Pharmacodynamics Flashcards
pharmacodynamics
what the drug does to the body
mechanism of action
how drug achieves its effect at the site of action
mechanism of action (5)
- provides new drug therapy treatment
- optimize drug dosage
- reduce drug resistance
- discover new indications for existing drug
- safer drug therapies
factors that affect degree of drug binding and response
- recognition of drug at receptor
- concentration of drug at site of the receptor
- amount of drug needed to produce effect
- density of receptors on cell surface
fundamentals of drug action
D + R ↔ DR Complex → Effect
threshold
minimum number of drug receptor complexes required for a response to occur
Saturation
point when all receptors are bound/occupied by drug
most receptors are proteins
true
drug receptors are commonly named for the substance it interacts best with and stimulates/activates (ie insulin)
true
drug-receptor actions
determine quantitative relationship between dose & effects,, receptor binding affinity determines drug concentration
factors affecting drug-receptor responses
- affinity
- selectivity
- drug efficacy
- potency
affinity
strength of binding between a drug and its receptor
drug affinity is dictated by:
- size
- shape
- bonding (IMF)
- stereochemistry
K1 < K2
dissosiate
K1 > K2
form
K3
events that occur following receptor binding
affinity drug size
< 1000 MW units allows movement
> 1000 MW units unable to diffuse between body compartments
affinity drug shape
chirality, enantiomers (mirrored image)
enantiomers
diffuse in their ability to bind to and alter the function of receptors
racemic mixture vs S isomers
racemic mixture (S/R isomers)
S isomers increase absorption and longer half life
affinity drug receptor binding
depends on type of chemical bonds that can be established between drug and receptor (covalent vs non-covalent)
Seletivity
preference for acting at certain binding sites or receptors. may equate to less side effects
receptor distribution
nonselective antagonists are not used, preferred method is using selective drugs that target specific area.
amount of drug bound is affected by
quantity of receptor binding sites, receptor and tissue type, amount of drug available
drug efficacy
ability of drug to initiate biological effect or stimulate receptor in a way that produces a pharmacological response
drugs can have affinity but lack efficacy
true
drug efficacy is dependent on
drug receptor complexes and intrinsic activity of drug
Emax
maximal efficacy of drug (assuming all receptors are occupied by drug and no increase in response observed with higher concentrations of drug)
intrinsic activity
ability of the receptor bound drug to activate the receptor and initiate downstream events
drugs are categorized based on intrinsic activity at a given receptor
agonist and antagonist
receptor agonist
drugs that interacts with and activates receptors (can resemble naturally occurring hormone)
types of agonist
full, partial, inverse
full agonist
maximal efficacy
partial agonist
less than maximal
inverse agonist
produce < 0 response
receptor antagonist
intrinsic activity of 0, no effect, block action of endogenous agonists (possess affinity, lack efficacy)
types of antagonists
competitive, noncompetitive, functional
competitive antagonist
reversible, competes with an agonist, decreases potency same efficacy
noncompetitive antagonist
irreversible, decreases maximum efficacy
allosteric antagonist
binds to another site and prevents activation by agonist
functional/physiologic antagonist
2 drugs causing opposing effects
potency
amount of drug needed to produce an effect
dose response curve
effect of dose on magnitude of pharmacologic response
EC50
concentration of drug producing 50% of max response
measure of drug potency
↓ EC50, ↑ potency
Arithmetic scale dose response curve
rate of change rapid at first, becomes progressively smaller as dose increase, difficult to analyze
logarithmic scale dose response curve
proportionate doses occur at equal intervals, able to plot drugs with different dose ranges on same scale
logarithmic scale used to
compare drug potencies
drug dosage goal
maximize efficacy limit toxicity
subtherapeutic
too low of dose = ineffective
supretherapeutic
too high of a dose = adverse side effects
therapeutic index
measure of drug safety
LD50 vs TD50
lethal dose vs toxic dose
LD50
dose that kills 50% subjects
TD50
dose that poisons 50%
ED50
dose that produces a therapeutic effect in 50%
large therapeutic index
increased margin of safety, wide therapeutic window (nicotine)
small therapeutic index
narrow therapeutic window, small difference in concentration between desired therapeutic effect and unwanted side effects (warfarin)
certain safety factor
accounts for different line slopes LD1/ED99
you want a certain safety factor
greater than 1 to indicate safety
Enzymes
control a number of metabolic processes, requires selective toxicity
enzyme inhibition
competitive, non-competitve, irreversible blockage at substrate or cofactor binding site
reverse transcriptase
turns viral RNA into DNA
integrase
integration into host DNA
protease
final cutes and packaging new HIV
transport systems
transmembrane proteins involved in movement of ions/molecules
targets of drug actions
enzymes, transport systems, receptors
transport systems
facilitated diffusions / active transport
ligand gated ion channel
increase/decrease opening of an ion channel to let ions pass in/out of cell
transporters
molecules that are too large or not lipid soluble require transport into cells
receptors
most drugs act on receptors/transduction (receptor coupling)
drug receptor interactions
type of receptor a drug interacts with depends on chemical nature
hydrophilic drug
interacts with receptors on cell surface
lipophilic drug
enters cells through cell membrane, interacts with receptors
G protein coupled receptors
7 transmembrane domans, largest and most diverse group. external to cell, drug binding occurs on extracellular side
activation of G protein coupled receptor
GTP binds to Beta-gamma subunit, BY migrates and interacts with other molecules & G protein is hydrolyzed and converted to GDP
second messagers
small, non-protein water soluble molecules or ions (cAMP, Ca2+)
albuterol (therapeutic GPCR)
activates b-adrenergic GPCRs
Antipsychotic agents
block GPCR that normally bind to dopamine or serotonin
enzyme linked receptors
drug binds to extracellular domain of a receptor, activates multiple signaling pathways (insulin receptor)
intracellular receptor
not located on plasma membrane, able to pass through (lipid soluble ligand) –> steroids/hormones
targets of intraceullar ligands
proteins, enzymes, RNA, ribosomes
signal transduction
- signal amplification
- Protect cell from excessive stimulation
signal amplifcation
G protein linked receptor, enzyme linked receptor GOAL is to multiple original signal
desensitization / downregulation
repeated or continuous administration of an agonist
tachyphyllaxis
receptor is desensitized after repeated stimulation
the time it takes to recover
refractory period
