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Toronto Notes 2019 Pharmacodynamics Pharmacodynamics
• studyof“whatthedrugdoestothebody”
Dose-Response Relationship
• gradeddose-responserelationships:relatesdosetointensityofeffect
Efficacy
• themaximumbiologicalresponseproducedbyadrug
• measured by Emax (the maximal response that a drug can elicit in a RCT or under optimal
Clinical Pharmacology CP7
circumstances)
Potency
• measured by EC50 (the concentration of a drug needed to produce 50% of Emax) • a drug that reaches its EC50 at a lower dose is more potent
Efficacy vs. Potency
• Efficacy measures the maximal effect of a drug
• Potency measures the concentration of a drug needed to produce a certain effect
100
60 50
30
Emax of A and C
Emax ofB
A
EC50 ofB log(dose)
B
C
Potency: A>B>C (both B and C are less potent than A)
Efficacy: A=C>B
© Jason Raine
EC50 ofA
EC50 ofC
Figure 5. Log(dose)-response curve illustrating efficacy and potency
A
B
C
log(dose)
A􏰀C increasing dose of competitive antagonist
At each dose of antagonist, increasing the concentration of agonist can overcome the inhibition
Figure 6. The log(dose)-response curve for competitive reversible antagonism
A
B
D log(dose)
A → D increasing dose of irreversible antagonist. With co-administration of antagonist, increasing dose of agonist does not completely overcome antagonism, as seen in B. Eventually with high enough antagonism concentrations, no amount of agonist can elicit a response, as seen in D
Figure 7. The log(dose)-response curve for irreversible antagonism
Effects of Drugs on Receptors
Agonists
• drugsthatmimictheeffectsoftheendogenousligandandevokearesponsewhenboundtothereceptor ■ affinity:theabilityoftheagonisttobindtothereceptor(e.g.theβ2-agonistsalbutamolhasgreater
affinity for β2-receptors than β1-receptors)
■ efficacy:theabilitytorecapitulateendogenousresponseviathereceptorinteraction(e.g.bindingof
salbutamol to β2-receptors results in smooth muscle relaxation)
◆ drug efficacy in an RCT is different than efficacy in the context of pharmacological principles
• full agonists: can elicit a maximal effect at a receptor (e.g. methadone and morphine on the μ opioid receptor system)
• partialagonists:canonlyelicitapartialeffect,nomattertheconcentrationatthereceptor(i.e.reduced efficacy compared to full agonists) (e.g. buprenorphine on the μ opioid receptor system)
Antagonists
• drugsthatreducetheactionofanagonistorofanendogenousligand
• chemicalantagonism:directchemicalinteractionbetweenagonistandantagonistpreventsagonist-
receptor binding (e.g. chelating agents for removal of heavy metals)
• physiological/functionalantagonism:twoagoniststhatactindependentlyatdifferentreceptors
and have opposite physiological effects (e.g. acetylcholine at the muscarinic receptor compared to
epinephrine at the adrenergic receptor)
• pharmacologicalantagonism:antagonistinhibitsagonistthroughactingonreceptororalternative
effector site
• reversibleandirreversiblecompetitiveantagonism
■ drugs that exert no direct effect upon binding to a given receptor (i.e. zero efficacy)
■ reversible competitive antagonists reversibly bind to the same receptor as the agonist, thus
displacing it (e.g. naloxone is an antagonist to morphine or heroin)
■ irreversible antagonists form a covalent bond with the receptor, thus irreversibly blocking substrates
from binding (e.g. phenoxybenzamine forms a covalent bond with adrenergic receptors preventing
adrenaline and NE from binding)
• non-competitiveantagonism
■ antagonist binds to an alternate site near the agonist site, producing allosteric effects that change the ability of the agonist to bind (e.g. organophosphates irreversibly bind acetylcholinesterase)
C
Response
Response
Response (%)