Lec 3 Pharmacodynamic د.رياض

Receptors and Signal Transduction

• Drugs act as signals, and their receptors act as signal detectors.
• Agonist refers to a naturally occurring small molecule or a drug that binds to a site on a receptor protein and activates it.

Signal Amplification

• G protein–linked and enzyme-linked receptors can amplify signal intensity and duration via the signal cascade effect.
• Only a fraction of the total receptors for a specific ligand may need to be occupied to elicit a maximal response in systems with spare receptors.
• Spare receptors provide an immense functional reserve, ensuring adequate response.
• Example: Insulin receptors - about 99% are spare, ensuring adequate glucose entry into the cell.
• Example: β adrenoceptors in the heart - only about 5% to 10% are spare.

Receptors and Signal Transduction

• Drugs act as signals, and their receptors act as signal detectors.
• Agonist refers to a naturally occurring small molecule or a drug that binds to a site on a receptor protein and activates it.

Signal Amplification

• G protein–linked and enzyme-linked receptors can amplify signal intensity and duration via the signal cascade effect.
• Only a fraction of the total receptors for a specific ligand may need to be occupied to elicit a maximal response in systems with spare receptors.
• Spare receptors provide an immense functional reserve, ensuring adequate response.
• Example: Insulin receptors - about 99% are spare, ensuring adequate glucose entry into the cell.
• Example: β adrenoceptors in the heart - only about 5% to 10% are spare.

Signal Amplification

• G protein–linked and enzyme-linked receptors can amplify signal intensity and duration via the signal cascade effect.
• This amplification allows for a maximal response with only a fraction of the total receptors occupied, resulting in spare receptors.
• Spare receptors provide a functional reserve, ensuring adequate responses to ligands.
• For example, 99% of insulin receptors are spare, while only 5-10% of β adrenoceptors in the heart are spare.

Upregulation and Downregulation of Receptors

• Upregulation occurs when receptor activity is lower than usual, resulting in an increase in the number of receptors.
• Example: long-term administration of beta-blockers upregulates β adrenoreceptors, leading to rebound hypertension when stopped.
• Downregulation occurs due to repeated or long-term administration of an agonist, resulting in a decrease in the number of receptors.
• Desensitization of the receptor to the drug may also occur, making it unresponsive to the drug (tachyphylaxis).

Dose–Response Relationships

• Graded dose–response relationships occur when the concentration of a drug increases, resulting in a gradual increase in pharmacologic effect.
• Plotting the magnitude of response against increasing doses of a drug produces a graded dose–response curve shaped like a rectangular hyperbola.
• Potency is a measure of the amount of drug necessary to produce an effect of a given magnitude, often measured as EC50 (the concentration producing 50% of the maximum effect).
• Efficacy is the magnitude of response a drug causes when it interacts with a receptor.

Therapeutic Index

• The therapeutic index (TI) is calculated as TI = TD50 / ED50.
• A narrow therapeutic index indicates a small difference between the dose producing the desired effect and the dose producing toxicity.
• Examples: warfarin (narrow therapeutic index) and penicillin (wide therapeutic index).

Drugs Antagonism

• Pharmacological antagonists:
  • Competitive: antagonists compete with agonists at the same receptor site, and can be overcome by increasing the concentration of the drug agonist.
  • Non-competitive: antagonists bind irreversibly to a site on the enzyme, and cannot be overcome by increasing the concentration of the drug agonist.
• Physical antagonism: based on physical properties of drugs, such as adsorption (e.g., charcoal in alkaloidal poisoning).
• Chemical antagonism: based on drug-drug interaction, such as neutralization (e.g., NaHCO3 + HCl in hyperacidity).
• Physiological/Functional Antagonism: opposite effects of two drugs on different types of receptors, such as histamine and adrenaline.
• Pharmacokinetic antagonism: increasing the metabolism and excretion of a drug, such as enzyme induction.
• Allosteric antagonism: antagonist binds to another site on the receptor, such as verapamil on Ca++ receptors.