Pharmacodynamics: Affinity, Potency, Efficacy in Biology

Pharmacodynamics: Affinity, Potency, Efficacy

PK & PD
28/05/2025, 09:05
PK & PD
PD & PK

Pharmacodynamics: Affinity, Potency, Efficacy

• Drug Actions:
  • Agonists: Activate receptors.
  • Antagonists: Block receptors.
• Affinity Details: Binding strength/Drug-receptor attraction.
  • The strength of the attraction (stick/bond) between a drug and its receptor
  • A high affinity means the drug binds strongly, while a low affinity means it binds weakly.
  • Law of mass action, Kd (Ka/Kb).
  • Relative affinity = selectivity (on/off-target effects).
  • Binding strength; can be identical for full and partial agonists.
• Potency Details: Amount needed for effect
  • Amount of drugs required to produce a specific effect.
  • A highly potent drug produces its effect at a low concentration, while a less potent drug requires a higher concentration.
  • Potency is often expressed as the EC50 (the concentration of a drug that produces 50% of the maximum effect).
  • Not affinity/selectivity/efficacy.
  • Concentration-response curves show differences.
  • Influenced by:
    • Drug properties (affinity, efficacy).
    • Tissue properties (receptor number, stimulus-response coupling).

Pharmacokinetics (drug delivery to the target).
O Disease-related changes in receptor density or signaling pathways affect drug responses, especially for partial agonists.

Efficacy Details: Magnitude of Drug's Effect

• Drug's ability to activate a response once bound to its receptor.
• Agonists have intrinsic efficacy (they activate receptors).
• Antagonists, in contrast, have zero intrinsic efficacy (they block receptors). However, antagonists can have clinical efficacy, by blocking the action of endogenous agonists.
• Agonists can be further divided into full and partial agonists.
• Ability to activate a response; differs between full and partial agonists.

Full vs. Partial Agonists

• Partial agonists have therapeutic uses, not just pharmacological interest.

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• They elicit a response, but not to the same extent as full agonists or endogenous ligands.
• Examples:
  • Salbutamol (§2-adrenergic receptor partial agonist): Respiratory applications.
  • Nalbuphine (opioid receptor partial agonist): Opioid addiction treatment.
  • ß-blockers (ß-adrenergic receptor partial agonists): Cardiovascular disease.
• Partial agonists are more sensitive to changes in receptor number compared to full agonists.

Efficacy and Stimulus-Response Coupling

• Binding alone does not fully explain the magnitude of the response.
• Efficacy is influenced by:
  • Receptor number.
  • Stimulus-response coupling (second messenger systems).
• Full agonists can elicit a maximal response without occupying all receptors (receptor reserve).
• Partial agonists require full receptor occupancy for their maximal response (no receptor reserve).
• This difference explains their increased sensitivity to receptor number changes.

Competitive Surmountable and Insurmountable Antagonism

Competitive surmountable (reversible) and competitive insurmountable (slowly reversible) antagonism.

Competitive Antagonism

• Involves agonists and antagonists binding to the same receptor site.
• Antagonists block agonist activity without activating the receptor themselves.
• Competitive antagonism can be surmountable or insurmountable.

Competitive Surmountable (Reversible) Antagonism

• Agonists and antagonists compete for the same active site.
• Only one molecule can bind at a time.
• Agonist concentration-response curves shift rightward in the presence of the antagonist.
• The degree of the shift depends on antagonist concentration.
• Higher agonist concentrations can overcome the antagonist effect (surmountable).
• Parallel rightward shifts occur with increasing antagonist concentrations.
• Maximum agonist response remains unchanged.
• Apparent reduction in agonist potency.
• Similar effects are seen with both full and partial agonists.
• Concentration ratios (degree of rightward shift) are used to determine antagonist affinity and potency.

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• Clinically, this means an antagonist overdose can be counteracted by increasing agonist concentration.

Competitive Insurmountable (Slowly Reversible) Antagonism

• Rightward shift of the agonist curve with a depression of the maximum response.
• Seen with both competitive antagonists and non-competitive inhibitors.
• Differential effects on full and partial agonists:
  • Full agonists: Appear competitive at low antagonist concentrations, insurmountable at higher concentrations.
  • Partial agonists: Immediate depression of the maximum response.
• Mechanism:
  • Competitive antagonists with very high affinity (slowly reversible binding).
  • Reduced receptor availability limits maximal response, especially for partial agonists (no receptor reserve).
  • Reversal requires time and pharmacokinetics for the antagonist to dissociate.
  • Accidental overdose may require supportive care until the antagonist effect wears off.

Key Differences in Antagonism

• Surmountable: Parallel rightward shift, maximum response maintained, reversible by high agonist concentrations.
• Insurmountable: Rightward shift with depressed maximum, slowly reversible, less responsive to increased agonist.

Drug Selectivity

• Selectivity is crucial for understanding drug action and identifying appropriate targets.
• Example: Noradrenaline vs. Angiotensin II:
  • Both cause vasoconstriction, but through different receptors.
  • Prazosin selectively blocks noradrenaline's vasoconstriction (a-adrenergic receptor antagonist) but not angiotensin II's, demonstrating different receptor mechanisms.
• Noradrenaline Receptor Subtypes:
  • al-adrenergic receptors: Vasoconstriction (prazosin sensitive).
  • ß1-adrenergic receptors: Increased heart rate (heart, kidney).
  • ß2-adrenergic receptors: Smooth muscle relaxation (bronchi, skeletal muscle vessels).
  • Adrenaline preferentially activates ß2 receptors.
• Clinical Application:
  • Knowing receptor locations and effects informs drug therapeutic uses.
  • Agonists: Treat deficiencies.
  • Antagonists: Treat overactivity.
• Selectivity & Clinical Decisions:
  • Isoprenaline (non-selective ß-agonist): Effective bronchodilator but caused severe cardiac palpitations.

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• Salbutamol (ß2-selective partial agonist): Effective bronchodilator with fewer cardiac side effects.
• Propranolol (non-selective ß-blocker): Effective for hypertension, but contraindicated in asthma.

Non-Competitive Antagonism

• Mechanisms beyond direct receptor competition:
  • Chemical antagonism: Drug inactivation (e.g., protamine sulfate inactivates heparin).
  • Allosteric modulation: Binding at a site distinct from the agonist site (e.g., benzodiazepines enhance GABA activity).
  • Pathway inhibition: Targeting steps in the signaling cascade (e.g., calcium channel blockers).
  • Functional antagonism: Opposing actions at different receptors (e.g., noradrenaline vs. acetylcholine on heart rate).

Examples of Non-Competitive Antagonism

• Chemical Antagonism:
  • Protamine sulfate neutralises heparin's anticoagulant effect.
• Functional Antagonism:
  • Noradrenaline (B1-agonist): Increases heart rate.
  • Acetylcholine (muscarinic agonist): Decreases heart rate.
• Pathway Inhibition:
  • Noradrenaline (§1-agonist) activates G protein -> adenylyl cyclase -> cAMP -> protein kinase -> calcium channels.
  • Calcium channel blockers inhibit calcium influx, reducing cardiac rate.
• Allosteric Modulation:
  • GABA (inhibitory neurotransmitter) activates chloride channels.
  • Benzodiazepines enhance GABA's effect by binding to an allosteric site on the GABA receptor.

Pharmacodynamics Summary

• Drugs bind to specific molecular targets (affinity).
• Selectivity is crucial for therapeutic effects and minimising adverse effects.
• Agonists:
  • Full or partial.
  • Elicit a response (efficacy).
  • Require a specific dose (potency).
• Antagonists:
  • Competitive or non-competitive.
  • Inhibit agonist actions.
  • Have potency (inhibition of agonist response).

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• Concentration-response curves are essential for understanding drug actions.
• Avoid drawing conclusions from single concentrations.

Pharmacokinetics: Getting the Drug to the Target

• "Pharmacokinetics addresses how the body affects drug concentration at the target site.
• Administration route significantly impacts drug levels (e.g., intravenous vs. oral).
• Understanding drug absorption, distribution, metabolism, and excretion (ADME) is essential for optimizing dosing.
• Pharmacokinetics informs how much drug is in the body, whereas pharmacodynamics informs what the drug does at the molecular level."

Absorption and Distribution

• Absorption:
  • "Drug properties, such as molecular size and lipid solubility, determine membrane permeability.
  • Mechanisms include passive diffusion, aqueous diffusion (ethanol), carrier-mediated transport, and pinocytosis (for large molecules).
• Distribution:
  • "Distribution depends on blood flow, membrane permeability, and plasma protein binding (e.g., albumin).
  • Only free drugs can reach tissues and be eliminated.
  • Barriers like the blood-brain barrier limit drug access to specific areas.
  • Distribution is typically very fast, reaching equilibrium rapidly."

Routes of Administration

• "Oral administration is common, but other routes (sublingual, buccal, intramuscular, subcutaneous) are used for specific drugs or patient needs.
• Bioavailability (the fraction of drug reaching systemic circulation) is crucial, especially for non-intravenous routes.
• Topical administration allows for local effects, minimising (slow/limiting systemic absorption and distribution, which eventually metabolised and excreted from the body.

Pharmacokinetics: Bioavailability, First-Pass Metabolism, and Plasma Protein Binding

Pharmacokinetics: Bioavailability, First-Pass Metabolism, and,Plasma Protein Binding

Absorption After Oral Administration

• Gastrointestinal pH:
  • O The gastrointestinal tract's pH varies, affecting drug absorption.

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• Most drugs are weak acids or bases, maximising absorption in the small intestine's large surface area.
• Neutral pH favors non-ionized, lipid-soluble forms, enhancing absorption.
• Stronger acids/bases may be absorbed in the stomach or colon.
• Mechanisms of Absorption:
  • Passive lipid diffusion is common.
  • Aqueous diffusion,
  • carrier-mediated transport (active/facilitated), and
  • Pinocytosis (for large molecules) also contributes."
• pH and Absorption:
  • Acids are better absorbed in acidic environments, bases in basic environments.
  • Inflammation can alter local pH, affecting both absorption and pharmacodynamics.
  • Local anesthetics are a prime example of drugs affected by localised pH."
• Bioavailability:
  • Not all ingested drugs reach systemic circulation.
  • Bioavailability is the fraction of drug reaching the circulation, determined by comparing plasma concentrations after oral vs. intravenous administration.
  • Factors like enzyme activity, pH level and gastric motility influence absorption rate."
• First-Pass Metabolism:
  • Metabolism before systemic absorption reduces bioavailability.
  • The liver is the primary site, rich in metabolic enzymes.
  • Orally administered drugs pass through the liver via the portal vein.
  • First-pass metabolism can inactivate drugs, necessitating alternative administration routes For e.g.,
    • Nitrates used for angina (transdermal, sublingual - warm, rich-vascular area, blood circulation, which allows absorption of the drug)
    • Peptides (injection - SC. IM - don't have to pass through the GI system, which surpasses any metabolic processes).
  • Prodrugs are inactive until metabolised in the liver/passess through liver.
  • Enzymes in salivary glands and the gastric system can also contribute to first pass metabolism, especially for peptides.

Plasma Protein Binding

• Only free (unbound) drugs reach tissues and are eliminated.
• Plasma protein binding (e.g., to albumin) is usually reversible, allowing drug release.
• Age and disease can affect protein binding.
• Drug-drug interactions can occur due to displacement from binding sites, though this is usually less of a concern than bioavailability and first-pass metabolism.
• Highly protein binding drugs bind a fraction of total available protein

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