Drug Action Flashcards
Physiological variables affecting drug responses
- body weight and size (surface area)
- age (eg infants and elderly-different renal fxn)
- gender differences in lean/fat mass
Pathologic variables affecting drug responses
- renal insufficiency
- hepatic disease
- acid/base imbalance (changes charged species)
- altered electrolyte status
Genetic variables affecting drug responses
variations in :
- biotransformation
- functional proteins and enzymes
- receptor proteins
Nonspecific drug action
drugs that act by physicochemical processes
- laxatives (surfactants, inorganic ions)
- metal chelators (EDTA)
- osmotic diuretics (urea, mannitol)
- acids, bases (antacids)
Specific drug action
-Drugs that act on receptors, enzymes, transporters, or other identified components of the cell
Domains of nuclear drug receptor
- transcription activating domain-interacts w/ DNA->gene expression
- DNA binding domain-blocked by heat shock protein when no ligand bound
- Ligand binding domain-ligand binding causes conformational change, HSP dissociates, receptor translates into nucleus and binds
desensitization
response diminishes over seconds/mins, even in continued presence of agonist
Gs
- stimulatory
- B-adrenergic amines, glucagon, histamine, serotonin, hormones
- activates adenylyl cyclase-> increase cAMP
Gi 1, 2, and 3
- inhibitory
- a2-adrenergic amines, acetylcholine (muscarinic), opiods, serotonin
- inhibits adenylyl cyclase->decrease cAMP
- activates cardiac K+ channels->hyperpolarize->decrease HR
Gq
-Activates phospholipase C->increase IP3, DAG, intracellular Ca
Kd
equilibrium dissociation constant
k2/k1
50% of binding sites are occupied if [D]=Kd
low Kd=tight binding=high affinity
EC50
Effective [ ] for 50% response
ED50
effective dose for 50% response
Spare receptors
fractional occupation of total receptor population can generate full response
with spare receptors, EC50
Potency
- dose required to produce a specified response
- different drugs may require different doses to produce the same response
Agonist
activates receptor to initiate a sequence of events leading to a biological response (stabilize active form)
has intrinsic efficacy
full agonist elicits maximal response
Partial Agonist
- agent which is less effective at activating receptor
- elicits a response that is less than the maximal response produced by a full agonist
- has less efficacy than a full agonist
- appears to be antagonist in presence of full agonist due to occupation of agonist receptor sites
- sometimes may be useful-blunting response
Antagonist
- Agent which does not activate receptor upon binding
- has no intrinsic efficacy
- blunts effect of agonists
- have zero efficacy, but not necessarily zero effect
Competitive antagonism
antagonist competes for agonist binding site on receptor
surmountable
Noncompetitive antagonism
-antagonist produces nonfunctional complex or has post-receptor site of action
-insurmountable
-antagonist binds allosteric receptor site, change affinity of receptor for agonist OR blocks step beyond receptor activation OR two agonists produce opposite pharmacodynamic response
eg NE and histamine
-ED50 remains unchanged (but % response of changes compared to without antagonist)
Irreversible antagonism
- form of noncompetitive antagonism
- drug forms covalent antagonist-receptor complex; antagonism cannot be washed out
Physiological antagonism
- drugs produce opposing responses by acting on different systems
- each drug has intrinsic activity
- eg phenylephrine and nitroglycerin
Chemical antagonism
- antagonist acts directly on agonist to chemically alter it
- protamine and heparin
Allosteric modulators
- regulate activity of agonist, can either enhance or inhibit
- no effect in absence of receptor activation by agonist
- eg benzodiazepines enhance action of GABA on GABAa receptor
- B-carbolines decrease action of GABA on GABAa receptor
