3. PHARMACOKINETICS

Introduction

Pharmacokinetics deals with what the body does to a drug after it is administered. It includes the processes of absorption, distribution, metabolism and excretion (ADME). These steps determine the onset of action, intensity and duration of drug effects. Understanding pharmacokinetics helps in choosing the correct dose, route and frequency of drug administration.

Mechanisms of Drug Movement Across Membranes

Most drugs must cross biological membranes to reach the bloodstream or site of action. The major mechanisms are:

1. Passive Diffusion

  • Most common method.
  • Drug moves from higher to lower concentration.
  • No energy required.
  • Lipid-soluble and unionised drugs cross easily.

2. Filtration

  • Movement through membrane pores.
  • Depends on molecular size and weight.
  • Small molecules cross easily.

3. Specialized Transport

a) Active Transport

  • Moves drugs from lower to higher concentration.
  • Energy-dependent process.
  • Examples: choline uptake, levodopa absorption.

b) Facilitated Diffusion

  • Carrier-mediated but does not require energy.
  • Moves from high to low concentration.
  • Example: glucose transport via GLUT.

Absorption

Absorption is the movement of a drug from the site of administration to the bloodstream.

Factors Affecting Absorption

  • Physical state: Liquids absorb faster than solids.
  • Lipid solubility: Unionised, lipid-soluble drugs absorb better.
  • Particle size: Smaller particles absorb faster.
  • Disintegration and dissolution time: Faster breakdown improves absorption.
  • Formulation factors: Additives may increase or reduce absorption.
  • Route: IV bypasses absorption; oral has variable absorption.
  • pH and ionisation: Acidic drugs absorb in stomach; basic in intestine.
  • Food: Food may increase or decrease absorption.
  • Drug interactions: Example: antacids reduce tetracycline absorption.
  • Disease states: GI disorders alter absorption.

Bioavailability

Bioavailability is the fraction of an administered dose that reaches systemic circulation in active form.

Factors Affecting Bioavailability

  • All factors affecting absorption.
  • First-pass metabolism: Drug is metabolised in gut or liver before reaching circulation.
  • Hepatic disease: Increases bioavailability for drugs with high first-pass metabolism.
  • Enterohepatic cycling: Some drugs re-enter circulation from bile, increasing bioavailability.

Distribution

Distribution is the reversible transfer of a drug from blood to tissues.

Volume of Distribution (Vd)

It is a hypothetical volume into which a drug appears to distribute. High Vd indicates high tissue binding; low Vd indicates drug stays in plasma.

Factors Influencing Distribution

  • Molecular size: Large molecules remain in plasma.
  • Lipid solubility: Lipid-soluble drugs enter tissues easily.
  • Plasma protein binding: Highly bound drugs stay in blood and act longer.
  • Blood flow: High-perfusion organs receive drug first.
  • Body composition: Fat stores lipophilic drugs.

Special Considerations

Blood-Brain Barrier

  • Allows only lipid-soluble, unionised drugs.
  • Inflammation increases permeability.

Placental Barrier

  • Most drugs cross placenta and can affect fetus.
  • Large and ionised molecules cannot cross easily.

Drug Reservoirs

  • Some drugs accumulate in tissues like bone, fat, liver or heart.
  • Example: tetracycline in bone, digoxin in heart.

Redistribution

Lipid-soluble drugs like thiopentone act on brain initially but redistribute to muscle and fat, ending their effect quickly.

Metabolism (Biotransformation)

Metabolism is the chemical alteration of a drug in the body. The liver is the main organ for metabolism.

Objectives of Metabolism

  • Convert lipid-soluble drugs into water-soluble forms.
  • Facilitate excretion.
  • Inactivate drugs or sometimes activate prodrugs.

Phase I Reactions

Non-synthetic reactions that introduce or unmask functional groups.

  • Oxidation: Most common; CYP450 enzymes involved.
  • Reduction
  • Hydrolysis
  • Cyclization and decyclization

Phase II Reactions

Conjugation reactions that attach endogenous groups to drugs, making them water-soluble.

  • Glucuronidation
  • Acetylation
  • Sulphation
  • Methylation
  • Glutathione conjugation
  • Glycine conjugation

Factors Affecting Metabolism

  • Age: Neonates and elderly metabolize slower.
  • Genetics: Slow acetylators, atypical enzymes.
  • Disease: Liver disease reduces metabolism.
  • Diet: Poor nutrition reduces enzyme activity.
  • Drug interactions: Enzyme induction or inhibition.

Enzyme Induction

  • Increased enzyme synthesis.
  • Reduces drug effect by faster metabolism.
  • Examples: rifampicin, phenytoin, barbiturates.

Enzyme Inhibition

  • Decreases drug metabolism.
  • Increases risk of toxicity.
  • Examples: erythromycin, ciprofloxacin.

Excretion

Excretion is removal of drugs from the body. Main route is kidneys.

Renal Excretion

  • Glomerular filtration: Free drugs filtered.
  • Tubular reabsorption: Depends on pH and ionisation.
  • Active secretion: Carrier-mediated transport.

Other Routes

  • Lungs: volatile anaesthetics, alcohol.
  • Bile: enterohepatic recycling increases duration.
  • Faeces: unabsorbed drugs.
  • Saliva: lithium, metronidazole.
  • Milk: basic drugs appear in breastmilk.

Detailed Notes:

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