Pharmacodynamics & Mechanisms of Drug Action

• Pharmacodynamics refers to the mechanisms of drug action.
• Drugs can act through receptor or non-receptor mechanisms.

Receptor-Mediated Mechanism

• Receptors are specific cellular structures that interact with a drug to mediate its pharmacological effect.
• Agonists bind to receptors and produce an effect, showcasing affinity and efficacy.
• Antagonists block the effect of agonists.

Types of Agonists

• Full agonists produce maximal efficacy.
• Partial agonists produce less than maximal efficacy and can block the effect of full agonists.
• Inverse agonists bind to the receptor to decrease constitutive activity (-ve efficacy).

Types of Antagonists

• Pharmacological antagonists bind without activating the receptor, preventing activation by an agonist.

Competitive Antagonists

• Bind reversibly to the receptor.
• Can be displaced by increasing the concentration of the agonist.
• Duration of antagonism depends on the relative plasma concentrations of the agonist and antagonist.

Irreversible Antagonists

• Bind irreversibly to the receptor.
• Cannot be displaced by increasing the concentration of the agonist.
• Duration of antagonism depends on the rate of synthesis of new receptors.
• Physiologic antagonists counter the effects of another drug by binding to a different receptor, causing opposing effects.
• Chemical antagonists counter the effects of another drug by binding to the agonist drug itself.

Signal Transduction System

• Ligand-gated ion channel receptors: Drug binding to these receptors leads to ion flux.
• G-Protein Coupled receptors: An agonist binds to the receptor, activating a G protein responsible for producing a response.
• Catalytic receptors (enzyme linked receptor): Insulin binding to the extracellular component stimulates the intracellular component and tyrosine kinase enzymes, which are like receptors linked to tyrosine kinase (such as the insulin receptor).
• Intracellular receptors: Corticosteroids cross the cell membrane and bind to cytoplasmic receptors.

Non-Receptor Mediated Mechanisms

• Drugs can act on enzymes, such as choline esterase inhibitors like Neostigmine.
• Drugs can act on plasma membranes; digoxin inhibits Na+-K+ ATPase.
• Drugs can act through physical means, such as lubricants like liquid paraffin in constipation.
• Drugs can act through chemical mechanisms, such as antacids neutralizing HCl in peptic ulcers.

Dose-Response Relationship

• Efficacy reflects the ability of the drug-receptor complex to produce a response.
• Maximal efficacy: The maximal response produced by the drug.
• Potency is the amount of drug needed relative to its effect; a lower amount needed for the same effect indicates higher potency (example: 1mg of drug A produces the same response as 5mg of drug B, A is more potent).
• ED50 is the dose that cures 50% of cases.
• LD50 is the dose that kills 50% of animals; a lower LD50 indicates higher toxicity.

Therapeutic Index (TI)

• TI is the ratio between LD50 and ED50 (TI = LD50/ED50).
• TI represents the estimate of drug safety margins.
• A larger TI indicates the drug is less toxic.
• Drugs with a small therapeutic index include aminoglycosides, theophylline, hypoglycemic agents, and anticoagulants.

Therapeutic Window (TW)

• TW represents the safe dosage range between the minimum effective therapeutic dose and the minimum toxic dose.
• TW determines the acceptable plasma level range when designing a dosing regimen.
• TW = (Minimum effective therapeutic dose - Minimum toxic dose).

Adverse Drug Reactions

• Type A (Augmented): Dose-related, common, related to the drug's pharmacology, predictable, and have low mortality.
• Type B (Bizarre): Non-dose-related, uncommon, not related to pharmacology, unpredictable, and have high mortality.
• Type C (Chronic): Dose-related and time-related, uncommon, related to cumulative dose.
• Type D (Delayed): Time-related, uncommon, usually dose-related, and become apparent some time after use.
• Type E (End of use): Related to withdrawal, uncommon, and occur soon after stopping the drug.

Examples of Adverse effects

• Antihistamines can cause sleepiness (Type A).
• Minoxidil can cause increased hair growth (Type A).
• Immunological reactions such as penicillin hypersensitivity (Type B) and Idiosyncrasy (Type B).
• Corticosteroids can cause adverse drug reactions in long-term treatment and Tolerance develops, requiring higher doses for the same effect (Type C).
• Teratogenesis and Carcinogenesis, e.g., bladder cancer from cyclophosphamide therapy, occurring 1-10 years post-treatment (Type D).
• Opiate withdrawal syndrome (Type E).

Drug Allergy

• Type I: Immediate, involves IgE antibodies, symptoms appear within seconds to minutes. Example: Anaphylactic reactions.
• Type II: Cytotoxic, involves IgG and IgM antibodies, time to expression of symptoms occur after minutes to hours. Example: Autoimmune hemolytic anemia.
• Type III: Involves immune complex-mediated reactions, IgG and IgM antibodies, symptoms set in after several hours. Example: Serum sickness (fever, arthritis, rash).
• Type IV: Delayed hypersensitivity, involves T cells, symptoms set in hours to days later. Example: Allergic contact dermatitis.

Explore pharmacodynamics, focusing on receptor and non-receptor mechanisms of drug action. Learn about agonists (full, partial, inverse) and antagonists (pharmacological, competitive). Understand how drugs interact with receptors to produce pharmacological effects and how antagonists can block these effects.