Pharmacodynamic Principles (Guillespie) Flashcards
processes of clinical reasoning
- data acquisition
- problem representation
- hypothesis generation (Ddx)
- hypothesis testing (selecting, comparing, contrasting illness scripts)
- diagnosis
- treatment
agonists
stimulatory
antagonists
inhibitory
chemical antagonists
drugs interact directly with other drugs to inhibit activity
receptors
interact with drug to initiate observed effect
acceptors
interact with drug but DO NOT directly change biochemical or physiological processes
mechanisms of action
specific DNA sequences can function as receptors
most drug receptors are PROTEINS
most drugs act on receptors that ALTER CELLULAR SIGNALING PATHWAYS
increase in concentration of drug
DOES NOT EQUAL and increase in effect/response
- [drug] will reach an inflection point and the effects will decrease → may become toxic
- hormetic drug curve
Achetylcholinesterase Inhibition
drug-receptor interaction affecting endogenous ligand concentration
- achetylcholinesterase terminates the effects of acetylcholine at synaptic cleft
- inhibition = persistence of cholinergic effect
Kx
intrinsic activity
binding DOES NOT equal activity
termination
metabolize drug to drive equation to the left
diffuse away/uptake into another cell
Kd
a measure of binding affinity (constant)
NO INFO on whether ligand is agonist/antagonist
Concentration of ligand required to occupy 50% of binding sites
lower Kd = higher affinity
ideal plot
hyperbolic curve
real plot
some drug may bind to nonspecific binding sites, meaning it is not easily saturable
total binding - non-specific binding = specific binding
specific binding is used to calculate Kd
The “Log-Dose Response Curve”
percent of maximum is plotted as a function of dose of drug
ED50
dose required for 50% of the population to obtain therapeutic effect
how potent a drug is
potency can only be used when drugs act on the SAME RECEPTOR
EC50
dose required for an INDIVIDUAL to experience 50% of the maximum effect
primary agonist
binds to same site as endogenous ligand to activate receptor
allosteric agonist
binds to a distinct site and potentiates the activity of primary agonist (increases power of)
inverse agonist
binds to same site as primary agonist, but paradoxically decreases baseline activity of receptor
primary agonists using same mechanism of action
log-dose response curves will be parallel/have same slope
full agonist
intrinsic activity of 1
partial agonist
intrinsic activity <1
intrinsic activity
reflects ability to initiate maximum response attainable by that receptor
maximum effect of drug is determined by:
number of drug receptor complexes formed (Kd)
intrinsic ability of drug to initate response (Kx) → same proportion of receptors can be occupied with different responses
Partial agonist with full agonist
as the concentration of the partial agonist increases, the response of the full agonist decreases (partial agonist competes and binds to receptors)
the portion of the response caused by the partial agonist increases, but the total response decreases until it reaches the value produced by the partial agonist alone
allosteric agonist effects
increases effect of primary agonist (increases potency but not intrinsic activity)
does NOTHING alone
inverse agonists effect
interacts with excitatory receptors but decrease response of tissue
simple occupancy model
direct, linear relationship between percent of receptors occupied and maximum response
for a full response, all receptors must be activated
spare receptor model
receptors exist in excess of number required to produce a full effect
increases sensitivity to agonists and decreases sensitivity to antagonists (more receptors must be taken out to reduce response)
antagonists activity
lack intrinsic activity- must have agonist or NO EFFECT
competitive antagonist
binds to same site as primary agonist
COMPETES with ligand for receptor occupancy
normal response but must add more agonist → curve shifts right
Rightward, parallel shift in log dose-response curve for agonist without diminishing its maximum response; ED50 is shifted right
pseudo-irreversible agonist
binds with HIGH AFFINITY to the same site as the primary agonist
every receptor not inactivated is NORMAL
ED50 won’t change but effect drops (decrease in maximum response to agonist)
Allosteric antagonist
binds to DISTINCT site from the primary agonist to DECREASE response to the agonist receptor
ED50 is shifted right (increased)
IC50
response to antagonist is calculated as a percentage of the initial contraction of the tissue and plotted as a function of the antagonist dose
half maximum inhibitory concentration
RISES with increasing ligand concentration
Ki
equivalence of Kd for an agonist
measures binding affinity of agonist
Cheng Prusoff equation
determines Ki from the IC50 value
graded dose-response curve
measures magnitude of response in an individual
quantal dose-response curve
based on the frequency of a response in a POPULATION
Response of predetermined magnitude is defined
→ subjects falling below threshold: non-responders
→ subjects exceeding threshold: responders
LD50
lethal dose for 50% of a group
certain safety factor
TD1/ED99
TD1 is the dose producing toxicity in 1%
ED99 is the dose that produced a therapeutic effect in 99% of the population
