8/8/16 Pharmacodynamics - Pilch Flashcards
definitions
drug
pharmacodynamics vs pharmacokinetics
drug: any substance that brings about change in biological fx (ideally in a therapeutically useful way)
dynamics: what a drug does, physiological effects (what the drug does to you)
kinetics: what your body does to the drug to change it, eliminate it, etc
majority of drugs have MW 100-1000
why?
sweet spot for size
much smaller? sacrifice specificity bc the number/type of interactions is ltd
- bad bc then you’re subject to more side effects
much larger? issues with transporting to site where it needs to act
receptor concept
most drugs fx by interaction with a cognate receptor that plays regulatory role as a trigger → sets off cascade of downstream events → observed effect
receptors are macromolecules - mostly proteins, but some lipids/nucleic acids/etc
diff drugs show diff mechs of drug binding → pharmacological response
3 models
- agonism
- partial agonism
- antagonism
- agonism
- drug mimics action of endog compounds/ligands, bind to specific receptor → induce full scale response
- INDUCERS
- partial agonism
- type of agonist that also induces a response BUT does not produce max response that we know the receptor is capable of producing
- if max response isn’t achieved when receptors are saturated, partial agonist
- antagonism
- bind to receptors, prevent agonists from inducing their response
- no response to antagonist binding, BUT serve to block the response you’d see with an agonist
relationship between drug dose and pharmacologic response
RECEPTORS are at the heart of this relationship
- affinity of receptor/drug for each other (Kd = dissociation constant)
- number of receptors available for binding (and number that need to be hit for max response)
eqn for E (pharmacologic effect)
E = [D]*Emax / [D]+EC50
E : pharmacologic effect
[D] : drug conc
Emax : maximal effect
EC50 : effective drug conc that elicits 50% of max effect
- on semilog plot, EC50 is the inflection point of sigmoidal curve
potency
potency ratio
potency : measure of how much drug req to elicit a HALF-MAX response
potency ratio : comparison of EC50 values
- more potent? lower EC50 → less drug needed to reach Emax
- potentially lesser chance of hitting toxicity
efficacy
measure of maximal response
- drug with the higher Emax is more efficacious
clinical significance of potency and efficacy
efficacy → informs drug selection
- also side effects, toxicity
potency → informs drug dosage
- antagonism
* how do you plot a dose-response curve?*
two types
block effect of endogenous agonists
- do NOT induce an effect; rather, prevent inducers from inducing their effect
- how do you plot a dose-response curve?*
plot response to an agonist IN PRESENCE OF DIFF DOSES OF ANTAGONIST!!!
types of antagonists
- competitive : compete with ligand for binding to receptor
- noncompetitive (irreversible)
competitive antagonists
- what they do
- how they can be overcome & why
- what type of plot youll see
bind to recepter to interfere with binding/action of agonist
- effects can be overcome by adding more agonist (i.e. outcompeting the antagonist)
why?
bc binding is typically reversible!
- binding AFFINITY is important to consider here
plot: at increasing [antagonist]
Emax stays the same, EC50 increases → reduces potency of the agonist!!!!
therapeutic implications of competitive antagonists
- degree of inhibition produced depends on the [antagonist]
* interindivid variation in pl levels of ant might require dosage adjustments - clinical response depends on [endog agonist] competing for binding to receptors
- episodic variation in agonist levels can interfere with antagonist action!
- patient’s condition also influences effect
noncompetitive (irrev) antagonists
permanent blockers of receptors (ex. via covalent binding)
implication: NO AMOUNT OF INCREASE OF ENDOG AGONIST CAN OVERCOME EFFECT OF NONCOMP ANTAGONISM
- receptor can be replaced by body over time, which is why permanent blocking is ok
ex. Prilosec (PPIs)
another implication: only requires a v low dose!
noncomp antagonist plot
in increasing concentration of noncompetitive/irreversible antagonist,
- Emax drops (less functional receptor available → cant induce as high an effect)
- EC50 stays the same
effectively changes an agonist into a partial agonist!
noncompetitive antagonists: adv and disadv
advantage: maintains blockage even through episodic [agonist] changes
disadvantage: overdose is a big issue, difficult to tackle
other mechs of antagonism
1. chemical antagonism
- a drug may bind to and inactivate another drug
- ex. Protamine antagonizes heparin via electrostatic binding
2. physiologic antagonism
- a drug may antagonize the physio response that another induces [opposing effects]
- ex. glucocorticoids lead to side effect increase in blood sugar → insulin can counter it
3. pharmacokinetic antagonism
- one drug induces metabolism of another drug [can be increased or decreased metab! → lack of efficacy or increased tox]
- ex. phenobarbital triggers metabolic clearance of warfarin
selectivity of drug binding and action
binding influenced by molecular size, shape, and electrical charge
sensitivity to a drug/selectivity for a particular tissue can be conferred by concentration of receptor
- overexpression of a particular receptor makes a tissue hypersensitive
- “spare receptors”
- can be used to target particular tissues
spare receptors and tissue sensitivity
spare receptors allow an agonist to induce Emax WITHOUT binding to all available receptors!
- more receptors expressed than needed for response
- increase likelihood of ligand being bound at low conc of drug
how can you tell if your tissue has spare receptors?
- administer a noncomp antagonist
- if you see that there is an increase in EC50 followed by an decrease in Emax…
SPARE RECEPTORS
why?
as drug hits the spares, Emax isn’t affected because they’re extras - still have enough to hit Emax
once you knock out spares tho, Emax will drop
limitations of graded dose-response curves
how do you overcome them?
- what’s plotted
- what’s ED50
- hard to construct for quantal events (either/or…occurence or non-occurence of an event)
- quantitative DR relationship for one person might not hold for everyone due to individ variability
enter. ..QUANTAL DOSE-RESPONSE CURVE
- plot cumulative % of individuals “responding” however you want to track vs. log(dose)
- diff: ED50 aka efficacious dose = dose at which 50% of pop shows response
therapeutic index
TD50
what if TI is lousy?
allows you to see a drug’s measure of toxicity, TD50 (dose that produces toxic response in 50% of recipients)
therapeutic index = TD50/ED50
[typically desire at least 10]
measure of safety because it gives you margin of safety in dosage
you might still use a drug with a lousy TI if you have no alternatives!
