Pharmacology 3

Question 1

what is minimum effective concentration (MEC)?

Answer 1

concentration of drug in plasma required to achieve an affect

Question 2

what is the maximum tolerated concentration (MTC)?

Answer 2

concentration of drug in plasma which would cause significant unwanted effects

Question 3

how is therapeutic window found?

Answer 3

concentrations between MEC and MTC

safest drugs have largest therapeutic window

Question 4

how is therapeutic ratio (or index) calculated?

Answer 4

MTC/MEC

Question 5

what does the quantal dose response relationship describe?

Answer 5

the fraction of the population that responds to a given dose of drug against the drug dose
(response is quantal not graded - i.e either responds or it doesn’t)
generalises the effect of a drug to a population rather than the graded effect of different drug doses upon an individual

Question 6

how is quantal dose response of a drug used?

Answer 6

doses of a drug which produces a response in 50% of the population are significant
e.g if specific dose of drug is toxic in 50% of population = median toxic dose
median effective dose, median lethal dose etc

Question 7

what drugs are more likely to cause adverse drug interactions?

Answer 7

those with steep dose-response curves and serious dose related toxicities

Question 8

what defines a drug interaction?

Answer 8

when the effects of one drug are increased or decreased by the previous or concurrent administration of another

Question 9

describe pharmacodynamic mechanisms of drug interactions

Answer 9

drug A modifies the pharmacological effect of drug B without altering its concentration in tissue fluid
can occur in many different ways but usually predictable from a knowledge of the pharmacology of the drugs

Question 10

describe pharmacokinetic drug interactions

Answer 10

drug A modifies the concentration of drug B that reaches its site of action
can involve changes in
- absorption
- distribution
- metabolism
- excretion

Question 11

how can changes in drug absorption occur?

Answer 11

some drugs can change the rate of stomach emptying which may affect absorption
some drugs eg antibiotics can reduce enterohepatic recirculation (e.g of oral contraceptives reducing efficacy of them) - occurs bc gut bacteria normally releases the steroid from the conjugated form secreted in the bile allowing reabsorption

Question 12

how can changes in distribution occur?

Answer 12

drugs bound to plasma protein may be displaced by a second drug increasing their free concentration (not that significant unless drug is extensively protein bound or has a low therapeutic range as increases plasma conc drives increased rate of elimination)

Question 13

how can changes in metabolism occur?

Answer 13

induction of hepatic enzymes by a drug can decrease the efficacy of other drugs metabolised by the same enzyme
conversely enzyme inhibitors may potentiate the effect of other drugs metabolised by the same enzyme

Question 14

give examples of drugs which alter metabolism of otherr drugs?

Answer 14

phenytoin induces CYP3A4 enzyme which metabolises warfarin - causes decreased efficacy of warfarin as its metabolised quicker
cimetidine inhibits CYP2C9 enzyme which metabolises warfarin - causes increased efficacy of warfarin as its metabolised slower

Question 15

how can changes in excretion occur?

Answer 15

drugs which share a common transporter compete for excretion

e.g probenecid in the proximal tubule of nephron

Question 16

give an example of a pharmacodynamic interaction

Answer 16

man taking organic nitrate purchases Viagra online

Viagra potentiates the action of organic nitrates causing severe hypotension and potential collapse etc

Question 17

give an example of pharmacokinetic interaction?

Answer 17

woman taking warfarin for many years is prescribed oral fluconazole then notices blood in urine
fluconazole inhibits cytochrome P450 enzyme (CYP3A4) that metabolises warfarin potentiating its effect resulting in bleeding

Question 18

list some common pharmacokinetic drug interactions

Answer 18

simvastatin + grapefruit juice = myopathy
warfarin + clarithromycin = enhanced anticoagulation
phenytoin + omeprazole = phenytoin toxicity
azathioprine + allopurinol = azathioprine toxicity
catecholamines + monoamine oxidase inhibitors = hypertensive crisis
lithium + diuretics = lithium toxicity
methotrexate + NSAIDs = methotrexate toxicity

Question 19

list some common pharmacodynamic interactions

Answer 19

salbutamol + beta blockers = inhibits bronchodilator effect
benzodiazepines + alcohol = sedation and fall risk
ACE inhibitors + NSAIDs = renal impairment risk
digoxin + diuretics = digoxin toxicity due to hyperkalaemia
warfarin + aspirin/NSAIDs = bleeding

Question 20

what can cause a higher than desired plasma concentration of a drug?

Answer 20

normal variation
saturable metabolism
genetic enzyme deficiency
renal failure
liver failure
old age
very young age
enzyme inhibition
(all can cause increased dosage and/or decreased clearance)

Question 21

what can cause a lower than desired plasma concentration?

Answer 21

normal variation
poor absorption
high first pass metabolism
genetic hypermetabolism
enzyme induction
non-compliance 
(all can cause dose too low or increased clearance)

Question 22

competitive vs non-competitive enzyme inhibition?

Answer 22

competitive = higher Km but same Vmax
non-competitive = same Km but lower Vmax

Question 23

what is Vmax?

Answer 23

maximum rate of reaction

Question 24

what is Km?

Answer 24

concentration of substrate that allows enzyme to achieve half of Vmax

Question 25

Vmax and Km in enzyme induction?

Answer 25

same Km
higher Vmax
(small concentration of substrate causes higher reaction rate)

Question 26

impact of liver disease in drug metabolism?

Answer 26

liver has large excess capacity for drug metabolism so severe liver disease can impair drug metabolism, particularly for extensively metabolised drugs (high first pass metabolism) with a low therapeutic range
due to decreased enzyme metabolising capacity and/or decreased liver blood flow

Question 27

drug dosage is adjusted in liver disease for what type of drugs?

Answer 27

high clearance drugs (as affected by blood flow and enzyme capacity)
low clearance drugs (as affected by enzyme capacity only)

Question 28

how can liver disease later response to drugs?

Answer 28

reduced synthesis of plasma proteins (hypoproteinaemia)
reduced synthesis of clotting factors
impaired excretion of drugs eliminated by the bile
altered pharmacodynamics (due to hepatic encephalopathy, ascites etc)

Question 29

how does hypoproteinaemia alter response to drugs?

Answer 29

causes increased toxicity of highly protein bound drugs with low therapeutic range (e.g phenytoin)

Question 30

how does reduced synthesis of clotting factors alter response to drugs?

Answer 30

causes enhanced sensitivity to oral anti-coagulants (warfarin, thrombin inhibitors)

Question 31

what can cause impaired excretion of drugs eliminated by bile?

Answer 31

cholestasis (where the flow of bile to the duodenum is compromised)

Question 32

what is hepatic encephalopathy?

Answer 32

deterioration of brain function associated with severe liver disease
worsened or precipitated certain drug classes (sedatives, opioids etc)

Question 33

what is ascites?

Answer 33

accumulation of fluid in the peritoneal cavity associated with severe liver disease
may be worsened by drugs that cause fluid retention (NSAIDs)

Question 34

how does renal impairment affect drugs in the body?

Answer 34

if drug (or active metabolite) is eliminated mainly by the kidneys it will accumulate (so the maintenance dose must be reduced)

Question 35

how can renal impairment be measured?

Answer 35

eGFR (lower when impaired)
creatinine clearance (clearance from skeletal muscle) is a measure of GFR

Question 36

how is drug dose adjusted in renal impairment?

Answer 36

adjustment can be determined from the rate of creatinine clearance and knowledge of the fraction of drug that is excreted by the kidney in unchanged form (fu)
if fu = 1 then adjust dose in direct proportion to degree of impairment in CrCl
if fu = 0.5 then adjust dose for the fraction cleared by the kidney
if fu = 0 then no adjustment needed

Question 37

what are the 3 grades of renal impairment?

Answer 37

mild = CrCl 20-50ml/min
mod = 10-20ml/min
severe = <10ml/min

Question 38

how can the total daily maintenance dose be reduced?

Answer 38

reducing size of individual doses while keeping interval the same
increasing interval between doses while keeping individual dose the same

Question 39

altered dosing in children?

Answer 39

dose by body weight (or body surface area)

Question 40

why is dosing different in neonates?

Answer 40

altered pharmacokinetics and pharmacodynamics

• inefficient renal filtration
• relative enzyme deficiencies
• inadequate detoxifying systems (delayed excretion)

Question 41

why are elderly patients more vulnerable to adverse effects of drugs?

Answer 41

impaired renal elimination
increased sensitivity of target organs to drugs
polypharmacy
clearance of drugs with high fu is impaired
clearance of metabolised drugs is usually impaired
other additional considerations like swallowing difficulty and cognitive impairment

Question 42

what are the main issues with drugs in pregnancy?

Answer 42

(should avoid if at all possible)
teratogenicity
(foetus most at risk in 1st trimester)
pharmacokinetic handling of drugs changes in pregnancy (vomiting in early stages, decreased plasma albumin, increased GFR)