Pharmacology 3 Flashcards
what is minimum effective concentration (MEC)?
concentration of drug in plasma required to achieve an affect
what is the maximum tolerated concentration (MTC)?
concentration of drug in plasma which would cause significant unwanted effects
how is therapeutic window found?
concentrations between MEC and MTC
safest drugs have largest therapeutic window
how is therapeutic ratio (or index) calculated?
MTC/MEC
what does the quantal dose response relationship describe?
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
how is quantal dose response of a drug used?
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
what drugs are more likely to cause adverse drug interactions?
those with steep dose-response curves and serious dose related toxicities
what defines a drug interaction?
when the effects of one drug are increased or decreased by the previous or concurrent administration of another
describe pharmacodynamic mechanisms of drug interactions
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
describe pharmacokinetic drug interactions
drug A modifies the concentration of drug B that reaches its site of action can involve changes in - absorption - distribution - metabolism - excretion
how can changes in drug absorption occur?
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
how can changes in distribution occur?
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)
how can changes in metabolism occur?
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
give examples of drugs which alter metabolism of otherr drugs?
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
how can changes in excretion occur?
drugs which share a common transporter compete for excretion
e.g probenecid in the proximal tubule of nephron
give an example of a pharmacodynamic interaction
man taking organic nitrate purchases Viagra online
Viagra potentiates the action of organic nitrates causing severe hypotension and potential collapse etc
give an example of pharmacokinetic interaction?
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
list some common pharmacokinetic drug interactions
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
list some common pharmacodynamic interactions
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
what can cause a higher than desired plasma concentration of a drug?
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)
what can cause a lower than desired plasma concentration?
normal variation poor absorption high first pass metabolism genetic hypermetabolism enzyme induction non-compliance (all can cause dose too low or increased clearance)
competitive vs non-competitive enzyme inhibition?
competitive = higher Km but same Vmax non-competitive = same Km but lower Vmax
what is Vmax?
maximum rate of reaction
what is Km?
concentration of substrate that allows enzyme to achieve half of Vmax
Vmax and Km in enzyme induction?
same Km
higher Vmax
(small concentration of substrate causes higher reaction rate)
impact of liver disease in drug metabolism?
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
drug dosage is adjusted in liver disease for what type of drugs?
high clearance drugs (as affected by blood flow and enzyme capacity)
low clearance drugs (as affected by enzyme capacity only)
how can liver disease later response to drugs?
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)
how does hypoproteinaemia alter response to drugs?
causes increased toxicity of highly protein bound drugs with low therapeutic range (e.g phenytoin)
how does reduced synthesis of clotting factors alter response to drugs?
causes enhanced sensitivity to oral anti-coagulants (warfarin, thrombin inhibitors)
what can cause impaired excretion of drugs eliminated by bile?
cholestasis (where the flow of bile to the duodenum is compromised)
what is hepatic encephalopathy?
deterioration of brain function associated with severe liver disease
worsened or precipitated certain drug classes (sedatives, opioids etc)
what is ascites?
accumulation of fluid in the peritoneal cavity associated with severe liver disease
may be worsened by drugs that cause fluid retention (NSAIDs)
how does renal impairment affect drugs in the body?
if drug (or active metabolite) is eliminated mainly by the kidneys it will accumulate (so the maintenance dose must be reduced)
how can renal impairment be measured?
eGFR (lower when impaired) creatinine clearance (clearance from skeletal muscle) is a measure of GFR
how is drug dose adjusted in renal impairment?
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
what are the 3 grades of renal impairment?
mild = CrCl 20-50ml/min mod = 10-20ml/min severe = <10ml/min
how can the total daily maintenance dose be reduced?
reducing size of individual doses while keeping interval the same
increasing interval between doses while keeping individual dose the same
altered dosing in children?
dose by body weight (or body surface area)
why is dosing different in neonates?
altered pharmacokinetics and pharmacodynamics
- inefficient renal filtration
- relative enzyme deficiencies
- inadequate detoxifying systems (delayed excretion)
why are elderly patients more vulnerable to adverse effects of drugs?
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
what are the main issues with drugs in pregnancy?
(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)
