Pharmacology 2: Pharmacokinetics and dynamics, drug interactions and toxicology

Question 1

4 principle classes of receptor type?

Answer 1

receptors, enzymes, carriers or transporters, ion channels

RICE

Question 2

what is the response of a drug generally proportional to?

Answer 2

the number of receptor sites bound by the drug

Question 3

how does EC50 differ between use of competitive and non-competitive antagonists?

Answer 3

competitive: changes as increasing concentration of agonist is required to overcome antagonism, but maximal effect value for agonist stays the same
non-competitive: EC50 stays the same as agonist not competing to occupy binding site, but maximal effect will be depressed proportional to degree of antagonist binding to receptor.

Question 4

define therapeutic window

Answer 4

concentration range of a drug over which it exerts a clinically useful effect without significant toxic effects

Question 5

where do ACEIs act primarily in the body?

Answer 5

pulmonary and coronary arterial endothelial surfaces

Question 6

which drug groups commonly contribute to drug-drug interactions?

Answer 6

anticonvulsants e.g. phenytoin and carbamazepine
anticoagulants e.g. warfarin
antiarrhythmics e.g. amiodarone
antidepressants e.g. mono-amine oxidases
antibiotics e.g. quinolones, macrolides and rifampicin

Question 7

why might circulating albumin levels be low?

Answer 7

hepatic failure
nephrotic syndrome
malnutrition

Question 8

why must lidocaine, a Na+ channel blocker used in arrhythmias, be given parenterally?

Answer 8

extensively metabolised by the liver if given orally, so has a very small bioavailability

Question 9

what is the primary mechanism by which CYP 450 induction takes places?

Answer 9

increased transcription to increase enzyme expression

but increased translation, and reduced degradation can play a role

Question 10

a drug that induces the CYP 450 system can increase metabolism of a drug so that it is no longer therapeutically effective, and can increase the metabolism of itself e.g. carbamazepine, but why else can it be problematic?

Answer 10

can result in production of toxic levels of reactive drug metabolites, resulting in tissue damage.

Question 11

importance of a pharmacodynamic drug-drug interaction in DVT prophylaxis?

Answer 11

e.g. after hip replacement surgery, pateints given prophylactic warfarin for no. wks but therapeutic level in plasma may not be reached for several days so heparin may be give aswell. both together can produce supratherapeutic levels of anticoagulation, so patient may experience significant bleeding.

Question 12

what does the clinical effectiveness of a drug, after it is stopped, depend on?

Answer 12

therapeutic window

minimal plasma conc of drug which is effective

Question 13

why does penicillin have few SEs in terms of its selectivity? and what transporter is used for its secretion at the PCT of the kidney nephron?

Answer 13

inhibits transpeptidase enzyme involved in bacterial cell wall synthesis, and mammalian cells do not have a cell wall.
organic anion transporter

Question 14

difference between drug selectivity and drug specificity?

Answer 14

selectivity: how selective is a drug in binding to its target. High selectivity= lower chance it will interact with different targets to produce SEs
specificity: high specificity= drug interacts only with 1 specific receptor subtype so has less action on other organs.

Question 15

why is cranberry juice used therapeutically in the treatment of UTIs? why if on warfarin should patient be advised not to drink this?

Answer 15

inhibits bacterial adherence to urothelium

enzyme inhibitor- warfarin therefore has reduced clearance so there is increased risk of haemorrhage

Question 16

when is there high risk of adverse drug reactions?

Answer 16

drugs with narrow therapeutic indexes
polypharmacy
patients with multiple conditions
patients at extremes of age- altered PK profile, and co-morbidities
ignorant, inappropriate or reckless prescribing
drugs being used near their minimum effective conc- increased risk of tment failure if increased drug metabolism

Question 17

problem with using plasma creatinine level as a measure of renal function in elderly patients when determing drug doses?

Answer 17

elderly= less muscle mass, so plasma creatinine may be in normal range despite mild to moderate renal failure, so dose which you administer based on presumption that normal renal function is present can result in serioud drug OD producing toxicity as renal clearance will be reduced in renal failure.

Question 18

equation for oral bioavailability?

Answer 18

AUC oral/AUC iv

Question 19

what factors relating to a drug can affect its apparent volume of distribution?

Answer 19

formulation- slow or fast release e..g. particular coating
lipophilicity/hydrophobicity
charge
ability to bind to proteins

Question 20

which drugs are likely to distribute to the blood plasma?

Answer 20

highly plasma protein-bound e.g. warfarin, very large, very charged
e.g. heparin

Question 21

which drugs are likely to distribute to AT?

Answer 21

highly lipophilic e.g. diazepam

Question 22

examples of drugs with very large volumes of distribution and hence may require higher initial does to achieve plasma concentrations which are therapeutically effective?

Answer 22

digoxin- reduces HR
azithromycin- used in chlamydia tment
amiodarone- K+ channel blocker, prolongs QT interval

Question 23

why does plasma protein binding tend to reduce the amount of drug capable of diffusing into the target tissues?

Answer 23

only free drug capable of crossing the cell membrane to enter tissues

Question 24

how can the age of a patient affect drug distribution?

Answer 24

younger- tends to have more skeletal muscle mass than an older patient, so muscle uptake would act to reduce the plasma concentration of a drug more in a younger person than an older person.

Question 25

Accumulation of fat in a patient can affect a drug’s volume of distribution. What else can accumulate to affect a drug’s volume of distribution (Vd)?

Answer 25

fluid e.g. ascites- liver failure, ovarian cancer, heart failure- peripheral oedema, pleural effusion- lung cancer

Question 26

why does age of a patient affect volume of distribution?

Answer 26

proportion of each body compartment varies with age e.g. less muscle in elderly

Question 27

which drugs are largely excreted in the bile?

Answer 27

digoxin
steroid hormones
some cancer chemotherapeutic agents

Question 28

pros of enteral drug administration?

Answer 28

simple
inexpensive
painless
no infection
convenient

Question 29

pros of parenteral drug adminstration?

Answer 29

not subject to 1st pass metabolism of harsh GI environment
rapid delivery to site of pharmacologic action
high bioavailability

Question 30

cons of enteral drug administration?

Answer 30

subject to 1st pass met and harsh GI environ
requuires GI absorption
slow delivery to site of pharmacologic action

Question 31

cons of parenteral drug administration?

Answer 31

infection risk
requires skilled personnel- expensive
irreversible
pain
fear

Question 32

what factors determine the maintenance dose to give after a loading dose?

Answer 32

age

renal function

Question 33

digoxin= must give loading dose as long t1/2 and large Vd, but if digoxotocitity what can we do?

Answer 33

can give an antidote which will bind to digoxin to deactivate it
may also have to give in hypokalaemia as this potentiates digoxin toxicity.

Question 34

examples of factors affecting drug 1/2 life?

Answer 34

factors affecting Vd: age
obesity
pathlogic fluid

factor affecting clearance: renal disease- reduced drug filtration and secretion into renal tubules
hepatic disease- affect enzyme function and decrease biliary excretion
CVS disease
cytochrome p450 induction and inhibition- affect drug metabolism

Question 35

in terms of theapeutic dosing, what does absorption of a drug determine?

Answer 35

potential routes and optimal drug dose

Question 36

what does the elimination rate of a drug influence with respect to drug dosing?

Answer 36

the frequency required to maintain therapeutic plasma levels as elimination rate is inversely proportional to t1/2

Question 37

what is the maintenance dose rate of a drug dependent on bearing in mind what is required to reach a steady state drug concentration?

Answer 37

clearance

as rate in= rate out at steady state

Question 38

why is the volume of distribution (Vd) described as an apparent volume?

Answer 38

the volume for a drug can differ between individuals. A value is calculated based on studies on healthy male adults weighing 70 kg, so no excess fat or muscle. With different body compositions, the Vd will vary.

Question 39

if a drug is highly lipohilic e.g. haloperidol, why will the t1/2 be higher in an obese patient?

Answer 39

the drug will have a greater Vd as haloperidol will readily be taken up into AT, and the plasma conc of the drug will be lower for a given equivalent dosing of the drug.

Question 40

CYP450 inducers?

Answer 40

PCBRAS
phenytoin
carabmazepine
barbiturates
rifampicin
alcohol (chronic)
St john's wort and sulphonyureas-diabetes

Question 41

CYP450 inhibitors?

Answer 41

O DEVICES
omeprazole
disulfarim
erythromycin
valproate
isoniazid
cimetidine and ciprofloxacin
ethanol (binge drink)
sulfonamides

and grapefruit juice, cranberry juice

Question 42

examples of non anti-arrhytmic drugs which can prolong QT interval?

Answer 42

antibiotics e.g. erythromycin
anti-psychotics e.g. haloperidol
cocaine
anti-fungal e.g. ketoconazole

Question 43

describe how renal disease-drug interaction occurs?

Answer 43

reduced GFR will result in reduced clearance of renally excreted drugs e.g. digoxin
kidney function will be damaged further by nephrotoxins e.g. gentamicin
electrolyte disturbances may predispose to toxicity e.g. hypokolaemia potentiates digoxin toxicity- e.g. bradycardia, arrhythmias, vomiting, yellow vision (xanthopsia), confusion.

Question 44

describe how hepatic disease-drug interaction occurs?

Answer 44

reduced clearance of liver secreted drug
reduced CYP 450 activity
longer t1/2s
e.g. opiates can accumulate in liver cirrhosis, causing COMA

Question 45

describe how cardiac disease-drug interaction occurs?

Answer 45

reduced clearance following reduced perfusion of liver and kidneys
excessive response to hypotensive agents

Question 46

what are type A and B adverse drug effects?

Answer 46

A= augmented pharmacologic effects: known to occur from pharmacology of drug and related to drug dose. seldom fatal and quite common.
e.g. haemorrhae with anticoagulants, hypoglycaemia with insulin injection.
B= bizarre effects: unpredictable, uncommon, often high rate of morbidity and mortality e.g. anaphylaxis with penicillin, acute hepatic necrosis with halothane
result of unique indiv disposition.

Question 47

describe the difference between on and off target adverse drug interactions

Answer 47

on target= exaggerated therapeutic effect of drug e.g. following increased dosing, e.g. 1 or more agents together treating hypertension, causing hypotension- dizziness, unsteadiness= type A ADRs.
off target= interaction with other receptors, or metabolites acting as toxins.

Question 48

define drug efficacy

Answer 48

once bound to a receptor, how good is the drug at activating the receptor

Question 49

define antagonist

Answer 49

a molecule capable of binding to a receptor (so has affinity), but is unable to activate it (so has zero efficacy), and prevents an agonist from binding, hence reduces number of available receptors for agonist to bind to.

Question 50

passive factors affecting drug absorption?

Answer 50

lipophilicty
molecular size e.g. heparin=large
pH- affects ionisation state

Question 51

active factors affecting drug absorption?

Answer 51

presence of AT systems
splanchnic blood flow- reduced in shock and HF
drug destruction by gut and/or bacterial enzymes
1st pass metabolism
*P-glycoprotein- reduces drug absoption into blood by transporting drugs into intestinal lumen

Question 52

examples of a group of drugs which slow renal elimination?

Answer 52

NSAIDs

Question 53

difference between a therapeutic window and a therapeutic index?

Answer 53

window= range of concentration values of a drug over which it exerts a therapeutic effect, without toxic side effects. The values will be located between the TD50= dose which is toxic in 50% of pop, and ED50= the dose which is effective in 50% of population.
index= calculated from window, and is the TD50 divided by the ED50.

Question 54

2 types of distribution once a drug is in the plasma?

Answer 54

bulk flow: via large veins and arteries over large distances

diffusion: capillaries allow distribution over short distances

Question 55

where are CYP450s located within hepatocytes?

Answer 55

on the external face of the ER