(4B) - Pharmacodynamics: Drug response – Partial and full agonists

Inverse agonist

• Binds same receptor site as agonist

• ↓ receptor's basal activity

• Produces opposite effect of agonist

Constitutive activity

receptor activity without ligand

Give me the drugs and their effect on normal receptor activity…

Drug	Effect vs baseline

Full agonist

↑ activity

Partial agonist

Partially ↑ activity

Antagonist

No change

Inverse agonist

↓ activity

Inverse agonist mechanism:

Constitutively active receptor
→ inverse agonist binds
→ stabilizes receptor in inactive state
→ ↓ basal receptor activity

Inverse agonists only work this way when…

the receptor already has constitutive/baseline activity.

Inverse agonist

examples (DOUBLE CHECK WITH AI)

1. GPCR signaling:

   1. active signaling → GTP

   2. inverse agonist → favors inactive state → GDP

2. antihistamines

   1. Histamine receptor already has some basal activity

   2. Histamine → ↑ activity

   3. Antihistamine inverse agonist → ↓ basal activity

3. hyperpolarization → biological activity moves downward.

How popular are inverse agonist?

least common

Dose-response curve

• Shows dose/concentration → biological response

• X-axis → dose/concentration

• Y-axis → response

• Log dose → sigmoid/S-shaped curve

Dose-Response Curves

main points?

1. Emax = maximum biological effect. Located at the plateau/ceiling

2. EC50 = concentration producing 50% of Emax

3. Efficacy = maximum effect (how high the curve goes) → measured by Emax

4. Potency = amount of drug needed for an effect → measured using EC50

5. Therapeutic Index (TI)

Efficacy vs. Potency

	Efficacy	Potency

Measure

Emax

EC50

Graph

Height/plateau

Left vs right

Higher

↑ Emax

↓ EC50

More potent

—

Curve farther left

Potency

LEFT shift →
RIGHT shift →

↓ EC50 →
↑ EC50 →

LEFT shift → ↑ potency
RIGHT shift → ↓ potency

↓ EC50 → ↑ potency
↑ EC50 → ↓ potency

TI =

TI = TD50 / ED50

• TD50 → toxic dose

• ED50 → effective dose

Wide TI

→ therapeutic and toxic doses farther apart
→ wider safety margin

Narrow TI

→ therapeutic and toxic doses close
→ greater toxicity risk
→ careful monitoring

Narrow TI examples:

• Warfarin

• Digoxin

• Lithium

  • monitor blood levels to prevent toxicity.

• Amiodarone

Why use narrow-TI drugs?

They may still have:

• clinical benefit

• low cost

• convenient dosing

→ no drug is “100% perfect.”

• Super agonist →

• Full agonist →

• Partial agonist →

• Antagonist →

• Inverse agonist →

• Super agonist → response above standard full-agonist reference

• Full agonist → maximal response

• Partial agonist → lower/submaximal response

• Antagonist → baseline activity stays the same

• Inverse agonist → ↓ activity below baseline

Inverse agonists may also be:

• Partial inverse agonists

• Full inverse agonists