Singh - Pharmacodynamics Flashcards
2 key principles of pharmacodynamics
- dose of the drug is linked to the bodies response
2. drugs act through receptors (rely on kinetics)
drug receptor leading to response
can have response immediately (short lasting) or can have response that takes longer (longer lasting)
- drug + receptor –> response
- drug + receptor –> effector –> response
- drug + receptor –> cell signaling –> response
- drug inhibiting enzymes that metabolize compounds
how does interaction lead to biological response?
bind to more receptors –> more response and effect of drug
-linear up to 50% of response then becomes saturated
Kd - dissociation constant
[] of drug that occupies 50% of receptors
- high affinity drug –> low Kd –> high potency
- low affinity drug –> high Kd –> low potency
- drug receptor interaction does not make product like enzyme/substrate complex
how does drug amount affect drug receptor binding curve?
helps determine the dose needed to have max response & help determine affinity
2 state model for receptor activation
receptor can be in active or inactive state - depends on the type of drug you give
-increase or decrease endogenous chemicals
agonist
binding to receptor making receptor active
-intrinsic activity of 1 - max response
antagonist
binds to inactive conformation of receptor –> no response
-intrinsic activity is 0
partial agonist
binds to active or inactive conformation equally
- can have response but not to extent of agonist
- used in treating addiction - prevent withdrawal
- agonist on its own, antagonist when other drug is present
- intrinsic activity <1
potency
dose of drug needed to produce 50% of response bc 50% of receptors are bound
-high potency –> less [] needed to bind those receptors
efficacy
max effect drug produces, not potency
- clinical effectiveness deals with efficacy
- want drug to have max efficacy
inverse agonist
drugs that act on constitutively active receptors bringing response to 0
-lower dose response curve - decrease basal activity of drugs
agonist vs. antagonist
- agonist - binding activates receptors either increasing or decreasing endogenous chemicals
- antagonist - no response when bound; receptor stays in inactive form; can lower agonist binding
competitive/reversible antagonist
max response possible when increasing dose of agonist (curve shifts to right when present)
- still achieve max response, but with higher dose
- Kd increases bc potency decreases
- get response if agonist dose exceeds competitive antagonist
noncompetitive/irreversible antagonist
- max response limited bc drug stays bound to receptor
- lower response bc there is no receptor to occupy (lowers # of available receptors)
- no change in Kd –> does not affect drug/receptor interaction
- CAN get same response only if # of receptors needed for max response are available
- dose needed to produce 50% of response dose not change
drug receptor interaction
drug binds to receptor then comes off due to non covalent interaction
-stays bound with covalent
chemical antagonism
binding of one drug to another making it unavailable to bind to receptor
-protamine sulfate (+ charge) neutralizes heparin excess
physiological antagonism
2 drugs have opposite effects
- want to stop drug response but cannot interfere with drug/receptor interaction
- activate a receptor that produces opposite effects
- ex. increase insulin with high glucose
allosteric modulation
drug binds to receptor at different site than agonist binds
-benzodiazopine does not activate, but increases likelihood of GABA binding
graded vs. quantal dose response curve
- graded - may not work due to studying only single patient (everyone is different)
- quantal - study dose response by looking at population
- determine how many responded to different doses (ED50)
therapeutic index/window
range at of doses at which it was effective but did not produce toxic effects
- range of minimum effective dose to minimum toxic dose
- LD or TD50 divided by ED50
ED50
dose where half the population will respond to drug
LD50
dose tested where half the animals will not survive
CSF (certain safety factor)
estimate of safety of drug
specificity vs. selectivity
- specificity - drug has one effect only
- selectivity - acting on more than one receptor when reaching high []
- stay within therapeutic index to bind to specific receptors
narrow therapeutic index (NTI)
small differences in dose may lead to toxic effects –> side effect when exceeding therapeutic window
- ED50 is high, LD50 is low
- need more drug to reach effect but is close to toxic dose
- higher TI –> safer the drug
intracellular receptors
nuclear receptors
- ex. corticosteroids, lipid soluble
- receptors exist in cytosol
- can stimulate intracellular enzyme or alter gene transcription
- no effect of drug if body metabolizes proteins
- slower response for gene transcription but longer lasting
plasma membrane bound receptors
ligand regulated transmembrane enzymes
- ex. RTK
- receptors in inactive state - need ligand binding for activation, dimerization, autophosphorylation, protein docking, and signaling to occur
- another ex. GPCR
cytokine receptors
- no cytokine function without (ex. interleukins)
- cytokine binding –> recruit JAK for phosphorylation –> docking and phosphorylation of STAT –> STAT dissociates, dimerizes, and goes to nucleus
- response lasts long time even if you stop taking drug
Ligand gates channel
drug binds to receptor opening it –> influx of Na+ and Ca++ depolarizing the cell –> signal by AP
- fast response - rapid transmission
- regulated by phosphorylation and endocytosis
- synaptic plasticity –> learning and memory
GABA and glycine
hyper polarize receptor by Cl- influx –> inhibition
-GABA in brain, glycine in spinal cord
ACh, glutamate, serotonin 3
depolarize receptor through Na+ and Ca++ influx and K+ efflux –> excitatory
GPCR
contain G protein –> multiple subunits
- stimulate or inhibit effects of adenylate cyclase or PLC
- GDP –> GTP to start signaling cascade –> activate adenylate cyclase, cAMP, PKA –> phosphorylation
- GTP hydrolyzed back to GDP to stop signal
- do NOT have to activate all receptors to get desired response
cholera
bacteria cause continued activation of G protein by binding to GTP –> open Cl- channel through phosphorylation –> water follows Cl- –> diarrhea
cannabinoids and opioids
stops pain signal to brain by inhibiting GPCR –> analgesia
increased responsiveness
- chronic disuse of receptor from antagonist can increase response when reexposed to agonist –> get rid of receptors then upregulate them
- cutting neural signal –> denervation supersensitivity by up regulating receptors
tolerance
decreased response to drug or hormone over time by downregulating receptors –> adaptation
- increase dose to maintain response
- ex. B-adrenergic bronchodilators and alpha-adrenergic vasoconstrictors
mechanism of tolerance
- phosphorylation of receptor
- post receptor adaptation - desensitization –> uncouple G protein from receptor
- receptor down regulation - remove receptor on membrane
therapeutic vs. side effect
deals with dose and how receptor signals
- benefits and toxicity arise downstream of of separate receptors, which are both activated by the same drug due to low specificity
- ex. 3 types of histamine receptors coupled to G protein –> produces different responses
- ex. drug increasing ACh level activating autonomic and skeletal muscle
receptor regulation
make receptor nonfunctional by removing G protein or another cytosolic protein, or by removing receptor from membrane
- too much agonist –> can internalize receptor avoiding response
- stop taking drug –> dephosphorylate receptor and travel back to membrane
