Pharmacodynamics

PHARMACODYNAMICS

 

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Introduction

·       Pharmacodynamics refers to the study of how drugs exert their effects on the body, including the biochemical, physiological, and molecular mechanisms involved.

·       It encompasses understanding how drugs interact with specific receptors or targets in the body to produce a therapeutic response or adverse effects.

·       This field also explores the relationship between the dose of a drug and its effects, as well as factors such as drug metabolism, distribution, and elimination.

·       In essence, pharmacodynamics seeks to elucidate the actions of drugs within biological systems and how these actions influence the body's functions and processes.

Drug Toxicity & Drug Allergy

A. Drug Toxicity (Adverse Drug Reactions due to Overdose or Sensitivity)

Definition: Toxicity occurs when a drug produces harmful, unwanted effects, especially when:

• Given in excessive doses,
• Accumulates in the body, or
• Reacts in a genetically susceptible individual.

Types:

1. Acute Toxicity:
• Develops soon after a single large dose.
• Example: Paracetamol overdose causing acute liver failure.
2. Chronic Toxicity:
• Occurs after long-term exposure, even at therapeutic doses.
• Example: Long-term NSAID use causing gastric ulcers or renal damage.

Target Organs:

• Liver (Hepatotoxicity) – e.g., INH, paracetamol
• Kidney (Nephrotoxicity) – e.g., aminoglycosides
• Heart (Cardiotoxicity) – e.g., doxorubicin
• Nervous system (Neurotoxicity) – e.g., vincristine
• Bone marrow (Myelotoxicity) – e.g., chloramphenicol

B. Drug Allergy (Immunological Hypersensitivity Reaction)

Definition: An immune system overreaction to a drug, not dose-dependent and unpredictable.

Mechanism: Requires prior sensitization → repeated exposure leads to allergic reaction.

Types (Gell & Coombs Classification):

1. Type I – Immediate (IgE mediated):
• Reaction occurs within minutes.
• Example: Anaphylaxis from penicillin.
2. Type II – Cytotoxic (IgG/IgM mediated):
• Drug binds to cells → body attacks them.
• Example: Hemolytic anemia from methyldopa.
3. Type III – Immune Complex (IgG/IgM):
• Drug-antibody complexes deposit in tissues.
• Example: Serum sickness.
4. Type IV – Delayed (T-cell mediated):
• Occurs after 24–48 hours.
• Example: Tuberculin reaction, contact dermatitis.

Drug Resistance

Definition: Reduced or no response to a drug that once worked.

Types:

• Natural Resistance: Organism inherently insensitive (e.g., gram-negative bacteria to vancomycin).
• Acquired Resistance: Organism evolves through mutation or gene transfer after drug exposure.

Mechanisms:

1. Enzymatic Degradation: Bacteria produce enzymes that destroy the drug (e.g., penicillinase).
2. Altered Target Site: Mutation in receptor/protein reduces drug binding.
3. Efflux Pumps: Actively remove drug from cell.
4. Decreased Permeability: Drug cannot enter the target cell.
5. Bypass Mechanism: Alternate metabolic pathway is used.

Clinical Issues: Leads to treatment failure, prolonged illness, increased cost, and complications (e.g., MRSA, MDR-TB).

Mechanism of Drug Action & Factors Affecting Drug Action

A. Mechanism of Drug Action

1. Through Receptors:
• Drugs bind to specific cellular receptors → alter function.
• Example: β2-agonist salbutamol binds to β2-receptors → bronchodilation.
2. Enzyme Inhibition:
• Drug inhibits a key enzyme.
• Example: Aspirin inhibits COX enzyme → reduces prostaglandins.
3. Ion Channel Blockade:
• Blocks sodium/potassium/calcium channels to alter membrane potential.
• Example: Lidocaine blocks Na⁺ channels → anesthesia.
4. Transport Protein Modulation:
• Affects neurotransmitter uptake/release.
• Example: SSRIs block serotonin reuptake → increased serotonin in synapse.
5. Non-Specific Mechanism:
• No specific receptor or target.
• Example: Antacids neutralize gastric acid directly.

B. Factors Affecting Drug Action

1. Age: Neonates have immature liver/kidney; elderly have reduced metabolism.
2. Body Weight/Composition: Obese patients may need higher doses for fat-soluble drugs.
3. Genetic Factors: Variations in enzymes (e.g., slow acetylators react differently to INH).
4. Disease Conditions: Liver/kidney diseases delay metabolism & excretion.
5. Tolerance: Repeated use reduces response (e.g., morphine).
6. Drug Interactions: One drug may enhance or block another.
7. Route of Administration: IV acts faster than oral.
8. Time of Administration: Some drugs more effective if taken with/without food.

Drug Response Relationship

Definition: Relationship between dose of a drug and the magnitude of response.

Types:

1. Graded Dose-Response Curve:
• Individual response increases gradually with dose.
• Example: Gradual rise in BP with adrenaline.
2. Quantal Dose-Response Curve:
• Measures number of individuals showing response at each dose.
• Useful for defining ED₅₀, LD₅₀, TD₅₀.

Key Terms:

• ED₅₀ (Effective Dose 50%): Dose at which 50% of people show a therapeutic effect.
• LD₅₀ (Lethal Dose 50%): Dose that kills 50% of the test population.
• TD₅₀ (Toxic Dose 50%): Dose causing toxic effect in 50%.

Therapeutic Index (TI):

• Indicates drug safety.
• Formula:

TI = LD₅₀/ED₅₀

• Higher TI = safer drug (e.g., penicillin); Low TI drugs (e.g., digoxin) require monitoring.

Drug Potency & Efficacy

A. Potency

• Definition: Amount of drug needed to produce a specific effect.
• A more potent drug acts at lower dose.
• Example: Fentanyl is more potent than morphine.
• Potency is relative – depends on comparison.

B. Efficacy

• Definition: Maximum effect a drug can produce, regardless of dose.
• A drug with higher efficacy produces greater therapeutic effect.
• Example: Morphine > paracetamol for pain.

Key Point:

• High potency ≠ high efficacy. A highly potent drug may not be as effective in some conditions.

Drug Antagonism

Definition: One drug reduces or blocks the action of another.

Types:

1. Chemical Antagonism:
• Drugs neutralize each other chemically.
• Example: Chelating agents bind heavy metals.
2. Physiological Antagonism:
• Two drugs act on different receptors with opposing effects.
• Example: Insulin lowers blood sugar; glucagon raises it.
3. Pharmacological Antagonism:
• Two drugs compete for same receptor.
• Competitive (Reversible):
• Can be overcome by increasing dose of agonist.
• Example: Atropine vs. acetylcholine on muscarinic receptors.
• Non-competitive (Irreversible or Allosteric):
• Cannot be overcome by more agonist.
• Example: Phenoxybenzamine binds irreversibly to α-receptors.

 

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