What are the patient-related problems when it comes to safe-prescribing?
Some problems that could increase the rate of medication errors
[*] More rapid throughput (turnover) of patients
[*] New drug developments, extending medicines into new areas
[*] Increasing complexity of medical care
[*] Increased specialisation
[*] Increased use of medicines generally
[*] Sicker and older patients, more vulnerable to adverse effects
[*] Increasing numbers
[*] Elderly patients with:
Multiple drugs (therapeutic soup!)
Increased risk of side effects
[*] Vast numbers of new drugs
[*] Clinical evidence is usually with drug used in isolation in:
Selected relatively healthier patients
And/or young volunteers initially
[*] Some side effects come to light only during post marketing surveillance
[*] Blind adherence to guidelines leads to prescription where contraindications or serious interactions exist.
What are the doctor-related problems?
No room for error
Expected to be perfect from day 1
Experience from medical school
[*] Level of teaching
[*] Level of examining
On-Call Medicine (not only perfect from day 1 but have to do it sleep deprived with limited support)
[*] Sleep-deprived junior doctors have more attentional failures, and make more clinical errors and incorrect diagnoses
[*] Exhaustion erases recent learning
[*] Junior doctors have more road traffic accidents when tired.
[*] Shift Work and Reduced Hours
- Lower exposure to teaching etc
- Working alone more often (due to staffing issues)
- Less ward teaching and feedback (less team involvement)
- Poorer morale
- Lack of continuity of care
[*] Lack of Pharmacology training
[*] Too many students!?!?!?
[*] Errors more likely to occur
[*] Rarely know patient
[*] Routine – “boring jobs”
- Re-write drug charts
- Prescribe fluids
- Prescribe new unfamiliar drugs
- Prescribe old drugs in absence of results
Compare the Person Approach to the System Approach
[*] Person Approach
- Aberrant mental processes
- “Bad things happen to bad people”
- Countermeasures centred on person e.g. fear, retraining, litigation, naming and shaming
[*] System Approach
- Errors seen as consequences
- Unable to change human condition
- Countermeasures centred on barriers and safeguards
When errors occur, rarely due to a single individual.
Differentiate between Slip, Lapse, Mistake and Violation
Slips: lack of concentration, can be skill-based (erroneous skill)
Lapse: in concentration and memory in giving instructions (erroneous memory)
- Confuse rules
- Doesn’t have knowledge base
Describe the primary components of the Reason's Model
Reason’s Model of Error Causation suggests why errors occur, blaming both the system and the individual, with a further component being a set of defences. Ideally, these defences should be inherent within the system and the individual.
The primary components of the Reason’s Model are:
- Latent conditions – processes inherent to an organisation or management decisions
- Error producing conditions – poor environment or lack of communication
- Active failures – these commonly occur individually and can be either errors or violations. Whilst violations are when an individual intentionally goes against others’ judgement or clinical guidelines, error can be broken down into mistakes (knowledge or ruled based), slips (erroneous performance), or lapses (erroneous memory).
- The defences in the system can limit the chances or errors occurring. Examples of such defences can be senior reviews, pharmacy reviews, nurses’ review, or electronic system reviews.
Describe the Swiss Cheese Model
A further useful analogy in understanding how errors generated in the system can produce accidents is the ‘Swiss Cheese Model’. The defences put in place are inherently imperfect, allowing “holes” in the “layers” to develop, yet the more defences (safeguards) put in place, the less chance of all the holes lining up. When the holes line up, an error can pass through all the layers and cause a serious adverse event.
How should you write a prescription? What should you consider beforehand?
Before you write a prescription, confirm:
[*] Name of drug(s)
[*] Duration of treatment
[*] Allergies/adverse effects
[*] GMC Guidance – to prescribe within competencies
Document allergy status
[*] Be written in indelible ink
[*] Patient identification (x2)
- Name and address
[*] DOB (if under 12 – nowadays recommended regardless of age)
[*] Name and address of practitioner
[*] Additional requirements for controlled drugs
[*] Name and address of practitioner
[*] Additional requirements for controlled drugs
What are the Good Practice Requirements?
[*] Approved drug name
[*] Route of administration
[*] Units in full
[*] Special (additional) instructions
Drug name – ‘generic’ (internationally recognized)
[*] Generic drugs are supplied
[*] Brand prescribing increases likelihood of missed doses (pharmacists are unable to give a generic drug)
[*] Brand name may be misinterpreted
- Avoid abbreviations
- Route – multiple?
- Consider weight of patient when calculating dose
- Know conversions between dose units (1 microgram is 0.001 milligrams)
- Talk to patient – tell them about changes made
How do you amend a prescription?
[*] Depends on type
[*] Outpatient Rx – sign your amendment
[*] Re-prescribe rather than just handwrite amendment
What is the Yellow Card Scheme? What should be reported?
The Yellow Card Scheme (considers adverse drug reactions, concept of pharmaco-vigilance)
What should be reported?
[*] Black triangle drugs and unlicensed herbal preparations
- Report all suspected reactions, however trivial the reaction
[*] Established products and vaccines
- Report all suspected serious reactions, even if the reaction is well known and recognised
[*] All paediatric reactions
What is a Black Triangle drug? What is a Serious Reaction?
What is a Black Triangle drug?
[*] One which is being intensively monitored
[*] Generally one which has been
- Newly released
- Changed indications
- Changed formulations
- Combination product
What is a serious reaction?
- Any reaction which results in or prolongs hospitalisation
- Serious reactions also include those that are
Describe Electronic Prescribing?
- Increasingly common
- Ensure you are trained
- Beware of decision support aids
- Avoid ‘work arounds’
- Read the prescription before sending
- Avoid hand-written alterations (re-prescribe if error)
Define Pharmacokinetics, Pharmacodynamics & Pharmacogenetics
Pharmacokinetics: study of the movement of a drug into and out of the body “what the body does to the drug”
Pharmacodynamics: study of drug effect and mechanisms of action “what the drug does to the body”
Pharmacogenetics: the effect of genetic variability on the pharmacokinetics or dynamics of a drug on an individual
Why is Pharmacokinetics essential? Describe translation into clinical practice? What key factors affect PK?
Essential part of drug regulation: MHRA/FDA
Elucidates the mechanisms of drug interactions
[*] Drug elimination
[*] Intra-subject variability
[*] Drug-Drug interactions
Translating into clinical practice:
[*] Understanding about bioavailability leads to the correct formulation
[*] Estimating half-lives allows dosing regimens to be devised
[*] Understanding 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
What are the Four Main Processes involved in Drug Therapy?
- Pharmaceutical Process: is the drug getting into the patient?
- Pharmacokinetic Process: is the drug getting to its site of action?
- Pharmacodynamic Process: is the drug producing the required pharmacological effect?
- Therapeutic Process: is the pharmacological effect being translated into a therapeutic effect?
List the four stages of the Pharmacokinetic Process?
NB: Therapeutic Window: the range of drug dosages which can treat disease effectively without having toxic effects (TD50/ED50)
What are the routes a drug can be administered?
Drugs can be administered by a number of methods including oral, enteral (enter via the GI tract e.g. sublingual or rectal), or parenteral (any other routes that doesn’t include the GI tract, e.g. via IV, SC or IM).
Absorption: what is meant by F and AUC?
[*] F = Bioavailability = the amount of drug which reaches the systemic circulation in an unchanged form (once overcome all barriers to its absorption) relative to that if administered via IV thus can be calculated as (amount of drug reaching systemic circulation / total amount of drug administered)
[*] For an intravenous bolus, bioavailability is 100%
[*] For other routes, compare amount reaching the body compartment by that route with intravenous bioavailability i.e. F = AUC(oral)/AUC(IV). This can be used to determine the optimal route a drug needs to be given to reach its therapeutic concentration. It also determines the amount of drug the oral formulation needs to be given in.
[*] AUC = Area Under the Curve = Total drug Exposure
What factors affect bioavailability?
- Drug formulations (long vs short acting; modified release - leads to delayed absorption, more constant beneficial as more constant therapeutic effect - see diagram)
- Food: lipid-soluble > water-soluble
- Vomiting/malabsorption etc
Consequently bioavailability is subject to variation between patients.
[*] First pass metabolism (extraction ratio)
When drugs are given orally, both the rate of uptake of a drug and first pass metabolism can affect the peak plasma concentration of the drug and the time it spends in the body. Systemic entry of the drugs can be affected by gastrointestinal motility, splanchnic blood flow, molecular size, pH levels or even presence of active transport systems.
What is meant by First Pass Metabolism? And where can it occur?
[*] Any metabolism occurring before the drug enters the systemic circulation (the ‘first-pass’ effect). It can occur in
- Gastric acid, proteolytic enzymes, grapefruit juice
- E.g. Benzylpenicillin, insulin, ciclosporin
- P-glycoprotein efflux pumps drugs out of the intestinal enterocytes back into the lumen e.g. ciclosporin
Liver (via portal venous circulation) - predominantly
- E.g. Propranolol is extensively metabolised
The result of first pass metabolism is significantly reduced amounts of available drug in the systemic circulation (as measured by the extraction ratio).
What is meant by Distribution and list the 3 main factors affecting distribution?
Once a drug gets into the bloodstream, it is first distributed around the body over large distances by bulk flow in the bloodstream and then over shorter distances by diffusion. The distribution of a drug refers to its ability to “dissolve” in the body
The main factors affecting the distribution of a drug throughout the body are:
[*] Protein binding
[*] Volume of distribution (Vd)
What is meant Lipophilicity/Hydrophilicity?
[*] The more liphophilic a drug is, the greater it will partition out of the blood plasma into tissues with higher lipid content. Hence, lipid-insoluble drugs are mainly confined to the plasma and interstitial fluid (so do not enter the brain during acute dosing) and lipid-insoluble drugs reach all the body compartments and accumulate in fat.
What is meant by Protein Binding?
[*] Once in the systemic circulation, many drugs are bound to circulating proteins
- Albumin (acidic drugs)
- Globulins (hormones)
- Lipoproteins (basic drugs)
- Acid glycoproteins (basic drugs)
[*] 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
[*] Drug Binding to Proteins
- Free drug determines its action at receptor
- Displacement of drugs from binding sites causes Protein Binding Drug Interactions
Differentiate between object and precipitant drugs
Most drugs are protein-bound in the circulation; object drugs (e.g. Warfarin) have number of drugs administered lower than the binding site numbers whereas precipitant drugs (e.g. Phenytoin, aspirin or sulphonamides) have number of molecules administered higher than the number of binding sites, so administration of a precipitant drug will displace binding of object drug.
When are changes in protein binding important?
[*] Changes in protein binding can occur, causing changes in drug distribution. These are only important if 3 criteria are met:
- High protein binding
- Low Vd
- Has a narrow therapeutic ratio
What factors affect protein binding?
- Renal failure
- Displacement by other drugs
Describe Tissue Distribution and what is Vd?
[*] The body can be divided into separate compartments where separate water is stored and drug molecules must cross barriers in unbound form to enter these different compartments. Within each aqueous compartment, drugs exist in free solution and unbound form.
[*] The extracellular fluid compartments comprise of plasma (5% of body weight), interstitial fluid (16%), intracellular fluid (35%), and transcellular fluid (2%), with also fat (20%). Passive movement of drugs between these fluid compartments will mainly be determined by lipophilicity, although some drugs are actively carried or transported across these fluid compartments. The apparent ‘volume’ for any given drug is dependent on how much binding capacity there is for a given drug.
[*] [Text Box: Vd (l/kg) = Total Amount of Drug in the Body Plasma Concentration of Drug (at time = 0)] Drug that is not bound to plasma proteins is available for distribution to the tissues of the body. Some are distributed only to the body fluids, while others are bound extensively in body tissues.
[*] One measure of distribution is the apparent Volume of distribution (Vd)
What does Vd mean?
[*] Vd is a measure of how widely a drug is distributed in body tissues – to see how well a drug distributes throughout the body systems.
[*] It is a hypothetical measure, but it can be useful in understanding dosing regimens e.g. 100mg gentamicin dose, peak plasma concentration 5mg/l, then the Vd will be 20 litres.
[*] Consequently, if the drug (once injected) cannot leave the plasma compartment, as it is not lipid soluble or is highly plasma bound, then the plasma concentration will remain high and Vd will be low, and conversely if the drug can diffuse out of the plasma compartments and pass into other fluid compartments (taken up by muscle, fat etc), then the plasma concentration will fall and Vd can be very high.
[*] The larger the Vd, the more the drug distributes throughout the body.
[*] (half-life) is proportional to Vd (and clearance). Drugs that are confined to the plasma compartment will have a Vd of around 0.11.kg^-1, confined to the extracellular fluid around 0.41.kg^-1, and throughout the body water grater than 11.kg^-1.
What else can tissue distribution be affected by?
[*] Specific receptor sites in tissues
[*] Regional blood flow
[*] Active transport
[*] Disease states
[*] Drug interactions
How would you calculate Vd?
[*] As drug concentration changes over time, in order to effective calculate the Vd, the plasma concentration must be taken as if from t=0. This is calculated by extrapolating along the log drug concentration curve until it reaches t=0 (i.e. ignoring the distribution phase of the drug).
[*] The Vd is normally expressed in l.kg^-1 as units, yet can be expressed just in litres under the assumption of a healthy 70kg individual.
[*] Vd is likely to be affected by changes in protein binding throughout both fluid and tissue compartments. Acute increases in Vd are seen in sepsis (due to increase in vascular permeability), concurrent drugs (binding sites are taken up by other drugs) or hypoalbuminaemia (amount of unbound drug in the plasma increases, which moves from plasma to other compartments).
Metabolism: What are the two key areas?
- Metabolism of a pharmacologically inactive compound to one with pharmacological activity (‘Pro-drugs’):
[*] Inactive Enalaprilat to active enalapril
[*] L-Dopa is metabolised to a more active metabolite to improve distribution (crosses blood-brain barrier)
- Metabolism of a pharmacologically active compound to other active compounds e.g. codeine to morphine/losartan to EXP3174
Differentiate between Phase 1 and Phase 2
Phase 1: catabolic reactions (e.g. oxidation, reduction or hydrolysis), producing products that are chemically reactive. This then serves as a ‘point of attack’ for the conjugating system.
Phase 2: anabolic reactions which involve conjugation, normally resulting in inactive products produced.
Both phases decrease lipid solubility and so increasing renal elimination, and both phases mainly occur in the liver.
Describe Phase 1
[*] Oxidation and Reduction are in part dependent on the cytochrome p450 family of enzymes
[*] The activity of these enzymes can be influenced by enzyme-inducing and enzyme-inhibiting drugs that alter the rate of metabolism of other drugs
[*] Other influences: age, liver disease, hepatic blood flow, cigarette and alcohol consumption
Describe the Cytochrome CYP 450 family
[*] Haem proteins, made up by a few genetic subfamilies (the main of which are CYP1, CYP2 and CYP3)
[*] Present mainly in the liver (some gut and lung)
[*] Big ones: CYP2D6, 2C9, 2C19, 3A4
[*] Super family of isoforms responsible for approximately 90% human drug metabolism through oxidative reactions
[*] Metabolise toxins such as carcinogens and pesticides
[*] Genetic differences in metabolism
[*] They are induced by Phenytoin, Carbamazapine, Barbiturates, Rifampicin, Alcohol and Sulphonylureas (PCBRAS) and inhibited by Omeprazole, Disulfiram, Erythromycin, Valproic acid, Isoniazid, Cimetidine, Ethanol (acute and Sulphonamides (O-DEVICES).
[*] So overall, CYPs act as generalists and metabolise large array of molecules, yet they can be induced or inhibited by other drugs.
Describe CYP 450 3A
[*] Metabolism of:
- Calcium channel blockers
- HIV protease inhibitors
- Most statins
- Most non-sedating antihistamines
[*] CYP 3A Inhibitors
- Grapefruit juice
[*] CYP 3A Inducers
- St John’s Wort
Describe CYP 2D6
[*] Absent in 7% Caucasians
[*] Hyperactive in 30% East Africans
[*] Inhibited by:
Describe CYP 2C9
[*] Absent in 1% Caucasian and Blacks
Most NSAIDs (inc. COX2)
[*] Inhibited by: Fluconazole
[*] Induced by: Carbamazepine, Ethanol
Describe CYP 2C19
[*] Absent in 30% Asians and 5% Caucasians
[*] Metabolises: Diazepam, Phenytoin, Omeprazole
[*] Inhibited by: Ketoconazole, Omeprazole, Isoniazid, Fluoxetine, Ritonavir
[*] Induced by: Rifampicin
What other factors affect metabolism?
[*] Important for drug prescribing (common esp. novel drug development)
[*] Consider OTC and food as drug-drug interactions (charcoal grill 1A+; grapefruit juice 3A-)
[*] Other Factors:
- Race (development of pharmacogenetics)
- Age (reduced in aged patients and children)
- Sex (women slower ethanol metabolisers)
- Species (drug development)
- Clinical or physiological condition
Describe Phase 2 Metabolism
Phase 2 Metabolism: following from Phase 1 metabolism, the molecule is now susceptible to conjugation, becoming pharmacologically active and less lipid-soluble than its precursor, to be excreted in urine or bile. Glucuronyls, sulphates, methyls or acetyls can be conjugated
The main route of drug elimination is the kidney
Other routes include the lungs, breast milk, sweat, tears, genital secretions, bile and saliva
3 processes determine the renal excretion of drugs – overall rate is a balance is these processes:
[*] Glomerular Filtration
[*] Passive tubular reabsorption
[*] Active tubular secretion
The processes are affected by renal blood flow, plasma protein binding and urinary tubular pH.
What is meant by Clearance?
Clearance = ability of body to excrete drug (mostly = GFR) – measure of both hepatic clearance and renal clearance. Rate of elimination of drug from the body.
[*] If the GFR is reduced then clearance is reduced
[*] Half life is inversely proportional to clearance
[*] A reduction in clearance (or GFR) increases t1/2
What is meant by OAT and OCT?
Organic Anion and Cation Transporters (OAT and OCT) act as renal transporters (via active transport) that transport drugs from the plasma to the nephron lumen. They are located on the PCT and have parallels with CYP450s as they have a versatility to transport wide range of molecules.
What factors affect clearance?
Clearance is a combination of hepatic (i.e. hepatic metabolism and bile secretion) and renal clearance and is simply defined as the rate of elimination of a drug from the body. Clearance is affected by HRH factors of:
[*] Heart – Cardiovascular system factors affect blood flow to the main organs of elimination
[*] Renal – factors affecting renal elimination
[*] Hepatic –factors affecting hepatic elimination
Differentiate between 1st Order and Zero Order Kinetics?
1st Order Kinetics – Linear (when log y axis plotted against time)
[*] Rate of elimination is proportional to drug level
[*] Constant fraction of drug eliminated in unit time
[*] Half life can be defined
Zero Order Kinetics – Non-Linear
[*] Rate of elimination is a constant
[*] Straight line when linear y axis scale plotted against time
[*] Drug monitoring is essential
What does half life mean? How can you calculate it?
[*] How long a drug stays in the body for can be determined simply by Vd and clearance levels, and both these terms can be utilised to produce one value to determine a time length for this, the half life (t1/2)
[*] k = Elimination Rate Constant = Cl/Vd
[*] In plot of linear kinetics gives a straight-line
[*] ln [drug]t = ln [drug]t0 – kt
[*] t1/2 = ln2 - k
[*] t1/2 = 0.693.Vd/Cl
[*] Half life can be defined as ‘the amount of time over which the concentration a drug in plasma decreases to one half of the concentration value it had when measured’. The half life is affected by cardiovascular factors, renal elimination and hepatic metabolism (same as clearance).
Explain why linear kinetics is important clinically and when do drugs start exhibiting non-linear kinetics?
Most drugs taken alone at therapeutic levels have linear kinetics due to their CYPs and kidneys being able to deal with them effectively. However, at higher levels, elimination of drugs will become saturated and become non-linear elimination.
This can also happen when the Vd – HRH factors all act to reduce affect half-life and clearance for example in the very ill or elderly.
With poly-pharmacy, possibility of non-linear clearance increases for many drugs.
Relatively few drugs exhibit saturated kinetics over therapeutic doses. There are a number of important drugs taken by very large numbers of patients, including high dose aspirin, phenytoin, verapamil, fluoxetine (Prozac). Non-therapeutic drugs with non-linear kinetics include alcohol and MDMA
The possibility of non-linear clearance kinetics increases with polypharmacy, especially if there is competition for the same CYP or renal transporter or if one drug acts to inhibit one of these.
What is meant by Zero Order Toxicity? And when is drug monitoring especially important?
[*] Zero order drugs are more likely to result in toxicity
[*] Fixed rate of elimination per unit time
[*] “Small’ dose changes may
Produce large increments in dose
Lead to toxicity
[*] No half life is calculable
[*] Several PK reasons:
- Zero order kinetics
- Long half-life
- Narrow therapeutic window
- At greater risk of drug-drug interactions
[*] Others include:
- Know toxic effects (e.g. bone marrow suspension or alteration in U+Es)
- Monitoring therapeutic effect (e.g. BP, glucose etc)
Describe Multiple Dosing
- During repeated drug administration, a new steady state (Steady State Concentration in Plasma (CpSS)) is achieved in 3-5 half lives , allowing levels to stay within a therapeutic window.
- Generally this is irrespective of dose or frequency of administration
- A simplified equation to calculate CpSS : CpSS = dose rate / clearance
- CpSS will never be an actual “steady state” but will be seen in peaks and troughs.
What is meant by Loading Dose?