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Pharmacokinetics Notes

B.Pharm IV Semester - Pharmacology 1

1. Introduction to Pharmacokinetics

Definition: Pharmacokinetics is the study of what the body does to a drug - the movement of drugs within the body over time.

Key Processes: ADME

  • Absorption
  • Distribution
  • Metabolism
  • Excretion

Importance:

  • Determines drug dosage and dosing intervals
  • Predicts drug concentration at site of action
  • Helps in rational drug therapy
  • Essential for drug development

2. Drug Absorption

Definition

The process by which drug molecules move from the site of administration into the systemic circulation.

Mechanisms of Absorption

2.1 Passive Diffusion

  • Simple Diffusion: Movement across lipid membranes down concentration gradient
  • Facilitated Diffusion: Carrier-mediated transport without energy
  • Filtration: Movement through aqueous pores based on molecular size

2.2 Active Transport

  • Requires energy (ATP)
  • Can work against concentration gradient
  • Carrier-mediated and saturable
  • Examples: Levodopa, methyldopa

2.3 Pinocytosis

  • Engulfment of drug particles by cell membrane
  • Important for large molecules like proteins

Factors Affecting Absorption

2.4 Physicochemical Factors

  • Lipophilicity: Lipid-soluble drugs absorbed better
  • Molecular size: Smaller molecules absorbed faster
  • pH and pKa: Affects ionization and absorption
  • Dissolution rate: Rate-limiting step for solid dosage forms

2.5 Physiological Factors

  • Blood flow: Higher flow increases absorption
  • Surface area: Larger area enhances absorption
  • Contact time: Longer contact improves absorption
  • GI motility: Affects drug residence time

2.6 Formulation Factors

  • Particle size: Smaller particles dissolve faster
  • Salt form: Affects dissolution rate
  • Excipients: Can enhance or retard absorption
  • Dosage form: Tablets vs capsules vs solutions

Routes of Administration

2.7 Enteral Routes

Oral (PO):

  • Advantages: Convenient, safe, economical
  • Disadvantages: First-pass metabolism, variable absorption
  • Factors: pH, food, GI diseases

Sublingual:

  • Rapid absorption, avoids first-pass metabolism
  • Limited to small doses

Rectal:

  • Useful when oral route not feasible
  • Partial avoidance of first-pass metabolism

2.8 Parenteral Routes

Intravenous (IV):

  • 100% bioavailability
  • Immediate onset
  • Risk of adverse reactions

Intramuscular (IM):

  • Rapid absorption from aqueous solutions
  • Depot preparations for sustained release

Subcutaneous (SC):

  • Slower than IM
  • Suitable for self-administration

2.9 Other Routes

  • Inhalation: Rapid absorption, local and systemic effects
  • Transdermal: Sustained delivery, avoids GI tract
  • Topical: Local effects, minimal systemic absorption

3. Drug Distribution

Definition

The process by which drugs are transported from the systemic circulation to tissues and organs.

Factors Affecting Distribution

3.1 Physiological Factors

  • Cardiac output: Determines rate of drug delivery
  • Regional blood flow: Highly perfused organs receive more drug
  • Capillary permeability: Varies between tissues
  • Tissue binding: Affects drug accumulation

3.2 Physicochemical Factors

  • Lipophilicity: Determines tissue penetration
  • Molecular size: Large molecules have limited distribution
  • Protein binding: Bound drug is pharmacologically inactive
  • Tissue affinity: Some drugs accumulate in specific tissues

Plasma Protein Binding

3.3 Major Binding Proteins

  • Albumin: Binds acidic drugs (warfarin, phenytoin)
  • α1-acid glycoprotein: Binds basic drugs (propranolol, lidocaine)
  • Globulins: Bind hormones and vitamins

3.4 Clinical Significance

  • Only free (unbound) drug is pharmacologically active
  • Drug interactions due to displacement
  • Disease states can alter protein binding
  • Affects drug elimination

Volume of Distribution (Vd)

3.5 Definition and Calculation

  • Theoretical volume in which drug would be distributed if present at same concentration as in plasma
  • Formula: Vd = Dose / C₀ (initial plasma concentration)

3.6 Clinical Significance

  • Low Vd (0.1-0.2 L/kg): Drug confined to plasma (warfarin)
  • Moderate Vd (0.6-0.7 L/kg): Distribution to extracellular fluid
  • High Vd (>1 L/kg): Extensive tissue distribution (digoxin)

Special Distribution Sites

3.7 Blood-Brain Barrier

  • Selective barrier protecting CNS
  • Limits entry of hydrophilic drugs
  • P-glycoprotein efflux pump
  • Clinical implications for CNS drugs

3.8 Placental Barrier

  • Most drugs cross placenta
  • Lipophilic drugs cross easily
  • Teratogenic potential
  • Important in pregnancy

4. Drug Metabolism (Biotransformation)

Definition

The biochemical modification of drugs by living organisms, primarily in the liver.

Phases of Metabolism

4.1 Phase I Reactions (Functionalization)

Oxidation:

  • Most common reaction
  • Cytochrome P450 enzymes
  • Examples: Hydroxylation, dealkylation, deamination

Reduction:

  • Less common than oxidation
  • Examples: Chloramphenicol, warfarin

Hydrolysis:

  • Ester and amide hydrolysis
  • Examples: Aspirin, procaine

4.2 Phase II Reactions (Conjugation)

Glucuronidation:

  • Most important conjugation reaction
  • UDP-glucuronosyltransferase enzymes
  • Increases water solubility

Sulfation:

  • Important for phenols and alcohols
  • Limited by sulfate availability

Acetylation:

  • Genetic polymorphism (fast/slow acetylators)
  • Examples: Isoniazid, hydralazine

Methylation:

  • Examples: Catecholamines, histamine

Cytochrome P450 System

4.3 Major CYP Enzymes

  • CYP3A4: Most abundant, metabolizes 50% of drugs
  • CYP2D6: Genetic polymorphism, 25% of drugs
  • CYP2C9: Warfarin, phenytoin
  • CYP2C19: Omeprazole, genetic polymorphism
  • CYP1A2: Theophylline, caffeine

4.4 Drug Interactions

Enzyme Induction:

  • Increased enzyme synthesis
  • Examples: Phenobarbital, rifampin
  • Results in decreased drug effect

Enzyme Inhibition:

  • Competitive or non-competitive
  • Examples: Cimetidine, grapefruit juice
  • Results in increased drug effect

Factors Affecting Metabolism

4.5 Genetic Factors

  • Genetic polymorphisms
  • Ethnic differences
  • Examples: CYP2D6, CYP2C19 polymorphisms

4.6 Age Factors

  • Neonates/Infants: Immature enzyme systems
  • Elderly: Decreased metabolic capacity
  • Dosage adjustments required

4.7 Disease States

  • Liver disease: Decreased metabolic capacity
  • Heart failure: Reduced hepatic blood flow
  • Kidney disease: Affects some metabolic pathways

4.8 Environmental Factors

  • Smoking: Induces CYP1A2
  • Alcohol: Chronic use induces CYP2E1
  • Diet: Affects enzyme activity

First-Pass Metabolism

4.9 Definition and Mechanism

  • Metabolism before reaching systemic circulation
  • Primarily hepatic, also intestinal and pulmonary
  • Reduces oral bioavailability

4.10 Clinical Significance

  • High first-pass drugs: Morphine, propranolol, verapamil
  • Alternative routes to avoid: Sublingual, transdermal, rectal

5. Drug Excretion

Definition

The process of drug elimination from the body, primarily through kidneys.

Renal Excretion

5.1 Mechanisms

Glomerular Filtration:

  • Passive process dependent on molecular size
  • Only free drug is filtered
  • GFR = 120 mL/min in healthy adults

Tubular Secretion:

  • Active transport process
  • Organic anion and cation transporters
  • Examples: PAH, creatinine
  • Can be saturated

Tubular Reabsorption:

  • Passive and active processes
  • pH-dependent for weak acids and bases
  • Affects drug elimination

5.2 Factors Affecting Renal Excretion

  • Kidney function: GFR, renal blood flow
  • Urine pH: Affects ionization and reabsorption
  • Urine flow rate: High flow reduces reabsorption
  • Protein binding: Only free drug filtered
  • Drug interactions: Competition for transporters

5.3 Renal Clearance

  • Definition: Volume of plasma cleared per unit time
  • Formula: CLᵣ = (Urine concentration × Urine flow) / Plasma concentration
  • Normal values: Creatinine clearance = 120 mL/min

Non-Renal Excretion

5.4 Biliary Excretion

  • Important for large molecules (MW > 300)
  • Active transport process
  • Enterohepatic circulation
  • Examples: Rifampin, contrast agents

5.5 Pulmonary Excretion

  • Volatile anesthetics
  • Alcohols
  • Rate depends on ventilation and blood flow

5.6 Other Routes

  • Sweat: Minimal contribution
  • Saliva: Passive diffusion, reflects plasma levels
  • Breast milk: Important in lactating mothers

6. Pharmacokinetic Parameters

Clearance (CL)

6.1 Definition and Types

  • Total body clearance: Sum of all elimination processes
  • Renal clearance: Kidney elimination
  • Hepatic clearance: Liver elimination
  • Formula: CL = Rate of elimination / Plasma concentration

6.2 Clinical Significance

  • Determines maintenance dose
  • Reflects organ function
  • Used in dosage calculations

Half-Life (t½)

6.3 Definition and Calculation

  • Time required for plasma concentration to decrease by 50%
  • Formula: t½ = 0.693 × Vd / CL
  • Independent of dose and concentration

6.4 Clinical Applications

  • Determines dosing interval
  • Time to steady state (5 half-lives)
  • Duration of drug action
  • Washout period

Bioavailability and Bioequivalence

6.5 Bioavailability (F)

  • Absolute bioavailability: Fraction of dose reaching systemic circulation
  • Formula: F = (AUCₒᵣₐₗ / AUCᵢᵥ) × (Doseᵢᵥ / Doseₒᵣₐₗ)
  • Factors affecting: First-pass metabolism, absorption

6.6 Bioequivalence

  • Comparison between different formulations
  • Same rate and extent of absorption
  • AUC and Cmax parameters
  • Regulatory requirement for generics

7. Pharmacokinetic Models

One-Compartment Model

7.1 Assumptions

  • Body behaves as single, homogeneous compartment
  • Instantaneous distribution
  • First-order elimination kinetics

7.2 Equations

  • IV bolus: C = C₀ × e⁻ᵏᵗ
  • First-order absorption: C = (F×D×ka)/(Vd(ka-k)) × (e⁻ᵏᵗ - e⁻ᵏᵃᵗ)

Two-Compartment Model

7.3 Characteristics

  • Central and peripheral compartments
  • Distribution and elimination phases
  • More complex equations
  • Better describes many drugs

Non-Linear Pharmacokinetics

7.4 Saturation Kinetics

  • Zero-order kinetics: Constant amount eliminated per unit time
  • Examples: Ethanol, phenytoin, salicylates
  • Characteristics: Non-linear increase in AUC with dose

7.5 Michaelis-Menten Kinetics

  • Equation: v = (Vmax × C) / (Km + C)
  • Km: Concentration at half-maximal velocity
  • Vmax: Maximum elimination rate

8. Clinical Applications

Therapeutic Drug Monitoring (TDM)

8.1 Indications

  • Narrow therapeutic window
  • Poor correlation between dose and effect
  • Suspected toxicity or therapeutic failure
  • Drug interactions

8.2 Examples of Drugs Monitored

  • Digoxin: Therapeutic range 1-2 ng/mL
  • Theophylline: 10-20 μg/mL
  • Phenytoin: 10-20 μg/mL
  • Lithium: 0.6-1.2 mEq/L

Dosage Regimen Design

8.3 Loading Dose

  • Purpose: Rapidly achieve therapeutic levels
  • Formula: Loading dose = Vd × Target concentration / F
  • Indications: Long half-life drugs, urgent therapy

8.4 Maintenance Dose

  • Purpose: Maintain steady-state levels
  • Formula: Maintenance dose = CL × Target concentration × τ / F
  • τ: Dosing interval

Special Populations

8.5 Pediatric Pharmacokinetics

  • Absorption: Higher gastric pH, faster GI transit
  • Distribution: Higher body water, lower protein binding
  • Metabolism: Immature enzyme systems at birth
  • Excretion: Reduced renal function in neonates

8.6 Geriatric Pharmacokinetics

  • Absorption: Reduced gastric acid, slower GI transit
  • Distribution: Increased fat, decreased water and albumin
  • Metabolism: Decreased hepatic mass and blood flow
  • Excretion: Reduced renal function

8.7 Pregnancy

  • Absorption: Delayed gastric emptying
  • Distribution: Increased plasma volume
  • Metabolism: Altered enzyme activity
  • Excretion: Increased renal clearance

9. Drug Interactions

Pharmacokinetic Interactions

9.1 Absorption Interactions

  • Chelation: Tetracycline + antacids
  • Adsorption: Cholestyramine + warfarin
  • pH changes: Affecting ionization

9.2 Distribution Interactions

  • Protein binding displacement: Warfarin + aspirin
  • Tissue binding competition: Quinidine + digoxin

9.3 Metabolism Interactions

  • Enzyme induction: Phenobarbital + warfarin
  • Enzyme inhibition: Cimetidine + theophylline
  • Competitive inhibition: Same CYP enzyme

9.4 Excretion Interactions

  • Renal tubular competition: Probenecid + penicillin
  • pH changes: Affecting reabsorption
  • Renal function impairment: Aminoglycosides + NSAIDs

10. Key Equations and Formulas

Essential Formulas

  1. Bioavailability: F = (AUCₒᵣₐₗ / AUCᵢᵥ) × (Doseᵢᵥ / Doseₒᵣₐₗ)
  2. Clearance: CL = Rate of elimination / Plasma concentration
  3. Half-life: t½ = 0.693 × Vd / CL
  4. Volume of Distribution: Vd = Dose / C₀
  5. First-order elimination: C = C₀ × e⁻ᵏᵗ
  6. Steady state: Css = (F × D/τ) / CL
  7. Loading dose: LD = (Vd × Target concentration) / F
  8. Maintenance dose: MD = (CL × Target concentration × τ) / F
  9. Renal clearance: CLᵣ = (Urine conc. × Urine flow) / Plasma conc.
  10. Extraction ratio: E = (Ca - Cv) / Ca

11. Important Points for Examination

Key Concepts to Remember

  1. ADME processes and their clinical significance
  2. Factors affecting each ADME process
  3. Pharmacokinetic parameters and their clinical applications
  4. Drug interactions and their mechanisms
  5. Special populations and dosage adjustments
  6. Therapeutic drug monitoring indications and examples
  7. Mathematical calculations using pharmacokinetic equations
  8. Bioavailability vs bioequivalence concepts
  9. Linear vs non-linear pharmacokinetics
  10. Clinical applications of pharmacokinetic principles

Common Exam Questions Types

  1. Define and explain pharmacokinetic processes
  2. Factors affecting absorption, distribution, metabolism, excretion
  3. Calculate pharmacokinetic parameters
  4. Explain drug interactions with examples
  5. Dosage adjustments in special populations
  6. Therapeutic drug monitoring - when and why
  7. Compare and contrast different routes of administration
  8. Clinical significance of pharmacokinetic parameters

These notes cover the essential topics in Pharmacokinetics for B.Pharm IV semester. Regular revision and practice with numerical problems will help in better understanding and exam preparation.

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    Pharmacokinetics Notes - B.Pharm IV Sem | Claude