Response Variation To Drugs Flashcards
Genetic factors contributing to pharmacokinetic differences
Absorption - type of stomach, pH
Distribution - variation in protein binding among species
Metabolism - differences in Biotransformation enzymes, sex differences
Excretion - birds v mammals
Effect of age on drug absorption
Absorption - as age, GI blood flow dec (splanchnic blood flow), acid secretion decreases —> decreases in absorption
Effect of age on drug distribution
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
Efect of age on drug metabolism
Decreased metabolism in neonates + aged
Hepatic enzyme activity - dec metabolism rate with age
Liver weight
Hepatic blood flow (dec with age)
Effect of age on excretion
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
Overall effect of aging on drug pharmacokinetics
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
Pharmacodynamic factors in neonates
Low number of receptors
Different receptor types
Altered receptor affinity
Pharmacodynamics in aged patients
May have altered receptor affinity
Altered coupling to receptors
Altered receptor numbers
Mechanism of drug induced loss of response
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)
Effects of disease or altered physiological states
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
Drug interactions
Reaction between two drugs
Effects on pharmacokinetics and/or pharmacodynamics of drugs involved
Adverse (toxic) or beneficial (reduce toxicity, enhance efficacy, delay resistance)
Sites of action of drug interactions
External (in vitro incompatibilities - precipitation, chemical combination)
Internal (GI tract, receptor, RNA-DNA, metabolic pathways)
Mechanisms of drug interactions
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
Pharmacokinetic mechanisms: absorption
Drug that affects GI function can alter absorption profiles of additional drugs taken by patient
Changes in GI tract affecting absorption
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
Mechanisms of pharmacokinetic changes affecting distribution
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
Mechanisms affecting pharmacokinetics of metabolism
Enzyme induction or inhibition
(I.e. phenobarbital induce CP450 —> metabolism of other drugs in system)
Pharmacokinetic mechanisms affecting excretion
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
Pharmacodynamic mechanisms of drug interaction
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
Adverse drug reactions
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
