Pharmacology: Receptors

P = [D] / {[D] +K_D}

Overview of Pharmacology

• Focuses on drug interactions with biological systems, encompassing two main areas:

  • Pharmacokinetics (PK): What our body does to the drug. This involves the ADME process:

    • Absorption: Movement from site of administration to the blood.

    • Distribution: Movement from blood to interstitial/intracellular fluids.

    • Metabolism: Enzymatic biotransformation of the drug (primarily in the liver).

    • Elimination/Excretion: Removal of the drug or its metabolites from the body (primarily via kidneys).

  • Pharmacodynamics (PD): What the drug does to our body, including the biochemical and physiological effects and their mechanisms of action at the molecular level.

General Learning Objective (Pharmacodynamics)

• By the end of this module, students should be able to:

  • Explain how drugs interact with biological systems to produce their effects.

  • Apply fundamental principles of pharmacodynamics to understand:

    • Drug–receptor interactions: Binding and activation processes.

    • Dose–response relationships: How changes in concentration affect biological output.

    • Determinants of drug efficacy and potency: Quantifying how well a drug works and at what concentration.

Specific Learning Objectives

At the end of these lectures, students will be able to:

• Define: The term receptor and identify it as a macromolecular protein target.

• Differentiate: Classify drugs into functional groups:

  • Full Agonists: Possess high efficacy and produce a maximal response (100%100%).

  • Partial Agonists: Bind to sensors but produce only a sub-maximal response, even at full occupancy.

  • Antagonists: Bind to the receptor but produce zero biological effect; they block the action of agonists.

  • Inverse Agonists: Bind to the same receptor as an agonist but induce a pharmacological response opposite to that of the agonist (reducing constitutive activity).

• Describe: The relationship between receptor occupancy (PP) and biological response, differentiating between Affinity (strength of binding) and Efficacy (ability to initiate a response once bound).

• Apply: Quantitative models like the Law of Mass Action to calculate constants like KD and maximum response (Emax).

Definition of a Drug and Toxicity

• A drug is a chemical substance that produces a biological effect.

• Therapeutic Index: The ratio between the dose that causes toxicity and the dose that produces a therapeutic effect (TI=TD50/ED50).

• Therapeutic Range: The window of dosage where the drug is effective without being toxic.

• Caffeine Example:

  • Dose-Response: The biological effect increases with dose as more receptors are occupied.

  • Thresholds: A standard cup (~95 mg) fits the therapeutic/stimulant range, while doses >400 mg can lead to tachycardia, anxiety, or toxicity.

Historical Context of Receptors

• Paul Ehrlich: Introduced the "lock and key" metaphor and the concept of selective toxicity. He believed "corpora non agunt nisi fixata" (substances do not act unless bound).

• J.N. Langley: Observed that nicotine and curare competed for the same "receptive substance" on the motor end-plate of skeletal muscle, which we now know as the Nicotinic Acetylcholine Receptor (nAChR).

Classification of Receptors by Structure and Speed

1. Ligand-gated ion channels (Ionotropic): Direct control of ion flux; acting in milliseconds (e.g., nAChR).

2. G-protein coupled receptors (Metabotropic): Indirect control via second messengers (cAMP, IP3/DAGIP3​/DAG); acting in seconds (e.g., Muscarinic ACh receptors).

3. Enzyme-linked (Kinase-linked) receptors: Direct protein phosphorylation; acting in hours (e.g., Insulin receptor).

4. Intracellular (Nuclear) receptors: Control of gene transcription; acting in hours to days (e.g., Steroid receptors).

Quantitative Receptor Pharmacology: The Law of Mass Action

• According to the law, the rate of a chemical reaction is proportional to the product of the concentrations of the reactants.

• Binding Equation: [D]+[R]⇌[DR]→Effect[D]+[R]⇌[DR]→Effect

  • [D][D] = Free drug concentration

  • [R][R] = Free receptor concentration

  • [DR][DR] = Drug-receptor complex

• Fractional Occupancy (PP): The proportion of receptors occupied by the drug is defined by:

  • P=[D][D]+KD

  • P=[D]+KD​[D]​

• Dissociation Constant (KD​): The concentration of drug required to occupy 50% of the receptor population.

  • Lower KD​ = Higher Affinity.

Properties & Binding Sites

• Saturability: Because there are a finite number of receptors per cell (BmaxBmax​), the response follows a rectangular hyperbola that plateaus when all receptors are occupied.

• Selectivity: Ability of a receptor to distinguish between similar molecules.

  • beta-adrenoreceptors favor Isoprenaline.

  • αα-adrenoreceptors favor Noradrenaline.

• Molecular Size: Most drugs are small (~200 Da) to allow for easy diffusion and precise fit into the receptor's binding pocket.

Experimental Techniques: Radioligand Binding

• Saturation Binding: Used to determine KD and Bmax. Involves increasing concentrations of a radioactive ligand.

• Competition Binding: A fixed amount of radioligand is inhibited by increasing amounts of an unlabelled 'test' drug. This calculates the Inhibition Constant (Ki​) using the Cheng-Prusoff equation:

  • Ki=IC501+([Ligand]/KD)

  • Ki=1+([Ligand]/KD​)IC50​

  • IC50​ is the concentration of competitor that displaces 50% of the radioligand.