(5) Pharmacodynamics: Drug response – Competitive and non-competitive antagonists

Antagonist

• Binds receptor

• Does NOT activate receptor

• Blocks/reduces an agonist's effect and ↓ biological response

Antagonist mechanism

Antagonists have no intrinsic efficacy → they do not activate the receptor themselves.

Agonist - example

Epinephrine
→ adrenergic receptor activation
→ ↑ HR

Antagonist - example

Beta blocker (Propranolol)

→ blocks β-adrenergic receptors
→ prevents/reduces epinephrine's effect
→ ↓ HR

2 types of Antagonists?

• Competitive antagonist

• Non-competitive Antagonists

Competitive antagonist

• Binds same site as agonist

• Same site = orthosteric site

• Competes with agonist for receptor

• ↑ agonist can overcome antagonist

• → ↓ agonist potency

Competitive Antagonists

Dose-response curve

→ RIGHT shift (you need more agonist to get the same effect)
→ ↑ EC50
→ ↓ potency
→ Emax stays SAME

Competitive Antagonists

Why does Emax stay the same?

↑ agonist
→ can outcompete antagonist
→ original maximum response can still be reached.

Competitive Antagonists

Examples

• Atropine → muscarinic antagonist

• Naloxone → Fentanyl/opioid antagonist

• Propranolol → β-adrenergic antagonist

Competitive Antagonists

Naloxone / Narcan Example

• Severe overdose may require multiple naloxone doses because a high amount of agonist may require more antagonist to compete.

• Fentanyl/opioid agonist
  → miosis = constricted pupil

• Naloxone
  → opioid antagonist
  → reverses opioid effect
  → pupil dilation in professor's example

• Opioid overdose
  → respiratory depression

Non-competitive Antagonists

1. Allosteric binding

Antagonist binds a different site from agonist.

2. Irreversible orthosteric binding

Antagonist irreversibly inactivates the receptor. → ↓ Emax

3. Increasing agonist
→ cannot restore full effect

Non-competitive Antagonists

Dose-response curve

→ ↓ Emax
→ ↓ efficacy

EC50:

• May or may not change

• Mixed mechanism may also shift curve right

Non-competitive Antagonists

Example

Ketamine = non-competitive NMDA antagonist

→ blocks ion-channel function
→ ↓ receptor response

↑ agonist → cannot overcome ketamine's effect

Non-competitive Antagonists vs.Competitive Antagonists

Competitive → POTENCY changes

Non-competitive → EFFICACY changes

	Competitive	Non-competitive
Where binds?	Same site	Different site or irreversible
↑ agonist overcome?	Yes	No
Curve	Right shift (curve moves RIGHT)	Lower plateau (curve moves DOWN)
EC50	↑	May/may not change
Potency	↓	—
Emax	Same	↓
Efficacy	Same	↓
Main thing affected	Potency	Efficacy

Clinical Implications

Competitive antagonists

• Can be overcome with ↑ agonist

• Useful for short-term/titratable blockade

• Can be used as reversal agents

• Main example → naloxone

Clinical Implications

Non-competitive antagonists

• ↑ agonist does not restore response

• May last longer

• Useful for sustained inhibition/Harder to reverse

Antagonist vs Inverse Agonist

Drug	What happens to normal receptor activity?
Full agonist	↑↑
Partial agonist	↑
Antagonist	No change → blocks agonist → baseline activity stays the same
Inverse agonist	↓