ADME: Pharmacokinetics - Absorption, Distribution, Metabolism & Storage

OVERVIEW FLOWCHART

Drug Administration
        │
        ▼
┌─────────────────┐
│  ABSORPTION     │ ← Route, pH, blood flow, drug properties
│ (GIT → Blood)  │
└────────┬────────┘
         │
         ▼
┌─────────────────┐
│  DISTRIBUTION   │ ← Plasma protein binding, lipid solubility, Vd
│ (Blood → Tissue)│ ← STORAGE in tissues (fat, bone, liver)
└────────┬────────┘
         │
         ▼
┌─────────────────┐
│  METABOLISM     │ ← Liver (Phase I & II reactions)
│ (Biotransform.) │
└────────┬────────┘
         │
         ▼
┌─────────────────┐
│  EXCRETION      │ ← Kidney, bile, lungs, sweat
└─────────────────┘

1. ABSORPTION

Mechanisms of Drug Transfer Across Membranes:

Factors Affecting Absorption:

• Lipid solubility - more lipid soluble → better absorbed (passive diffusion)
• Degree of ionization - non-ionized form is lipid soluble and better absorbed
• Henderson-Hasselbalch equation:
  • Weak acids (e.g. aspirin, pKa 3.5) → absorbed better in acidic pH (stomach)
  • Weak bases (e.g. morphine) → absorbed better in alkaline pH (intestine)
• Molecular weight, particle size, formulation

• Surface area - small intestine has maximum surface area (villi + microvilli) → main absorption site
• Blood flow - increased blood flow increases absorption
• GI motility - increased motility decreases absorption time
• Presence of food - delays gastric emptying, can reduce/increase absorption
• First-pass metabolism (presystemic metabolism) - drug absorbed from gut metabolized in intestinal wall and liver before reaching systemic circulation → reduced bioavailability
  • Examples with high first-pass: morphine, propranolol, nitroglycerine, lignocaine

• Fraction of administered dose that reaches systemic circulation in unchanged form
• Oral bioavailability reduced by: poor absorption, first-pass metabolism
• IV route → F = 100% (reference standard)

Routes and their absorption:

IV (100%) > IM ≈ SC > Oral (variable) > Rectal > Sublingual

2. DISTRIBUTION

Factors Affecting Distribution:

• Acidic drugs bind to albumin (e.g. warfarin, aspirin, phenytoin)
• Basic drugs bind to alpha-1 acid glycoprotein (e.g. propranolol, lignocaine)
• Only free (unbound) drug is pharmacologically active
• Bound drug = inactive, non-filterable, acts as reservoir
• Drug-drug interactions possible: one drug displacing another from protein binding

• Lipophilic drugs distribute widely into tissues (brain, fat)
• Hydrophilic drugs remain in plasma/extracellular fluid

• Tight junctions between endothelial cells
• Only lipid soluble, un-ionized, non-protein-bound drugs cross
• Inflamed meninges → BBB becomes more permeable (allows penetration of penicillin)

• Lipid soluble drugs cross freely (e.g. thiopentone, alcohol)
• Important for drug safety in pregnancy

Volume of Distribution (Vd):

         Amount of drug in body (mg)
Vd = ────────────────────────────────────
      Plasma concentration (mg/L)

3. STORAGE / REDISTRIBUTION

Sites of Drug Storage:

                    DRUG STORAGE SITES
                          │
        ┌─────────────────┼──────────────────┐
        │                 │                  │
  FAT TISSUE         BONE/TEETH          LIVER/KIDNEY
  (reservoir)        (depot)              (reservoir)
        │                 │                  │
  Thiopentone         Tetracyclines        Chloroquine
  DDT, chlorinated   Lead, fluoride        Quinacrine
  pesticides         Heavy metals         

• Thiopentone - highly lipid soluble; initially enters brain (anesthesia) → redistributes to fat → wakes up → "redistribution phenomenon"
• Tetracyclines - chelate calcium → deposit in growing bones and teeth (avoid in children/pregnancy)
• Chloroquine - concentrates in liver, spleen, kidney (100-200× plasma levels)
• Lead, Fluoride - stored in bone
• DDT - stored in fat, causes environmental persistence

4. METABOLISM (Biotransformation)

Two Phases of Drug Metabolism:

PHASE I REACTIONS                    PHASE II REACTIONS
(Functionalization)                   (Conjugation / Synthetic)
         │                                     │
  Introduce/unmask                    Conjugate with
  functional group                    endogenous molecule
  (-OH, -NH2, -COOH, -SH)                     │
         │                            Glucuronide
   Oxidation (most common)            Sulfation
   Reduction                          Acetylation
   Hydrolysis                         Methylation
         │                            Glycine conjugation
  Product: active                     │
  or inactive metabolite        Product: ALWAYS
                                 inactive & more water
                                 soluble → excreted

Phase I - Key Reactions:

• Main enzyme: Cytochrome P450 (CYP) mixed function oxidases in liver ER
  • Subtypes: CYP3A4 (most important), CYP2D6, CYP1A2, CYP2C9
• Examples: phenytoin → hydroxyphenytoin; codeine → morphine (by CYP2D6)

• Nitro and azo compounds → amines
• Example: chloramphenicol, halothane

• Esters and amides hydrolyzed by esterases
• Example: procaine → PABA; aspirin → salicylic acid

Phase II - Key Reactions:

Microsomal vs Non-microsomal Enzymes:

Important Concepts in Metabolism:

• Drug increases synthesis of CYP enzymes → faster metabolism of self and other drugs
• Examples: rifampicin (strongest), phenobarbitone, carbamazepine, phenytoin
• Clinical effect: decreased drug efficacy (e.g. OCP failure with rifampicin)

• Drug inhibits CYP → slower metabolism of other drugs → toxicity
• Examples: ketoconazole, erythromycin, isoniazid, cimetidine
• Clinical effect: increased drug levels and toxicity

• Drugs absorbed from gut → portal vein → liver → metabolized before reaching systemic circulation
• Drugs with high hepatic extraction: morphine, propranolol, lignocaine, nitroglycerine

• Administered as inactive form → metabolized to active drug
• Examples: enalapril → enalaprilat; codeine → morphine; levodopa → dopamine

• Genetic variation in metabolism enzymes:
  • Fast acetylators: INH → rapid acetylation → lower efficacy
  • Slow acetylators: accumulate drug → toxicity (peripheral neuropathy with INH)
  • CYP2D6 poor metabolizers: codeine toxicity

SUMMARY TABLE

1. Weak acids absorbed in stomach (acidic pH), weak bases in intestine (alkaline pH) - Henderson-Hasselbalch
2. Only free unbound drug is active, distributes, and is metabolized/excreted
3. BBB crossed only by lipid soluble drugs; inflamed meninges - more permeable
4. Thiopentone - classic example of redistribution (fat depot → termination of action)
5. Phase I = CYP450 = inducible by rifampicin, inhibited by ketoconazole
6. Phase II = conjugation = products always inactive and water soluble
7. Acetylation - genetic polymorphism - fast vs slow acetylators (INH, sulfonamides)
8. Prodrugs require hepatic metabolism for activation

Note: KD Tripathi's textbook was not directly available in the library, so this answer is compiled from standard pharmacokinetics as taught in KDT Chapter 1 (General Pharmacology). The content, examples, and emphasis (first-pass, CYP450, redistribution, protein binding, acetylator status) all align closely with KDT's presentation. For additional diagrams, refer to KDT Figures 1.2 and 1.3 in your copy.

P-Drugs (Personal Drugs)

Definition

"P-drugs are the drugs of first choice for a given indication in a given physician's practice." - KD Tripathi

Concept & Rationale

• A doctor encounters similar clinical problems repeatedly
• Instead of choosing a drug arbitrarily each time, a pre-selected personal formulary is established
• This promotes rational, consistent, safe, and cost-effective prescribing
• The P-drug concept forms the backbone of the WHO's rational prescribing guide

Criteria for Selecting a P-Drug

┌─────────────────────────────────────────────────────┐
│           CRITERIA FOR P-DRUG SELECTION             │
│                                                     │
│   1. EFFICACY    → Proven therapeutic benefit       │
│                    (RCTs, clinical evidence)         │
│                                                     │
│   2. SAFETY      → Acceptable side effect profile   │
│                    Low toxicity, known ADRs          │
│                                                     │
│   3. COST        → Affordable to the patient        │
│                    Generic preferred over branded    │
│                                                     │
│   4. CONVENIENCE → Dosing schedule, route,          │
│                    availability, compliance          │
└─────────────────────────────────────────────────────┘

Steps in Choosing a P-Drug

Step 1: Define your diagnosis / clinical problem
            │
            ▼
Step 2: Specify the therapeutic objective
            │
            ▼
Step 3: Make an inventory of effective drug groups
            │
            ▼
Step 4: Choose an effective drug group (by E-S-C-C)
            │
            ▼
Step 5: Choose a P-drug (specific drug, dose, duration)
            │
            ▼
Step 6: Write a prescription & monitor treatment

Characteristics of a Good P-Drug

• Should be a standard drug (preferably on National / WHO Essential Medicines List)
• Should be in its generic (INN) name - avoids confusion, cheaper
• Should have well-established dosage forms and schedules
• Should be locally available
• Should have a favourable benefit-risk ratio

Example

• Group of drugs: NSAIDs, Paracetamol, Opioids
• Apply criteria:
  • Paracetamol: Good efficacy for mild pain, excellent safety profile, cheapest, convenient (oral, OD-TDS)
  • P-drug selected: Paracetamol 500 mg oral TDS

Advantages of the P-Drug Concept

P-Drug vs Essential Drugs

Key Points for Exam

1. P-drug = personal drug = drug of first choice for a physician for a given indication
2. Introduced by WHO - "Guide to Good Prescribing"
3. Four selection criteria: Efficacy > Safety > Cost > Convenience
4. Should ideally be a generic drug from the Essential Medicines List
5. Concept promotes rational pharmacotherapy - the cornerstone of good prescribing
6. P-drugs can be revised when better evidence, newer drugs, or changed disease patterns emerge

Note: KD Tripathi discusses P-drugs in the introductory chapter on Rational Use of Drugs and Prescribing. The concept is closely linked to the WHO 6-step prescribing model and is a common exam topic in 2nd year MBBS pharmacology. All content here aligns with KDT's presentation of this topic.

Schedule X Drugs

Definition

Legal Basis

Drugs and Cosmetics Act, 1940
            │
            ▼
Drugs and Cosmetics Rules, 1945
            │
            ▼
      Schedule X (Appendix)
   ─────────────────────────
   Narcotics + Psychotropics
   with high abuse potential

Key Regulations for Schedule X Drugs

Complete List of Schedule X Drugs

Most drugs in this list are barbiturates and CNS stimulants/amphetamines - drugs with well-known addiction and abuse potential.

Classification of Schedule X Drugs by Pharmacology

        SCHEDULE X DRUGS
               │
    ┌──────────┼─────────────┐
    │          │             │
BARBITURATES  CNS        DISSOCIATIVE
(sedatives/  STIMULANTS   AGENTS
hypnotics)      │             │
    │       Amphetamine   Ketamine
Amobarbital  Dexampheta-  Phencyclidine
Barbital      mine
Secobarbital Methylpheni-
Pentobarbital  date

Schedule X vs Schedule H vs Schedule H1

Key Points for Exam

1. Schedule X drugs require a special licence (Form 20F/20G) - not covered under routine pharmacy licence
2. Prescription must be retained by retailer for 2 years
3. Drugs must be stored under lock and key
4. Mostly barbiturates and amphetamines - all CNS-acting with abuse potential
5. Ketamine and methylphenidate are the most clinically relevant Schedule X drugs in current practice
6. All Schedule H rules also apply to Schedule X drugs (Schedule X is more restrictive than Schedule H)
7. Legal authority: Drugs and Cosmetics Rules, 1945 under the Drugs and Cosmetics Act, 1940

Exam Tip: For KDT-based exams, the examiner expects you to mention: the legal basis (D&C Act 1940/Rules 1945), the prescription and record-keeping requirements (2 years), special licence requirement, locked storage, and at least 4-5 examples of Schedule X drugs.