads to the correct formulation

Half-life - allows dosing regimens to be devised

Drug elimination

Intra-subject variability - allows appropriate dosing regimens for special patient groups, helps determine why a patient may fail to respond to a treatment or why a drug has caused toxicity

Drug-Drug interactions


LO 2.3 Recognise the main routes of drug administration in to the body

Enteral delivery includes drug routes via the GI tract:
o Oral
o Rectal
o Sublingual

Parental Delivery are the drug routes not via the GI tract:
o Intramuscular
o Intravenous / Intravenous Infusion
o Intrathecal
o Topical
o Subcutaneous


LO 2.4 Understand the factors affecting drug Absorption

When drugs are given orally, both the rate of uptake of a drug and first pass metabolism can affect the peak plasma concentration of a drug and the time it spends in the body.

Passive Factors:
o Drug Liphophilicity.
o Molecular size
o pH changes

Active Factors:
o Presence of active transport systems
o Splanchnic blood flow (reduced in shock and heart failure)
o Drug destruction by gut and/or bacterial enzymes


LO 2.4 Understand the factors affecting drug Distribution and the factors affecting protein binding (what makes it worse, and what proteins bind to what)

The major factors affecting the distribution of a drug are:

o Lipophilicity / Hydrophobicity

o Tissue Protein Binding (e.g. muscle)

o The mass or volume of tissue and density of binding sites within that tissue - This can vary significantly between individuals, for example in a patient with a large muscle mass, Digoxin binding would be effected as it has a very high affinity to Na/K ATPase.

o Protein Binding -Once in the systemic circulation, many drugs are bound to circulating proteins. However, most drugs must be unbound (free) to have a pharmacological effect. Only the fraction of the drug that is not protein bound can bind to cellular receptors, pass across tissue membranes, gain access to cellular enzymes etc. Displacement of drugs from binding sites due to Protein Binding drug interactions raises the free concentration of the displaced drug. These changes in drug distribution are only important if three criteria are met:
High protein binding
Low volume of distribution
Drug has a narrow therapeutic ratio

Factors affecting protein binding include:
Renal failure
Displacement by other drugs

Protein Binding
o Albumin -Acidic drugs
o Globulins - Hormones
o Lipoproteins - Basic drugs
o Acid Glycoproteins - Basic drugs


LO 2.5 Understand the factors affecting drug metabolism

Phase I
Most drug molecules are stable and relatively unreactive (pro-drugs) so in Phase I metabolism a reactive group is exposed on the parent molecule or added to the molecule via Oxidation, Reduction and Hydrolysis reactions. The process requires Cytochrome P450 and NADPH. These enzymes are both Inducible and Inhibitable, and are located on the external face of the endoplasmic reticulum in hepatocytes. A wide range of factors, including sex, age, genetics, cardiac output, and a disease state affects the metabolism of drugs. Some drugs already have a reactive group on their molecule so they can bypass Phase I. Morphine is a good example of this.

CYP Inducer
Alcohol (Chronic)
Sulphonylureas & St. John’s Wort

CYP Inhibitor
Grapefruit Juice
Cimetidine & Ciprofloxacin
Ethanol (Acutely)

Phase II
The reactive intermediate from Phase I is conjugated with a polar molecule to form a water-soluble complex. The process is also known as conjugation.

Glucoronic acid is the most common conjugate, as it’s an available by-product of cell metabolism. Drugs can also be conjugated with sulphate ions and glutathione. Phase II metabolism requires specific enzymes and a high-energy cofactor, uridine diphosphate glucuronic acid (UDPGA).


LO 2.5 How does drug excretion occur and understand the factors affecting excretion

Metabolism causes drugs to become more ionic, increasing the ability of the kidney to excrete them via passive glomerular filtration and active tubular secretion.

Excretion out of plasma is then offset by diffusion back across the tubule, especially for lipophilic drugs, which is why the liver goes to so much effort to make them more ionic in nature.

Organic Anion and Cation Transporters (OAT % OCT) are also responsible for transporting drugs across the tubule into the urine.

Factors affecting Renal Excretion
Balance between the above processes and the factors that affect them
o Renal Blood Flow
o Plasma Protein Binding
o Tubular Urinary pH (affects the proportion of weak acids/bases diffusing back into the blood)


LO 2.5 Understand the difference between linear and non-linear kinetics

First Order (Linear) Kinetics -Metabolism is Proportional to Drug Concentration. Give a straight line when a log scale is on the Y-axis versus time.

Half-life is the rate of decline of plasma drug level proportional to drug level.

Zero Order (Non-Linear) Kinetics:
In a situation where drug is used at a concentration much greater than Km. The enzymes (e.g. CYP450s) are saturated. The rate of decline of plasma drug level is a constant, regardless of concentration. Because of this Zero Order drugs are more likely to result in toxicity. Zero order kinetics gives a straight line when normal (not log) plasma concentration (Y) is plotted against time (X).

During drug administration, a steady state will be reached within 5 half-lives of that drug. If an immediate effect is necessary, a Loading Dose is needed, bringing the concentration of the drug up to the level it wouldhave been after 5 doses.


LO 2.6 Appreciate how Steady State therapeutic levels in plasma (CpSS) are reached and how Loading Doses are employed to reach CpSS more rapidly

Reaching Steady State Concentration in Plasma (CpSS)

With controlled, continuous infusion therapeutic levels are determined by dose rate and clearance.
Steady State Concentration in Plasma = (Dose Rate)/Clearance

Repeated Dosing
When, as in the majority of cases, drugs are given as repeated doses a steady is not obtained, instead the steady state will have peaks and troughs related to the dosing intervals. This is not strictly a ‘steady state’, but if the peaks and troughs are averaged out they are considered to be roughly therapeutically equivalent to the steady state.

Loading Dose
In repeated dosing the time then taken to reach a steady state concentration in plasma is 4-5 half-lives of the drug. If clinicians want to achieve a therapeutic concentration as quickly as possible without waiting for these 4-5 half-lives, they can use a loading dose. A loading dose aims to fill the compartments contributing to the drugs volume of distribution by using a larger than normal dose. The size of the loading dose is calculated using the known Vd of the drug and the desired therapeutic concentration. When using a high dose of a drug means the risk of toxic side effects is increased.

Loading Dose = Vd ×CpSS


LO 2.7 What is Pharmacodynamics, how do drugs exert their effects and what is the effect of concentration on this?

Pharmacodynamics – What the drug does to the body

Drug molecules bind to a range of biological receptor molecules. The four principle classes of receptor site are:
o Receptors
o Enzymes
o Carriers/Transporters
o Ion Channels

Drug Concentration
o The response to a drug is generally proportional to the number of receptor sites bound to by the drug.
However, as target receptors can exist at different tissues throughout the body, actual expression levels in different tissues may vary widely and the receptors in only one of these tissue types may actually serve as the desired site of action.
o Pharmodynamic response can be directly proportional to drug concentration.
o However, as the concentration of drug increases the number of sites generating a therapeutic response can become saturated. The Pharmodynamic response will then show a non-linear response to further increases in drug concentration.


LO 2.8 Be able to describe the major types of drug-receptor interaction

Agonist – Bind to and stabilise receptor sites in the Active conformation

Antagonist – Bind to and stabilise receptor sites in the Inactive conformation

Partial Agonist/Antagonist – When drugs act as a mixture of both of the above, they are said to act as Partial Agonists or Partial Antagonists. The overall action of the drugs is dependent on the proportion of receptor sites it stabilises in the Active or Inactive confirmation.


LO 2.9 Define Affinity, Efficacy, Types of Agonmist and Potency and appreciate the idea of a Therapeutic Window and give the value they are each measured in.

Affinity – The tendency of a drug to bind to a specific receptor site.
Kd – Concentration at which half available agonist receptors are bound
Ki – Concentration at which half available antagonist receptors are bound

Efficacy – The maximal effect of a drug when bound to a receptor. Expressed in terms of percentage response, with 100% response when no increase in drug concentration brings about any further increase (non-linear response)
Agonists – Aim for 100% efficacy
Antagonists – Aim for 0% efficacy

Potency (Agonist) (EC50) – Concentration that produces 50% of maximal response
Potency (Antagonist) - Concentration that reduces maximal activation by 50%
Can only be measured in vitro

Competitive Antagonism
In competitive antagonism agonist efficacy can be restored, by increasing agonist concentration. This increases the competition for receptor sites.
In this case Potency (EC50) changes as more of the drug is needed to produce 50% of the maximal response, but the maximal effect stays the same.

Non-Competitive Antagonism
In non-competitive antagonism the antagonist can bind in two ways:
At the same site for the agonist binding irreversibly or unbinding very slowly
At a separate site to the agonist either reversibly or irreversibly
In this case, no matter how much agonist is added, the maximal effect will be depressed proportional to the degree of antagonist binding. However, because the agonist does not have to compete to occupy its binding site, the EC50 remains the same.

Therapeutic Window
The therapeutic window is the concentration of drug that is high enough to have a therapeutic effect, but not so high that is has a toxic effect.

Some drugs have extremely narrow therapeutic windows, e.g. Phenytoin meaning they have to be closely monitored.

Therapeutic Index
Therapeutic Index= (Toxic Dose in 50% of People (TD50))/(Effective Dose in 50% of People (ED50))


LO 2.10 Describe with examples pharmacokinetic and pharmacodynamic drug interactions

Pharmacokinetic Drug-Drug Interactions (ADME)

Drugs given via the oral route can be affected by co-administration of other agents affecting gut motility and passive or active absorption by the gut.
o E.g. Metoclopramide acts as a dopamine antagonist. It is an antiemetic and gastroprokinetic. This will increase the rate of gastric emptying and can therefore increase the rate of uptake via the small intestine.

The distribution phase can be affected by competition between drugs at protein/lipid binding sites. For the most part, drugs that exhibit linear kinetics and have a reasonable therapeutic window, these effects are offset by an increased clearance.
If the drug has non-linear (Zero Order) Pharmacokinetics and/or a narrow therapeutic window, e.g. Phenytoin, this can lead to serious toxicity.

Drugs can significantly affect metabolism of themselves or other drugs by two mechanisms – Induction and Inhibition of the CYP450 enzymes.

The primary mechanisms affecting drug excretion include changes in:
o Protein Binding - Decreased binding increases the amount of free, unbound rug, accelerating its removal
o Tubular secretion - Inhibition of tubular secretion will result in increased plasma levels of drug. This can be used to improved therapeutic effect in some cases, if tubular secretion is very rapid
E.g. Probenecid was specifically developed to enhance the therapeutic action of Penicillin by reducing its renal excretion.
NSAIDs can also reduce tubular secretion.
o Urinary pH - Affects the proportion of weak acids/bases diffusing back into the blood.

Pharmacodynamic Drug-Drug Interactions
Pharmacodynamic Interactions involve a direct conflict between the effects of drugs. This conflict results in the effect of one of the two drugs being enhanced or reduced. For example:
o Propranolol, a non-selective β-Receptor Antagonist given for angina and hypertension will reduce the effect of Salbutamol, a β2-Receptor Agonist given for the treatment of asthma. The administration of β-blockers to asthmatics should, therefore, be avoided, or undertaken with caution.

Drug classes in which Drug-Drug Interactions Commonly Arise
o Phenytoin
o Carbamezepine
o Warfarin
o Monoaimine Oxidases
o Rifampicin
o Macrolides
o Quinolones
o Amiodarone


LO 2.11 Understand induction and inhibition of the Cytochrome P450 system

Induction of CYP450 Enzymes
o Individual members of the CYP450 enzyme family affected by increased transcription, translation or slower degradation.
o More rapid elimination.
o Induction typically occurs over 1-2 weeks and monitoring of drug levels/therapeutic effect needs to take this into account.
o Withdrawal of the inducing agent without a change in the therapeutic agent can lead to toxicity if dosing is not re-adjusted.
o Induction may lead to increased production of a toxic metabolite

Inhibition of CYP450 Enzymes
o Drug half-lives increasing and drug clearance decrease.
o Inhibition of CYP450s can either be competitive or non-competitive and usually takes place over a few days.
o Introduction of an inhibiting agent without a change in the therapeutic agent can lead to toxicity if dosing is not re-adjusted
o Withdrawal of an inhibiting agent without a change in the therapeutic agent can lead to concentrations falling to a sub-therapeutic level

Alcohol (Chronic)
Sulphonylureas & St. John’s Wort

Grapefruit Juice
Cimetidine & Ciprofloxacin
Ethanol (Acutely)

CYP450 Pharmacogenetics
Variation in CYP450 expression accounts for a large amount of inter-patient variability in drug response.
o Warfarin – CYP2C9
o Codeine – CYP2D6


LO 2.12 Outline how hepatic, renal and cardiac disease drug interaction occurs and the effect of certain foods

Drug Disease Interactions

Hepatic Disease
Reduced clearance of hepatic metabolised drugs
Reduced CYP450 activity
o This leads to drugs having much longer half-lives, which in turn leads to toxicity.
o E.g. Opiates in Cirrhosis – Small doses accumulate, leading to coma.
Hypoalbuminaemia (malnutrition, nephrotic syndrome)
o Less albumin for drugs to bind to, free drug plasma levels higher

Renal Disease
Falling GFR (acute or chronic)
Reduced clearance of renally excreted drugs (Digoxin, aminoglycosides)
Electrolyte disturbances may predispose to toxicity
o E.g. Aminoglycosides are nephrotoxic, and can further enhance their own and other drug toxicities by reducing GFR

Cardiac Disease
Reduced Organ Perfusion
o Reduced hepatic and renal blood flow and clearance
Excessive response to hypotensive agents

Drug-Food Interactions
Grapefruit and Cranberry Juice can Inhibit CYP450 enzymes. This can reduce in significantly reduced clearance of a number of drugs, including Statins and Warfarin.


LO 2.13 Recognise the main ADR target types and give examples of these, which groups are most at trisk of ADR's

On Target Adverse Drug Reactions
On Target ADRs are due to an exaggerated therapeutic effect of the drug, most likely due to increased dosing or another factor affecting the drugs pharmacokinetics or pharmacodynamics.

For example Hypertension treatment leading to hypotension and causing dizziness, unsteadiness, syncope
On Target ADRs often consist of effects on the same effector, but in different tissues. Like Antihistamine H1 receptor antagonists acting on Immune System H1 Receptors which also act on CNS H1 Receptors causing drowsiness

Off Target Adverse Drug Reactions
Off Target ADRs are interactions with other receptor types secondarily to the one intended for therapeutic effect. Virtually all drugs do this.
Off Target ADRs can also occur with metabolites that subsequently act as a toxin.
Paracetamol in overdose

Groups Prone to Adverse Effects
Pregnant Women - Teratogenicity/Thalidomide
Breast Feeding Women - Many drugs can be passed on in the breast milk
Elderly - Polypharmacy/Reduced renal clearance/Nervous system is more sensitive to drugs
Patients with genetic enzyme defects - Glucose-6-Phosphate Dehydrogenase deficiency, resulting in haemolysis if an oxidant drug (e.g. aspirin) is taken


LO 2.14 Recognise circumstances in which drug interactions are most likely to occur

The risk of adverse drug reactions increases with every drug a patient takes. Hospital patients are often on a cocktail of 8 or more drugs, which takes the overall chance of an ADR to 80%.


LO 3.1 Understand the hormonal regulation of the female reproductive cycle

Beginning of Cycle
Oestrogen, Progesterone, Inhibin levels low
GnRH secretion due to lack of inhibition
LH and FSH rise, FSH more due to low Inhibin levels so less inhibition at the pituitary
FSH, followed by LH causes Follicles to Grow

Antral Phase
LH binds to Theca Interna in the ovaries - Producing androgens
FSH binds to Granulosa cells in the ovaries - Produce enzymes which convert Androgens -> Oestrogen
As the follicle grows, more oestrogen is produced for a given amount of LH and FSH

Pre-Ovulatory Phase
Follicle has grown, and is producing a high amount of Oestrogen
LH receptors develop in outer layers of Granulosa Cells
[High] Oestrogen positively feeds back
LH Surge produced ~12 – 14 days into the Cycle
o Timing may be influenced by environmental factors
o Stimulates ovulation
o Follicle size increases, collagenase activity
o FSH still being inhibited by Inhibin

Luteal Phase
Remains of follicle reorganise into Corpus Luteum
LH stimulates the Corpus Luteum
Produces Oestrogen and Progesterone
o Rising Oestrogen does not positively feedback on LH because Progesterone levels are also rising
o Prevents new follicles from developing (reduced FSH)
As the Corpus Luteum grows, more steroids are produced for a given LH level

Follicular Phase
Steadily rising titres of Oestrogen
Fallopian Tube - Increased Secretion, motility, cilia
Myometrium - Increased Growth, motility
Endometrium - Thickness, glandular invaginations, Secrete a watery fluid, conductive to sperm
Cervical Mucus - Thin, alkaline, conductive to sperm
Vaginal Epithelium - Increased Mitosis
Mildly anabolic
Effects on CVS

Luteal Phase
Action of Progesterone on Oestrogen-Primed Cells
Fallopian Tube - Reduced Motility, secretion, cilia
Myometrium - Further thickening, reduced Motility
Endometrium - Further thickening, increased secretion, Development of Spiral Arteries
Cervical Mucus - Thickening, acidification. Inhibits sperm transport
Mildly Catabolic
Elevates basal body temperature
Promotes change in Na+ and H2O excretion - With Oestrogen leads to net Na+ and H2O retention

14 Days after Ovulation
In the absence of pregnancy the Corpus Luteum regresses spontaneously
Progesterone and Oestrogen levels fall
Triggering a menstrual bleed
o The elaborate secretary epithelium of the endometrium collapses
o Apoptotic cell death
o Dead tissue shed as menstrual bleed.
o Spiral arteries contract to reduce bleeding.
Relieves inhibition on GnRH, FSH and LH, triggering the development of new follicles and the beginning of a new cycle
Sudden Fall in Progesterone and Oestrogen Levels

If Conception has Occurred
The implanted embryo develops a placenta, which secretes Human Chorionic Gonadotrophin (hCG)
hCG prevents the regression of the Corpus Luteum
Continues to secrete Oestrogen and Progesterone
Supports early weeks of pregnancy (Until about 12-14 weeks)
Maintains suppression of the ovarian cycle


LO 3.2 Outline the general pharmacology of Oestrogens

Mild anabolic
Sodium and water retention**
Raise HDL, Lower LDL
Decrease Bone Resorption
Impair Glucose Tolerance
Increase Blood Coagulability

Side Effects
Breast tenderness
Nausea, vomiting
Water retention
Increased Coagulability
Impaired glucose tolerance
Endometrial hyperplasia & cancer


LO 3.2 Outline the general pharmacology of Progesterones

Secretory endometrium
Increase bone mineral density
Fluid retention
Mood changes**

Side Effects
Weight gain
Fluid retention
Nausea vomiting
Lack of concentration
Pre-menstrual syndrome (marked exaggeration of mood changes)


LO 3.2 Outline the general pharmacology of Testosterones

Male secondary sex characteristics
Voice changes

Side Effects
Metabolic adverse effect on lipids


LO 3.2 Outline in general how Sex Steroids are transported around the body, the site of metabolism and their mechanism of action.

Transported bound to Sex Hormone Binding Globulin (SHBG) (except progesterone) and albumin (mainly progesterone).
Metabolism is via the Liver, Progesterone is almost totally metabolised in one passage through the liver
Metabolites excreted in the Urine (as glucuronides and sulphates)

Mechanism of Action
Like all steroid hormones, sex steroids exert their effect via Nuclear Receptors. These receptors are found in the cytoplasm, complexed with heat shock proteins. Following the diffusion (or possibly transport) of their ligand into the cell and high-affinity binding, these receptors form a Homodimer with another ligand-receptor complex and translocate to the nucleus.
In the nucleus, the steroid-receptor complex homodimers can Transactivate or Transrepress genes by binding to Positive or Negative Hormone Response Elements. Large numbers of genes can be regulated in this way by a single ligand.
Steroids may also bind to receptors that are already present inside the nucleus, which will then bind to the HRE.


LO 3.3 Understand the differences in contraceptive mechanisms of COCP

Hormonal Contraception

Thick, ‘hostile’ cervical mucus plug
o Prevents sperm from entering uterus
o Main contraceptive action of progesterone
Negative feedback to hypothalamus / pituitary
o Decreases frequency of GnRH pulses
o Inhibits follicular development

Oestrogen negatively feeds back on anterior pituitary
Loss of positive feedback mid-cycle so No LH surge

The COCP contains both an Oestrogen and a Progestogen (a Progesterone analogue). They work by mimicking the luteal phase of the menstrual cycle and suppress the release of gonadotrophins via negative feedback. As a result, follicular selection and maturation, the LH surge and consequently ovulation, do not take place. There is also an adverse effect on cervical mucus and the endometrium.

Route of Administration
Oral - One a day for 21 days, then break, placebo or iron pill for 7 days

Contraception and Menstrual Symptoms

Pregnancy, breast feeding, history or risk factors of heart disease, hypertension, hyperlipidaemia or any prothrombotic coagulation abnormality, diabetes mellitus, migraine, breast or genital tract carcinoma, liver disease

Adverse Effects
Venous thromboembolism, Hypertension, decreased glucose tolerance, headaches, mood swings, acne, flushing, nausea, vomiting, headache, amenorrhoea of variable duration on pill cessation


LO 3.3 Understand the differences in contraceptive mechanisms of the POP

The POP consists of low-dose Progestogen (a Progesterone analogue). This causes thickening of cervical mucus, preventing sperm penetration. It also has an adverse effect on the endometrium, affecting implantation. Contraception is less reliable than the COCP. It also causes suppression of gonadotrophin secretion, and occasionally ovulation, but the latter effect does not occur in the majority of women. During treatment with the POP ovulation still takes place and menstruation is normal.

Route of Administration
Oral - Daily, at the same time, starting at day 1 of menstrual cycle. If delay in taking the pill is greater than 3 hours, contraceptive effect may be lost

Contraception – More suitable for heavy smokers and patients with hypertension or heart disease, diabetes mellitus, or other contraindications for oestrogen therapy

Pregnancy, arterial disease, liver disease or breast or genital tract carcinoma

Adverse Effects
Menstrual irregularities, nausea, vomiting and headache, weight fain, breast tenderness


LO 3.4 Appreciate the main side effects and drug interactions of COCPs

COCP - Adverse Effects
Venous Thromboembolism (rare)
Amenorrhoea of variable duration on pill cessation
Flushing, headaches, nausea, acne, mood swings, weight gain (common)

COCP - Drug Interactions
Metabolism is by CYP450
o Therefore effected by inducers/inhibitors
o Enzyme inducers can lower levels of COCP causing contraception failure such as carbamezepine and phenytoin (anti-epileptics)
o Broad spectrum antibiotics (e.g. Amoxicillin)
Enterohepatic recirculation of oestrogen increases the efficacy of the COCP. If gut flora is killed by a broad spectrum antibiotic this is reduced and may cause contraception failure


LO 3.5 Understand differences in sex steroid PKs are related to administrative route

o Most common route (HRT, contraception, fertility)

o May reduce risk in turns of DVT, Thromboembolism by bypassing the Liver and giving smaller doses
o Important for people who complain of GI side Effects
o Slow, gradual release of steroid (Progestin)

o Slow, gradual release of steroid (Progestin)




LO 3.6 Be aware of the clinical management options for other contraception and emergency contraception

Other Contraception
Depot progesterone
Intramuscular implant of progesterone, giving long term contraception
Same mechanism of action as POP

Emergency Contraception
‘Morning after pill’ – Up to 72hrs after sex
Very high oral doses of progesterone (1.5mg) alone, or a Progestogen with an oestrogen to prevent implantation of fertilised egg
o 75% effective
o Indications – Emergency Contraception after unprotected sex
o Contraindications – Oestrogen contraindications, need to ask about cycle and when they had sex to determine if the woman is already pregnant. If this is the case it would be illegal to prescribe (abortion).

Up to 120 hours after sex
o Progesterone receptor modulator – delays or inhibits ovulation
o Copper IUD


Describe the menopause and symptoms you get

The point where there is a cessation of menstrual cycles, usually from the age of 50 onwards. There are no more follicles which can be stimulated by GnRH. There is a dramatic decrease in oestrogen levels and FSH and LH levels will rise. The sudden rise in FSH is due to decrease amount of inhibin.

Changes that occur:
o Vascular changes - Transient rise in skin temperature and flushing
o Changes to oestrogen sensitive tissue - Shrinking of endometrium/cervix, Loss of vaginal rugae, Involution of breast tissue and Skin/Bladder changes
o Decreased bone mass - Oestrogen inhibit osteoclast function, therefore loss of oestrogen leads to osteoclast activity being greater than osteoblast activity. Leads to osteoporosis


LO 4.8 Understand the role of lipids in the pathophysiology of atherosclerosis

Atherosclerosis Pathophysiology

Endothelial injury due to
o Raised LDL
o ‘Toxins’ e.g. cigarette smoke
o Hypertension
o Haemodynamic stress

Endothelial injury causes
o Platelet adhesion, PDGF release, smooth muscle cell proliferation and migration
o Insudation of lipid, LDL oxidation, uptake of lipid by smooth muscle cells and macrophages
o Migration of monocytes into intima

Stimulated SMC produce matrix material

Foam cells secrete cytokines causing
o Further SMC stimulation
o Recruitment of other inflammatory cells

Pro-Atherogenic effects of Oxidated-LDL
o Inhibits macrophage motility
o Induces T-cell activation and vascular smooth muscle cell division/differentiation
o Toxic to endothelial cells
o Enhances platelet aggregation


LO 4.9 Recognise the potential for pharmacological manipulation of lipid metabolism and list the main lipid transporters

Studies have shown that both total and LDL cholesterol concentrations correlate with clinical coronary atherosclerosis. Importantly, increasing HDL levels reduces CHD risk.

Prevention of Atherosclerosis
o Lifestyle changes (diet, exercise) can reduce LDL and increase HDL
o Statins
o Cholesterol absorption inhibitors
o Fibrates
o Niacin
o Bile Acid Sequestrants

Lipoprotein Transporters
o Chylomicrons -Transport dietary triacylglycerols from the intestine to tissues such as adipose tissue.
o VLDL -Transport of triacylglycerols synthesised in the liver to adipose tissue for storage.
o LDL -Transport of cholesterol synthesised in the liver to tissues.
o HDL -Transport of excess tissue cholesterol to the liver for disposal as bile salts.


LO 4.11 Recognise the main drug groups used in reducing LDL cholesterol - Statins

o Simvastatin - Short half life = 1-4 hours therefore is given at night
o Atorvastatin - Half life = 20 hours therefore can be given at any point in the day, has a superior efficacy
o Rostuvastatin - Contains sulphur, is more potent than simvastatin. Half life = 20 hours, so can be given at any time of the day
o Pravastatin

Route of Administration - Oral

Hyperlipidaemia which has not responded to changes in diet and exercise
Secondary prevention in patients with serum cholesterol greater than 5.5mmol/L (value varies depending on local policy)

Contraindications - Pregnancy, breastfeeding, liver disease

Mechanism of Action
o HMG-CoA Reductase inhibitor. Prevents cholesterol synthesis in the liver. Lower liver cholesterol concentration stimulates the production of LDL receptors, increasing the rate of LDL removal from plasma

Adverse Drug Reactions - Serious ADRs tend to be limited, even at the highest does of statin given.
o Increased transaminase levels - rapidly reversible, no evidence of chronic liver disease
o Myopathy - Diffuse muscle pain, primarily seen when used in combination with cyclosporine and occasionally erythromycin & niacin. Can test levels of creatinine kinase if symptomatic to confirm the presence of myopathy
o GI Disturbances
o Arthralgia
o Headaches

o Drug-Drug Interactions
o CYP450 inducers/inhibitors.
o Inhibitors significantly increase the risk of myopathies as the drugs spends more time in the plasma and therefore is more likely to interact with muscle tissue


LO 4.11 Recognise the main drug groups used in reducing LDL cholesterol - Fibric Acid Derivatives (Fibrates)

Fibrates can be used in conjunction with statins, but typically are only used as first line choices in hypertriglyceridemias.

o Bezafibrate
o Ciprofibrate
o Gemfibrozil

Route of Administration - Oral

Indications - Hyperlipidaemia which does not respond to dietary control

Contraindications - Pregnancy, breast feeding, gall bladder disease, severe renal or hepatic impairment, Hypoalbuminaemia

Mechanism of Action
o Peroxisome Proliferator-Activated Receptor-α (PPAR-α) agonist
o LDL lowering (variable amount)
o HDL increases of 15-25% in hypertriglyceridemia
o Decreases Triglycerides 25-50%

Adverse Drug Reactions
o Gastrointestinal disturbances
o Dermatitis, pruritus, rash
o Impotence
o Headache, dizziness, blurred vision

Drug-Drug Interactions - Increased chance of myalgia and myopathies when taken with statins


LO 4.11 Recognise the main drug groups used in reducing LDL cholesterol - Cholesterol Absorption Inhibitors

It is normally given as monotherapy in statin intolerant patients, however it will reduce LDL by a further 20% when given in combination with a statin. This is a better reduction than is gained by doubling statin dose and also reduces the risk of statin ADRs.

Examples - Ezetimibe

Route of Administration - Oral

o Hyperlipidaemia resistant to dietary control, in statin intolerant patients
o Given in combination with a statin

Contraindications - Breastfeeding

Mechanism of Action
o Blocks NPC1L1 in the intestinal brush border, inhibiting cholesterol absorption, increasing LDL receptor upregulation leading to further reducitons
o Reduce LDL levels by 15-20%
o Ezetimibe also undergoes enterohepatic circulation, increasing its half-life.

Adverse Drug Reactions
o Gastrointestinal disturbances (Diarrhoea, pain)
o Headache


LO 4.11 Recognise the main drug groups used in reducing LDL cholesterol - Bile Acid Sequestrants

o Colestyramine
o Colestipol

Route of Administration - Oral

Indications - Elevated cholesterol resulting from a high LDL concentration

Contraindications - Biliary obstruction

Mechanism of Action
o Bile acids are produced from cholesterol. The bile acid sequestrants will bind to bile acids in the intestine. This prevents their reabsorption and further conversion of hepatic cholesterol into bile acids. Lower levels of hepatic cholesterol leads to increased LDL receptor expression and lowered plasma cholesterol concentration.

Adverse Drug Reactions
o GI disturbances – Nausea, vomiting, constipation, abdominal pain, flatulence, heart burn
o Very few systemic side effects as they are not absorbed


LO 4.11 Recognise the main drug groups used in reducing LDL cholesterol - Niacin


Used to increase HDL levels and is also found to decrease the risk of cardiovascular events. Inhibits lipoprotein-a synthesis

Side effects include
o Skin flushing and itching
o Dry skin
o Skin rashes -Eczema exacerbations or Acanthosis nigricans (thickened brown, leathery patches of skin)


LO 4.12 Appreciate differences in statin PKs and PDs and be able to relate this to Drug Interactions

There are considerable variations in pharmacokinetics and pharmacodynamics within the statin drug group

o Intestinal absorption varies between 30 – 85%
o Hepatic first pass uptake is extensive as it may occur either by diffusion or active transport by OATP2
o Systemic availability may fall to 5 – 30% of administered dose
o Hepatic elimination includes CYP3A4 for some statins, whilst others are only metabolised by Phase 2 pathways
o Exhibit Non-Linear Pharmacokinetics - Doubling of a dose results in ~6% reduction in LDL

Short Acting Statins
o Simvastatin - Half-life 1-4hrs, given at night to coincide with peak cholesterol in early morning

Long Acting Statins
Atorvastatin - Half-life ~20 hours. Given any time of day.
Rostuvastatin - Half-life ~20 hours. Given any time of day.


LO 4.3 Understand the general pharmacology of the major groups of oral hypoglycaemics and differentiate their main side effects with regards to therapeutic use -Sulphonylureas

Sulphonylureas (Insulin Release Stimulants)

o Tolbutamide (t½ ~ 4hrs, duration of action 6-12hrs)
o Glibencamide (t½ ~ 10hrs, duration of action 18-24hrs)
o Glipizide (t½ ~ 7hrs, duration of action 16-24hrs)

Indications - Diabetes mellitus, in patients with residual β-cell activity

Contraindications - Breastfeeding women, elderly, renal and hepatic insufficiency

Route of Administration - Oral

Mechanism of Action
o Sulphonylureas antagonise β-cell K+/ATP activity, resulting in depolarisation. Voltage gated Ca2+ channels open, Ca2+ entry causes insulin vesicle fusion with cell membrane

Adverse Drug Reactions
o Hypoglycaemia
o GI disturbance
o Weight gain

Drug-Drug Interactions
o Highly protein bound (90-99%)


LO 4.3 Understand the general pharmacology of the major groups of oral hypoglycaemics and differentiate their main side effects with regards to therapeutic use - Biguanides

Biguanides (Insulin Sensitisers)

Examples - Metformin

Indications- Type II diabetes – Endogenous insulin presence required

o Compromised HRH function
o In respiratory disease

Mechanism of Action
o Unknown
o Increases insulin receptor sensitivity, enhancing skeletal and adipose glucose uptake
o Inhibits hepatic gluconeogenesis
o Reduces hyperglycemia, but does not induce hypoglycemia
o Tends to be give 2-3 times a day prior to meals to provide acute negative feedback on top of a basal endogenous insulin signal

Adverse Drug Reactions
o GI disturbances – ameliorated by slow dose titration
o Lactic Acidosis


LO 4.3 Understand the general pharmacology of the major groups of oral hypoglycaemics and differentiate their main side effects with regards to therapeutic use - Thiazolineinediones

o Rosiglitazone
o Pioglitazone

Indications - Uncontrolled non insulin dependant diabetes

o Compromised HRH function
o Especially heart failure – can cause oedema

Mechanism of Action
o PPAR-γ agonist. Agonistically bind to a nuclear hormone receptor site.
o Reduction in gluconeogenesis and an increased glucose uptake into muscles

Adverse Drug Reactions
o GI disturbance
o Weight gain

Drug-Drug Interactions - Very heavily protein bound (~99%)


LO 4.3 Understand the general pharmacology of the major groups of oral hypoglycaemics and differentiate their main side effects with regards to therapeutic use - Meglitidines

o Repaglinide
o Nateglinide

Indications - Uncontrolled non insulin dependant diabetes

Mechanism of action
o K+/ATP channel antagonists on β-cells, resulting in depolarisation, calcium entry and fusion of insulin containing vesicles with membrane

Adverse Drug Reactions
o Relatively lower risk of hypoglycaemia than Sulphonylureas
o Not associated with weight gain – useful in treating obese patients


Which hypoglycaemic agents would you give first?

Metformin is the first hypoglycaemic drug that you would use. If the patient is intolerant to Metformin, or is not overweight then Gliclazide (sulphonylurea) would be a better option as the first line of treatment.

Pioglitazone is the second line treatment, which is added to Metformin or a sulphonylurea. This happens if:
- Metformin and a sulphonylurea are not tolerated
- Metformin or sulphonylureas are contraindicated.


LO 4.4 Understand the use of the main categories of Insulin analogues and how they are used in Type I and II diabetes

Insulin analogues are manufactured on a large scale, using recombinant DNA technologies. There aqre many variations meaning that different formulations of insulin can be prepared, so the rate of uptake following sub-cutaneous injection can be varied. A mixture of these different insulins can be used together in a mix to give the best control.

Ultra Rapid
3 – 4 Duration
Meals/Acute hyperglycaemia

Short Acting
2 – 5 Duration
Meals/Acute Hyperglycaemia

4 – 10 Duration
Basal Insulin/Overnight control

Intermediate/Long Acting
8 – 30 Duration
Basal Insulin/Overnight Control

Due to the absence of properly functioning control systems, the best way to mimic the optimal actions of insulins is to utilise mixtures of analogues. There are two main mixtures used:

o Basal Bolus Regimen involves utilising a long acting insulin as background and then a fast acting insulin with meals. This involves injecting around 5 times a day yet does provide good flexibility.

o Pre-mixed Insulin Regime involves administration of both fast and slow acting insulin twice a day. Whilst this does not provide optimised glycaemic control, it involves less injecting for the patient.


LO 4.5 Describe the main steps used in Type II combination therapy

o Begin with no pharmacological intervention, therapy starting with Diet, Exercise and Lifestyle changes

o A Biguanide (Metformin) started when necessary

o Over time if HbA1c levels go above 7%, a Sulphonylurea (e.g. Tolbutamide) is added to therapy

o Over time if HbA1c levels go about 7.5% a Thiazolidinedione (e.g. Rosiglitazone) may be added, or a newer hypoglycaemic, or start insulin therapy

o If on this regime if HbA1c levels go above 7.5%, doses will be titrated upwards to regain adequate glycaemic control


LO 4.6 The crucial role played by patient and clinical monitoring in acute and chronic treatment

Monitoring in Acute Treatment
In patients with advanced diabetes, monitoring several times a day is required to determine dosing level with insulin. The regime in non-insulin therapies is frequently determined by dietary habit. With careful monitoring and control of their diet, patients can stay within normal glucose ranges.

Monitoring in Chronic Treatment
Glycosylated Haemoglobin - Glucose in the blood will react with the terminal valine of the haemoglobin molecule to produce glycosylated haemoglobin (HbA1c). The percentage of HBA1c is a good indicator of how effective blood glucose control has been. As RBCs normally spend ~3 months in the circulation the %HbA1c is related to the average blood glucose concentration over the preceding 2-3 months. Poorly controlled diabetics can have a HbA1c value above 10%.


LO 4.7 Recognise the main types of anti-obesity agents

Mechanism of Action
o Gastric and pancreatic lipase inhibitor, reducing the conversion of up to 30% of dietary fat to fatty acids and glycerol
Adverse Drug Reactions
o Broad GI disturbances
o (Soft fatty stools, flatus, faecal discharge/incontinence)

Mechanism of Action
o Noradrenaline and serotonin re-uptake inhibitor leading to appetite suppression, increased thermogenesis
Adverse Drug Reactions
Increased heart rate and blood pressure

Mechanism of Action - Endocannabinoid antagonist
Adverse Drug Reactions - Depression – currently withdrawn in the UK by NICE


LO 5.1 Generally overview factors in antibiotic use

Bacteria are prokaryotic organisms. The chemotherapy of infections aims to selectively target the invading bacterial while having minimal effect upon the host. This is achieved by exploiting the differences that exist between the structure and physiology of the prokaryotic bacterial cells and the host eukaryotic cells.

Antibacterial agents can be considered as bacteriostatic (inhibit bacterial growth, but do not kill them), or bactericidal (kill the bacteria).


LO 5.2 Understand the selective targeting of microbial biochemistry that underlies their use

Site - Peptidoglycan cell wall
Reason - Peptidoglycan cell wall only present in prokaryotic cell.
Antibacterial Drugs:
o Penicillins
o Cephalosporins
o Glycopeptides

Nucleic Acids
Bacterial genome is a single, circular strand of DNA unenclosed by a nuclear envelope, in contrast to eukaryotic chromosomal arrangement within the nucleus
Antibacterial Drugs:
o Antifolates
o Quinolones
o Rifampicin

Protein Synthesis
Bacterial ribosome (50s+30s subunits) is different to the mammalian ribosome (60s+40s subunits)
Antibacterial Drugs:
o Aminoglycosides
o Tetraclyclines
o Macrolides
o Chloramphenicol
o Fusidic acid

Cytoplasmic Membrane
Bacterial plasma membrane does not contain any sterols, unlike mammalian.
Antibacterial Drugs:
o Polymyxins


LO 5.3 Recall the major sites of action of antibiotics

DNA, Protein, Cell Wall Synthesis


LO 5.4 Primary therapeutic reasons for use of antibiotics

Prophylaxis of Bacterial Infections
Prophylactic antibiotics are given to people who are at an increased risk of infection.
o Peri-operative (Prevention of surgical site infections)
o Short term - e.g. Meningitis contacts
o Long term - e.g Asplenia (encapsulated bacteria) or Immunodeficiency

Treatment of Significant Bacterial Infections
o Treatment of cultured, proven infection
o Empirical treatment of suspected infection


LO 5.5 Understand the factors governing antibiotic choice accounting for likely infectious agent AND patient

The ideal antibiotic therapy is one that gives:
o Clean killing of infecting bacteria with minimal impact on non-target commensal organisms and leaves no resistance in any surviving pathogens
o No adverse effects on patient

Factors to help determine the likely infectious agent
o Anatomical Site
o Duration of illness
o Past medical history
o Occupational history
o Travel history
o Time of year
o Age
o Personal background

Factors determining which antibiotics are likely to be effective
o Community or healthcare onset?
o Severity of infection
o Baseline rate of resistance
o Immune status of patient - Immunocompromised patients will need IV Antibiotics immediately

Which antibiotic is the best choice?
o Efficacy
o Cost
o Administration Route
o Safety
o Patient age
o Patient organ function
o Patient Allergies
o Toxicity and Drug Interactions
o Pregnancy, breast feeding


LO 5.7 Understand the main genetic mechanism underlying antimicrobial resistance

Chromosomal Gene Mutation
o Chromosomal gene mutates in one bacteria in a population, conferring a resistance to antibiotic
o Antibiotic kills all other bacteria, acting as a selection pressure, giving resistant bacteria an advantage
o Population of antibiotic resistant bacteria daughter cells

Horizontal Gene Transfer
o Transformation
Bacteria with antibiotic resistance gene releases DNA
Uptake of DNA by recipient cell, conferring antibiotic resistance

o Transduction
Phage infected, antibiotic resistant Bacterial donor cell Phage passes the DNA conferring resistance to recipient cell

o Conjugation
Connection is made between antibiotic resistant donor cell, and recipient cell
Plasmid containing resistance gene is replicated and passes from donor cell to recipient cell
Plasmid may even become incorporated into recipient cell DNA


LO 5.8 Briefly describe biochemical mechanisms of antibiotic resistance

Antibiotic Inactivation -Production of enzyme that inactivate the drug
E.g. β-lactamase which inactivates Penicillins

Alteration of Drug Binding Site - so drugs no longer have affinity for them
E.g. Bacterial ribosome alteration, meaning Aminoglycosides and Erythromycin cannot bind

Alteration of Metabolic Pathways - Development of altered metabolic pathways
E.g. bacteria can become resistant to Trimethoprim due to acquired changes in their Dihydrofolate Redctase enzyme, which gives it very little affinity for the drug

Reduced Intracellular Antibiotic Concentration
o Active Efflux Mechanisms
E.g. Active transport mechanisms used (e.g. p-glycoprotein) to pump a drug out of the bacterial cell because it accumulates to an effective level
o Decreased permeability
E.g. Some bacteria become resistant to Tetracycline because they alter their cell membrane to make it impermeable to the drug


LO 5.9 Be aware of scale of emergent patterns of antibiotic resistance and name the main organisms e.g. MRSA

Patterns of Emergence of Antibiotic Resistance
o Local selection (e.g. in a hospital)
o Clonal dissemination (e.g. around the country)
o Global spread

Main Antibiotic Resistant Organisms
o Methicillin Resistant Staphylococcus Aureus (MRSA)
o Glycopeptide Intermediate susceptibility Staphylococcus Aureus (GISA)
o Glycopeptide Resistant Enterococci (GRE)
o Extended Spectrum Beta Lactamase enterobacteriaceae (ESBLs)
o Extensively Drug Resistant Klebsiella Pneumoniae (XDR-KP)


LO 5.10 List the main steps to avoid spread of resistance

Antimicrobial Stewardship
o Right antibiotic
o Right time
o Right dose, frequency and duration
o Right route

Infection Control
Prevent the spread of recognised resistant bacteria
o Isolation or cohorting
o Hand hygiene
o Decolonisation of patients
Prevent bacterial exposure to antibiotics
o Minimise risk of infection
o Monitor and control antibiotic prescribing


LO 5.11 What are the methods of adminitration and elimination of antibiotcs. Define MIC, time dependent and concentration dependent killing

Administration - Oral or Intravenous (Required for Immunocompromised patients)

Metabolism/Elimination - Renal or Hepatic

o Time dependent killing
Prolonged antibiotic presence at the site of infection, but not high concentration
o Concentration dependent killing
High antibiotic concentration at the site of infection, but short duration

Minimum Inhibitory Concentration – MIC
The MIC is the lowest concentration of an antibiotic that will inhibit the visible growth of a microorganism after overnight incubation. A MIC is generally regarded as the most basic laboratory measurement of the activity of a microbial agent against an organism.


LO 5.12 Understand the process of viral replication and describe the main steps involved use example of infleunza

1. Influenza virus binds to cell via Hemagglutinin onto sialic acid sugars on the surface of epithelial cells.

2. Entry of virus into cell via endocytosis

3. ATP driven proton entry into the endosome, allowing fusion of the viral membrane with the internal endosomal membrane

4. Entry of protons into the virus itself via the viral M2 Ion Channel. Low pH inside the virus results in breakdown in the viral coat of the nucleocapsid core. This releases viral RNA into the host cytoplasm

5. Virus replicates using host cell machinery

6. Viral protein assembly

7. New virus buds off the cell membrane, but many remain attached by re-attaching to the sialic acid on the cell surface

8.Viral Neuramidase enzyme breaks this bond, allowing viral release


LO 5.13 Recognise the main classes of Influenza Virus

Influenza A
o Multiple host species which are able to infect humans
o Antigenic drift and shift
- Drift = different each year
- Shift = leads to an epidemic

Influenza B
o No animal reservoir
o Lower mortality than influenza A

Influenza C
o Common cold like


LO 5.14 Describe the general pharmacology of M2 ion channel blockers and the main ADRs associated with M2 Ion Channel Blockers

o Amantadine
o Rimantadine

Route of Administration - Oral

o Prophylaxis and treatment of acute Influenza A in groups at risk.

Mechanism of Action
o Inhibits the un-coating of a virus, therefore preventing it from being able to infiltrate into the cell. This occurs by the action of:
o Inhibits H+ influx into the cell, therefore preventing the change in pH which stimulates the viral un-coating.
o Blocks M2 Ion Channel, preventing breakdown of viral coat and release of viral RNA into host cell.

Adverse Drug Reactions
o Amantadine has more marked ADR risk than Rimantadine of ~5-10%, therefore Rimantadine is usually preferred
o Dizziness
o Hypotension
o GI disturbance
o Confusion, insomnia and hallucination can be problematic in the elderly (CNS)
o Is nephrotoxic in high doses

Therapeutic Notes
o Limited to Influenza group A, ineffective against group B
o Rapid emergence of M2 mutations in H5N1 viruses
o Resistance can develop quickly as only a single point mutation is needed in order to change the shape. This causes the binding site to move away from the channel, so that when the drug binds it will no longer block the channel E.g. amantadine in chicken feed leading to resistance


LO 5.15 Describe the general pharmacology of Neuramidase Inhibitors and the main ADRs

o Zanamivir
o Oseltamivir

Route of Administration
o Zanamivir – Inhaled
o Oseltamivir – Oral (80% bioavailability)

o Treatment of Influenza A or B virus within 48 hours after onset of symptoms when influenza is endemic in the community

Contraindications - Breast feeding

Mechanism of Action
o Inhibits neuraminidase enzyme which cleaves the virus from receptors on the membrane, once the virus has been produced. It causes aggregation of the virus at the cell surface, therefore preventing the virus from spreading throughout the body and therefore to other people also.
o Sialic acid analogues, with very high binding affinities for Neuramidase.
o The receptor is not involved with antigenic shift or drift

Adverse Drug Reactions
o Headache
o Nose bleed
o Respiratory depression (rarely)
o Bronchospasm
o GI disturbances

Therapeutic Notes
o Zanamivir has low bioavailability therefore is given as a dry powder inhalant. It is not used for prophylaxis.
o Oseltamivir is a pro-drug and by contrast is well absorbed, with 80% bioavailability. This enables it to be given orally for both treatment and prophylaxis.
o Gives rise to:
• 35-38% reduction in severity
• 25-36% reduction in duration when given as soon after infection as possible


LO 5.16 Explain the results arising from the clinical trials with Neuramidase Inhibitors and appreciate how these have informed dosing strategy

Initiation of Treatment
The earlier treatment is started after symptom onset, the shorter the duration of symptoms. The time window for significant reduction goes up to 48 hours, little benefit accrues after this time.

Oseltamivir could offer ~70% reduction in risk of mortality according to one Canadian study. This was achieved when dosing was delayed as long as 64 hours after symptom onset.

Treatment for six weeks with 75mg significantly reduced incidence of flu in both healthy adults and frail elderly subjects.


LO 5.17 Appreciate how emergence of resistance of different viral strains to Neuramidase Inhibitors will affect therapy

Some resistance has been reported to Oseltamivir in H1N1 viral strains. Virus still remains sensitive to Zanamivir.


LO 6.1 Review relevant previous module material on respiration and asthma, epidemiology, symptoms, examinations

Asthma is a chronic disorder characterised by Airway Wall Inflammation and Re-modelling. It is a Reversible Airflow Obstruction (greater than 12% reversibility with salbutamol). Airways in asthma have thickened smooth muscle and basement membranes (collagen deposition in BM). Triggers cause the airway smooth muscle to contract, reducing airway radius, increasing resistance and reducing airflow.

Asthma is increasing in prevalence, more common in the developed world and increasing in populations who move from developing -> developed countries
o 5.4 million people in the UK current receive treatment
o Genetic risk
o Sensitisation to airborne allergens such as House Dust Mite, Pollens, Air pollution and tobacco smoke (Pre-/post natal exposure, active)
o Hygiene hypothesis

The diagnosis of asthma is a clinical one. There is no standard definition of the type, severity or frequency of symptoms, nor of the findings on investigation. Asthma is defined as more than one of the following recurring symptoms:
o Wheeze - High pitched, expiratory sound, Polyphonic
o Dry cough - Often worse at night (Lack of sleep, poor performance at school) - Exercise induced
o Breathlessness - With exercise
o Chest Tightness
o Variable Airflow Obstruction

o Chest - Scars, deformities, Hyper-expansion (Barrel Chest)
o General health - Eczema, hay-fever, Lethargy, speaking?
o Percussion - Hyper-resonant
o Auscultation - Polyphonic wheeze

Spirometry – Flow Volume Loop
o Low PEFR
o Low FEV1/FVC Ratio
o >12% increase in FEV1 following salbutamol

Allergy Testing
o Skin prick to aero-allergens, e.g. cat, dog, HDM
o Blood IgE levels to specific aero-allergens

Chest X-Rays
o Performed to exclude other diseases/inhalation of foreign body/pneumothorax


LO 6.2 Understand autonomic innervation pharmacology of bronchial smooth muscle

Sympathetic Innervation
Sympathetic activity results in Bronchodilation, with nerves innervating bronchial blood vessels and glands, but not bronchial smooth muscle. However, β-adrenoreceptors are abundantly expressed on airway smooth muscle, epithelium, glands and mast cells (especially β2). Binding at these sites of β-agonists results in bronchodilation, reduced histamine release and increased mucociliary clearance.

Parasympathetic Innervation
Parasympathetic activity is normally dominant in maintaining smooth muscle tone in the airways. Muscarinic Receptors are present on airway and vascular smooth muscle and glands. The M3 Receptor is pharmacologically the most important.


LO 6.4 Know in detail the action of different bronchodilators and when they are used, namely: short and long acting B2 agonists

Mechanism of Action - β2 agonists act on the β2 receptors found on bronchial smooth muscle. The receptors are coupled to Gs Proteins, which cause an increase in cAMP and consequent decrease in intracellular [Ca2+]. This reduces the binding of Ca2+ by light myosin, causing smooth muscle dilation. Additionally, the decrease in intracellular Ca2+ will also increase Ca2+ activated K+ currents, thus hyperpolarising muscle cells further and augmenting bronchodilation.

Pharmacokinetics of β2 Agonists
β2 Agonists are administered by inhalation in aerosol, powder or nebulised form and can also be administered intravenously. Deposition within the pulmonary tract is related to particle size, with 1-5microns being optimal.
However, the majority of the drug (up to 90% depending on the inhaler device) is deposited in the upper airway and/or swallowed before being removed by the liver.

Fast Acting β2 Agonists
o Immediate Action
o Salbutamol – Duration of action 3-5hrs
o Terbutaline – Duration of action 3-5hrs

Long Lasting β2 Agonists
o Often given in adjunct with anti-inflammatories
o Formoterol – Duration of action 13hrs
o Salmeterol – Slower onset

Adverse Drug Reactions
o Inhaled high doses can cause skeletal muscle tremor (β2 activity)
o Even though β2 agonists are very selective, they can still antagonise cardiac β1 receptors enough to induce tachycardia and dysrhythmia

Drug-Drug Interactions
o β-blockers such as Propranolol, which bind to both β1 and β2 receptors


LO 6.5 Understand the broad mechanism of anti-inflammatory action of the corticosteroids. How long do they take to occur? And the pharmokinetics relating to ashtma.

Acts like normal steroid hormones, entering nucleus and binding to HRE. Therapeutic effects of changes in gene expression may only be apparent some hours after administration. Steroids may also bind to receptors that are already present inside the nucleus, which will then bind to the HRE.

Anti-inflammatory Effects
Reduced production of acute inflammatory mediators, especially eicosanoids (prostaglandins, leukotrienes), due to the production of Lipocortin, an enzyme that inhibits Phospholipase A2, preventing the formation of Arachidonic Acid and its metabolites.

Glucocorticoids also reduce the number of circulating immunocompetent cells (neutrophils and macrophages) and decrease the activity of cells involved in the chronic stages on inflammation (macrophages, fibroblasts), decreasing inflammation and decreasing healing.

Use of Glucocorticoids in Asthma
They have both an anti-inflammatory action and increase the expression of β2 Receptors. Optimal effects are seen after weeks/months of therapy.

10-50% of an inhaled dose is delivered to the lungs, depending on the inhaler device. A major proportion of the drug is deposited in the upper airway and/or swallowed and metabolised by the liver. Newer drugs are designed to undergo hepatic first pass metabolism to reduce ADR risk.


LO 6.6 Be able to outline the general steps in the management of asthma

Step 1
Mild Intermittent Asthma
Inhaled short acting β2 Agonist as required (E.g. Salbutamol)

Step 2
Introduction of regular preventer therapy
Inhaled short acting β2 Agonist as required (E.g. Salbutamol)
Regular preventer therapy – corticosteroid (e.g. Beclometasone)

Step 3
Add on therapy
Inhaled short acting β2 Agonist as required (E.g. Salbutamol)
Regular preventer therapy – corticosteroid (e.g. Beclometasone)
Regular long acting β2 Agonist (E.g. Salmeterol)

Step 4
Trial additional therapy Inhaled short acting β2 Agonist as required (E.g. Salbutamol)
Regular preventer therapy – corticosteroid (e.g. Beclometasone)
Trial of additional therapy, such as Muscarinic Antagonist (e.g. Ipratropium Bromide), Leukotriene Receptor Antagonist, Methylxantine (e.g. Theophylline)

Step 5
Continuous or frequent use of oral steroids (e.g. Prednisolone)


LO 6.7 Describe the steps in management of severe acute asthma and describe its features

Severe Acute Asthma – Status Asthmaticus

Severe Acute Asthma/Status Asthmaticus is defined as any one of:
o Unable to complete sentences
o Pulse ≥ 110 bpm
o Respiration ≥ 25 per minute
o Peak expiratory flow 33-50% of best or predicted
Life Threatening features include:
o Peak expiratory flow < 33%
o PaO2 < 8kPa
o PaCO2 > 4.5kPa
o Silent chest
o Cyanosis
o Feeble respiratory effort
o Hypotension, bradycardia, arrhythmia
o Exhaustion, confusion, coma
Severe, acute asthma is near fatal if PaCO2 is > 6kPa. Mechanical ventilation is required.

Management of Severe Acute Asthma (Status Asthmaticus)
o Oxygen – High flow, aim to keep O2 94-98% saturation
o Nebulised Salbutamol, continuous if necessary
o Intravenous Hydrocortisone
o Oral Prednisolone - ~40mg daily for 10-14 days

If no response to above treatment, add:
o Add nebulised Ipratropium Bromide
o Consider IV Magnesium Sulphate 1.2-2g over 20 minutes
o Consider IV Aminophylline if no improvement and life threatening features not responding to above treatment
Beware if taking oral Theophylline


LO 6.9 Appreciate the general mechanisms underlying autoimmune disease, particularly Rheumatoid Arthritis (RA)

Autoimmunity is the state that is present when an individual has made an immune response to self-antigens. In many cases the presence of autoantibodies in serum provides evidence for autoimmunity, and these may be helpful in diagnosing and monitoring autoimmune diseases.

Autoimmune Disease
Autoimmune disease is the term applied to a disease in which autoimmunity is thought to play a significant pathogenic role. (I.e. where the tissue damage results from the autoimmune response). Autoimmune disease can be classified as being organ specific. i.e. the target antigen is located in one organ or non-organ specific, i.e. the target antigen is located on many different tissues/organs.

Organ – Specific
- Hashimoto’s
- Thyrotoxicosis
- Primary myxoedema
- Chronic atrophic gastritis
- Pernicious anaemia
- Addison’s Disease
- Myasthenia gravis
- Diabetes mellitus (type 1)
- Premature ovarian failure
- Male infertility

Intermediate / Mixed
- Goodpasture’s syndrome
- Primary biliary cirrhosis
- Autoimmune haemolytic disease
- Ulcerative colitis

Non-Organ specific
- Systemic Lupus Erythematosus
- Rheumatoid arthritis
- Sjogren’s syndrome
-Progressive systemic sclerosis


LO 6.10 Recognise the main therapeutic uses of immunosuppressants and Disease Modifying Anti Rheumatic Drugs (DMARSs) - Glucocorticoids

o Prednisolone (Oral)
o Beclometasone (Topical/Inhaled)
o Hydrocortisone (Cortisol) (Oral for replacement, IV for status asthmaticus and anaphylactic shock)

o Immunosuppression
o Anti-inflammatory therapy
o Replacement of endogenous corticosteroids

Contraindications - Systemic infection

Mechanism of Action
o Diffuse into cytoplasm and bind receptor. Complex moves to nucleus and binds Hormone Response Element (HRE). Inducers/Inhibits transcription.

Adverse Drug Reactions
o Cushingoid effects
o Suppression of HPA axis
o Osteoporosis
o Suppression of growth in children
o Mineralocorticoid effects if the glucocorticoid also has those actions

Therapeutic Notes - Long term therapy must be withdrawn slowly, due to HPA suppression


LO 6.12 Appreciate the pharmacological rationale for using Immunosuppressants in treating certain cancers

Some immunosuppressants work by inhibiting the division of cells - E.g. Azathioprine, Methotrexate, Cyclophosphamide, Cyclosporin

Some cancers are the uncontrolled division of immune cells and therefore immunosuppressants will work to suppress the cancer


LO 6.10 Recognise the main therapeutic uses of immunosuppressants and Disease Modifying Anti Rheumatic Drugs (DMARSs) - Azathioprine

o Rheumatoid Arthritis, Inflammatory Bowel Disease
o Prevention of graft and transplant rejection
o Autoimmune conditions where corticosteroid therapy o alone inadequate
o Leukaemia

Route of Administration - Oral / IV

Mechanism of Action
o Azathioprine is a pro-drug, which is converted into 6-Mercaptopurine in the liver
o 6-Mercaptopurine is a fraudulent purine nucleotide that impairs DNA synthesis and has a cytotoxic action on dividing cells

Adverse Drug Reactions
o Myelosuppression -> Leukopenia, thrombocytopenia, anaemia
o Increased infection susceptibility
o GI disturbances (nausea, vomiting, diarrhoea)
o Drug-Drug Interactions
o Interacts with Allopurinol (treats gout), necessitates lowering of dose

Therapeutic Notes
6-Mercaptopurine is eliminated by the enzyme TPMT, which is subject to a high rate of genetic polymorphism. High levels of TPMT expression will lead to under-treatment, low levels of TPMT expression gives toxicity.


LO 6.10 Recognise the main therapeutic uses of immunosuppressants and Disease Modifying Anti Rheumatic Drugs (DMARSs) - Cytotoxic Alkylating Agents

Examples - Cyclophosphamide

Indications - Immunosuppression/Cancer chemotherapy

Contraindications - Pregnancy

Mechanism of Action
o Pro-drug, that is activated by CYP450s.
o Alkylating agent, which creates cross-links in DNA so that it cannot replicate. Therefore it selectively acts on cells with a higher mitotic rate.

Adverse Drug Reactions
o Induction of bladder cancer (urine concentration of acrolein metabolite)
o Lymphoma and Leukaemia
o Infertility & Teratogenesis

Drug-Drug Interactions - Pro-drug is activated by CYP450s (inducers/inhibitors)


LO 6.10 Recognise the main therapeutic uses of immunosuppressants and Disease Modifying Anti Rheumatic Drugs (DMARSs) -
Calcineurin Inhibitors

Cyclosporin (Binds Cyclophilin)
Tacrolimus (Binds Tacrolimus-Binding-Protein)

o Prevention of graft and transplant rejection
o Prevention of graft vs. host disease
o Atopic dermatitis, psoriasis

Route of Administration - Oral, intravenous

Mechanism of Action
o Reduction in IL-2 synthesis and release, via Calcineurin inhibition suppressing both cell-mediated and antibody-specific adaptive immune responses. Active against T helper cells.
o Ciclosporin binds to Cyclophilin and Tacrolimus binds to Tacrolimus-Binding-Protein
o Drug/Protein complexes bind to and inhibit Calcineurin, which normally has a phosphatase activity on the Txn factor for IL-2. Therefore, inhibition of Calcineurin reduces IL-2

Adverse Drug Reactions
o Nephrotoxic (proximal tubule), renal damage almost always occurs
o Hypertension in 50% of people
o GI disturbances

Drug-Drug Interactions
o Metabolism is by CYP450, so is affected by inducers/inhibitors

Therapeutic Notes
Unlike most immunosuppression agents, Cyclosporin does not cause myelosuppression


LO 6.10 Recognise the main therapeutic uses of immunosuppressants and Disease Modifying Anti Rheumatic Drugs (DMARSs) - Methotrexate

Antirheumatic Drugs (DMARDs)

Indications - Immunosuppression and Cancer chemotherapy

Contraindications - Pregnancy

Route of Administration - Orally, intravenously, intramuscularly, intrathecally

Mechanism of Action
o Antifolate
o Competitively antagonises Dihydrofolate Reductase (DHFR), preventing the regeneration of intermediates (tetrahydrofolate) essential for the synthesis of purines and thymidine, thus inhibiting DNA synthesis.

Adverse Drug Reactions
o Mucositis
o Myelosuppression
o Hepatitis, cirrhosis
o Increased infection risk
o Teratogenesis

Drug-Drug Interactions
o Adverse DDIs with drugs affecting renal blood flow and renal elimination, e.g. NSAIDs

Therapeutic Notes
o Essential to carry out clinical monitoring
o Baseline chest X-ray, FBC, LFT, U+E + Creatinine
o Monthly FBC, LFT, U+E + Creatinine
o Oral bioavailability is dose dependent, so usually given IV
o Plasma protein binding ~50% - NSAIDs displace, raising plasma concentration
90% renal elimination – glomerular active and tubular secretion
o Intracellular/hepatic metabolism to polyglutamates. These polyglutamates accumulate in cells and also bind very strongly to DHFR. Polyglutamates can be retained in cells for weeks to months
o Weekly, not daily dosing


LO 6.10 Recognise the main therapeutic uses of immunosuppressants and Disease Modifying Anti Rheumatic Drugs (DMARSs) - Aminosalicylates

Antirheumatic Drugs (DMARDs)

Examples - Sulfasalazine

o Rheumatoid arthritis
o Inflammatory bowel conditions

o Renal impairment
o Hypersensitivity

Mechanism of Action
o Sulfasalazine is broken down in the gut to the active component 5-aminosalicylate (5-ASA) and sulfapyridine, which acts as a vehicle to transport the drug to the colon.
o Inhibition of T-cell proliferation and IL-2 production. Reduced Neutrophil chemotaxis and degranulation.

Adverse Drug Reactions
o Mostly due to sulfapyridine (10-45% of patients)
o Myelosuppression
o Hepatitis
o Rash
o GI disturbances (Nausea, vomiting, abdominal pain)

Therapeutic Notes
o Few ADRs/DDIs seen in Pregnancy
o Treating Rheumatoid Arthritis
o Only 30-40% 5-ASA is absorbed
o Molecular mechanism does not involve COX inhibition
o Inhibit T-cell proliferation and IL-2 Production, reduced neutrophil chemotaxis and degranulation
o Treating Inflammatory Bowel Disease
o 5-ASA reaches the colon in large quantities, but acts via an unknown mechanism (again not COX inhibition)


LO 7.1 Appreciate the main features of Gate Theory

Pain Perception
Activation of Nociceptors
Noxious thermal, chemical or mechanical stimuli can trigger firing of primary afferent fibres, through the activation of Nociceptors in the peripheral tissues. (Sharp Stabbing Pain - Alpha/Delta Fibres, Dull Nagging Pain C-Fibres)

Transmission of Pain Information
Transmission of pain information from the periphery to the dorsal horn of the spinal cord is inhibited or amplified by a combination of local (spinal) neuronal circuits and descending tracts from high brain centres. This constitutes the ‘Gate-Control Mechanism’.

In the Gate-Control Mechanism:
o Primary afferent fibres synapse in Lamina I, II and V of spinal cord dorsal horn
o Transmitter peptides are involved in ascending pain pathways - Substance P, Calcitonin, Bradykinin, Glutamate, Nitric Oxide
o The activity of the dorsal horn relay neurons is modulated by several inhibitory inputs. These include:
- Local inhibitory interneurons, which release opioid peptides
- Descending inhibitory noradrenergic fibres from the locus ceruleus area of the brainstem
- Activated by opioid peptides
- Descending inhibitory serotonergic fibres from the Nucleus Raphe Magnus and Periadueductal grey areas of the brainstem
- Activated by opioid peptides

Onward Passage of Pain Information
The onward passage of pain information is via the Spinothalamic Tract, to the higher centres of the brain. Here, there is coordination of the cognitive and emotional aspects of pain and control of appropriate reactions.

Opioid peptide release in both the spinal cord and brainstem can reduce the activity of the dorsal horn relay neurons and cause analgesia, known as ‘shutting the gate’.


LO 7.3 Understand the general Pharmacology of NSAID action on COX-1 and COX-2 and the 3 main types of inhibitor for it

The main action of all the NSAIDs is inhibition of the enzyme Cyclooxygenase (COX). This enzyme is involved in the metabolism of Arachidonic Acid to form Prostanoids, i.e. the ‘classic prostaglandins’, Prostacyclin and Thromboxane A2.
Inhibition of cyclooxygenase can occur by several mechanisms:

Irreversible inhibition
E.g. Aspirin causes acetylation of the active site. This is the basis for Aspirin’s effect on platelets

Competitive inhibition
E.g. Ibuprofen acts as a competitive substrate

Reversible, non-competitive inhibition
E.g. Paracetamol has a free-radical trapping action that interferes with the production of hydroperoxidases, which are believed to have essential role in cyclooxygenase activity.


LO 7.4 Understand therapeutics/ADRs in terms of action on COX-1 and COX-2

Cyclooxygenase exists in two enzyme isoforms. Generally, NSAID action on COX-1 is rapid and competitive, on COX-2 is slower and often irreversible.

Expressed in most tissues, especially platelets, gastric mucosa and renal vasculature
Involved in physiological cell signalling
Most adverse effects of NSAIDs are caused by COX-1 Inhibition

Induced at sites of inflammation and produces the Prostanoids involved in inflammatory responses
Analgesic and Anti-inflammatory effects of NSAIDs are largely a result of inhibition of COX-2


LO 7.5 Appreciate the use of NSAIDs as Analgesics, Anti-inflammatories and Anti-pyretics

NSAIDs as Analgesics
NSAIDs act as analgesics by reducing synthesis of Prostaglandins that sensitise Nociceptors to inflammatory mediators.
Thought to reduce headache pain by cerebral vasodilation mediated by prostaglandins.
May also have a secondary effect on prostaglandin facilitation of afferent pain signal in spinal cord dorsal horn neurones.

Along with Prostaglandins, there are a number of other mediators involved in the inflammatory response. Therefore NSAIDs will have an effect proportionate to prostaglandin involvement.
Primarily reduce erythema, swelling and pain response associated with swelling.

Fever due to bacterial endotoxins trigger macrophage release of endogenous pyrogen IL-1. This stimulates hypothalamic production of Prostaglandin E that elevates the set point on central ‘thermostat’. NSAIDs reduce PG-E synthesis.


LO 7.6 Recognise the differences in NSAID pharmacokinetics specifically aspirin pharmacokinetics

NSAIDs are typically given orally, but there are also many topical preparations for local delivery to injured soft tissue.

Most NSAIDS generally show First Order Elimination Kinetics

Many heavily bound to plasma protein 90-99%

Some NSAIDs have short half-lives (< 6 hours)
o Ibuprofen – t½ = 2hrs
Some NSAIDs have long half lives (> 10 hours)
o Naproxen – t ½ = 14hrs

Aspirin Pharmacokinetics
o Low doses - First Order Elimination Kinetics (Dose dependant)
o High doses (>12 300mg tablets) - Zero Order Elimination Kinetics


LO 7.7 Describe the major ADRs / Drug Interactions associated with NSAIDs

NSAID group ADRs at therapeutic levels are mainly due to COX-1 Inhibition.
o PGE2 is involved in protection of gastric mucosa
o Inhibition of PGE2 increases mucosal permeability and decreases mucosal blood flow and protection
o NSAIDs can cause damage to stomach directly on ingestion
o Ulceration, haemorrhage and even perforation seen with long term high dose elderly users
o GI ADRs can be offset (long term) with PPIs or Misoprostol (synthetic prostaglandins)

Renal ADRs can occur in susceptible individuals, although therapeutic dosage in otherwise healthy patients does not cause problems. Neonates, the elderly and patients with compromised HRH function or reduced blood volume are particularly at risk.
o Prostaglandins responsible for vasodilation of afferent arteriole
o Reversible reduction in GFR occurs as a result of PGE2 and PGI2 inhibition

Other ADRs
o Skin reactions (15% for some NSAIDs)
o Asthmatic bronchospasm (10% incidence)
o Allergic response
o Prolongation of bleeding time (platelet inhibition)
o Aspirin is associated with risk of the post-viral Reye’s Syndrome in children

Selective COX-2 Inhibitors
Since most NSAID ADRs are due to COX-1 inhibition, drugs have been developed that only inhibit COX-2. Unfortunately their use was associated with an increased risk of hypertension and cardiac and renal failure.

NSAID Drug-Drug Interactions
Due to their wide availability some patients may already be self-medicating with NSAIDs. It is therefore appropriate to question patients prior to prescription to name other drugs they may be taking.

o Aspirin is highly plasma protein bound and can displace other drugs, increasing their active free concentration. Competitive displacement of these drugs may require dose adjustment to avoid changes in PK and PDs.

Warfarin - Increased Concentration -> More Bleeding

Methotrexate - Increased Concentration -> Wide ranging, serious ADRs

Sulphonylureas - Increased Concentration -> Hypoglycaemia

NSAIDs can interact with ACE inhibitors and attenuate their action, blocking the production of vasodilating prostaglandins


LO 7.8 Understand the mode of action of NSAIDs on platelet function exemplified by Aspirin and its role in cancer prophylaxis

Aspirin is used as the reference NSAID for efficacy and ADR severity. It is the only NSAID to irreversibly inhibit COX enzymes, via acetylation. It also has a unique pharmacokinetic profile, as its t½ is less than 30 minutes – it is rapidly hydrolysed in plasma to salicylate, which has it’s own t½ of ~4 hours.

Atherothrombotic Disease
The use of low dose (75mg) Aspirin in reducing platelet aggregation is very widespread in treating a range of conditions with a vascular component. Aspirin irreversibly inhibits COX-1 activity that drives pro-aggregative activity in both platelets and vessel walls to reduce the likelihood of thrombotic formation.

GI Cancer Prophylaxis
There is evidence that aspirin may reduce the risk of GI cancer of the colon, rectum and possibly upper GI. This is because these cancers synthesise PGE2, which promotes tumour growth. Clinical trials are on going.


LO 7.9 Appreciate the special case of Paracetamol as an Analgesic/Antipyretic

Paracetamol is a unique ‘non-NSAID’, as it has virtually no anti-inflammatory action. It is very effective for mild/moderate analgesia and fever.

At therapeutic doses (8x500mg tablets a day) is has a much better ADR than other NSAIDs, making it the agent of choice. Its pharmacokinetics is first order in a healthy patient, with a t½ of 2-4hrs.

Paracetamol’s mechanism of action is currently unknown. It is possibly a weak COX-1/COX-2 inhibitor, but may also act in the CNS, possibly on a COX-3 isoform.


LO 7.10 Recognise the main features of Paracetamol overdose and toxicity and its treatment

At therapeutic levels, Paracetamol has Linear Pharmacokinetics, and is conjugated with Glucuronide (60%) or Sulphate (30%) in Phase II Drug Metabolism. A small amount also undergoes Phase 1 Oxidation, to produce the toxic metabolite N-acetyl-p-benzo-quinone imine (NAPQI).

If a toxic dose of Paracetamol is taken the Phase II pathways quickly become saturated and much more Paracetamol undergoes Phase I metabolism (Zero Order Kinetics), producing more NAPQI. Not only is NAPQI toxic to hepatocytes but it also undergoes Phase II conjugation with Glutathione, which is an important anti-oxidant, resulting in further damage from reactive oxygen species. Liver failure occurs over a period of several days.
Unconjugated NAPQI is highly is highly reactive and binds with cellular macromolecules/mitochondria. Precipitous loss of function primarily leads to necrotic hepatic cell death. A single dose of over 10g (20 tablets) is potentially fatal.

Treatment of a Paracetamol Overdose
Paracetamol overdose must be treated as soon as possible and guided by blood levels of the drug. Treatment is time dependent, as delayed hepatotoxic effects peak at 72-96 hours post ingestion.

Within 0-4 hours treat with Activated Charcoal orally which reduces uptake by 50-90%
Within 0-36 hrs Start N-Acetylcysteine or Methionine by mouth if N-Acetylcysteine cannot be given promptly


LO 7.12 Know the general classification of endogenous and exogenous opioids

Endogenous opioids are found distributed in specific parts of the CNS and peripheral nervous system, that play important roles in processing pain signals – The limbic system, thalamus, spinal cord and primary afferent peripheral terminals.
Endogenous opioids are peptides derived from precursor proteins. There are three different forms, however the first four amino acids of all the endogenous opioids are conserved.

o Enkephalins -Precursor: Proenkephalin
o Endorphins - Precursor: Pro-opiomelanocortin (POMC)
o Dynorphins - Precursor: Prodynorphin

Exogenous Opioids
Exogenous opioids include the natural, semi-synthetic and synthetic agents with actions on endogenous opioid receptors. These are chemically distinct from the endogenous opioids.


LO 7.13 Appreciate the different classes of Opioid Receptors

Three major types of opioid receptors have been identified. They are expressed in the CNS both pre and post-synaptically.

o Mu (μ) (MOP) - Evidence for supraspinal analgesia in the CNS

o Kappa (κ) (KOP) - Evidence for analgesia in the spinal cord

o Delta (δ) (DOP) - Enkephalins. Widely distributed.

Binding to μ or δ receptors causes hyperpolarisation of the neuron by opening potassium channels, decreasing excitability. They also inhibit voltage gated calcium channels and subsequently the release of Substance P.
Binding to κ receptors inhibits voltage gated calcium channels and subsequently the release of Substance P.

All opioid receptors are G-protein coupled receptors. They all have Gi mediated action, reducing cAMP levels.


LO 7.14 Understand the basic pharmacology of Opiates in reducing pain

Exogenous opiates work the same way as endogenous opiates. The majority of therapeutic effects are mediated by the μ receptor (MOP). Binding of an Opioid to the μ receptor causes hyperpolarisation of the neurone by opening of potassium channels and inhibition of voltage gated calcium channels. This reduces neuronal excitability and decreases the amount of Substance P neurotransmitter release. This inhibits the pain transmission pathway, reducing the feeling of pain.

Exogenous Opioids – Agonists, Partial Agonists and Antagonists

Full Opioid Agonists
o Higher affinity for μ receptor
o Morphine, Codeine, Methadone (Codeine and Methadone are relatively weak agonists compared to Morphine and lack dependence )

Partial Opioid Agonist
o Developed to have mixed effects at all three receptors
o Can provide excellent analgesia without euphoria
o Nalbuphine - Mixed agonist/antagonist effects at μ, Partial agonist at κ, Weak against δ

Full Opioid Antagonists
o Bind predominantly to μ receptors and used to reverse potentially fatal agonist effects (Respiratory Depression)
o Naloxone


LO 7.15 Recognise the key importance of Opiate pharmacokinetics in therapeutic/toxic balance including route of admin

Route of Administration
o Oral (70% removed by first pass metabolism, necessitating larger doses)
o Rectal
o Intravenous - Most rapid response, avoids first pass metabolism, so often used for severe pain, with patient controlling the level of analgesia
o Intramuscular
o Intrathecally

Dose adjustment necessary for Oral preparations. Normally the t½ of Morphine is about 2 hours. However, one of its metabolites Morphine-6-Glucoronide is at least pharmacologically equivalent to Morphine with a t½ of 4-5 hours. This extends the period of effective analgesia.

Hepatic and Renal failure can increase half lives up to 50 hours, thus is a serious factor to consider in palliative care patients.

Methadone has an oral bioavailability of ~90%. It also has a t½ of about 24 hours, making it more suitable for treating chronic pain.

Codeine Pharmacokinetics
Codeine is an important opiate, which is given orally. It needs to be metabolised by CYP2D6 into Morphine to become pharmacologically active.

CYP2D6 is subject to Genetic Polymorphism, so that 10% of the Caucasian population cannot effectively convert Codeine to Morphine. Another polymorphism seen in Chinese people means codeine is less effectively converted to Morphine and dose may need to be adjusted upwards in this ethnic group.


LO 7.16 Describe major therapeutic uses of opiates

Strong Opioids are used in the treatment of moderate to severe pain, particularly:
o Visceral
o Postoperative
o Cancer-related
o Myocardial infarction
o Pulmonary Oedema
o Peri-operative analgesia

Weak Opioids are used in the relief of mild to moderate pain, and as antidiarrhoeals:


LO 7.17 Recognise side effects of Opiods group and factors that predispose to ADRs

Respiratory Depression
The most serious opioid ADR is Respiratory Depression, and is the single greatest cause of death following opiate overdose. This is due to a μ receptor mediated action of opiates on CO2 sensitivity. Normally therapeutic levels do not cause excessive depression, but when combined with sleep, pulmonary deficit or other depressant drugs such as anaesthetics, alcohol or sedatives the risk of death can be much greater.

Other Opiate ADRs
o Miosis (Important overdose sign)
o Euphoria
o Confusion
o Psychosis
o Coma
o Tolerance and dependence
o GI disturbances (nausea, vomiting, constipation)
o Rarely anaphylactic responses, due to non-opiate receptor effects on mast cells, causing the release of histamine, leading to bronchoconstriction & hypotension


LO 7.18 Management of intentional or accidental opiate overdose

Treat with Naloxone, which is an antagonist of the μ receptor, rapidly reversing adverse agonistic effects, such as respiratory depression. Naloxone has a short t ½ (1 hour) therefore repeated doses may be needed.


LO 7.19 Cover the medico-legal aspects of opiate prescription

Some opioid analgesics are controlled drugs
o Misuse of Drugs Act 1971
o Misuse of Drugs Regulations 2001

Schedule 2 (controlled drugs)
o Diamorphine (heroin)
o Morphine
o Remifentanil
o Pethidine

Schedule 5 (controlled drug – invoice)
o Includes preparations of certain controlled drugs (e.g. Codeine)


LO 2.4 Understand the factors affecting drug Bio availability, what is oral bio availability, how do you measure it and what is first pass metabolism.

Bioavailability is the fraction of a dose that finds its way into a body compartment, usually the blood. For an IV bolus, bioavailability is 100%. Factors affecting bioavailability include:
o Drug formulation
o Age
o Food (water soluble drugs are less likely to be affected by food)
o Vomiting
o Malabsorption
o First pass metabolism.

Oral Bioavailability is the proportion of a dose given orally (Or by any other route other than intravenous) that reaches the systemic circulation in an unchanged form. Bioavailability can be expressed as amount or rate.

Amount – Measured by are under curve of blood drug level vs. time
Rate – Measured by peak height and rate of rise of drug level in blood

Oral Bioavailability(F)=(AUC oral)/(AUC IV) × 100

First Pass Metabolism
Any metabolism occurring before the drug enters the systemic circulation is referred to as the first pass effect. This can occur in:
o The Gut Lumen -Gastric acid, proteolytic enzymes, grapefruit juice
o The Gut Wall - P-glycoprotein efflux pumps drugs out of the intestinal enterocytes back into the lumen, e.g. cicosporin
o The Liver - Substances absorbed in the ileum enter the portal circulation and are taken to the liver, where enzyme systems metabolise them
E.g. only 90% of an oral dose of paracetamol reaches systemic circulation
E.g. Popranolol is extensively metabolised


LO 2.4 Understand the factors affecting the Volume of Distribution of a drug, what is the equation of VoD and at what volume is each compartment indicated.

The Volume of Distribution is a measure of how widely a drug is distributed in body tissues. It is a calculated pharmacokinetic space into which a drug is distributed.

Volume of Distribution (Vd)= (Total Amount of Drug in Body)/(Plasma Concentration of Drug at Time Zero)

Vd values that amount to less than that of a certain body compartment volume indicate that the drug is contained within that compartment.
o When the volume of distribution is less than 5 Litres, it is likely that the drug is restricted to the vasculature.
o If it is less than 15 Litres, this implies that the drug is restricted to the extracellular fluid
o Greater than 15 Litres suggests distribution within the total body fluid.

Some drugs (usually basic) have a volume of distribution that exceeds body weight, in which case tissue binding is occurring. These drugs tend to be contained outside the circulation and may accumulate in certain tissues. For example, very lipid-soluble drugs, such as general anaesthetics (e.g. Thiopental), can build up in fat, meaning the drug has a much longer half-life in an obese patient.


LO 2.4 What is Clearance of a drug and Understand the factors affecting it, how its calculated. What is half life and how is it calculated.

The volume of plasma that is completed cleared of drug per unit time

Hepatic, renal and other secondary forms of elimination such as sweating or biliary elimination are measured in terms of Clearance. Hepatic and Renal Clearance are simply added together when calculating removal, so that:
Total Clearance = Hepatic Clearance + Renal Clearance

Calculating Renal Clearance
The renal artery is the input to the kidney and the kidney has two possible outputs, the renal vein and the ureter. Therefore, if a substance is not metabolised or synthesised, an equal amount must leave in the urine and the renal venous blood. Renal clearance can be calculated with the equation:

Clearance=(Amount in urine × Urine flow rate)/(Arterial Plasma Concentration)

E.g. Substance X is present in the urine at a concentration of 100mg/ml. The urine flow rate is 1ml/min. The excretion rate of substance X is therefore:
Excretion rate = 100mg/ml x 1ml/min = 100mg/min
If Substance X was present in the plasma at a concentration of 1mg/ml then its clearance would be:
Clearance=100/1=100 ml per min
100ml of plasma would be completely cleared of substance X per minute.

Factors Affecting Clearance
Heart – CVS/Circulatory factors affecting blood flow to the main organs of elimination
Renal – Factors affecting Renal elimination
Hepatic – Factors affecting Hepatic elimination

Half-Life (t½)
The half-life of a drug is the amount of time over which the concentration of a drug in plasma decreases to one half of the concentration value it had when it was first measured.

Half Life= (0.693 × Volume of Distribution)/Clearance


LO 8.1 Recognise the names of example inhalational and IV anaesthetics

Inhalational (Volatile) Agents
o Nitrous Oxide (N2O)
o Isoflurane
o Desflurane
o Sevoflurane

Intravenous Agents
o Propofol
o Ketamine


LO 8.2 Know the range of effects on the CNS produced during general anaesthesia

o Reticular Formation (Reticular Activating System) Depressed (Hindbrain, midbrain, thalamus)
o Thalamus - Transmits and modified sensory information
o Hippocampus depressed - Memory
o Brainstem depressed - Respiratory and some CVS
o Spinal cord
- Dorsal horn (analgesia )
- Motor neuronal activity (MAC)


LO 8.3 Appreciate the different types of anaesthesia used in modern practice

General Anaesthesia
Affects the whole body and typically involves use of intravenous and inhalational anaesthetics with adjuvants. They reversibly inhibit sensory, motor and sympathetic nerve transmission in the CNS to produce unconsciousness and absence of sensation.

Regional Anaesthesia
This involves rendering large, specific regions of the body insensate. The region is determined by transmission block between that part of the body and the spinal cord. Both spinal and epidural anaesthesia can achieve this. The patient remains conscious, but may also be administered adjuvants depending on the procedure.

Local Anaesthesia
Involves a more defined peripheral nerve block with injection of a local anaesthetic. Used for tooth extraction, or for example, procedures on the hand and fingers, foot or big toe, or internally in the urethra when performing cystoscopy.

Dissociative Anaesthesia
Uses agents such as ketamine that inhibit transmission of nerve impulses between higher and lower centres of the brain. Used in children and the elderly for short procedures, as they are less susceptible to its postoperative hallucinogenic effects.


LO 8.4 Recognise the proposed pharmacological mechanisms of action of the example agents acting at LGICs

Anaesthetics mediate their effects by affecting postsynaptic transmission of both inhibitory and excitatory Ligand Gated Ion Channels.

Importantly for inhalational agents, the interactions at these sites are very weak and easily reversed – an essential feature of anaesthesia. To carry out their action, they need to reach high concentrations in the cell membranes.

Anaesthetic effect may be mediated by action at more than one target site.

Inhibitory Ligand Gated Ion Channels

GABAA Activated Chloride Channels
o Many inhalational and IV anaesthetics have a primary effect on GABAA (Propofol exerts its main sedative effect on this channel)
o Bound anaesthetics increase sensitivity to GABA and increase Cl- currents
o This Hyperpolarises the neurone and decreases its excitability
o There are multiple binding sites, depending on the anaesthetic being used

Glycine Activated Chloride Channels
o Bound anaesthetics increase sensitivity to Glycine and increase Cl- currents
o This Hyperpolarises the neurone and decreases its excitability
o Glycine ligand gated ion channels are especially important in signalling inhibitory neurotransmission in the spinal cord and brainstem and act to reduce the response to noxious stimuli

Excitatory Ligand Gated Ion Channels

Neuronal Nicotinic (N) Ach Receptors
o Bound anaesthetics inhibit some subtypes of neuronal Nicotinic Ach receptors
o This reduces excitatory Na+ currents caused by Ach binding
o This is considered to likely contribute to analgesia and amnesia rather than sedation

NMDA Receptors
o NMDA receptors are responsive to glutamate, the major excitatory neurotransmitter in the brain
o Nitrous Oxide (N2O) and Ketamine exert their action here
o Bound anaesthetics reduce Ca2+ currents, which are involved in further modulation of synaptic responses


LO 8.5 Understand the main terms used in describing inhalational pharmacokinetics and the importance of re-distribution between tissue compartments for fluranes and Propofol

All inhalational agents require careful titration using specialist equipment to vaporise the modern inhalational Fluranes, which exist as volatile liquids at room temperature. The principal anaesthetic agent is then mixed with a carrier of oxygen, air and often with Nitrous Oxide. This is then fed to the respiratory system by mask under spontaneous or controlled respiration.

Minimum Alveolar Concentration (MAC)
The alveolar concentration (at 1 atmosphere of pressure) at which 50% of subjects fail to move to surgical stimulus (unpremedicated breathing O2/air)

The lower the MAC value, the more potent the inhaled anaesthetic is, as the MAC closely relates to its lipid solubility (able to get to the necessary high concentrations in the cell membrane easier). For modern Fluranes, MAC falls between 1-6% by volume of the inspired gas mixture. In anaesthetic practice, the MAC forms a standardised unit of delivery, e.g. 1 or 2 MACs for any inhalational anaesthetic. Surgical depth is typically achieved within 1.2 – 1.5 MAC.
The MAC for individual agents can be significantly reduced when given in combination with other agents, such as Nitrous Oxide (N2O) or the potent opiate Fentanyl. Physiological states such as reduced cardiac output, ventilation rate or shock can significantly affect management of anaesthesia.

Blood:Gas Coefficient
Inhaled agents very readily pass down their concentration gradients from the alveoli into the bloodstream. The concentration of inhalational agents in the alveoli directly determines their concentration when they reach their target sites in the CNS.

The blood:gas coefficient describes the volume of gas in litres that can dissolve in one litre of blood.
o E.g. Isoflurane – Blood:Gas coefficient is 1.4
So a litre of blood could dissolve 1.4 litres of Isoflurane
The higher the blood:gas coefficient, the more readily the gas will enter the blood.

Blood Supply to Organs
Once the gas is dissolved in the blood, it is then distributed by the vascular system to all tissues. However, the distribution around the body varies depending on two major factors; the relative blood supply to each organ or tissue and the specific tissue uptake capacity for the anaesthetic (the Tissue:Blood coefficient).

Relative blood supply at rest is
o Brain, Liver and Kidneys – 75%
o Muscle – 18%
o Fat – 5%
Tissue:Blood Coefficients
Once the anaesthetic is in the blood, the Tissue:Blood coefficient determines how readily it will move into the tissues. This is specific to tissue type:

o Entry into the CNS
The Brain:Blood Coefficient is 1.6
For an equivalent volume of brain to blood, the brain will take up 1.6 times as much anaesthetic.
o Entry into Muscle
The Muscle:Blood Coefficient is 2.9
So at equilibrium, the muscle tissue compartment takes up proportionately almost double the amount of Isoflurane than the brain
o Entry into Fat
The Fat:Blood Coefficient is 45
Fat absorbs nearly 30 times the amount of Isoflurane than the brain
This gives a very large reservoir of anaesthetic that can redistribute during the recovery phase

Modern Fluranes undergo little transformation by hepatic metabolism, and does not contribute significantly to their elimination.

Elimination is the reverse of distribution and absorption. As the surgery is finished the anaesthetist carries out a controlled withdrawal of anaesthesia, ensuring adequate oxygenation.

As the concentration in the blood drops, the anaesthetic moves out of the cell membranes and back into the venous blood. This travels back to the alveolus to be eliminated unchanged. The rate of recovery is similar to the rate of induction for inhalational agents. The elimination is led by the well-perfused tissues (Brain, kidneys, liver), followed by muscle and then fat.

Redistribution of Anaesthetics
Importantly, full recovery from anaesthesia can take hours or days. The removal of the anaesthetic from the lungs occurs in a first order manner, but it is also free to redistribute around the body and gain entry back into the CNS.

The levels achieved during this recovery phase can still very markedly affect conscious function. The duration of recovery is directly related to the length of procedure and the degree of loading of the muscle and fat compartments with anaesthetic agent.

Pharmacokinetics of Intravenous Anaesthetics
Induction of anaesthetic depth sufficient for surgery with inhalational agents alone would take a number of minutes. In contrast, use of an intravenous agent, most commonly Propofol, can result in sufficient anaesthetic depth within 20 seconds. This also bypasses the confusion of ‘excitement/aggression’ during Stage II of anaesthetic depth.
However, use of IV agents requires further vigilance as their dose related effects are not easily reversed once administered. Their use is further complicated by a two-stage distribution profile as the drugs move between tissue compartments served by different rates of vascular supply
Administration (Absorption) and Distribution of Propofol
o IV bolus in the arm results in rapid distribution to the well vascularised CNS, with proportionately lower distribution to muscle and fat
o Propofol then rapidly redistributes from the CNS to the other compartments
 For a single dose, surgical anaesthesia is maintained for about 5 minutes
 Muscle and fat have a much larger capacity for Propofol than the CNS
o Further supplementary doses may be given if the anaesthetist is using Propofol as an adjunct in order to lower the fluranes MAC. It can also be used alone for surgical procedures of short duration of about 20-30 minutes.

Metabolism and Elimination
Unlike the fluranes, Propofol undergoes hepatic and extrahepatic conjugation. These result in a t½ of about 2 hours.

This elimination means Propofol does not contribute to a prolonged post procedural ‘hangover’ during recovery.


LO 8.6 Be able to relate the differing pharmacodynamic modes of action to the example agents acting at the excitatory and inhibitory LGICs

Inhibitory Ligand Gated Ion Channels
Glycine/ GABAA Activated Chloride Channels
o Bound anaesthetics increase sensitivity to Glycine or GABAA, increasing Cl- currents
o This Hyperpolarises the neurone and decreases its excitability
Lower level of Glycine or GABA is needed to produce the same effect
EC50 is lowered (measure of potency)
Therefore, anaesthetics act to increase the potency of Glycine/GABA
Pharmacodynamically this is known as Positive Allosteric Modulation
o Propofol acts on GABA receptors

Excitatory Ligand Gated Ion Channels
Neuronal Nicotinic (N) Ach Receptors
o Bound anaesthetics inhibit some subtypes of neuronal Nicotinic Ach receptors
o This reduces excitatory Na+ currents caused by Ach binding NMDA Receptors
o NMDA receptors are responsive to glutamate, the major excitatory neurotransmitter in the brain
o Nitrous Oxide (N2O) and Ketamine exert their action here
o Bound anaesthetics reduce Ca2+ currents, which are involved in further modulation of synaptic responses

In Excitatory LGICs, the EC50 (potency) remains unchanged. However, the efficacy of the excitatory ligand decreases. This is typical of non-competitive allosteric antagonists.

This non-competitive effect means that once bound by the anaesthetic antagonist is inactivating the receptor. The reduced pool of bound anaesthetic receptors results in reduced efficacy, but the ligand binding affinity of the remaining unbound receptors is unchanged.


LO 8.7 Understand the key importance of Drug-Drug interactions by adjuvant drugs given in combination with a fluranes

Synergistic Interactions
Adjuvant drugs are required to produce an effective and balanced anaesthesia. Individual agents usually have a specific effect on CNS function related to their group. These are normally given as adjuvants with one of the fluranes acting as the principal inhalational anaesthetic producing unconsciousness:

o Benzodiazapines
E.g. Midiazolam
Exert agonist effect on GABAA receptors
Used to induce anxiolysis (anxiety inhibition) and amnesia
Given about an hour or so before surgery as a pre-med

o Propofol
Rapid induction of deep initial sedation

o Nitrous Oxide (NO2)
Reducing main inhalational agent MAC
Does not produce sufficient anaesthetic depth on its own
Allows for significant reduction in the effective MAC of fluranes.
Rapid controlled pulmonary elimination is highly advantageous in minimising recover time

o Opioids
For analgesia
Morphine and Fentanyl are two opiates commonly used during surgery
Fentanyl is much more potent (100x) inducing analgesia almost immediately and acting over 30-60 minutes.

o Neuromuscular blocking agents
Abolish reflexes that occur with significantly invasive procedures and induce muscle relaxation
Act as either competitive Nicotinic Ach receptor antagonists
Tubocurarine, Pancuronium
Or as Nicotinic Ach receptor depolarising agonists


LO 8.8 Recall the main example groups used in achieving balanced anaesthesia

Additive MAC Scale
o 50% [alveolar] NO2 = 0.5 MAC
o 0.6% [alveolar] Isoflurane = 0.5 MAC
These are added together to give a total of 1 MAC, which is nearly at the typical MAC of 1.2 – 1.5 needed for surgery.

Opiates reduce pain, allowing for an additional reduction in MAC. They also further reduce the risk of cardiovascular depression of the fluranes.


LO 8.9 Appreciate the range of physiological variables monitored during surgery

The anaesthetist is directly responsible for patient assessment before surgery and for monitoring during the operation and over recovery.

Pre-Surgical Review
Direct assessment of the patient, including:
o Age
o Prior medical and surgical history
o Current medication
o History of drug abuse
o Fasting time
o Airway assessment

Peri-Surgical Monitoring
o Direct control and monitoring of gaseous mixture calculation for % partial pressures of O2, Flurane, N2O, Nitrogen
o Mechanical rate of ventilation
o Comprehensive systemic physiological monitoring is carried out for:
o Cardiovascular function
o BP
o Respiratory function
o Pulse oximetry
o Expired CO2 used to assess ventilation state
o Thermoregulatory function
o Early detection of malignant hyperthermia

EEG monitoring may be used as a further measure of CNS activity and anaesthetic depth. This reduces the risk of under/overdosing and is a further monitor of the efficacy of adjuvant synergy and interaction


LO 8.11 Appreciate cardiovascular risk is related to high blood pressure and why modifiable risk factors should be addressed. How does high blood pressure lead to damage?

High blood pressure very rarely causes symptoms. It is therefore not a ‘disease’, but a risk factor for future vascular disease.

Higher Blood Pressure -> Increased arterial thickening -> Smooth muscle cell hypertrophy and accumulation of vascular matrix -> Loss of arterial compliance -> end organ damage
The organs affected by sustained hypertension are the brain, heart, arterial system, kidney and eye.

Epidemiologically, blood pressure is a strong predictor of risk of ischaemic heart disease and stroke.

Primary (Essential) Hypertension
o High BP without any single evident cause
o 90% of hypertensive population

Secondary Hypertension
o High BP with a discrete, identifiable underlying cause (e.g. Cushing’s)
o 10% of hypertensive population


LO 8.12 Understand that decisions about drug therapy are informed by both blood pressure level and total cardiovascular risk

The Role of Antihypertensive Drugs
The decision to offer drug therapy is influenced by:

o The sustained level of blood pressure
Hypertension is defined as 140/90mmHg
40% of the adult population of England are hypertensive
Lowering diastolic BP by 10mmHg is associated with 58% reduction in strokes and 37% reduction in coronary heart disease
≥ 160mmHg Systolic and ≥100mmHg diastolic justifies drug treatment

o The overall cardiovascular risk profile
At levels of 140-159 systolic and 90-99 diastolic the decision depends on overall CVS risk profile.
Is there > 15% risk of a cardiovascular event in the next 10 years?
Presence of end organ damage?
In the presence of diabetes the treatment threshold is 140/90mmHg

It is important to address the full range of modifiable risk factors such as smoking, cholesterol level, obesity and physical activity. For patients with diabetes, high blood pressure is particularly adverse and should be stringently controlled.

Non-Pharmacological factors
At the borderline, these measures may avoid the need for drug treatment.
o Optimum body weight (BMI 20-25 kg/m2)
o Regular physical activity (>30 mins a day)
o Moderation of alcohol and salt. (<3 units for men, < 2 units for women. < 6g salt)
o Smoking cessation should be strongly advised, and supported as necessary (e.g. nicotine replacement therapy)
British Hypertension Society Classification of Hypertension

Category Systolic BP (mmHg) Diastolic BP (mmHg)

Optimal <120 <80
Normal <130 <85
High Normal 130-139 85-89
Grade 1 (mild) 140-159 90-99
Grade 2 (moderate) 160-179 100-109
Grade 3 (severe) >180 >110
Isolated Systolic Hypertension
Grade 1 140-159 <90
Grade 2 >160 <90


LO 8.13 Describe the main classes of antihypertensive drugs, sites of action and main side effects - Angiotensin Converting Enzyme (ACE) Inhibitors

o Ramipril
o Lisinopril
o Captopril

Route of Administration - Oral

o Hypertension
o Heart failure
o Renal dysfunction

Contraindications - Pregnancy, renovascular disease, aortic stenosis

Mechanism of Action
o ACE inhibitors cause inhibition of Angiotensin Converting Enzyme, consequently reducing Angiotensin II and Aldosterone levels. This causes vasodilation and consequent reduction in peripheral resistance and reduced sodium retention.
o Reduce breakdown of the vasodilator Bradykinin

Adverse Drug Reactions
o Characteristic dry cough
o Angio-oedema (rare, but more common in black population)
o Renal Failure
o Hyperkalaemia
o Hypotension, dizziness and headache, diarrhoea and muscle cramps


LO 8.14 Appreciate how drug choices are made with the use of combination therapy

Combination therapy is commonly needed to achieve optimum blood pressure control. Although all of the above classes can be combined
o Apart from Verapamil and beta blockers, severe bradycardia and hypotension can occur

Step one – ACE inhibitor (under 55)/angiotensin receptor 2 blocker OR Calcium channel blockers (over 55 of african or Caribbean origin)

Step Two – add Ca2+ channel blocker or ACE inhibitor/Angiotensin 2 receptor blocker

Step Three – add a diuretic

Step Four – add a beta blocker
British Hypertension Society and NICE Hypertension Guidelines


LO 8.15 What is heart failure. Appreciate the main cause of systolic heart failure and other possible causes.

Heart failure is ‘a state in which the heart fails to maintain an adequate circulation for the needs of the body despite an adequate filling pressure’.

Ischaemic Heart Disease is the primary cause of Systolic Heart Failure.

Other causes of HF include:
o Hypertension
o Cardiomyopathies - Alcohol/Drugs/Poisoning, Iron overload, Pregnancy
o Valvular heart disease / Congenital
o Restrictive cardiomyopathy e.g. amyloidosis
o Hypertrophic cardiomyopathy
o Pericardial disease
o Arrhythmia


LO 8.16 Summarise the major principles underlying drug therapy in heart failure

o Correct underlying cause

o Non-pharmacological measures

o Pharmacological therapy
Symptomatic improvement
Delay progression of heart failure
Reduce mortality

o Treat complications/associated conditions/CVS risk factors
E.g. arrhythmias


LO 8.17 Describe the general sites of action of the major classes of drugs used in heart failure

Drugs used to Treat Heart Failure

B-blockers - Block B1 receptors on the myocardium

ACE-Inhibitors - Prevent conversion of Angiotensin I -> II

Ca2+ channel blockers - Reduce contractility of the myocardium

Organic Nitrates
Venodilator – Reduce preload on heart, lowering its O2 requirement
Vasodilator – Coronary arteries dilate, supplying more O2.

Cardiac Glycosides - Increase CO and heart contractility by inhibiting the Na/K pump. Raising intracellular Na inhibits NCX, so intracellular Ca2+ increases -> in. contractility


LO 9.1 List the pharmacology of agents affecting the renal tubules

Drugs Acting on the Renal Tubules
o Carbonic Anhydrase Inhibitors
o Osmotic Diuretics
o Loop Diuretics
o Thiazide Diuretics
o Potassium Sparing Diuretics
o Aldosterone Antagonists
o ADH Antagonists


`LO 9.2 Gain insight into the use of diuretics in clinical practice

Major Indications for Diuretic Use

Heart Failure
o Loop diuretics
o Thiazide diuretics
o (also ACE inhibitors/Angiotensin Receptor antagonists, β-blockers)

o Thiazide diuretics
o Spironolactone
o (also ACE inhibitors/Angiotensin Receptor antagonists, β-blockers)

Decompensated Liver Disease
o Spironolactone
o Loop diuretics


LO 9.3 Acknowledge the problems of prescribing in renal failure

When prescribing in renal disease there are two key issues:

1.Drugs may reduce kidney function by direct or indirect toxicity
o ACE inhibitors
o Aminoglycosides (e.g. Gentamicin)
o Penicillins
o Cyclosporin A
o Metformin

2.Drugs at normal doses may accumulate to toxic levels if they are excreted through the kidneys and renal function is impaired ACE inhibitors in Renal Disease
In Renal Artery Stenosis, Glomerular Filtration Pressure falls, leading to a drop in GFR, leading to the activation of RAAS. This causes vasoconstriction of the efferent arteriole to maintain Glomerular Filtration Pressure. If ACE inhibitors are given, inhibiting RAAS, the Glomerular Filtration Pressure will drop, causing Acute Renal Failure.

General Advice about Prescribing Drugs to Patients with Renal Failure
o Avoid nephrotoxins if at all possible
o Reduce dosages in line with GFR if metabolism or eliminated via the kidneys
o Monitor renal function and drug levels if narrow therapeutic range
o Hyperkalaemia is more likely
o Uraemic patients have greater tendency to bleed


LO 9.4 Describe the main factors involved in normal haemostasis and refer to Virchow’s Triad

Haemostasis is the body’s response to stop bleeding and loss of blood.

Successful Haemostasis depends on:
1) Blood Vessels
o Constrict to limit blood loss

2) Platelets
o Adhere to the damages vessel wall and to each other
o Form platelet plug

3) Coagulation
o Cascade, series of inactive components -> active components
o 1ml of blood can generate enough Thrombin to convert all of the fibrinogen in the body to fibrin, so tight regulation is required
o Balance of procoagulant and anticoagulant forces

4) Fibrinolytic System

Virchow’s Triad
o Changes in blood flow - Stagnation, turbulence
o Changes in vessel wall - Atheroma, injury, inflammation
o Changes in blood components - Smokers, pregnancy


LO 9.5 Understand the general features of thrombus formation and the causes of an arterial or venous thrombus

Thrombosis – The formation of a solid mass of blood within the circulatory system during life

Arterial Thrombi
o Ischaemia
o Infarction
o Depends on site and collateral circulation

Venous Thrombi
o Congestion
o Oedema
o Ischaemia (If Tissue Pressure due to Oedema > Arterial Pressure)
o Infarction


LO 9.6 Appreciate the Vitamin K antagonist action of ACAs (What type of ACA is a Vit K antagonist)

Vitamin K antagonists (e.g. Warfarin) block the reduction of vitamin K epoxide, to its active form.

The reduced, active form of Vitamin K is necessary for its action as a cofactor in the synthesis of:
o Factor II (Prothrombin)
o Factor VII
o Factor IX
o Factor X


LO 9.7 Describe the main therapeutic uses of Warfarin and understand the practical importance of Warfarin PKs in titrating doses

o Prophylaxis and treatment of deep vein thrombosis and pulmonary embolism
Deep Vein Thrombosis – Target INR of 2.0 – 3.0 for 3-6 months
Pulmonary Embolism – Target INR of 2.0 – 3.0 or 6 months
o Prophylaxis of embolization in atrial fibrillation/patients with prosthetic heart valves, Thrombosis associated with inherited thrombophilia conditions
Atrial Fibrillation – Target INR of 2.0 – 3.0 until Risk > Benefit
Prosthetic heartv valves – Target INR of 2.5 – 4.5

Good GI absorption - Oral dosing
o Slow onset of action - Heparin cover
o Slow offset - Need time to synthesise new clotting factors and need to stop 3 days before surgery
o Heavily Protein Bound - Caution with drugs that can displace it
o Hepatic Metabolism (CYP450 system)
Caution with Liver Disease
Caution with CYP450 inducers/inhibitors
Crosses Placenta - Do not give in 1st Trimester (Teratogen) or 3rd Trimester (Brain Haemmorhage)

These factors lead to extreme variation in individual dose requirement:
o Differing degrees of anticoagulation, depending upon condition
o Gradual onset of activity
o Persisting anticoagulant action on cessation of treatment
o Number drug-drug interactions resulting in altered anticoagulant effect


LO 9.8 Be familiar with the International Normalised Ratio (INR) in monitoring the effect of warfarin on blood clotting time/ What is the therapeutic target for INR values in normal and at risk patients

The effect of Warfarin is monitored via Prothrombin Time, which is expressed as the International Normalised Ratio (INR). This is calculated from the ratio of Prothrombin times of test and control samples. It is a measure of the Extrinsic Pathway of coagulation, measuring:
o Factor I – Fibrinogen
o Factor II – Prothrombin (Requires Vit. K for synthesis – Warfarin site of action)
o Factor V
o Factor VII (Requires Vit. K for synthesis – Warfarin site of action)
o Factor X(Requires Vit. K for synthesis – Warfarin site of action)

INR Values
o Treatment with Warfarin will Raise INR (inhibits coagulation)
o Therapeutic range of Warfarin is an INR of 2.0 – 3.0 (DVT/AF/PE)
o High risk patients (e.g. mechanical prosthetic valves) target INR of 2.4 – 4.5


LO 9.9 Be aware of important ADRs and DDIs with Warfarin and their particular importance in affecting therapeutic activity, e.g. risk of intracranial haemorrhage and raised INR > 4-5

Warfarin Adverse Effects
o Bleeding / Bruising - Intracranial, Epistaxis, Injection site, GI loss
o Teratogenic

Warfarin Drug-Drug Interactions

Drugs potentiating Warfarin (Increasing INR)
o CYP450 inhibitors - "GO-DEVICES"
o Inhibition of Platelet function - Aspirin (different site of action)
o Reduce Vitamin K from gut bacteria - Cephalosporin
o Displacement from plasma proteins (e.g. via NSAIDs)

Drugs inhibiting Warfarin (Decreasing INR)
o CYP450 inducers - "PCBRAS"


LO 9.10 Describe with reference to the INR the steps in managingw reversal of Warfarin action

o Stop Warfarin treatment

o Consider bleeding, INR, indication (e.g. if mechanical valve call cardiologist)

o IV Viatmin K
Slow acting, fresh clotting factors need to be synthesised

Will affect re-warfarinisation for 6 weeks
o Prothrombin Complex Concentrate (Fast acting)
o Fresh Frozen Plasma (Fast acting)
o Need to stop Warfarin 3 days before elective surgery


LO 9.11 Recognise the two major molecular Heparin groups and appreciate their: Differing PKs, sites, mechanisms of action and therapeutic uses

Unfractionated Heparin
Dose response: Non-Linear
Action: Variable - (Unpredictable due to binding to cells and proteins)
Action: Variable - (Monitor with APTT test)
Administration: IV
Initiation: Bolus then IV
Structure: Mix of variable long length heparin chains (12-15 kDaltons)
Mechanism of action: Binds to and Increases the activity of Anti-Thrombin III - Inactivates Thrombin, Factor Xa and factors V, VII, IX, XI

LMW Heparin
Dose response: Linear
Action: Predictable - (Less binding to cells and proteins)
No monitoring - (Little affect on APTT)Administration: Subcutaenous
Initiation: Once/Twice Daily
Low Molecular Weight Heparins (LMWH)
Structure: Smaller heparin chains (4-5 kDaltons)
High bioavailability (> 90%) and Long t½
Action: More predictable dose response - No macrophage/endothelial cell/plasma protein binding)
Mechanism of Action: Binds to Anti-Thrombin III - Inactivates Factor Xa ONLY AND DOES NOT INACTIVATE Thrombin (Factor IIa) (As not big enough to inactivater both, whereas unfractioned is bigger)
CLearnace: Cleared by Kidneys – careful with dose in Renal Failure


LO 9.12 Describe administration and monitoring of Heparin, the most serious ADRs and how to reverse Heparin effects by use of Protamine

Unfractionated Heparin
o Loading dose, then IV infusion
o Monitor APTT

Low Molecular Weight Heparin
o Prophylaxis SC once a day (until Warfarin loading is achieved)
o Treatment SC once/twice a day
o Never give Heparin Intramuscularly – Risk of Intramuscular Haemorrhage

Activated Partial Thromboplastin Time aPTT
o Used to monitor the Intrinsic Coagulation Pathway
o Plasma sample taken, mixed with an Intrinsic Pathway Activator (e.g. Silica) and time to form Thrombus measured
o Normal range 30 – 50 seconds

Heparin Adverse Effects
o Bleeding/Bruising - Intracranial, Injection sites, GI loss, Epistaxis
o Heparin Induced Thrombocytopenia (HIT)
Autoimmune response to Heparin on platelet surface, causing immune complex aggregation
Thrombosis and depletion of platelets due to aggregation
Lab assay for antibodies
Stop Heparin, add Hirudin

Heparin Reversal
o Stop Heparin
o Protamine Sulphate
Dissociates Heparin from Anti-Thrombin III
Irreversibly binds to Heparin
Given in allergy, anaphylaxis and if patient is actively bleeding
o Monitor APTT if using Unfractionated Heparin


Glycoprotein IIb / IIIa Inhibitors drug profile

Examples - Abciximab

Route of Administration - Intravenous

o Prevention of ischaemic cardiac complications in patients undergoing Percutaneous Coronary Intervention (PCI)
o Short term prevention of MI in unstable angina patients

Active bleeding

Mechanism of Action
o Monoclonal Antibody to Glycoprotein IIb/IIIa Receptors
o Prevents platelet aggregation

Adverse Drug Reactions
o Haemorrhage, nausea, vomiting, hypotension

Drug-Drug Interactions
o Works synergistically with Warfarin to decrease Coagulability


LO 9.14 Describe the pathway of events leading to MI and name the main sites of action of drugs used in treatment of MI

Myocardial Infarction (MI)
A MI is a complete occlusion of a coronary vessel, leading to an infarct (death) of the myocardium it supplies.

The fibrous cap of the Atheromatous plaque can undergo erosion or fissuring, exposing blood to the thombogenic material in the necrotic core. The platelet ‘clot’ is followed by a fibrin thrombus, which can either occlude the entire vessel where it forms or break off to form an embolism.

MI presents with typical ischaemic chest pain (see above) that is very severe, persistent, occurs at rest and often with no precipitant. It is not relieved by rest or nitrate spray. The patient may also be breathless, faint (due to LV dysfunction) have a ‘feeling of impending death’ and will have autonomic features present such as sweating, pallor, nausea and vomiting.

o Non ST Elevated Myocardial Infarction
o Infarct is not full thickness of myocardium
o ST Elevated Myocardial Infarction
o Infarct is full thickness of myocardium
Fibrinolytic Drugs
The normal clearance mechanism for thrombi is by Plasmin, an enzyme that cleaves Fibrin (and fibrinogen and several other coagulation factors). Plasmin is formed from its circulating precursor Plasminogen.

Fibrinolytic Drugs either generate Plasmin themselves (e.g. Tissue Plasminogen Activators (tPA) or bind to and activate endogenous plasminogen (e.g. Streptokinase).


LO 9.17 Understand the process by which patients are selected as suitable for thrombolytic therapy for acute MI based on inclusion and exclusion criteria

Acute MI Fibrinolysis
Fibrinolysis should be offered to people with an acute STEMI within 12 hours of onset of symptoms if Percutaneous Coronary Intervention (PCI) cannot be delivered within 120 minutes of the time when fibrinolysis could have been given.

(Window longer for venous thrombo-embolism, but only ~3 hours for ischaemic stroke)


LO 9.19 List the main ADRs of Thrombolytics and the conditions that may increase ADR risk

o Bleeding/Haemorrhage
o Anaphylaxis to Streptokinase
o Hypotension

o Peptic Ulcer (or other potential bleeding source)
o Recent trauma or surgery
o History of cerebral haemorrhage or stroke of uncertain aetiology
o Uncontrolled hypertension
o Coagulation defect
o Previous Streptokinase therapy


LO 10.2 How is the cardiac resting potential set up, what is it? (value). What is the change in potential over a heartbeat in the ventricle and pacemaker cells. How is the heart rate controlled?

Cardiac Resting Membrane Potential
The cardiac resting membrane potential is the potential inside a cardiac cell relative to the extracellular solution. The difference between the two is achieved by the selective permeability of the membrane to different ions, by way of channel proteins. The cell membrane of myocardial cells is mostly permeable to K+ ions. So the cardiac resting membrane potential of ~ -90mV is largely due to the K+ equilibrium potential of -80mv (see membranes and receptor module). K+ ions move down their concentration gradient, from the inside to the outside of the cell, taking their positive charge with them.

Ventricular Cells
o In diastole, the resting membrane potential of cardiac cells is close to the equilibrium potential of K+.
o Initial depolarisation due to spread of electrical activity from pacemaker cells. Once threshold has been reached, fast voltage gated sodium channels are opened, causing depolarisation towards Na+’s equilibrium potential .
o Following the rapid depolarisation, a brief repolarisation caused by the outward flow of K+ returns the membrane potential to ~0.
o Na+ channels deactivate, but the depolarisation causes the opening of voltage gated Ca2+ channels, which take longer to activate, keeping the membrane depolarised .
o Influx of Ca2+ causes the release of further Ca2+ from cellular stores, causing contraction (See M&R Session 5).
o After ~250ms, Ca2+ channels close.
o Efflux of K+ returns membrane potential to resting.

Pacemaker Cells
o The maximum –‘ve voltage of pacemaker cells is ~-60mv, less than the -90mv of ventricular muscle cells. This persistently less –‘ve membrane voltage causes the fast Na+ channels to remain inactivated.
o The spontaneous gradual depolarisation of pacemaker cells, the pacemaker or ‘funny’ current (If) is carried by Na+ ions through slow Na+ channels that open during the repolarisation of the cell as the potential approaches its most –‘ve values.
o Once the cell reaches its threshold voltage due to the If, Ca2+ channels open, giving a relatively slow depolarisation. This is due to the deactivation of the fast Na+ channels.
o Once Ca2+ channels close, the cell repolarises due to K+ efflux.

Increasing Heart Rate
The interval between beats depends on how fast the pacemaker potential depolarises. The interval is shortened by the action of the Sympathetic nervous system on the SAN. Noradrenaline (β1 Receptor) speeds up the heart rate by making the pacemaker potential steeper.

Decreasing Heart Rate
The interval between pacemaker potentials is lengthened by the action of the Parasympathetic nervous system on the SAN. Acetylcholine (M2 Receptor) slows the heart rate by making the pacemaker potential shallower.

Baroreceptors, located in the arch of the aorta and the carotid sinus have a role in controlling heart rate. When arterial blood pressure is high, the aorta/carotid arteries are stretched, activating the stretch sensitive baroreceptors.
The baroreceptors pass the information to the medulla, which in turn causes parasympathetic innervation of the SAN.
Parasympathetic innervation causes the pacemaker potential to become shallower, slowing the heart rate.
Low BP has the opposite effect.


LO 10.3 Understand the basic ways in which arrhythmias may occur/causes

Ectopic Pacemaker activity
o Damaged area of myocardium because depolarised and spontaneously active.
o Latent pacemaker region activated due to ischaemia
o Dominate over SA node

o Abnormal depolarisations following the action potential
o Thought to be caused by high intracellular Ca2+
o Longer AP leads to longer QT interval

Re-entry loop
o Conduction delay
o Normal spread of excitation disrupted due to damaged area (e.g. scar after MI)
o Incomplete conduction damage (uni-directional block)
o May be due to aberrant conduction pathway, e.g. Wolff-Parkinson-White

It is possible to get several small re-entry loops in the atria, e.g. from being stretched over time, leading to atrial fibrillation.


LO 10.4 Describe the classification of anti-arrhythmic drugs

Vaughn Williams Classification
Class I - Na+ Channel Blockers
Class II - β-blockers
Class III - K+ channel blockers
Class IV - Ca2+ Channel Blockers

Disopyramide Atenolol
Metoprolol Amiodarone
Sotalol Verapamil



Class 1 (Voltage Gated Na+ Channel Blockers)
Flecainide & Lidocaine are the most commonly used agents. They block fast, inward Na+ channels (Phase 0):
o Redcued Conduction velocity
o Increased Depolarisation threshold
o Reduced Automaticity
The sub-classes have different effects on the effective refractory period and duration of the action potential.
1a = increase in APD and ERP, moderate reduction in phase 0 slope = AF, SVT and VT
1b = decrease in APD and ERP, small reduction in phase 0 slope = VT
1c = no effect on APD and ERP, but greatly reduced phase 0 slope = life-threatening VT and SVT

Class II. (B-adrenoceptor antagonists)
β-blockers act on B1 receptors in the heart, blocking sympathetic action and decreasing the slope of the pacemaker potential in the SAN, decreasing chronotropy. This also inhibits adenyl cyclase, decreasing inotropy.
o Redcued Automaticity
o Redcued Phase 4 slope
o Increased Threshold for activation in SAN and AVN
o Increased AVN conduction time and refractory period

Class III. (Drugs that block K+ channels)
Prolong the action potential, by blocking K+ channels (responsible for repolarisation).
o Increased absolute refractory period
o Increased AP duration
o Suppress re-entry circuits by closing excitable gap
They are not generally used because they can also be pro-arrhythmic (Increased QT interval, increased risk of Torsades de Pointes).

Class IV (Drugs that block Ca2+ channels)
Decreases slope of pacemaker action potential at SA node and AV node.
o Increased Refractory Period
o Redcued Chronotropy and Inotropy


LO 10.5 How does excitation spread in systole

Spread of Excitation in Systole
1. The SA node fires an action potential, which spreads over the atria causing atrial systole. The AP reaches the AV node, where it is delayed for about 120ms.

2. From the AV node, excitation spreads down the septum between the ventricles

3. Excitation spreads from inner (endocardial) to outer (epicardial) surface

4. Ventricle contracts from the apex up, forcing blood towards the outflow valves.

Ventricular muscle is organised into figure of eight bands that squeeze the ventricular chamber forcefully in a way most effective for ejection through the outflow valve. The apex of the heart contracts first and relaxes last to prevent back flow.


LO 10.6 Give examples of drugs with action of inotropic drugs and vasodilators

Inotropic Drugs
o Digoxin

Vasodilator Drugs
o ACE inhibitors
o Angiotensin Receptor Blockers


LO 10.7 Understand the different effects on Cardiac Output of inotropic and vasodilator drugs

There are several routes that can improve ventricular stroke volume:
- Increasing preload
- Decreasing afterload
- Increasing inotropy

In heart failure (particularly systolic dysfunction), preload is already elevated due to ventricular dilation and/or increased blood volume. Increasing the preload further will not necessarily increase stroke volume because a heart in failure is usually functioning on the flat, depressed region of the Frank-Starling curve. Furthermore, increasing preload will exacerbate pulmonary or systemic congestion and edema, which occurs when end-diastolic pressure is greater than 20 mmHg. Therefore, increasing preload is not a viable option for increasing cardiac output in heart failure patients.

Decreasing afterload with vasodilator drugs significantly enhances ventricular stroke volume (figure: B→D) and ejection fraction in failing hearts because the afterload is often elevated in heart failure and this reduces ejection velocity. Therefore, reducing afterload has been found to be very effective in the treatment of systolic dysfunction because it increases stroke volume and decreases preload, thereby improving ejection fraction.

Increasing inotropy (figure: B→D) to increase stroke volume and ejection fraction is used in the treatment of heart failure; however, most positive inotropic drugs should only be used for acute systolic failure or end stage failure because prolonged use of these drugs have been shown to worsen the outcome and increase mortality in some patients. The short-term benefit of such drugs, and the reason why they are used in acute heart failure, is that they increase stroke volume, increase ejection fraction, and reduce preload, all of which are beneficial. However, inotropic drugs increase oxygen demand, which is deleterious with long-term use.


LO 10.8 Have a general appreciation of the development of therapeutic of cancer has grown over the past 70 years

Mustard Gas
Used in 1940s to treat lymphoma

Found when passing electric currents through E. coli, found that the platinum electrodes were found to be responsible

Chemical Engineering
o Paclitaxel – Tubulin poison. Found in pacific yew tree, which is very rare therefore is very expensive. Then used in chemical engineering in order to produce a synthetic compound.
o Find agents present in nature and investigate to see if these compounds have any effect in treatments and then chemically engineer them

Molecular Targeting Approaches
o Imatinib – Bcr-Abl tyrosine kinase inhibitor. Prevents development and progression of chronic myeloid leukaemia.
o Magic bullet, tumour selective, efficacious, few side effects


LO 10.9 Review main features of DNA structure and replication within cell cycle

DNA Structure

Nitrogenous Bases – There are two types:
o Purines – Two ring structure (G and A)
o Pyrimidines – One ring structure (C, T and U)
o A base pair is formed by one purine and one pyrimidine. G pairs with C and A with T.

DNA Double Helix
o 2 independent polymers
o Entirely complimentary and antiparallel to each other (Top strand 5’prime 3’, bottom 3’ prime 5’)
o One complete turn is 10 base pairs
o Space between base pairs is 0.34nm
o Purines and pyrimidines are planar and unsaturated
o Within structure of sugar-phosphate backbone, major (exposed bases) and minor grooves exist

DNA Replication
1) Initiation – recognition of an origin of replication. Helicase unravels the DNA double helix. Requires specific proteins to interact with DNA and recruit DNA polymerase (because DNA polymerase can only extend from 3’ ends of pre-existing chains to 5’, a special enzyme primase is required to initiate each strand)
2) Elongation – leading strand is replicated from 5’ prime 3’ as normal. However the lagging strand is replicated discontinuously in Okazaki fragments. These fragments are then joined by DNA ligase from OH group to Phosphate group covalently.
3) Termination – Replication forms move from the ends of the DNA strands towards each other. Lead strands move towards lagging strands and vice versa. The terms ‘leading’ and ‘lagging’ have no bearing once ligase has joined up all the fragments.


10.11 Understand tumour classification regarding sensitivity to chemotherapeutics

Highly Sensitive
Germ cell tumours
Small cell lung
Wilm’s tumour

Modest Sensitivity

Low Sensitivity
Renal cell
Brain tumours


LO 10.12 Recognise main routes for administration of chemotherapy

For many types of cancer, chemotherapy regimen will consist of a number of different drugs (combination chemotherapy), although a drug may also be given on its own.

Common Routes of Administration:
o Intravenous - Most common – Bolus, infusional bag, continuous pump infusion
o Oral - Dependent on bioavailability. Most convenient
o Subcutaneous - Convenient in community setting
o Into a body cavity - Bladder, pleural effusion
o Intralesional - Directly into a cancerous area
o Intrathecal - By lumbar puncture of omaya reservoir (directly into ventricles)
o Topical
o Intramuscular - Rarely


LO 10.13 Be able to name the major ADRs with cancer chemotherapy outlined in this lecture

Multifactorial, but includes direct action of chemotherapy drugs on central chemoreceptor trigger zone. Patterns of emesis:
o Acute Phase – 4 to 12 hours
o Delayed Onset – 2 to 5 days later
o Chronic Phase – May persist up to 14 days

o Hair thins at 2-3 weeks
o May be total
o May regrow during therapy
o Marked with Doxorubicin, Vinca Alkaloids, Cylophosphamide
o Minimal with Platinums
o Scalp cooling may help

Skin Toxicity
o Irritation and thrombophlebitis of veins
o Extravasation
o Bleomycin - Hyperkeratosis, Hyperpigmentation, Ulcerated pressure sores
o Busulphan, Doxorubicin, Cyclophosphamide, Actinomycin D - Hyperpigmentation

o GI tract epithelial damage
o May be profound and involve the whole tract
o Most commonly worst in Oropharynx
o Presents as sore mouth/throat, diarrhea, GI bleed

o Cardio-myopathy
o Arrhythmias

Lung Toxicity
o Pulmonary fibrosis

Haematological Toxicity
o Most frequent dose limiting toxicity
o Most frequent cause of death from toxicity
o Different agents cause variable effects on degree and lineages - Neutrophils and Platelets


LO 10.14 Know the importance of Pharmacokinetics regarding chemotherapeutics

What causes variability in Chemotherapy

o Nausea and vomiting – May vomit drugs back up
o Compliance
o Gut problems – E.g. mucositis

o Weight loss
o Reduced body fat
o Ascites

o Liver dysfunction, other medications

o Renal dysfunction

Protein binding abnormalities
o Low albumin
o Drug-Drug Interactions


LO 10.15 Recognise some of the main DDIs with cancer chemotherapy

o Vincristine and Itraconazole (commonly used antifugngal) - Neuropathy

o Capecitabine (oral 5FU) and Warfarin - Very important interaction!! Increases bleeding risk

o Capecitabine (oral 5FU) and CYP450 enzyme inhibitors - GO-DEVICES

o Methotrexate and penicillin, NSAIDs


LO 10.16 Understand the necessity of monitoring to assess benefit but also to minimize serious ADRs and DDIs

Chemotherapy Monitoring
o Response of the Cancer
o Radiological imaging
o Tumour marker blood tests
o Bone marrow/cytogenics
o Drug Levels
o Methotrexate drug assays taken on serial days to ensure clearance from blood after folinic acid rescue
o Checks for Organ Damage
o Creatinine clearance
o Echocardiogram


LO 10.17 What is the log kill ratio and what are the main chemotherapy agents

Log-Kill Ratio
Need to kill a certain proportion of the cancer cells in order for a treatment to be describe as effective. Needs to kill 10*4 of cancer cells which equates to 99.9% of the total cells (start off with 10*9 as this is when clinical effects tend to be seen and when the tumour is the size of a small grape).
o Need to weigh up the kill rate for cancer cells against the kill rate for healthy cells.
o Difficult to access all cells at once – some are on the outside, some are one the inside (compartment A vs. compartment B)
o Rate of regrowth of healthy cells in between chemotherapy sessions must be ahead of the rate of regrowth of cancer cells.

These are analogues of certain products needed for DNA synthesis. Therefore antagonising the action of producing DNA.
e.g. methotrexate
o Inhibits action of dihydrofolate reductase which prevents cell from producing tetrahydrofolate
o Reduced folate production means a reduced production of purine and pyrimidine production
e.g. Fluoruracil
o Analogue of uracil, which inhibits thymidilate synthase and another co-enzyme so that they cannot release any stable product.
o Causes thymidine-less cell death

Spindle Poisons
Arrests the cell in metaphase as it prevents correct spindle formation
e.g. Vinca alkaloids (vincristine and vinblastine)
o Polymerise the B-tubulin subunit to prevent formation of microfilaments which stimulates apoptosis.
e.g. Taxanes (paclitaxel)
o Stabilises microtubules to prevent their disassembly. Cannot pull apart the chromosome. Stimulates apoptosis.

DNA Alkylating Agents
Causes DNA cross-links to form between strands. Prevents replication and can cause strand breakage.
e.g. Cipsplatin.
o Has maximum effect in S phase as this is where DNA is most exposed

DNA Intercalating Agents
Intercalates between base pairs of DNA and acts to interfere with topoisomerase II.
e.g. Anthracycline Antibiotics (doxorubicin and daunorubicin)
o Molecular ring structure makes the intercalates inbetween base pairs (DNA intercalation)
o Interfere with topoisomerase II, which interferes with DNA replication and repair


LO 11.1 What is epilepsy and Appreciate the general criteria used in determining whether a patient is epileptic

Epilepsy is an episodic discharge of abnormal high frequency electric activity in the brain leading to seizure. It is a common condition (Prevalence 0.5-1%, 450,000 in the UK). 70% of patients treated therapeutically

Diagnosis required evidence of recurrent seizures unprovoked by any other identifiable causes.

Epilepsies should be viewed as a symptom of underlying neurological disorder, not a single disease entity


LO 11.2 Know the general classification of epilepsy based on partial and generalised seizures and what is an prolonged seizure called.

Epilepsy at the Neuronal Level
o Increased Excitatory activity
o Reduced Inhibitory activity
o Loss of homeostatic control
o Spread of Neuronal hyperactivity - This determines the type of seizure

Classification of Epilepsy

Partial (or focal) seizures
o Simple (conscious) or Complex (impaired consciousness)
o Loss of local excitatory/inhibitory homeostasis
o Increased discharged in focal cortical area
Symptoms reflect affected area
Involuntary motor disturbance
Behavioural change
Impending focal spread accompanied by Aura, e.g. unusual smell or taste, déjà vu, jamais vu
o May become secondarily generalised

Generalised Seizures
o Generated centrally and spread through both hemispheres
o Loss of consciousness
o Tonic (Initial Rigidity)-Clonic (Shaking) Seizures
Grand Mal
o Absence Seizures (loss of expression, stare blankly, patient not aware of them)
Petit mal

Status Epilepticus
Most seizures are short lived, from seconds up to 5 minutes. However, some seizures are prolonged beyond this, or experienced as a series of seizures without a recovery interval. This is referred to as Status Epilepticus, and can occur for any type of epilepsy. Prolonged seizures are medical emergencies.


LO 11.4 Describe some of the major recognised precipitants of epilepsy

Sensory Stimuli
o Flashing lights/strobes
o Any other periodic sensory stimuli

Brain Disease/Trauma
o Brain injury
o Stroke/Haemorrhage
o Drugs/Alcohol
o Structural abnormality/Lesion

Metabolic Disturbances
o Hypoglycaemia
o Hypocalcaemia
o Hyponatraemia

o Febrile convulsions in infants

o Some drugs can lower fit threshold
o Anti-Epileptic Drugs and Polypharmacy


LO 11.5 Understand the broad models of how epilepsy is generated within the brain

Epilepsy at the Neuronal Level
o Increased Excitatory activity
o Redcued Inhibitory activity
o Loss of homeostatic control
o Spread of Neuronal hyperactivity
This determines the type of seizure


LO 11.6 Appreciate that untreated epilepsy can be a life-threatening condition

Dangers in Severe Epilepsy
o Physical injury relating to fall/crash
o Hypoxia
o SUDEP – Sudden death in Epilepsy
o Varying degrees of brain dysfunction/damage
o Cognitive impairment
o Serious psychiatric disease
o Significant adverse reactions to medication
o Stigma/Loss of livelihood


LO 11.7 Recognise the major drug classes used to treat epilepsy and their general sites of action

Antiepileptic drugs generally act by inhibiting the rapid, repetitive neuronal firing that characterises seizures. They act by:
o Inhibition of channels involved in neuronal excitability e.g. Voltage gated Sodium channels
o Enhancement of inhibitory activity e.g.GABA-mediated inhibition

Voltage Gated Sodium Channel Blockers (VGSC Blockers)
VGSC blockers act by binding to the channel and keeping it in an inactivated state. This reduces the probability of high abnormal spiking activity. VGSC blockers only gain access to the channel binding site during depolarisation, hence are voltage dependent. They are also self regulating, as they detach from the binding site. VGSC blockers prolong inactivation state to return firing rates back to normal.

Enhancing GABA Mediated Inhibition
GABA plays a major role in post-synaptic inhibition, 40% of synapses in the brain are GABA-ergic. Increase in GABA is a natural anticonvulsant.

The general mechanism is an increase in Chloride current into the neurone, increasing the threshold for action potential generation. This reduces the likelihood of epileptic neuronal hyper-activity.

Pharmacological targets:
o Binding with GABAA receptor
o Direct GABA agonists
o Benzodiazepine Site – Enhance GABA action
o Barbiturate Site – Enhance GABA action

Sodium Valproate


LO 11.8 Describe the major and use limiting side effects of commonly prescribed anti-convulsants

LO 11.9 Describe safe prescribing principles in epilepsy, particular relating monotherapy, drug interactions, liver enzyme induction and inhibition and cessation of therapy

Anti-Epileptic Drugs – Basic Prescribing Rules
o ADRs with AEDs are very common
o Adjunctive drug use and Polypharmacy with epilepsy is very common - Monotherapy is the aim though!

o Systematic use of one drug, replace if ineffective
o Patients must remain under review
o Variation in AED plasma levels – Monitor and titrate to therapeutic window
o ITU sedation is a treatment


LO 11.10 Describe the safety concerns of anti-convulsant therapy in pregnancy

The treatment of epilepsy in pregnancy is a balance of risk:
o Epilepsy vs. AED Teratogenicity
o In mild epilepsy, stop the treatment?
o In Severe disease or Status epilepticus how much harm will be done to the mother and baby if treatment is stopped?

AEDs and Pregnancy
o With multiple AEDs, the Teratogenic risk increases
Neural tube defects
Folate supplements reduce the risk
Facial and digit hypoplasia
Learning difficulties / mild neurological dysfunction
Vitamin K deficiency in newborn leading to coagulopathy and cerebral haemorrhage
Vitamin K supplement, 10mg/day in last trimester
AED risk of birth defects ~8%, compared to ~2% normally
o Use a single AED agent if possible at lowest dose
o Valproate is best avoided – Neural tube defects
o Lamotrigine may be the safest – Birth defect rate is ~2% (normal rate)

Failure of Contraception with AEDs
o Failure rate of OCP is 5-10% higher with Carbamazepine / Phenytoin
1-2% baseline OCP failure
5-10% failure rate with Carbamazepine / Phenytoin


LO 11.11 Appreciate the value of therapeutic drug monitoring in phenytoin therapy

o Sub-Therapeutic Levels
Linear Kinetics

Therapeutic Levels
Non-Linear Kinetics
Saturated enzymes
Plasma t½ increases as dose is increased
Steady State Concentration in Plasma (achieved with a daily dose) varies disproportionately with the dose (see image).
The therapeutic range of Phenytoin is quite narrow, 40-100μmol. Drug monitoring of the plasma levels of Phenytoin is required, as due to its pharmacokinetic properties this therapeutic range can be exceeded quite rapidly, causing adverse effects (see above).


LO 11.12 Apply the basic knowledge of anticonvulsant therapy to the management of a tonic clonic seizure and status epilepticus

Medical emergency
o Adult mortality ~20%
o Risk increases with the length of Status Epilepticus
Management of Status Epilepticus
o ABC approach
o Exclude hypoglycaemia
o Hypoventilation may result with high AED doses
o ITU for paralysis and ventilation if AEDs are failing

AEDs in Status Epilepticus
o Benzodiazepines
Lorazepam (0.1mg/kg)
Preferred to Diazepam due to longer t½
Given intravenously (rectal if IV access difficult)
Zero Order (Non-Linear) kinetics (15-20mg/kg)
Rapidly reaches therapeutic levels IC
Cardiac monitoring – Arrhythmias and hypotension

Drugs to be used for each type of seizure (NICE Guidelines)

o Absence = Ethosuximide or sodium valproate. If ineffective, move onto lamotrigine
o Tonic Clonic = sodium valproate, then lamotrigine, then carbemezepine and oxcarbazepine
o Focal Seizures = carbamazepine or lamotrigine
o Myoclonic seizures = sodium valproate first, then levtriacetam or topiramate if sodium valproate is not tolerated
o Tonic/Atopic seizures = Sodium valproate


LO 11.13 Understand the term Parkinsonism and what might cause it

Parkinsonism is a neurological syndrome categorised by:

Low frequency rest tremor
Abolished by movement
Low dopamine and disturbance of other neurotransmitters

Lead pipe rigidity / Cog-wheel
Low dopamine and disturbance of other neurotransmitters

Low Dopamine

Postural instability

Non-Motor Manifestations
o Mood changes
o Pain
o Cognitive change
o Urinary symptoms
o Sleep disorder
o Sweating

Causes of Parkinsonism
o Idiopathic Parkinson’s Disease
o Dopamine blocking or depleting drugs
Particularly antipsychotics


LO 11.15 Understand the pathophysiology of Parkinson’s and how this influences the choice of pharmacological treatment

Pathophysiology of Parkinson’s Disease

o Presence of neuronal inclusion called Lewy Bodies
Contain tangles of α-synuclein and ubiquitin
Gradually become more widespread as the condition progresses, spreading from lower brainstem -> Midbrain -> Cortex

o Loss of Dopaminergic Neurones from the pars compacta of the Substantia Nigra in the midbrain that project to the striatum of the basal ganglia.
Extent of nigrostriatal dopaminergic cell loss = degree of akinesia
No symptoms until there is 50% cell loss
Loss of pigment (dopaminergic cells in Substantia Nigra contain melanin)


LO 11.16 What are the Drug Classes that are commonly used to treat Parkinsons

Catecholamine Synthesis

Drug Classes in IPD
o Levodopa (L-DOPA)
o Dopamine receptor agonists
o MAOI Type B inhibitors
o COMT inhibitors
o Anticholinergics
o Amantadine


LO 11.17 Appreciate the range of ADRs with Parkinsonian agents and how they may be limited

To reduce side effects of L-DOPA, use another drug as well but and reduce dose.


LO 11.18 Understand the natural history of Parkinsons and the complications that can ensue

Prognosis in Parkinson’s Disease (15 year follow up)
o Dyskinesia – 94% (writhing movement due to L-DOPA treatment)
o Falls – 81%
o Cognitive Decline – 84% (50% have hallucinations)
o Somnolence – 80%
o Swallowing Difficulty – 50%
o Severe Speech Problems – 27%


LO 12.1 Appreciate the spectrum of peptic disease and be aware of the surgical treatment options where relevant

Peptic ulcer disease (PUD):
Peptic ulcer is break in superficial epithelial cells penetrating down into Muscularis mucosa of either stomach (GU) or duodenum (DU). Most DUs are found in duodenal cap and GUs are most commonly seen in lesser curvature of stomach

Leading cause in developed world is use of NSAIDs, which inhibit production of prostaglandins, prevents production of protective unstirred layer (innate protection against gastric acid). 50% of patients taking long term NSAIDs have mucosal damage and 30% when endoscoped have peptic ulceration but only 5% will be symptomatic and only 1-2% will have complication such as GI bleed.

Duodenal Ulcers found in ~10% adult population and are 2-3 times more common than GUs. Prevalence is falling for younger people (especially men) and increasing in older people (especially older women). In developed countries increased prevalence of NSAID-associated DUs and decreasing prevalence of H pylori associated ulceration

Clinical features
o Recurrent, burning epigastric pain (pain is often worse at night and when hungry with Duodenal Ulcers and relieved when eating). Pain may subside with antacids
Persistent, severe pain suggest penetration of ulcer into other organs
Back pain suggest penetrating posterior ulcer
o Can also get nausea, vomiting (though less common)
o With GUs can get weight loss and anorexia
o May be asymptomatic and present for first time with hematemesis when ulcer has perforated blood vessel(s)

o Investigate H pylori infection
o In older patients (over 55y/o) or with other alarming symptoms -> endoscopy to exclude cancer

o If due to H pylori infection -> Triple Therapy
Proton Pump Inhibitor – Omeprazole
Antibiotics – Clarithromycin / Amoxicillin
H2 Antagonist – Cimetidine
o If taking NSAIDs – stop or review – use alternatives (NSAIDs with lower risk of causing PUD), or use prophylactic PPI as well as NSAID
PPI – e.g. omeprazole

Surgical Treatment of Peptic Disease
o Resection of the Vagus Nerve
o Anti-reflux surgery

Complications of PUD
o Haemorrhage of blood vessel which ulcer has eroded -> presents with hematemesis and melena
o Perforation of the ulcer – more common in DUs than GUs – usually perforate into peritoneal cavity
o Gastric outlet obstruction  can be pre-pyloric, pyloric or duodenal. Occurs either because of active ulcer with oedema or due to healing of an ulcer with associated fibrosis (scarring). Gastric outlet obstruction normally presents as vomiting without pain.


LO 12.2 List the defensive and aggressive factors affecting the integrity of the gastric mucosa

Defensive Factors
Epithelial integrity
Cell replication and restitution
Mucous membrane barrier
Vascular supply
Mucus is Sticky, so is not easily removed from the stomach lining. It is also Basic, due to Amine groups on the proteins. The mucus forms a ‘unstirred layer’ that ions cannot move through easily.
H+ ions slowly diffuse in and react with the basic groups on mucus and with HCO3- that is secreted by surface epithelial cells.
Because of the unstirred layer, HCO3- stays close to the surface cells. This means the pH at the surface cells is well above 6. Mucus and HCO3- secretion from neck cells and surface cells respectively is stimulated by prostaglandins, which are promoted by most factors that stimulate acid secretion.

Agressive Factors
Breaching the Stomach’s Defences
o Alcohol
Dissolves the mucus, allowing the acid to attack the stomach
o H. Pylori
Surface cells become infected, inhibiting mucus/HCO3- production
Inhibit prostaglandins, therefore reducing defences
Some, like aspirin are converted to a non-ionised form by stomach acid, allowing them through the mucus layer into cells before they re-ionise.


LO 12.3 Describe the physiology & pharmacology of acid secretion by parietal cells. And the stages of gastric secretion.

Parietal Cells
Parietal cells have lots of mitochondria, allowing them to produce H+ at a high rate. The H+ ions are formed from dissociation of water. The hydroxyl ions which are also formed in this process quickly combine with CO2 to form a bicarbonate ion in a reaction catylased by carbonic anhydrase. However, these produced ions cannot accumulate in cells. To overcome this problem, parietal cells have invaginations in their cells walls called canaliculi.

Canaliculi have proton pumps, which expel H+ from parietal cells up a high concentration gradient. As the concentration gradient is high, this is a very energy intensive process.

The proton pumps in canaliculi are a key target for drug action, as if inhibited they will reduce the amount of acid in the stomach.

Control of Gastric Secretion
A complex of neural and endocrine systems controls acid secretion. Parietal cells are stimulated by Acetylcholine, Gastrin and Histamine, which act via separate receptors to promote acid secretion.

Ach is released from postganglionic parasympathetic neurones, stimulated by gastric distension as food arrives. It acts on muscarinic receptors on parietal cells.

Gastrin is released from endocrine cells in the stomach, G-Cells. It is a 17-amino acid polypeptide, which binds to surface receptors on parietal cells.
Gastrin secretion is stimulated by the presence of peptides and Ach from intrinsic neurones. It is inhibited by low pH in the stomach, which acts as a ‘feedback’ control.

Histamine is released from Mast Cells and diffuses locally to bind H2 surface receptors on parietal cells. Acid secretion is then stimulated via c-amp.
Gastrin and Ach stimulate mast cells, so Histamine works as an amplifier.

Phases of Control of Gastric Secretion

1. Cephalic Phase
The ‘brain led’ phase. The sight and smell of food, and the act of swallowing, activates the parasympathetic nervous system, which stimulates the release of Ach. This stimulates parietal cells directly and via histamine (Increased Acid).

2. Gastric Phase
Once food reaches the stomach, it causes distension, further stimulating Ach release, and subsequently parietal cells (Increased Acid).
The arrival of food will also buffer the small amount of stomach acid in the stomach in between meals, causing luminal pH to rise. This disinhibits Gastrin (Increased Acid).
Acid and enzymes will then act on proteins to produce peptides, further stimulating Gastrin release as the pH falls and the initial disinhibition is removed (INcreased Acid).

3. Intestinal Phase
Once chyme leaves the stomach in significant quantities, it stimulates the release of the hormones Cholecystokinin and Gastric Inhibitory Polypeptide from the intestines that antagonise Gastrin (Reduced Acid). Coupled with this, the small amount of acid left in the stomach is no longer being buffered by food, and the low pH inhibits Gastrin (Redcued Acid).

The low pH of the stomach between meals can aggravate ulcers. Because of this, pain from ulcers is particularly bad at night.


LO 12.4 Understand the mechanism of action of the major drug groups used to control acid secretion and provide gastric protections, PPIs and H2 antagonists

Acid secretion may be reduced by inhibition of:
o Histamine at H2 Receptors
E.g. Cimetidine
Removes the amplification of Gastrin/Ach signal by acting as a Histamine Receptor Antagonist

o Proton Pump Inhibitors (PPIs)
E.g. Omeprazole
Prevents H+ ions being pumped into parietal cell canaliculi by targeting ATPase


LO 12.5 Describe the use of drugs within general management of GORD/Oesophagitis

GORD/Oesophagitis Treatment
o Healing and maintenance
o Treat complications (Barrett’s oesophagus, peptic stricture)

Step Up Treatment Step Down Treatment
GP Setting, start with lifestyle modifications and move upwards Hospital settling, start with PPI treatment and work down
o Lifestyle
o Antacids
o H2 Receptor Antagonists


LO 12.6 Appreciate the main ADRs and DDIs of these PPI's and H2 antagonists

PPI Adverse Drug Reactions
o GI upset
o Nausea
o Headaches
o Risk of gastric atrophy with long-term treatment

H2 Receptor Antagonist Adverse Drug Reactions
o Dizziness
o Fatigue
o Gynaecomastia
o Rash


LO 12.7 What is H.Pylori (inc its unique features), how does it go on to cause gastric disease, and how is it diagnosed?

o H pylori is a gram negative, aerobic, helical, urease producing bacterium that resides in the stomach of infected individuals.
o Production of Urease produces ammonia, which neutralises acidic environment, which allows bacterium to survive.
o It colonises gastric epithelium – in mucous layer or just beneath. Damage to epithelia occurs through enzymes released and through induction of apoptosis. Damage also occurs due to the inflammatory response to the infection (inflammatory cells and mediators)

H pylori causing gastric disease:
o Gastritis
Usual effect of infection, which is usually asymptomatic.
Chronic gastritis causes hypergastrinaemia due to gastrin release from astral G cells -> this increased acid production is usually asymptomatic but can lead to duodenal ulceration (which will eventually produce symptoms)
o Peptic ulcer disease
Duodenal ulcers (DUs) -> prevalence of DU due to H pylori is falling due to decreased prevalence of H pylori infection. If ulcers due to H pylori infection, eradication of infection relieves symptoms and decreases chances of recurrence. The precise mechanism of ulceration is unclear (only occurs in 15% of infected people) -> factors implicated though are genetic predispositions, bacterial virulence, increased gastrin secretion and smoking
Gastric ulcers (GUs) -> associated with gastritis affecting the body as well as antrum, which can cause parietal cell loss -> reduction in acid production. Ulceration thought to occur due to reduction in gastric mucosal resistance due to cytokine production as a result of infection
o Gastric cancer

o IgG detected in serum (relatively good sensitivity and specificity)
o 13C-urea breath test (13C-urea ingested – if H pylori present the urease produced will break down 13C-urea to NH3 and CO2 – CO2 (where the carbon is 13C) will be exhaled on breath and detected).
o Can also take gastric sample by endoscopy and detect by histology and culture


LO 12.8How do you treat H. Pylori infection

Triple therapy.

Proton Pump Inhibitor – Omeprazole

Two Antibiotics – Amoxicillin / Clarithromycin

H2 Antagonist (if severe)

This standard eradication therapy, depending on local resistance, is successful at eradicating infection in 90% of patients. 7-14 day treatment – 14 days more effective but side-effects of treatment may put patients off finishing two week course


LO 12.9 Understand the significance of the enteric nervous system and its relationship to gastrointestinal motility

The enteric nervous system is a collection of autonomous nerves within the gut wall.

o Auerbach’s Plexus
Between circular and longitudinal muscle layers
o Meissner’s Plexus
o Henle’s Plexus
Circular muscle adjacent to submucosa
o Cajal’s Plexus
Circular muscle adjacent to longitudinal muscle

Together these autonomic gonglionated plexi control the functioning of the GI tract through complex local reflex connections between sensory neurones, smooth muscle, mucosa and blood vessels.
Extrinsic parasympathetic fibres from the vagus are excitatory, extrinsic sympathetic fibres are inhibitory.


LO 12.10 Recognise the role of neurohormonal integration in regulation of GI motility

Extrinsic Nerves
o Intestino-intestinal inhibitory reflex
Distension of one intestinal segment causes complete intestinal inhibition (Peristalsis)
o Anointestinal Inhibitory Reflex
Distension of anus causes intestinal inhibition
o Gastrocolic and Duodenocolic Reflexes
Stimulates motility after material has entered the stomach or duodenum

All endocrine hormones effective in the GI tract are peptides produced in endocrine cells of mucosa.


LO 12.11 Appreciate how gut motility is different in the fed and fasting state

Motility in Small Intestine
Intestinal contents must move very slowly (transit time in hours), whilst being gently agitated for effective absorption.
This is achieved by a pattern of motility called Segmenting, which is very different to peristalsis.

The small intestine is divided into sections, each with a pacemaker. The frequency of the pacemaker gets less from the duodenum to the terminal ileum (12 times a minute -> 8), a phenomenon known as the intestinal gradient.
Each pacemaker drives a small section of intestine, causing intermitted contraction of smooth muscle along its length.
These contractions separate the intestine into segments where the muscle is not contracted, whose contents are effectively mixed by movement from the portions that do contract. After a few seconds he contractions relax, and at the next pacemaker firing different areas contract.

Segmenting itself does not propel contents along the intestine, merely mixes the contents. The intestinal gradient however means that there is a net movement, albeit slow, in a caudal direction.
Motility in Large Intestine

Haustral Shuffling
The large intestine is divided naturally into segments known as Haustra, as the circular muscles are more complete than the longitudinal, which have been reduced to taenia coli (thick circular muscle, thin longitudinal – only 3 layers).
Contraction of the smooth muscle in the walls of the Haustra shuffles the contents back and forth, as the slow absorption of remaining water and salts forms faeces. The contents slowly progresses towards the sigmoid colon, with control like segmenting.

Mass Movement
Infrequently (once or twice a day), there is a Peristaltic, propelling pattern from the transverse through to the descending colon. This forces faeces rapidly into the rectum, which is normally empty, inducing the urge to defecate.
Mass movement is often triggered by eating, the Gastro-colic reflex. They often also happen at certain times of the day, as “people like to be regular”.


LO 12.13 Understand the effect of laxatives on the GI system, their ADRs and DDIs

Laxatives are drugs used to hasten transit time in the gut and encourage defecation. Laxatives are used to relieve constipation and to clear the bowel prior to medical and surgical procedures. It should be remembered that individual bowel habit can vary considerably. The frequency and volume of stool are best regulated by diet, but drugs may be necessary. The passage of food through the intestine can be hastened by:
o Bulk Laxatives
o Faecal Softeners
o Osmotic Laxatives
o Irritant / Stimulant Laxatives

What type of Laxative should be Used?

o History and/or examination reveals soft faeces
Stimulant Laxatives (E.g. Senna, Bisacodyl)

o History and/or DRE reveals hard faeces
Osmotic Laxatives (E.g. Lactulose, Movicol)
Bulk-Forming Laxatives (E.g. Ispaghula)


Anti-Motility Antidiarrhoeals Drug Profile

Codeine (opiate analgesic)
Imodium (opiate analogue)

Route of Administration


Inflammatory Bowel Disease – Toxic Megacolon

Mechanism of Action
Act on opioid receptors in the bowel
Reduce motility (increase time for fluid reabsorption)
Increase anal tone and reduce sensory defecation reflex

Adverse Drug Reactions
Nausea, vomiting, abdominal cramps, constipation drowsiness

Therapeutic Notes
Imodium is 40 times more potent than Morphine as an antidiarrhoeal agent, and penetrates the CNS poorly


LO 12.15 Recognise the main features of IBS

Irritable Bowel Syndrome
o Abdominal Pain
o Discomfort
o Bloating
o Alteration of Bowel Habits

Treat with Mebeverine, which has a direct effect on colonic hypermotility. This will relieve the spam of intestinal muscle, thus managing the most complained about symptom of IBS.


LO 12.16 Understand the physiology and pharmacology of emesis and how this relates to the pharmacology of a range of effective therapeutics

Vomiting (Emesis)
o Pyloric sphincter closes while the cardia and oesophagus relax
o Gastric contents propelled by contraction of abdominal wall and diaphragm
o Glottis closes with elevation of soft palate, preventing entry of vomit into the trachea and Nasopharynx
If vomiting is due to alcohol, or patient has a cranial nerve lesion they are at a higher risk of aspiration as this does not work properly


What leads to the Formulation of Psychiatric Disorders

o Biopsychosocial Model
Predisposing, precipitating and perpetuating factors

o Genetic vulnerability to the expression of the disease

o Live events (divorce, bereavement)

o Individuals personality, coping skills, social support

o Environmental influences (e.g. viruses during pregnancy, toxins, other diseases)


LO 13.3 Recognise the main mechanism of drugs affecting the CNS.

Actions of CNS Drugs
o Agonists or Antagonists of neurotransmitter receptors
May be competitive for neurotransmitter binding site

o Inhibitors of regulatory enzymes
Those that make or break down neurotransmitters
Less common


LO 13.4 Recognise the main CNS transmitter/modulatory pathways involved as targets

Key Transmission and Modulatory Pathways in the CNS
o Noradrenergic Pathways
o Dopaminergic Pathways
o Serotonergic (5HT) Pathways
o GABA-nergic pathways
o Cholinergic pathways
o Glutamate pathways


LO 13.5 Name the major conditions commonly treated – depression, psychoses, anxiety, mood disorders

Commonly Treated Psychiatric Illnesses
o Schizophrenia
o Depression
o Bipolar disorder
o Eating disorders
o Obsessive compulsive disorder


LO 13.6 Depression – What are the key diagnostic criteria for depression and what are the theory for its pathophysiology

Depression is extremely common. Everyone has a 10% lifetime risk of depression.

Core Symptoms – Two of Three needed for diagnosis
o Low mood
o Anhedonia (lack of enjoyment)
o Decreased energy

Secondary Symptoms
o Decreased appetite
o Sleep disturbance
o Physical aches and pains
o Irritability
o Self harm or suicidal ideas or acts
10% with a history of recurrent, severe depression commit suicide
o Can have psychotic symptoms

Pathophysiology of Depression

Theory 1 – Monoamine Hypothesis
o Depression is due to a deficiency of monoamine neurotransmitters (Noradrenaline and Serotonin)
o Monoamine Oxidase Inhibits (MAOIs) block the enzyme monoamine oxidase from destroying the neurotransmitters

Theory 2 – Neurotransmitter Receptor Hypothesis
o Depression is due to abnormality in the receptors for monoamine transmission

Theory 3 – Monoamine Gene Expression Hypothesis
o Deficiency in molecular functioning
o Hypothesised problem within the molecule events distal to receptor


LO 13.9 Schizophrenia/Psychosis – Recognise key symptoms of theories (and their limitations) describing psychotic illness and underlying pathophysiological mechanisms – relate these to major pharmacological targets

Paranoid Schizophrenia
o Lifetime risk is 1%
If one parent has Paranoid Schizophrenia, lifetime risk is 10%
If two parents have Paranoid Schizophrenia, lifetime risk is 45%
o Schizophrenia is an example of mental illness with Psychotic symptoms
Psychosis – a lack of contact with reality
o 10% of people with paranoid schizophrenia commit suicide

Symptoms of Paranoid Schizophrenia
o Disturbances of thinking
o Hallucinations
A perception in the absence of an external stimulus
Auditory, olfactory, visual, gustatory, tactile
Auditory – Person hears a voice (external through their ears, not from inside their head), either talking directly to them or several voices talking amongst themselves. Feels completely real to patient.
A fixed false belief that is out of keeping with someone’s cultural or religious beliefs
You can argue or give evidence, but they will not believe you. It is fixed.
E.g. “I am a member of the royal family”, “MI5 is watching me”
o Unusual speech-thought disorder
o Behavioural changes
o Lack of insight
o Negative symptoms
o 10%

No hypothesis completely explains schizophrenia. It is probably a result of a mix of:

Dopamine Theory of Schizophrenia
o Some evidence of increased dopamine function in schizophrenics
o Dopamine antagonists are the best treatment for schizophrenia
o Amphetamine causes symptoms similar to positive symptoms of schizophrenia
o But:
Amphetamines do not cause negative symptoms
Dopamine antagonists do not treat negative symptoms
Changes in dopamine function may be a response to long term drug treatment

Is schizophrenia associated with increased 5HT function?
o Many effective antipsychotics are antagonists at 5HT receptors
o Precursors of 5HT (e.g. tryprophan) exacerbate schizophrenia
o Under debate

Is schizophrenia associated with decreased cortical glutamate function?
o Non-competitive antagonist at NMDA-type glutamate receptors induces both positive and negative symptoms of schizophrenia
o Post mortem studies have shown increased cortical glutamate receptors
o Glutamate system is important, but mechanism unclear


Typical (First Generation) Antipsychotics Drug Profile


Route of Administration
Depot (every 2/3/4 weeks)

Mechanism of Action
Dopamine D2 Receptor Antagonist
Sedation – Within hours
Tranquilisation – Within hours
Antipsychotic – Several days or weeks

Adverse Drug Reactions
Extrapyramidal effects – Hours or days
Neuroleptic malignant syndrome – Severe rigidity, hyperthermia, autonomic instability, cognitive changes (delirium). Associated with elevated plasma creatine phosphokinase (CPK). Extremely rare, but very serious

ADR of all antipsychotics.
Weight gain
Endocrine changes (e.g. prolactinaemia)

CNS depression
Cardiac toxicity
Risk of sudden death with high dose
Prolonged QT interval  Torsades de points
Risk of sudden death with large dose

Therapeutic Notes
Haloperidol is safe in emergencies


LO 13.14 Anxiety – Recognise key symptoms of anxiety

o Fear out of proportion to situation

o Avoidance

o Fear of dying, going crazy

o Physical symptoms
Light headedness
Hot and cold flushes


What is the treatment of anxiety

Cognitive Behavioural Therapy
o First line treatment


Route of Administration
Oral, intravenous

Diazepam / Lorazepam – Status Epilepticus
Clonazepam – Absence seizures, short term use

Respiratory depression

Mechanism of Action
Act at a distinct receptor site on GABA Chloride channel
Binding of GABA or Benzodiazepines enhance each others binding, acting as positive allosteric effectors
Increases Chloride current into the neurone, increasing threshold for action potential generation

Adverse Drug Reactions
Tolerance with chronic use
Dependence/Withdrawal with chronic use
Confusion, impaired co-ordination
Abrupt withdrawal – seizure trigger
Respiratory and CNS depression

Drug-Drug Interactions
Highly protein bound (85-100%)
Some adjunct use

Therapeutic Notes
Well absorbed (90-100%), highly plasma bound (85-100%)
Linear Pharmacokinetics, t½s vary between 15-45hours
Side effects limit first line use
Overdose reversed by IV Flumazenil
Use may precipitate seizure/arrhythmia
Teratogenic – Cleft lip and palate


LO 13.17 Mood Disorders – Bipolar as for above but covered in less detail – note use of VGSC blockers (AEDs) and Lithium

Bipolar Disorder
o High genetic component
o Depression and hypomania/mania
o Feeling unusually excited, happy, optimistic or feeling irritable
o Overactive
o Poor concentration and short attention spam
o Poor sleep
o Rapid speech, jump from one idea to another
o Poor judgement (overspending)
o Increased interest in sex
o Psychotic symptoms – hallucinations, grandiose delusions

Mood Stabilisers
o Use of antidepressants may induce a manic episode

o Lithium
Also used in very treatment resistant depression

o Anti-Epileptic drugs, which are also potent mood stabilisers
Sodium Valproate
Lamotrigine (for depression, not mania)

o Atypical Antipsychotics


LO 5.6 Describe common antibiotics ADRs and mention therapeutic drug monitoring

o Toxicities
o Drug interactions -Allergic Reactions/Impact on normal flora
o Clostridium Difficile infection

Therapeutic drug monitoring is used to ensure and adequate, non-toxic dose. It is used with antibiotics such as:
o Gentomicin
- Aminoglycoside
- Dose related ototoxicity and nephrotoxicity at high plasma levels
o Vancomycin
- Glycopeptide
- Dose related ototoxicity and nephrotoxicity at high plasma levels
- Fever, rashes
- Local phlebitis at site of infection


LO 6.3 Be able to describe the main features underlying pathophysiology of asthma, including that responsible for early and late phase response

Smooth Muscle Dysfunction
o Increased Contraction/mass
o Increased Cytokines/Chemokines

o Immune cells (Th2 Response, Mast Cells)

Airway remodelling
o Mucus gland hyperplasia
o Airway wall thickening
o Increased smooth muscle mass
o Subepithelial fibrosis
o Epithelium desquamation

Early Phase Response
In allergic asthma, the initial response to allergen provocation is due to interaction with Mast Cell fixed IgE. This results in the release of Histamine and a host of potent spasmogens, leading to immediate Bronchospasm.

Late Phase Response
Co-release of a range of mediators and chemotaxins activate a complex immune system response that brings leucocytes to the area. This sets off a further chain of event leading to exacerbated bronchospasm and congestion due to:
o Epithelial damage - Increased exposure of the sensory irritant receptors, further exacerbating bronchial hyperactivity and sensitivity
o Thickening of the basement membrane
o Oedema
o Mucus production

Bronchial Hyperresponsiveness
A key factor contributing to airway dysfunction in asthma is bronchial hyperresponsiveness, leading to ‘twitchy’ airways. Bronchial hyper-responsiveness is defined as an exaggerated bronchoconstrictor response to direct pharmacological stimuli such as histamine, or indirect stimuli such as exercise. These indirect stimuli cause bronchoconstriction at least in part through the direct or indirect activation of airway mast cells. Mast cell mediators then induce the bronchoconstriction.


LO 6.4 Know in detail the action of different bronchodilators and when they are used, namely methylxanthines

o Theophylline
o Aminophylline

o Status asthmaticus

Mechanism of Action
o Antagonise Adenosine receptors

Adverse Drug Reactions
o Psychomotor agitation
o Tachycardia

Therapeutic notes
o ADR profile means methylxanthines are 3rd or 4th line use for Asthma
o Narrow therapeutic window


LO 6.4 Know in detail the action of different bronchodilators and when they are used, namely muscarinic receptor antagonists

o Ipratropium bromide
o Tiotropium bromide

o Adjuncts to β2 agonists in asthma treatment

Route of Administration
o Inhaled

Mechanism of Action
o Bind to and antagonise M3 cholinergic receptors on bronchial smooth muscle. This blocks the constricting effect of Ach and also inhibits mucus secretion.

Adverse Drug Reactions
o Not well absorbed through the lungs, avoiding major systemic ADRs
o Dry mouth


LO 6.10 Recognise the main therapeutic uses of immunosuppressants and Disease Modifying Anti Rheumatic Drugs (DMARSs) - Mycophenolate Mofetil

Indications - Transplant immunosuppression (agent of choice)

Mechanism of Action
o Inhibits the enzyme Inosine Monophosphate Dehydrogenase, which is required for Guanosine synthesis
o Impaired B-cell and T-cell proliferation

Adverse Drug Reactions
o Myelosuppression -> Leukopenia, neutropenia
o Increased risk of infection (especially viral)

Therapeutic Notes
o Highly selective. Spares other rapidly dividing cells, due to the presence of guanosine salvage pathways


LO 6.10 Recognise the main therapeutic uses of immunosuppressants and Disease Modifying Anti Rheumatic Drugs (DMARSs) - Anti-TNF Agents

o Infliximab (Monoclonal Antibody)
o Etanercept (Fusion protein)

Mechanism of Action
o Blocks the effects of TNF-α
o Decreased inflammation, decreased Angiogenesis, decreased joint destruction

Adverse Drug Reactions
o Increased infections
o Tiredness, dizziness
o Itching
o GI disturbances


Non-Steroidal Anti Inflammatory Drugs (NSAIDs) drug page (examples, mechanism etc)

o Ibuprofen
o Aspirin
o Paracetamol

o Musculoskeletal and joint disease
o Analgesia for mild to moderate pain
o Symptomatic relief in fever

o Gastrointestinal ulceration or bleeding
o Previous hypersensitivity to any NSAID
o Caution in asthma and when renal function is impaired

Mechanism of Action
o Inhibit Cyclooxygenase enzyme, preventing Prostaglandin synthesis

Adverse Drug Reactions
o GI – Ulceration
o Renal – Reversible drop in GFR
o Skin reactions (15% for some NSAIDs)
o Asthmatic bronchospasm (10% incidence)
o Allergic response
o Prolongation of bleeding time (platelet inhibition)

Drug-Drug Interactions
o Warfarin (protein binding reaction)
o Methotrexate (protein binding reaction)
o Sulphonylureas (protein binding reaction)
o ACE inhibitors – Attenuate action

Therapeutic Notes
o Aspirin is associated with risk of the post-viral Reye’s Syndrome in children
o Paracetamol overdose produces the toxic metabolite NAPQI via Phase I metabolism
o Paracetamol has virtually no anti-inflammatory action, it is used to treat mild to moderate pain and fever


Opiods drug page (examples, mechanism etc)

o Morphine
o Diamorphine
o Codeine
o Pethidine

o Strong opioids used in moderate to severe pain (particularly visceral, post-operative and cancer)
o Weak opioids are used in mild to moderate pain, and as antidiarrhoeals

o Acute respiratory depression
o Acute alcoholism
o At risk of paralytic ileus
o Head injuries (prior to neurological assessment)

Mechanism of Action
o Bind to endogenous opioid receptors
o Open K+ channels – hyperpolarise cells and reduce excitability
o Close voltage gated Ca2+ channels, inhibit release of Substance P neurotransmitter

Adverse Drug Reactions
o Respiratory Depression
o Miosis (Important overdose sign)
o Euphoria
o Confusion
o Psychosis
o Coma
o Tolerance and dependence
o GI disturbances (nausea, vomiting, constipation)
o Rarely anaphylactic responses, due to non-opiate receptor effects on mast cells, causing the release of histamine, leading to bronchoconstriction & hypotension

Drug-Drug Interactions
o Naloxone – Opioid receptor antagonist. Reverses the adverse agonistic effects. Rapidly reverses respiratory depression.

Therapeutic Notes
o Morphine is the gold standard against which other opioids are compared
o Diamorphine is twice as potent as Morphine, as it has greater penetration of the Blood-Brain Barrier. It is metabolised to 6-Acetylmorphine and therefore morphine in the body.
o Pethidine is more lipid soluble than morphine, and it has rapid onset and short duration of action, making it useful in labour.
o Buprenorphine has both agonist and antagonist actions at opioid receptors. May precipitate withdrawal symptoms in patients dependent on other opioids.
o Codeine has about one twelfth the analgesic potency of Morphine. It needs to be metabolised by CYP2D6 into Morphine to become pharmacologically active (10% of people lack this enzyme).


LO 8.10 Describe the main stages of anaesthetic procedure and anaesthetic depth

Stages of Anaesthesia

Propofol is normally administered and the beginning of inhalational agent delivery. Adjuvants will also be administered intravenously.

The anaesthetist keeps the adjuvants in balance to maintain adequate anaesthetic depth.

The agents are withdrawn and physiological function monitored closely to make sure it can be maintained without support. Antidotes may be given as necessary to facilitate this.

Depth of Anaesthesia
Anaesthetic depth is divided into four main stages. Called
Guedel’s Signs

Early effects on transmission in the Spinothalamic Tract

Delirium and aggressive behaviour are experienced. Now uncommon as induction occurs so rapidly with Propofol.

3.Surgical Anaesthesia
Profound CNS depression
Skeletal muscles fully relaxed
Breathing may need to be assisted and cardiac function affected
Attained with an effective integrated MAC between 1.2 and 1.5
Four levels describing increasing depth until breathing weak

4.Respiratory Paralysis and Death
Once above 2.2 MAC (Isoflurane) there is an increasing risk of Stage 4, with severe medullary depression leading to respiratory and cardiac arrest and death


LO 8.13 Describe the main classes of antihypertensive drugs, sites of action and main side effects - Angiotensin Receptor Blockers

o Examples
 Losartan
 Valsartan
o Indications
 Hypertension
o Contraindications
 Pregnancy, breastfeeding
 Caution in renal artery stenosis and aortic stenosis
o Mechanism of Action
 Bind to and antagonise the receptor for Angiotensin II – Angiotensin 1 Receptor (AT1 R).
 Inhibits vasoconstriction and aldosterone stimulation by angiotensin II.
o Adverse Drug Reactions
 Renal failure
 Hyperkalaemia


LO 8.13 Describe the main classes of antihypertensive drugs, sites of action and main side effects - Thiazide Diuretics

o Examples
 Bendroflumethiazide
 Metolazone
o Indications
 Hypertension
 Oedema secondary to congestive cardiac failure, liver disease or nephrotic syndrome
o Contraindications
 Hypokalaemia, Hyponatraemia, Hypercalcaemia
o Mechanism of Action
 Thiazide diuretics inhibit the Na+/Cl- co-transporter in the luminal membrane in the distal tubule of the kidney. This blocks the reabsorption of Na+ and therefore water. Result is lower blood volume and pressure.
o Adverse Drug Reactions
 Hypokalaemia, hyperuricaemia,
 Impaired glucose tolerance
 Hyponatraemia, hypermagnesemia, Hypercalcaemia,
 Metabolic alkalosis
 Cholesterol and triglyceride levels increase


LO 8.13 Describe the main classes of antihypertensive drugs, sites of action and main side effects - Beta-Adrenoceptor Antagonists (β-blockers)

o Examples
 Propranolol
 Atenolol
 Bisoprolol
 Metoprolol
o Indications
 Angina
 Post myocardial infarction
 Hypertension
 Arrhythmias
o Contraindications
 Non-selective β-blockers (e.g. Propranolol) must not be given to asthmatic patients.
 Bradycardia, hypotension, AV block, Congestive Cardiac Failure
o Mechanism of Action
 Antagonise β-adrenoreceptors. β1-receptors are found in the heart, when they are activated they cause increased Chronotropy and Inotropy.
 Inhibit renin release
o Adverse Drug Reactions
 Bronchospasm, fatigue and insomnia, dizziness, cold extremities, hypotension, bradycardia and decreased glucose tolerance in diabetic patients
o Drug-Drug Interactions
 Prevents Salbutamol working (β2-adrenoagonist)
 Verapamil – Both have –‘ve inotropic action


LO 8.13 Describe the main classes of antihypertensive drugs, sites of action and main side effects - Calcium Channel Blocking Drugs

There are three pharmacological classes of Calcium Channel Blocking drugs. All are effective in lowering blood pressure, but some are predominantly vasodilators (Dihydropyridines, e.g. Amlodipine) while others appear to act mainly or partially via an effect on myocardial contractility (Diltiazem and Verapamil).

Mechanism of Action
o Calcium channel blockers bind to specific alpha subunit of L-type calcium channel, reducing cellular calcium entry
o Vasodilates peripheral, coronary and pulmonary arteries
o No significant effect on veins
o Verapamil depresses SA node and slows A-V conduction

1. Dihydropyridine Calcium Channel Blockers
o Examples
 Nifedipine
 Amlodipine
o Properties
 Good oral absorption
 Protein bound > 90%
 Metabolised by the liver
o Adverse effects
 Sympathetic nervous system activation – tachycardia and palpitations
 Flushing, sweating, throbbing headache
 Oedema
 Swollen ankles with amlodipine
 Gingival hyperplasia (rare)
 Gynaecomastia (rare)
2. Phenylalkylamine Calcium Channel Blockers
o Examples
 Verapamil
o Properties
 Impedes calcium transport across myocardial and vascular smooth muscle cell membrane
 Class IV anti-arrhythmic agent (prolongs action potential/effective refractory period)
 Peripheral vasodilation and a reduction in cardiac preload and myocardial contractility
o Adverse Effects
 Constipation (can potentialte constipation that is already present)
 Risk of bradycardia
 Reduced myocardial contractility (-‘ve inotrope) so can worsen heart failure
3. Benzothiazepine Calcium Channel Blockers
o Examples
 Diltiazem
o Properties
 Impedes Calcium transport across the myocardial and vascular smooth muscle cell membrane
 Prolongs the action potential/effective refractory period
 Peripheral vasodilation and reduction in cardiac preload and myocardial contractility
 Verapimil-lite – does not work quite to the same extent as the others
o Adverse Effects
 Risk of bradycardia
 Negative inotropic effect (less than Verapamil) can worsen heart failure


LO 8.13 Describe the main classes of antihypertensive drugs, sites of action and main side effects - Direct Renin Inhibitor

o Examples
 Aliskiren
o Indications
 Hypertension
o Contraindications
 Pregnancy
 Caution in patients at risk of hyperkalaemia, Na+ and volume depleted patients, severe renal impairment and renal stenosis
o Mechanism of Action
 Antagonises Renin, preventing the conversion of Angiotensinogen  Angiotensin I.
 Reduces plasma renin activity by 50-80%
o Adverse Drug Reactions
 Angio-oedema, hyperkalaemia, hypotension, GI disturbances
o Drug-Drug Interactions
 Furosemide
o Therapeutic Notes
 t½ of ~40 hours, supporting once daily doses
 Mainly eliminated as an unchanged compound in faeces (78%)
 Not metabolised via CYP450


Outline the treatment of hyperkalaemia and any ECG changes seen

o Identify cause

o Reduce K+ effect on heart - IV Calcium Gluconate
o Shift K+ into ICF via glucose and insulin IV - Remove excess K+
o Dialysis

Longer Term
o Remove excess K+ - Dialysis
o Oral K+ binding resins to bind K+ in the gut - Reduce Intake
o Treat cause

Serum [K+] ECG Changes
6.5 -7 mmol/L Tall, peaked T waves
8 mmol/L Prolonged P-R Interval
Tall T waves
ST Segment depression
9 mmol/L Widened QRS Interval
10 mmol/L Ventricular fibrillation


Warfarin drug page (indications, mechanism etc)

Route of Administration - Oral

Prophylaxis and Treatment of DVT, PE, AF, Prosthetic Heart Valves

Cerebral thrombosis, peripheral arterial occlusion, peptic ulcers, hypertension, pregnancy

Mechanism of Action
Blocks Vitamin K’s reduction to its active form, which is require for its action as a cofactor in the synthesis of factors II, VII, IX & X

Adverse Effects
Bleeding/Bruising, Haemorrhage, Teratogenic

Drug-Drug Interactions
CYP450 Inducers
oPhenytoin, Carbamazepine, Barbiturates Rifampicin, Alcohol (chronic), St. John’s Wort
CYP450 Inhibitors
o Grapefruit Juice, Omeprazole, Disulfiram, Erythromycin, Volporate, Isoniazid, Cimetidine & Ciprofloxcain, Ethanol (acutely), Sulphonamides
o Highly protein bound, can be displaced, raising plasma conc.

Therapeutic Notes
o Use INR to monitor, measure of the Extrinsic coagulation pathway
o Reverse effects with Vitamin K IV (affects Warfarin use for 6 weeks), or Fresh Frozen Plasma, Prothrombin Complex Concentration


Heparin drug page (admin, mechanism etc)


Route of AdministrationUnfractionated – Intravenous
LMW – Subcutaneous

o Prophylaxis
Peri-operative (replace Warfarin)
Immobilised patients
o Treatment
DVT, PE, AF, MI, Unstable Angina

Haemophilia, Thrombocytopenia, Peptic Ulcers

Mechanism of Action
Activates Anti-Thrombin III
Unfractionated – Inhibits Thrombin (Factor IIa) and Factor XaLMW – Inhibits Factor Xa

Adverse Drug Reactions
Heparin Induced Thrombocytopenia

Therapeutic Notes
Immediate onset, so can be used in an emergency / Warfarin cover
Monitor Unfractionated with aPTT, LMWH no need to monitor
Reverse effects with Protamine Sulphate


LO 3.4 Appreciate the main side effects and drug interactions POPs

POP - Adverse Effects
Menstrual irregularities and poor cycle control
Nausea, vomiting and headache
Weight gain
Breast tenderness

POP - Drug Interactions
Metabolism is by CYP450
o Therefore effected by inducers/inhibitors
o Enzyme inducers can lower levels of POP causing contraception failure


What is the best method of control of uterine bleeding

Uterine Bleeding
The COCP can be used to manage abnormal uterine bleeding. Basically ‘tricks’ the body into thinking it is in the post ovulatory, luteal phase so offers a good method of cycle control.


Be aware of the benefits and risks of clinical management of the menopause

Hormone Replacement Therapy (HRT) can be used to control menopausal symptoms and can helpt to control well-being. Oestrogen and Progestogens are given to replace lost hormones either orally, topically via a patch or gel.

What types of HRT can you get?
o Combined HRT - With these, the patient is given the same dose of oestrogen and progesterone for 28 day continuously. The woman will have no withdrawal bleed, however this does have a risk of causing endometrial hyperplasia, so you will only give this form women who have had a hysterectomy
o Sequential Combined HRT - The patient is given oestrogen only up till day 14-16 and then you will add progesterone. This combination will stimulate a withdrawal bleed but will reduce the risk of endometrial cancer as endometrial hyperplasia does not occur and so is given to women who have not had a hysterectomy

Risks of HRT
o Unopposed oestrogen – Inc. endometrial and ovarian cancers
o Increase breast cancer risk
o Increased IHD and stroke risk (if introduced early in menopause, but should not be given solely for this reason)
o Increased risk of thromboembolism
o Uterine bleeding

Adverse effects
o Adverse effect on lipid profile
o Adverse effect on thrombophilia profile

-Reduced risk of colorectal cancer
-Improves sexual function (helps with dryness)
-Small reduction in bone loss


What are the other uses of HRT exept in the case of the menopause?

Anti-oestrogens - These drugs block the effects of oestrogen on oestrogen receptors. Examples include:
o Tends to be used in women who are having problems with fertility
o Induces ovulation by inhibiting the binding of oestrogen to the anterior pituitary. This will then increase GnRH levels and therefore LH and FSH levels also.
o Treatment for breast cancer and is also used for inducing ovulation
o Reduces oestrogen binding, therefore limiting progress/recurrence of breast cancer

This is a drug which antagonises the effects of progesterone.
o Used for the medical termination of pregnancy and for inducing labouro Sensitises the uterus to prostaglandins
o Is a partial agonist for the progesterone receptors and inhibits the action of progesterone.

Anti-androgen - Treatment for hirsutism and used in the COCP
o Has a weak progestogenic effect by competing with dihydrotestosterone
o Cyproterone

Selective Oestrogen Receptor Modulators
These are a group of drugs which act on oestrogen receptors, but have different actions depending on the tissue where the receptor is found.
e.g. Raloxifene, Tamoxifen

o Is used to protects against osteoporosis in postmenopausal women
o No proliferative effects on endometrium and breast
o Oestrogenic effects on bone, lipid metabolism and blood coagulation
o Reduced risk of invasive breast cancer in postmenopausal women with osteoporosis
o Increases hot flushes


Describe the physiology of the Kidneys

o Fluid balance
o Acid-base balanceo Electrolyte balance

o Waste products
o Drug Elimination – Glomerular filtration and Tubular secretion

o Renin-Angiotensin-Aldosterone System
o Erythropoetin
o Prostaglandins

Metabolism - Vitamin D andPolypeptides – Insulin and PTH


Describe the use Carbonic Anhydrase Inhibitors

o Given systemically it interferes with Na+ and HCO3- reabsorption, giving it a weak diuretic effect. Danger of metabolic acidosis.
Now only used to treat Glaucoma
e.g. Acetazolamide/ Dorzolamide


Osmotic Diuretics Drug Profile

Examples - Mannitol

Route of Administration - IV

Indications - Raised ICP

o Congestive heart failure
o Pulmonary oedema

Mechanism of Action
o Freely filtered at the glomerulus, but only partially, if at all, reabsorbed
o Passive water reabsorption is reduced by the presence of this non-reabsorbable solute within the tubule lumen
o Increases the osmotic gradients throughout the nephron, theredore causing excessive water loss. Is more historically used.
o Difficult to titrate
o Causes significant changes to ion levels, especially hyponatremia

Site of Action
o Tubular segments that are water permeable
o Proximal tubule, descending loop of Henle, collecting ducts

Adverse Drug Reactions
o Chills and fever

Therapeutic Notes
o Seldom used in heart failure, as expansion of blood volume can be greater than the degree of diuresis produced


Thiazide Diuretics Drug Profile

o Bendroflumethiazide
o Metolazone

o Hypertension
o Oedema secondary to congestive cardiac failure, liver disease or nephrotic syndrome

o Hypokalaemia, Hyponatraemia, Hypercalcaemia

Mechanism of Action
o Thiazide diuretics inhibit the Na+/Cl- co-transporter in the luminal membrane in the distal tubule of the kidney. This blocks the reabsorption of Na+ and therefore water. Result is lower blood volume and pressure.

Adverse Drug Reactions
o Hypokalaemia, hyperuricaemia, impaired glucose tolerance, Hyponatraemia, hypermagnesemia, Hypercalcaemia, metabolic alkalosis

Drug-Drug Interactions
o Steroids – Increased risk of hypokalaemia
o Beta-Blockers – Hyperglycaemia, Hyperlipidaemia, Hyperuricaemia
o Digoxin – Hypokalaemia increases digoxin binding and toxicity
o Carbamazepine – Increased risk of Hyponatraemia


Loop Diuretics drug profile

o Furosemide – 50% uptake
o Bumetanide – 90% uptake. More effective if there is presence of gut oedema, as the drug crosses the gut wall better. Can change to IV from oral to avoid this.
o Torasemide

Route of Administration
o Oral, intravenous or intramuscular. Intravenous route used in emergencies as therapeutic effect is much faster (30 mins compared to 4-6 hours orally).

o Acute pulmonary oedema
o Oliguria (acute renal failure)
o Resistant heart failure
o Hypertension

Contraindications - Severe renal impairment

Mechanism of Action
o Inhibit the Na/K/Cl co-transporter in the luminal membrane
o Blocks reabsorption of Na+ and therefore water. Can block up to 5% of Na reabsorption

Site of Action - TAL of the loop of Henle

Adverse Drug Reactions
o Hypokalaemia, Hyponatraemia, hyperuricaemia, hypotension, hypovolaemia, metabolic alkalosis
o Bumetanide can cause Myalgia (occasionally, not very common)
o Furosemide can cause Ototoxicity

Drug-Drug Interactions
o Cardiac Glycosides – Hypokalaemia caused by loop diuretics potentiates the action of cardiac glycosides, increasing the risk of arrhythmias
o Aminoglycoside Antibiotics – (E.g. Gentamycin) Will interact with loop diuretics and increase risk of ototoxicity and potential hearing loss
o Steroids – Increased risk of hypokalaemia


Potassium Sparing Diuretics/ Aldosterone Antagonist drug Profile

o Amiloride (Na+ channel blockers)
o Spironolactone (Aldosterone Antagonist)
o Canrenone

Route of Administration - Oral

o In conjunction with other diuretics in managing heart failure or hypertension. They are only mild diuretics.
o Aldosterone antagonists used in the treatment of hyperaldosteronism
o Primary – Conn’s Disease
o Secondary – Result of heart failure, liver disease or nephrotic syndrome

Contraindications - Renal failure

Mechanism of Action
o Na+ channel blockers
o Block Na+ reabsorption by principal cells
o Aldosterone Antagonist
o Competitive antagonist at aldosterone receptors. This reduces the secretion of Na+

Site of Action
Late distal tubule and collecting duct

Adverse Drug Reactions
o GI disturbances
o Hyperkalaemia (in patients in renal failure)
o Hyponatraemia
o Spironolactone – Gynaecomastia, menstrual disorders, erectile dysfunction due to androgenic cross-reactivity (interacts with oestrogen synthesis)

Drug-Drug Interactions
o Interaction with ACE inhibitors, increasing risk of hyperkalaemia


Digoxin (Simple in renal)

Inhibits tubular Na/K-ATPase

Drug-Drug interaction with Thiazide Diuretics. Hypokalaemia leads to increased digoxin binding and toxicity.

Atrial fibrillation or heart failure, Not used as a diuretic, as it has minimalm diuretic effects.


ADH Antagonists

Lithium and Demecocycline (Tetracycline antibiotic) have some action as ADH antagonists. By blocking the action of Anti-Diuretic Hormone, Aquaporin 2 is not inserted into the apical membrane of the co`llecting duct, meaning less water is able to be reabsorbed.


Describe Diuretic Resistance

Can have over-treatment as well as patients not responding as well to the treatment, perhaps because they have not made the necessary life-style changes.
o Incomplete treatment of primary disorder
o Continuation of high Na+ intake
o Patient non-compliance
o Poor absorption
o Volume depletion decreases filtration of diuretics
o Volume depletion increases serum aldosterone, enhancing Na+ reabsorption
o NSAIDs – Can reduce renal blood flow


Heparin Indications

o Prevention of Thrombo-Embolism
Peri-Operative (LMWH low dose)
Immobility (Heart failure, frail or unwell patient)
Used to cover thrombosis risk around operation in patients normally on warfarin, but who have had it stopped for surgery, as Heparin quick offset time allows cessation if bleeding occurs


Deep Vein Thrombosis, Pulmonary Embolism and Atrial Fibrillation . Administered prior to Warfarin, as quick onset will cover patient whilst Warfarin loading is achieved. LMWH often used unless fine control is required

Acute Coronary Syndromes
Reduces recurrence/extension of coronary artery thrombosis
MI, unstable angina

Can be used cautiously in pregnancy in place of Warfarin.


Aspirin Drug Profile (Anti Platelet)

Route of Administration - Oral

o Prevention and treatment of MI / Ischaemic stroke, Analgesic
o Anti-inflammatory agent

Contraindications - Children under 12 years who are at risk of Reye’s Syndrome, Breastfeeding, Haemophilia, peptic ulcers, known hypersensitivity

Mechanism of Action - COX-1 Enzyme inhibitor, Prevents the formation of Thromboxane A2 from Arachidonic Acid in platelets. Thromboxane A2 stimulates phospholipase C, increasing calcium levels and causing platelet aggregation

Adverse Drug Reactions - Bronchospasm, GI haemorrhage

Drug-Drug Interactions - Displaces Warfarin from plasma proteins (PKs)
Increases Anti-Coagulant effect of Warfarin at a different site (PDs)

Therapeutic Notes
Aspirin at 150mg daily after MI has been shown to decrease mortality


Dipyridamole drug profile

Route of Administration - Oral

o Used in conjunction with Warfarin in prophylaxis against thrombosis due to prosthetic mechanical heart valves

Mechanism of Action
o Inhibits Phosphodiesterase enzyme
o Phosphodiesterase increases cAMP, which increases Ca2+, which causes platelet aggregation

Adverse Drug Reactions
Hypotension, nausea, diarrhoea, headache

Drug-Drug Interactions
o Works synergistically with Warfarin to decrease Coagulability


Clopidogrel drug profile

Route of Administration- Oral

o Secondary prevention of cardiovascular/cerebrovascular events

Mechanism of Action
o ADP Antagonists
o Inhibits ADP-ADP receptor interaction, which aids platelet aggregation

Adverse Drug Reactions
o Haemorrhage
o GI disturbances – Discomfort, nausea, vomiting

Drug-Drug Interactions
o Works synergistically with Warfarin to decrease Coagulability

Therapeutic Notes
If patient is allergic to Aspirin, Clopidogrel can be used instead


LO 9.15 Describe the main features of the mechanism of action of Thrombolytics given IV
LO 9.16 Name the main conditions for which Thrombolytics are used


Route of Administration - IVIntravenous

Life-threatening venous thrombosis, pulmonary embolism, arterial thromboembolism, acute myocardial infarction

Recent haemorrhage, trauma, surgery, aortic dissection, coma, history of cerebrovascular disease

Mechanism of Action
Forms a complex with and activates Plasminogen  Plasmin

Adverse Drug Reactions
Nausea, vomiting, bleeding/haemorrhage

Drug-Drug Interactions
Often used in conjunction with anti-platelet and anti-coagulant drugs.

Therapeutic Notes
Streptokinase is derived from haemolytic streptococci, and is therefore antigenic. Repeated administration of streptokinase could therefore result in anaphylaxis.
If already used once previously, use t-PAs instead

Tissue Plasminogen Activators (t-PAs)
Examples - Alteplase/Reteplase

Route of Administration - Intravenous

Myocardial infarction, pulmonary embolism

Recent haemorrhage, trauma, surgery, aortic dissection, coma, history of cerebrovascular disease

Mechanism of Action
t-PAs are tissue-type plasminogen activators, Plasminogen -> Plasmin

Adverse Drug Reactions
Nausea, vomiting, bleeding/haemorrhage


Flecainide drug profile

Class 1 anti arrhythmic

Route of Administration
Oral (well absorbed)

Supraventricular tachyarrhythmias (Atrial arrhythmias)

Heart failure, history of MI

Mechanism of Action
Blocks fast, inward Na+ ion channels (Phase 0)

Adverse Drug Reactions
Dizziness, visual disturbances, arrhythmias

Drug-Drug Interactions
Metabolised by CYP2D6 and eliminated renally. Inducers/inhibitors


Lidocaine Drug Profile

Class 1 anti arrhythmic

Route of Administration

Ventricular arrhythmias following MI

AV block
Heart failure

Mechanism of Action
Blocks fast, inward Na+ ion channels (Phase 0)

Adverse Drug Reactions
Hypotension, bradycardia (negative inotrope)


β-Blockers Drug Profile

Propranolol (Non-Selective)
Atenolol (β1 Selective, Long acting)
Bisoprolol (β1 Selective, Long acting)
Metoprolol (β1 Selective, Short acting)

Post myocardial infarction

Non-selective β-blockers (e.g. Propranolol) must not be given to asthmatic patients.
Bradycardia, hypotension, AV block, Congestive Cardiac Failure

Mechanism of Action
Antagonise β-adrenoreceptors. β1-receptors are found in the heart, when they are activated they cause increased Chronotropy and Inotropy.
Inhibit renin release

Adverse Drug Reactions
Bronchospasm, fatigue and insomnia, dizziness, cold extremities, hypotension, bradycardia and decreased glucose tolerance in diabetic patients

Drug-Drug Interactions
Prevents Salbutamol working (β2-adrenoagonist)
Verapamil – Both have –‘ve inotropic action


K+ channel blockers Drug profile

Low Dose – Class II action
High Dose – Class III action

Route of Administration
Orally or intravenously

Ventricular and supraventricular arrhythmias

AV block

Mechanism of Action
Block K+ channels (Phase 3)

Adverse Drug Reactions
Can cause arrhythmias (Torsades de Pointes)

Drug-Drug Interactions
Amiodarone inhibits CYP3A4, CYP2C9 and P-glycoprotein
Dose reductions of Warfarin, Digoxin, Flecainide needed


Ca2+ Channel blockers Drug profile


Route of Administration

Supraventricular arrhythmias
Prophylaxis and treatment of angina and hypertension

Heart failure, bradycardia
AV Node Block

Mechanism of Action
Blocks Ca2+ channels responsible for depolarisation of pacemaker cells.

Adverse Drug Reactions
Hypotension, bradycardia, heart failure, heart block


Digoxin Drug Profile

Route of Administration
Oral bioavailability 70-80%

Supraventricular Arrhythmias (Atrial fibrillation), Heart Failure

Heart block, hypokalaemia

Mechanism of Action
Inhibits Na/K-ATPase
o Direct Cardiac Effects
o Increased Inotrope – Used in heart failure, no mortality benefit
o CNS Effects
o Decreased Sympathetic outflow
o Increased Parasympathetic outflow
o Sensitises baroreceptor reflex
o Combined Effects
o Decreased Automaticity of SAN and AVN
o Increased AVN refractory period
o Decreased Conduction velocity of AVN

Adverse Drug Reactions
Narrow therapeutic index
Toxicity enhanced with hypokalaemia
Cardiac toxicity – bradycardia, AVN block, atrial tachycardia

Drug-Drug Interactions
o Pharmacokinetic
Increased Digoxin Levels – Popafenone, Quinidine, Amiodarone, Verapamil, Spironolactone, Cylosporine
Redcued Digoxin Levels – Erythromycin, Tetracycline (gut bacteria metabolise digoxin)
o Pharmacodynamic
β-blockers, Verapamil, Diltiazem
Loop and Thiazide Diuretics (Hypokalaemia)

Therapeutic Notes
o Large volume of distribution, loading dose required for rapid onset
o Loading dose split into 2 doses to minimise toxicity risk.
o Plasma levels checked 6-8 hours after dose at steady rate
o 20-30% protein bound
o Digoxin clearance is proportional to GFR (Reduce dose in elderly and renal impairment)


Adenosine drug profile

o AV node blocker
o Decreased Automaticity
o Increased AVN refractory period
o t½ = a few seconds
o Given as rapid IV bolus to diagnose and treat supraventricular tachycardias

Can be useful in distinguishing SVT with aberrant conduction from VT


Angiotensin Converting Enzyme (ACE) Inhibitors drug profile


Route of Administration

Heart failure
Renal dysfunction

Pregnancy, renovascular disease, aortic stenosis

Mechanism of Action
ACE inhibitors cause inhibition of Angiotensin Converting Enzyme, consequently reducing Angiotensin II and Aldosterone levels. This causes vasodilation and consequent reduction in peripheral resistance and reduced sodium retention.
Reduce breakdown of the vasodilator Bradykinin

Adverse Drug Reactions
Characteristic dry cough
Angio-oedema (rare, but more common in black population)
Renal Failure
Hypotension, dizziness and headache, diarrhoea and muscle cramps


Angiotensin Receptor Blockers drug profile



Pregnancy, breastfeeding
Caution in renal artery stenosis and aortic stenosis

Mechanism of Action
Bind to and antagonise the receptor for Angiotensin II – Angiotensin 1 Receptor (AT1 R).
Inhibits vasoconstriction and aldosterone stimulation by angiotensin II.

Adverse Drug Reactions
Renal failure


LO 11.3 Understand the difference between primary and secondary causes of epilepsy

Primary Epilepsy
o No identifiable cause (Idiopathic) – ~65-60%

Secondary Epilepsy
o Medical conditions affecting the brain – ~30-35%
o Vascular disease
o Tumours


Phenytoin Drug Profile

Route of Administration
Oral, intravenous

All forms of epilepsy, except absence seizures

Mechanism of Action
Prolongs VGSC inactivation state
Stops the spread of excitation from focus

Adverse Drug Reactions
CNS effects – dizziness, ataxia, headache, Nystagmus, nervousness
Gingival Hyperplasia (20%)
Rashes – Hypersensitivity (Stevens-Johnson Syndrome 2-5%)

Drug-Drug Interactions
CYP450 Inducer
Many drug interactions, e.g. Warfarin, OCP
Cimetidine -> Phenytoin Increase
Well absorbed, 90% Protein Bound
Competitive binding, e.g. with Valproate, NSAIDs
Can exacerbate non-linear PKs

Therapeutic Notes
Phenytoin displays Non-Linear Pharmacokinetics at Therapeutic concentrations (linear at sub-therapeutic levels). This means close monitoring of free plasma levels is required.


Carbamazepine Drug Profile

Route of Administration
Oral, rectal

All forms of epilepsy, except absence seizures

AV conduction problems

Mechanism of Action
Prolongs VGSC inactivation state

Adverse Drug Reactions
CNS – Dizziness, drowsiness, ataxia, motor disturbances, numbness, tingling
GI disturbances – Vomiting
CVS – Variations in BP
Rarely myelosuppression – neutropenia

Drug-Drug Interactions
CYP450 Enzyme Inducer
Many drug interactions, e.g. Warfarin, OCP
Protein bound
Another protein binding drug can raise Carbamazepine conc.
Antidepressants (SSRIs, MAOIs, TCAs and TCA) interfere with Carbamazepine’s action

Therapeutic Notes
Well absorbed, 75% protein bound
Linear Pharmacokinetics
Initial t½ is ~30hrs, but is a strong inducer of CYP450s and therefore affects its own Phase I metabolism. In repeated use t½ falls to ~15hrs
Drug monitoring required to adjust dosing due to falling t½


Lamotrigine Drug Profile

Route of Administration

All forms of epilepsy

Hepatic impairment
Not first line use in paediatric patients due to ADRs

Mechanism of Action
Prolongs VGSC inactivation state

Adverse Drug Reactions
Less marked CNS dizziness, ataxia, somnolence (drowsiness)
Some mild (10%) and serious (0.5%) skin rashes, which limits child use

Drug-Drug Interactions
Adjunct therapy with other anti-epileptic drugs
Oral Contraceptives reduce Lamotrigine plasma levels
Valproate increases Lamotrigine plasma levels (protein binding)

Therapeutic Notes
Increasingly first line anti-epileptic drug
Appears to be safer in Pregnancy


Sodium Valproate Drug Profile

Route of Administration
Oral, intravenous

All forms of epilepsy

Acute liver disease/hepatic dysfunction

Mechanism of Action
Weak inhibition of GABA inactivation enzymes -> Increased GABA A
Weak stimulus of GABA synthesising enzymes -> Increased GABA A
Weak VGSC blocker and Weak Ca2+ channel blocker -> Redcued Discharge

Adverse Drug Reactions
Generally less severe than with other AEDs
CNS sedation – Ataxia, tremor
Weight gain
Hepatic Dysfunction – Transaminases increased in 40% of patients
Rarely hepatic failure

Drug-Drug Interactions
Adjust therapy with other AEDs
Care needed with adjunct therapy, as both Valproate and adjunct PKs are affected. E.g. displaces Lamotrigine and Phenytoin, raising their free plasma concentrations
Antidepressants (SSRIs, MAOIs, TCAs and TCA) inhibit Valproate
Antipsychotics antagonise Valproate, by lowering convulsive threshold
Aspirin displaces Valproate from plasma proteins, raising its free conc.

Therapeutic Notes
100% absorbed, 90% protein bound
Linear Pharmacokinetics, t½ = 15hrs
Close monitoring of free plasma concentration is required
Monitor for hepatic disorders


Benzodiazepines Drug Profile


Route of Administration
Oral, intravenous

Diazepam / Lorazepam – Status Epilepticus
Clonazepam – Absence seizures, short term use

Respiratory depression

Mechanism of Action
Act at a distinct receptor site on GABA Chloride channel
Binding of GABA or Benzodiazepines enhance each others binding, acting as positive allosteric effectors
Increases Chloride current into the neurone, increasing threshold for action potential generation

Adverse Drug Reactions
Tolerance with chronic use
Dependence/Withdrawal with chronic use
Confusion, impaired co-ordination
Abrupt withdrawal – seizure trigger
Respiratory and CNS depression

Drug-Drug Interactions
Highly protein bound (85-100%)
Some adjunct use

Therapeutic Notes
Well absorbed (90-100%), highly plasma bound (85-100%)
Linear Pharmacokinetics, t½s vary between 15-45hours
Side effects limit first line use
Overdose reversed by IV Flumazenil
Use may precipitate seizure/arrhythmia


Levodopa (L-DOPA) Drug Profile including its advantages

Route of Administration
Oral (only 1% reaches the brain due to peripheral metabolism)

Parkinsonism (excluding drug-induced extrapyramidal symptoms)

Closed angle glaucoma

Mechanism of Action
L-DOPA is the immediate precursor of Dopamine and is able to penetrate the blood brain barrier to replenish the dopamine lost in the Neostriatum.

Adverse Drug Reactions
Nausea and vomiting
Psychiatric side effects (Schizophrenia-like symptoms)
Cardiovascular effects (hypotension)

Drug-Drug Interactions
L-DOPA is given in combination with a peripheral DOPA decarboxylase inhibitor (Sinemet, Madopar), reducing necessary dose, side effects and increase the amount of L-DOPA reaching the brain
Vitamin B6 increases peripheral breakdown of L-DOPA

Therapeutic Notes
Extensive peripheral metabolism of L-DOPA means that large doses have to be given to produce therapeutic effects. These large doses are more likely to bring about adverse effects.
Absorbed in competition with amino acids (note – high protein meals)
90% inactivated in intestinal wall by MAO and DOPA decarboxylase
9% converted to dopamine in peripheral tissues
1% crosses BBB to enter the CNS (competes with amino acids)

Highly efficacious
Low side effects
Precursor, needing enzyme conversion#
Long term loss of efficacy and development of involuntary movements


Dopamine Receptor Agonists Drug Profile


Route of Administration
Apopmorphine is always given subcutaneously

Used in combination with L-DOPA in an attempt to reduce it’s late adverse effects, or when it does not control symptoms

Mechanism of Action
Agonists for Dopamine D2 Receptors

Adverse Drug Reactions
Similar to that of L-DOPA, but more common and more severe
Psychiatric symptoms

Therapeutic Notes
Bromocriptine is most used


Monoamine Oxidase Type B inhibitors (MAOIs) Drug Profile


Route of Administration

Used on their own in mild cases of parkinsonism
Used in conjunction with L-DOPA to reduce end-dose ADRs

Mechanism of Action
Selegiline selectively inhibits the MAOB enzyme in the brain that is normally responsible for the breakdown of dopamine. By inhibiting breakdown, the dose of L-DOPA

Adverse Drug Reactions
Psychiatric symptoms


Catechol-O-methyl Transferase Inhibitors Drug Profile


Route of Administration

Adjunct to L-DOPA therapy to reduce end-dose ADRs


Mechanism of Action
Inhibits the enzyme COMT, which degrades dopamine

Adverse Drug Reactions
Nausea and Vomiting
Abdominal pain


Anticholinergics Drug Profile


Route of Administration

Mechanism of Action
Antagonists at the muscarinic receptors that mediate striatal cholinergic excitation
Main action in treatment of Parkinson’s disease is to reduce excessive striatal cholinergic activity

Adverse Drug Reactions
CNS effects – Mild memory loss, acute confusional states
Dry mouth and blurred vision (less common)

Therapeutic Notes
Termination of anticholinergic treatment should be gradual, as parkinsonism can worsen when these drugs are withdrawn



Route of Administration

Synergistic effect when used in conjunction with L-DOPA

Mechanism of Action
Stimulates neuronal dopamine release and inhibition of its reuptake
Additional muscarinic blocking actions

Adverse Drug Reactions

Therapeutic Notes
Modest anti-parkinsonian effects, but it is only of short-term benefit, since most of its effectiveness is lost within 6 months


Myasthenia Gravis

o An autoimmune destruction of the end-plate ACh receptors
o Loss of junctional folds at the end-plate
o A widening of the synaptic cleft
The crisis point is when it affects respiratory muscles

Presenting Symptoms:
o Drooping eyelids
o Fatigability and sudden falling due to reduced ACh release
o Double vision
o Effected by general state of health and emotion

o Acetylcholinesterase inhibitors (e.g. Pyridostigmine)
Prevent breakdown of Ach in synaptic cleft
Can cause muscarinic side effects (parallel those effects seen with excessive release of Ach) - Miosis/SSLUDGE Syndrome
o Corticosteroids
Decrease immune response
o Plasmapheresis
Removes AchR antibodies and gives short term improvement

SSLUDGE Syndrome
o Muscarinic side effects
o Salivation
o Sweating
o Lacrimation
o Urinary Incontinence
o Diarrhoea
o GI upset and hypermotility
o Emesis


Proton Pump Inhibitors Drug Profile


Route of Administration

Short term treatment of peptic ulcers
Severe GORD
Confirmed oesophagitis
Eradication of H. Pylori (part of triple therapy)
Zollinger-Ellison Syndrome (Gastrin secreting pancreatic tumour)

Mechanism of Action
Irreversibly inhibit Na/K-ATPase that is responsible for proton secretion from parietal cells.

Adverse Drug Reactions
GI upset, nausea
Risk of gastric atrophy with long-term treatment

Drug-Drug Interactions
Omeprazole is a CYP450 enzyme inhibitor
Avoid use with patients being treated with Warfarin, Phenytoin etc.

Therapeutic Notes
PPI action is delayed as not all pumps are active all of the time. Maximum efficacy is after 2-3 days.
Restoration of stomach acid requires de novo synthesis, so after treatment stops it will take a few days for acid to return to normal


Histamine H2 Receptor Antagonists Drug Profile


Route of Administration

Peptic ulcer disease and GORD

Mechanism of Action
Competitively antagonist H2 receptors, blocking the amplifying action of Histamine on Parietal cells

Adverse Drug Reactions

Drug-Drug Interactions
Cimetidine is a CYP450 enzyme inhibitor
Avoid use with patients being treated with Warfarin, Phenytoin etc.

Therapeutic Notes
Given at night when acid buffering by food is at its lowest


Bulk Laxatives Drug Profile


Route of Administration

Constipation, particularly when hard stools are present

Intestinal obstruction (Adhesions, ulceration)
Colonic atony
Faecal impaction

Mechanism of Action
Increases the volume of the non-absorbable solid residue in the gut, distending the colon and stimulating peristaltic movement.

Adverse Drug Reactions
Abdominal distension
GI obstruction

Therapeutic Notes
A normal fluid intake is essential
Clinical effects may take several days to develop


Faecal Softeners Drug Profile

Arachis Oil

Route of Administration
Arachis Oil – Enema
Glycerol – Suppository

Faecal impaction
Anal fissures

Children less than 3 years old

Mechanism of Action
Lubricate and soften stools

Therapeutic Notes
Safe, but not always effective
Relatively slow to take effect


Osmotic Laxatives Drug Profile

Magnesium and Sodium Salts

Route of Administration
Lactulose – Oral
Magnesium and Sodium Salts – Rectal
Movicol – Orally with fluid (powder)

Lactulose - Liver failure (reduced production of ammonia)

Intestinal obstruction

Mechanism of Action
Increase water content of the bowel via osmosis
Lactulose – Disaccharide (galactose/fructose) that cannot be hydrolysed by digestive enzymes. The fermentation of lactulose by colonic bacteria gives acetic and lactic acid. This has an osmotic effect

Adverse Drug Reactions
Abdominal discomfort
Caution required to prevent intestinal obstruction

Therapeutic Notes
Magnesium and Sodium act quickly and are quite severe, so should be reserved for ‘resistant’ constipation if urgent relief is required
Lactulose takes 48 hours to work
Movicol takes 2-4 days to get relief


Irritant / Stimulant Laxatives Drug Profile

Anthraquinone Group

Route of Administration

Constipation and bowel evacuation prior to medical/surgical procedures

Intestinal obstruction

Mechanism of Action
Increase gastrointestinal peristalsis and water and electrolyte secretion by the mucosa. Possibly by excitation of sensory enteric nerves.

Adverse Drug Reactions
Colonic atony (thus constipation)
Hypokalaemia (Changing electrolyte balance in the gut)

Therapeutic Notes
Anthraquinone group is the most frequently used.
Senna can be bought O.T.C. (Senokot)
Abuse can be detected via Melanosis Coli (pigmentation of bowel wall)


Selective Serotonin Reuptake Inhibitors (SSRIs) Drug Profile

Fluoxetine (Prozac)

Route of Administration
Oral (almost completely absorbed from gut)


Mechanism of Action
Act with a high specificity for potent inhibition of serotonin reuptake into nerve terminals from the synaptic cleft
Only minimal effects on noradrenaline uptake

Adverse Drug Reactions
Common – Anorexia, nausea, diarrhoea (normally settles in 2-3 weeks)
Rare – Precipitation of mania, tremor, extrapyramidal syndromes

Drug-Drug Interactions
MAOIs – Used in combination can cause potentially fatal serotonergic syndrome of hyperthermia and cardiovascular collapse

Therapeutic Notes
First line treatment for depression
Citalopram is the most selective reuptake inhibitor
Paroxetine is the most potent reuptake inhibitor
Long elimination t½ (once daily dosage), metabolised in the liver
Relatively safe in overdose if taken on their own


Serotonin/Noradrenaline Reuptake Inhibitors (SNRIs) Drug Profile



Hypertensive patients, as Venlafaxine raises blood pressure

Mechanism of Action
Inhibit the reuptake of both serotonin and noradrenaline, thus potentiating neurotransmitter activity in the CNS
Dose dependent
Low dose blocks Serotonin
High dose blocks Noradrenaline

Adverse Drug Reactions
Common – Anorexia, nausea, diarrhoea (normally settles in 2-3 weeks)
Rare – Precipitation of mania, tremor, extrapyramidal syndromes
(Similar to SSRIs, but occur with less frequency)
Sleep disturbances
Dry mouth

Drug-Drug Interactions
MAOIs – Used in combination can cause potentially fatal serotonergic syndrome of hyperthermia and cardiovascular collapse

Therapeutic Notes
Second line treatment for depression
Similar to TCAs, but adverse effects are reduced as Venlafaxine has little affinity for histamine or α-adrenoreceptors
Relatively short t½ – may be a withdrawal syndrome on discontinuation


Tricyclic Antidepressants (TCAs) Drug Profile


Route of Administration

Amitriptyline – Chronic, neurological pain
Clomipramine – Good evidence for OCD treatment

Recent MI or arrhythmias (especially heart block)
Manic phase
Severe liver disease
Epilepsy (TCAs lower seizure threshold)

Mechanism of Action
Block serotonin and noradrenaline reuptake. Also have affinity for H1, muscarinic and α1 and α2 receptors.

Adverse Drug Reactions
Noradrenergic uptake block in the heart – Arrhythmias
Muscarinic blocking effects – Dry mouth, constipation
α-adrenergic blocking effects – Postural hypotension
H1 blocking effects – Sedation
Weight gain

Therapeutic Notes
Lipid soluble, long t½ (once/twice daily dose), metabolised by liver


Monoamine Oxidase Inhibitors (MAOIs) Drug Profile


Route of Administration


Mechanism of Action
MAOIs block the action of monoamine oxidase, the enzyme that metabolises monoamines (noradrenaline and serotonin). There are two subtypes, MAOA and MAOB. Inhibition of MAOA gives the best antidepressant efficacy.

Adverse Drug Reactions
CNS stimulation causing excitement and tremor
Dry mouth, blurred vision

Drug-Drug Interactions
MAOIs reduce the metabolism of barbiturates, opioids and alcohol.

Therapeutic Notes
Response to treatment with MAOIs may be delayed for ~3 weeks.


Atypical (Second Generation) Antipsychotics Drug Profile


Route of Administration

Mechanism of Action
Higher affinity for 5-HT2A receptors than Dopamine D2 Receptors
Sedation – Within hours
Tranquilisation – Within hours
Antipsychotic – Several days or weeks

Adverse Drug Reactions
Vary between drugs
Olanzapine – Significant weight gain, suppressed “full” signals
Risperidone – Increased prolactin
Extrapyramidal side effects at high doses

CNS depression
Cardiac toxicity
Risk of sudden death with high dose
Prolonged QT interval -> Torsades de points
Risk of sudden death with large dose

Therapeutic Notes
Atypical antipsychotics have less extrapyramidal side effects, so are therefore more acceptable to patients
First line treatment in schizophrenia


What is the treatment for Dementia

Dementia Medication
(Note – For Alzheimer’s Disease dementia, there is no medication for vascular dementia)

Acetylcholinesterase Inhibitors
Ach plays a role in arousal, memory, attention and mood. NICE guidance advises medication be made available for mild and moderate dementia. Treatment slows down the progression of Alzheimer’s Disease, giving you ~1 year extra at home before residential care.
o Donepezil
o Galantamine
o Rivastigmine
Important Adverse Drug Reactions
o Nausea, vomiting, anorexia, diarrhoea (most common)
o Fatigue, insomnia, headache
o Bradycardia (particularly with Polypharmacy, e.g. β-blockers)
o Worsening of COPD
o Gastric/Duodenal ulcers

NMDA Antagonists
Not used a lot as they are not as effective or as well tolerated as Acetylcholinesterase inhibitors, so are therefore a 2nd line treatment.
o Memantine
Common Adverse Drug Reactions
o Hypertension
o Dyspnoea
o Headache
o Dizziness
o Drowsiness


Lithium Drug Profile

Administered as Lithium Carbonate

Mood stabiliser (Antimanic and Antidepressant activity)
Prophylaxis of Mania and Depression in bipolar disorder
Augmentation of antidepressants in unipolar depression

Renal impairment (renal excretion)

Mechanism of Action (Theories)
Electrolytes and channels – May compete with Mg2+ and Ca2+ channels
Neurotransmitters – Lithium increase 5HT. Chronic Lithium may reduce 5HT receptor sites
Second messenger systems – Lithium attenuates the effects of neurotransmitters on their receptors, without altering receptor density

Adverse Drug Reactions
Memory problems (learning new information) – 52%
Thirst – 42%
Polyuria – 38%
Tremor (very fine) – 34%
Drowsiness – 24%
Weight gain – 18%
Hair loss

Toxic Effects
Coarse tremor (progression from fine tremor)
Dysarthria (difficulty speaking)
Cognitive impairment

Drug-Drug Reactions
NSAIDs will raise Lithium plasma concentration

Therapeutic Notes
Good evidence for reducing suicides
Drug monitoring for toxic levels in case of toxic effect
Toxicity is treated with supportive measures, anticonvulsants, increased fluid intake/IV fluids, Haemodialysis may be necessary


What are the risk factors for an MI

There are both modifiable and non-modifiable risk factors for coronary atheroma – and by extension Ischaemic Heart Disease.

Family history

o Hyperlipidaemia
o Smoking
o Hypertension
o Diabetes mellitus – Doubles IHD risk
o Exercise
o Obesity
o Stress


Describe ischaemic chest pain

Ischaemic Chest Pain
Any IHD can cause chest pain that is central, retrosternal, or left sided.
The pain may also radiate to the shoulders and arms, with the left side more common than the right along with the neck, jaw, epigastrium and back. It may even present with pain at these sites without chest pain.
The pain is described as ‘tightening’, ‘heavy’, ‘crushing’, ‘constricting’, and ‘pressure’. Occasionally the pain is described as burning epigastric pain, particularly in inferior MI.

The pain varies in intensity and duration, the onset, precipitating, aggravating and relieving factors and associated symptoms all vary and get progressively worse from stable angina  unstable angina  MI.