Response Variation To Drugs

Question 1

Genetic factors contributing to pharmacokinetic differences

Answer 1

Absorption - type of stomach, pH
Distribution - variation in protein binding among species
Metabolism - differences in Biotransformation enzymes, sex differences
Excretion - birds v mammals

Question 2

Effect of age on drug absorption

Answer 2

Absorption - as age, GI blood flow dec (splanchnic blood flow), acid secretion decreases —> decreases in absorption

Question 3

Effect of age on drug distribution

Answer 3

Distribution - alteration in fat/muscle mass, plasma proteins + protein binding in age; inc in fat w age —> inc lipid soluble drug sequestration; dec in water soluble drug; plasma protein drop with age

Question 4

Efect of age on drug metabolism

Answer 4

Decreased metabolism in neonates + aged

Hepatic enzyme activity - dec metabolism rate with age

Liver weight

Hepatic blood flow (dec with age)

Question 5

Effect of age on excretion

Answer 5

Renal excretion less efficient in neonates/aged animals

Low renal blood flow/glomeruluar filtration rate

Age: 50% of young adults
Neonates: 20% of young adults

Question 6

Overall effect of aging on drug pharmacokinetics

Answer 6

Distribution - lipophilic —> HL inc; bound by albumin —> dec HL
Metabolism - drug metabolized by liver —> inc HL
Excretion - GFR slows —> inc HL

Net effect —> inc in drug HL with age

Question 7

Pharmacodynamic factors in neonates

Answer 7

Low number of receptors
Different receptor types
Altered receptor affinity

Question 8

Pharmacodynamics in aged patients

Answer 8

May have altered receptor affinity

Altered coupling to receptors
Altered receptor numbers

Question 9

Mechanism of drug induced loss of response

Answer 9

Change in receptor conformation (drug binds but no effect)

Loss of receptors (down regulation/endocytosis)

Exhaustion of mediators (secondary messengers)

Increase metabolic degradation (enzyme induction)

Physiological adaptation (biochemical compensations)

Question 10

Effects of disease or altered physiological states

Answer 10

Absorption - gastric stasis, malabsorption, mucosal edem
Distribution - pH change, change in plasma proteins, impaired BBB
Metabolism - liver disease, hypothermia
Excretion - renal failure, proteins in tubular fluid binding drug

Pharmacodynamics - receptor numbers, signal transduction pathways

Question 11

Drug interactions

Answer 11

Reaction between two drugs
Effects on pharmacokinetics and/or pharmacodynamics of drugs involved

Adverse (toxic) or beneficial (reduce toxicity, enhance efficacy, delay resistance)

Question 12

Sites of action of drug interactions

Answer 12

External (in vitro incompatibilities - precipitation, chemical combination)

Internal (GI tract, receptor, RNA-DNA, metabolic pathways)

Question 13

Mechanisms of drug interactions

Answer 13

Physiologic - act at different sites to alter function (augment or offset(

Pharmacokinetic - one drug changes concentration of other (ADME)

Pharmacodynamic - on drug changes effect of other

Question 14

Pharmacokinetic mechanisms: absorption

Answer 14

Drug that affects GI function can alter absorption profiles of additional drugs taken by patient

Question 15

Changes in GI tract affecting absorption

Answer 15

Physicochemical - chelation, change in luminal pH —> drug ionization; absorption - activated charcoal, dissolution (mineral oil)

Change in GI motility - early or delayed gastric emptying; increased intestinal motility

Change in bacterial flora - antibiotics; affect ability to deconjugate drugs undergoing enterohepatic circulation

Mucosal dysfunction - damage GI mucosa, block transport/carrier systems

Question 16

Mechanisms of pharmacokinetic changes affecting distribution

Answer 16

Altered blood flow - alters clearance, first pass
Alter tissue uptake/protein binding - store of drug can be displaced; interfere with hepatic uptake + alter first pass
Alter active transporter at site of action - NT regulation
Alter plasma protein binding

Question 17

Mechanisms affecting pharmacokinetics of metabolism

Answer 17

Enzyme induction or inhibition

(I.e. phenobarbital induce CP450 —> metabolism of other drugs in system)

Question 18

Pharmacokinetic mechanisms affecting excretion

Answer 18

Glomerular filtration - increased by displacement from plasma proteins
Tubular reabsorption of drugs dec by some diuretics; alkaline pH for weak acids; acidic pH for weak bases
Tubular secretion dec by competitors for active transport
Increase urine flow by diuretics —> dec drug reabsorption, reduce drug conc and renal toxicity

Question 19

Pharmacodynamic mechanisms of drug interaction

Answer 19

Drug changes effect of another

Drug can act indirectly on another by changing intracellular/extracellular environment (pH, ion conc)

Drug effects - additive, synergistic, antagonistic

Large impact when therapeutic range of affected drug is narrow —> total loss of efficacy or induction of toxicity

Question 20

Adverse drug reactions

Answer 20

Dose related (renal disease, liver disease, altered receptors, altered pharmacokinetics) - change dose

Not dose related - pharmacokinetic variants, drug allergy, unknown (discontinue drug)

Common in - old, newborns, females; when combos are given