Pharmacodynamics I Flashcards
Differentiate between a biological receptor and a binding site.
RECEPTOR - capable of initiating a response when interacting with drug or endogenous substance
BINDING SITE - can interact with substances but does NOT initiate a response (ex: albumin)
What is the relationship between dose and receptor occupation? What is the relationship between dose and response?
- increases in dose => increased FO asymptotically (non-linearly, levels off near a maximum)
- receptor occupancy increases from 1-91% over 3Kds - increases in dose => positive increase in response, but not linearly
- increases in response can also be reached with agonists acting on a small # of receptors
Outline the main phases of drug action.
- pharmaceutical phase - dissolution of active substance; ready for absorption
- PK phase - ADME; biological availability
- PD phase - drug-receptor interaction in target tissue => effect
Define drug. What factors affect biological availability?
drug - anything that has an effect on living processes
- most drugs (but not all) bind to a receptor
bioavailability is determined by:
- dose
- drug
- selectivity
What is the clinical effectiveness of a drug dependent on?
Emax
NOT ED50
because…ED50 is the dose required to reach 50%Emax
Even if a drug is more potent (lower ED50), if it has a lower Emax….that ED50 eq
Construct and compare dose response curves for the following:
- full agonist
- partial agonist
- neutral antagonist
- negative antagonist (inverse)
FULL - intrinsic activity = 1
- causes maximal activation of a receptor
PARTIAL - intrinsic activity
Define Kd.
Kd = [D][R]/[DR] Kd = K2/K1
Kd = the drug concentration at which the drug is bound to 50% of the receptor population (ex: if Kd = 2, # of receptors = 100, then at D = 2, FO = 50%)
Kd ~ 1/affinity (higher Kd = lower DR = lower affinity; lower Kd = higher DR = higher affinity)
What parameters determine total # of receptors occupied by a drug? How does this relate to magnitude of response?
- fraction of receptor population occupied (FO)
- # of receptors in a tissue
Magnitude of response will be directly related to total # of receptors occupied
Define drug selectivity. What is its relationship to dose? Define selectivity window.
Most drugs have comparable affinity for a multitude of receptors
SELECTIVITY - drug’s ability to interact with only one type of receptor vs others
- as dose increases, selectivity decreases
SELECTIVITY WINDOW - concentration of drug that will allow selectivity for a particular receptor
Define simple occupancy theory.
predicted 1:1 relationship between dose and response (increase dose…increase response)
- magnitude of response is directly proportional to # of receptors occupied
- maximum response obtained when 100% receptors occupied
Define modified occupancy theory.
- magnitude of response is a positive (increase) function of receptor occupancy, but not linear
- able to reach maximum occupancy with an agonist binding to a small number of receptors
- different drugs have a varying capacity to reach response
Define modified occupancy theory.
- magnitude of response is a positive (increase) function of receptor occupancy, but not linear
- able to reach maximum occupancy with an agonist binding to a small number of receptors
- different drugs have a varying capacity to reach response
Define efficacy.
aka maximal efficacy; intrinsic activity
- determined from dose-response curve
- limit of the curve on the y-axis (where it plateaus)
- ability of a drug to elicit a response
- affected by # receptors occupied, ability of drug to activate receptor once bound, status of target tissue
Define potency.
drug concentration (dose) needed to reach 50% maximal efficacy (ED50)
- depends on affinity and ability to elicit a response
- relative potency can be determined by comparing ED50s of full agonists and partial agonists
Why is maximal efficiency used to determine clinical effectiveness of a drug?
- if 2 drugs have the same Emax, they have the same level of effect. Therefore, you would choose a drug based on potency, toxicity, individualized pharmacy.
- if drug A has a higher Emax than drug B, you would choose drug A because it will have the most effect regardless of the dose. If drug B is more potent it doesn’t matter because it will never reach the efficacy of drug A.
Describe the different pharmacological and non-pharmacological mechanisms by which antagonism works.
PHARMACOLOGICAL
- Competitive Antagonism (surmountable)
=> increases ED50, no change in Emax
=> you just need more agonist to bind to the same number of receptors
- Non-Competitive Antagonism (insurmountable)
=> no change in ED50, decrease in Emax
=> you need more receptors to get the same effect - Partial Agonist Antagonism
=> full + partial => decreased Emax
NON-PHARMACOLOGICAL
- Chemical Antagonism
=> ex: protamine (+) can inactivate heparin (-)
- Physiological Antagonism
=> use of opposing regulatory pathways to antagonize a drug
=> less specific, difficult to control compared to receptor-specific antagonism
=>
What happens when you increase concentration of a non-competitive antagonist in a system without spare receptors? with spare receptors?
WITH SPARE RECEPTORS
- total # of receptors decreases
- fractional occupancy increases
- potency decreases
WITHOUT SPARE RECEPTORS
- when total # receptors
What happens when you increase concentration of a competitive antagonist in a system without spare receptors? with spare receptors?
WITH SPARE RECEPTORS
- increase in ED50, no change in Emax
WITHOUT SPARE RECEPTORS
- increase ED50, same Emax (just need to add more agonist)
Describe the fundamental differences between graded and quantal dose-response relationships. What specific information can each type provide?
Quantal dose relationships are based on responses elicited in a population
- obtained from cumulative doses required to achieve a specific effect in a population
- used to obtain median effective dose (ED50 = 50% of individuals will elicit a desired effect)
- used to determine therapeutic index and safety (TD50/ED50 or LD50/ED50)
Dose-response provides:
- ED50
- Emax
Define coupling.
def: transduction between receptor occupancy and response
factors that determine coupling efficiency:
- full vs partial agonist (full is more efficient at inducing the conformational change)
- biochemical actions that are required for cellular response
- # receptors bound
==> ion-gated: response is linearly proportional to bound receptors
==> protein-gated: response is not linear to bound receptors
==> spare receptors: nonlinear linkage between occupancy and response
Describe temporal vs numerical spareness.
TEMPORAL
- agonist-receptor binding is short-lived
- but the effect (signaling cascade) it initiates is long-lasting
NUMERICAL
- depends on affinity and number of total compared to needed for Emax
Define therapeutic window
therapeutic window = TD50 (minimum toxic dose) - ED50 (minimum effective dose)
- clinically relevant
