Antagonists in Pharmacology

Antagonists

• An antagonist binds to a receptor but does not cause a biological response, it prevents the effects of an agonist.
• Intrinsic activity is the ability to produce a response, also known as efficacy.
• Intrinsic activity ranges from 0 to 1, with 1 representing a full agonist, 0 representing an antagonist, and values between 0 and 1 representing partial agonists.
• Inverse agonists induce the opposite signalling outcome to agonists.

Types of Antagonists

• Antagonists can be classified by how and where they bind, their binding strength, and their binding site.
• Competitive Antagonists bind to the same site as the agonist and compete with each other.
  • Reversible antagonists bind reversibly, and their effects can be overcome by increasing the agonist concentration.
  • Irreversible antagonists bind irreversibly and their effects cannot be overcome by increasing the agonist concentration.
• Non-competitive Antagonists bind to a different site on the receptor than the agonist, this is also called an "allosteric" antagonist.
  • They can also bind to a non-receptor site to inhibit the agonist, thus preventing agonist binding.

Competitive Antagonist Effects on Dose-Response Curve

• Competitive antagonists cause a parallel rightward shift in the log concentration-response curve.
• This shift is proportional to the antagonist concentration.
• The maximal response remains the same.

Non-competitive Antagonist Effects on Dose-Response Curve

• Non-competitive antagonists decrease the maximal response of the agonist, resulting in a downward shift in the log concentration-response curve.
• They also cause a rightward shift in the log concentration-response curve.

Antagonist Examples

• Competitive Antagonists
  • Reversible: beta blockers, antihistamines
  • Irreversible: clopidogrel, phenoxybenzamine
• Non-competitive Antagonists:
  • Allosteric Site: channel blockers, diltiazem, verapamil

Classifications of Antagonists

• Physiologic: Antagonists whose effects oppose each other.
  • Example: Salbutamol in asthma
• Pharmacokinetic: Antagonists that increase the metabolism of another drug.
  • Example: St John's wort, oestrogen
• Chemical: Antagonists that bind to the endogenous ligand.
  • Example: Etanercept, TNF-α and TNF-β

Two-State Model

• The two-state model explains drug interactions with receptors.
• Receptors exist in two states:
  • Resting state (R): inactive
  • Active state (R)*: active, capable of producing a signal.
• Agonists bind to the active state (R*) and stabilize it, thereby increasing the fraction of receptors in the active state.
• Inverse Agonists bind to the resting form (R) and stabilize it, thereby decreasing the fraction of receptors in the active state.
• Antagonists bind with equal affinity to both the resting and active states, thus preventing the agonist from stabilizing the R* state.

Desensitization and Tolerance

• Desensitization: The diminished effect of a drug given repeatedly or continuously.
• Tolerance: Similar to desensitization but develops more slowly.
• Causes of Desensitization and Tolerance
  • Change or loss of receptors (most agonists).
  • Exhaustion of mediators (amphetamine)
  • Increased metabolic degradation (alcohol).
  • Physiological adaption (diuretics -> RAS).

Biased Agonism

• A single receptor can switch on more than one signalling pathway.
• Biased agonists selectively trigger one of these signalling cascades.

Quantal Dose-Response Curves

• Quantal Dose-Response Curves are used for drugs that elicit "all-or-nothing" responses.
• Example: Sleep, death, infection, pregnancy, presence or absence of epileptic seizures.

Median Effective Dose (ED50)

• The ED50 is the dose required to produce a therapeutic effect in 50% of the population.
• It helps identify the drug dose needed for therapeutic benefit.

Antagonists

• Antagonists bind to a receptor but have no effect or prevent an agonist's effects.
• Antagonists can be classified based on how and where they bind, their binding strength, and the binding site.
• Reversible antagonists can be displaced by increasing agonist concentrations while irreversible antagonists cannot.
• Competitive antagonists bind to the same site as agonists, leading to surmountable effects with excess agonists.
• Competitive antagonists shift the dose-response curve to the right, increasing the EC50, but not affecting the maximal response.
• Non-competitive antagonists bind to a different site from agonists, leading to effects seemingly similar to irreversible competitive antagonists.
• Non-competitive antagonists can decrease the maximal response (Emax) and increase the EC50.
• Functional antagonism occurs when a drug blocks the effects of another drug without directly interacting with the receptor site, often by targeting a different pathway.
• Inverse agonists induce an opposite signaling outcome to agonists.
• The two-state model describes receptors existing in two states: active and inactive, with agonists binding to the active state and inverse agonists binding to the inactive state.
• Desensitization or tachyphylaxis occurs when the effect of a drug diminishes with repeated or continuous administration, potentially caused by changes in receptor numbers or function, exhaustion of mediators, increased metabolic degradation, or physiological adaptation.

Population Studies for 'All-or-None' Responses

• 'All-or-none' responses occur when the outcome is binary, such as presence or absence of an effect (e.g., sleep, death, infection).
• Frequency distribution or quantal dose-response curves help study drugs that elicit 'all-or-none' responses, plotting the percentage of individuals showing the response against the drug dose.
• The median effective dose (ED50) is the dose required to produce a therapeutic effect in 50% of the population.
• The ED50 helps determine the drug dose required for therapeutic benefit.

Antagonists

• An antagonist binds to a receptor but does not cause a response.
• Antagonists may prevent the effects of an agonist by binding to the receptor.
• Intrinsic activity (α) refers to the ability of a ligand to produce a response, a full agonist has α=1.
• An antagonist has α=0.

Competitive Antagonists

• Competitive antagonists bind to the same site as the agonist, competing for binding.
• This type of antagonism is surmountable by excess agonist.
• Competitive antagonists cause a parallel rightward shift of the concentration-response curve.
• The EC50 value increases with increasing antagonist concentration.
• The maximal response (Emax) remains the same.

Non-Competitive Antagonists

• Non-competitive antagonists bind to a site different from the agonist, known as an allosteric site.
• They can cause irreversible inhibition of receptor function.
• They cause a reduction in Emax and a non-parallel shift in the concentration-response curve.

Antagonist Classification:

• Antagonists can be classified based on various factors including how they bind, the strength of their binding, and their binding site:
• Reversible: The antagonist can be displaced from the receptor.
• Irreversible: The antagonist cannot be displaced from the receptor.
• Competitive: Binds to the same site as the agonist, and causes a rightward shift in the dose-response curve.
• Non-Competitive: Bind to a separate site from the agonist and impact the curve's shape.
• The specific mechanism of action and interaction is crucial for understanding their effects on drug response.

Inverse Agonists

• An inverse agonist induces an opposite signalling outcome to the agonist.
• They can be classified based on the two-state model, where the antagonist may have equal affinity for both the receptor (R) and the activated receptor (R*).

Desensitization and Tolerance

• Desensitization or tachyphylaxis: The effect of a drug diminishes when it is given repeatedly or continuously.
• Tolerance: Similar to desensitization, but develops more slowly.
• These effects can be caused by various mechanisms like:
• Loss of receptors
• Exhaustion of mediators
• Increased metabolic degradation
• Physiological adaption

Biased Agonists

• A receptor can activate more than one signalling pathway.
• A biased agonist selectively triggers one specific signalling cascade.

Measuring Drug Response in ‘All-or-None’ Effects

• When drug effects are 'all-or-none', quantal dose-response curves are used to measure potency and safety.
• ED50 (median effective dose) is the dose required to produce a therapeutic effect in 50% of the population