Dose-Response Curves

Agonists

bind to receptor at endogenous ligand site and activates it

full agonist

gives 100% efficacy at full receptor occupy

partial agonist

gives partial efficacy at full-receptor occupancy

allosteric agonist (positive allosteric modulator)

binds to receptor at a different site than the endogenous ligand site, but enhances the binding affinity and efficacy to the endogenous ligand

antagonist

binds to receptor and reduces agonist effect, intrinsic activity zero

inverse agonist

binds receptor and reverses (reduces) constitutive activity

Allosteric Potentiator (agonist)

Drug binds to the receptors allosterically and enhances (potentiates) the effect of the endogenous agonist, effecting both potency and efficacy

shifts left

effect of allosteric potentiators on dose response curve

increases

effect of allosteric potentiators on max response

competitive antagonist

drug competes with agonist for the same receptor binding site; can be overridden with high concentration of agonist

shifts right

effect of competitive antagonist on dose response curve

does not change

effect of competitive antagonist on maximum response

non-competitive antagonist

drug binds to receptor irreversibly, pseudo irreversibly, or allosterically

shift right

effect of non-competitive antagonist on dose response curve

decrease

effect of non-competitive antagonist on max response

partial agonist

result in a ceiling-limited pharmacological effect that is lower than the maximum tissue response; get a patient off of the full agonist

ED50

median effective dose

LD50

median lethal dose

safer

the higher the TI, the _____________ the drug

margin of safety

used to compare two drugs that have same LD50; takes into consideration at which concentration the drug first becomes toxic

LD1/ED99

wider

the __________ the therapeutic window, the safer the drug

narrower

the _________ the therapeutic window, the less safe the drug

therapeutic window

The range of steady state drug plasma concentration that provides therapeutic efficacy with minimum adverse effects

aminoglycosides, warfarin, phenytoin

drugs with a narrow therapeutic window

1. Start low and go slow (titrate dose slowly)

2. Tight drug serum concentration monitoring

3. Drug-drug interactions

Precautions with drugs with narrow therapeutic window

hyporeactivity

intensity of drug effect in individual patient is diminished compared to that seen in most individuals

hyperreactivity

intensity of drug effect in individual patient is increased compared to that seen in most individuals

hypersensitivity

usually refers to allergic or other immunologic responses to drugs

Tolerance

decrease in responsiveness as result of continued drug administration (NOT addiction)

Tachyphylaxis

responsiveness to drug diminishes rapidly after administration

paradoxical response

effect opposite to the expected one (ex: antihistamines in children)

sensitive

Polymorphisms in CYP2C9 lead to warfarin __________________ phenotype

resistant

Polymorphisms in VKORC1 leads to warfarin ______________ phenotype