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2nd MBBS Pharmacology - GI Drugs: Complete Notes

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PART A: PROKINETIC AGENTS

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1. METOCLOPRAMIDE

Definition / What it is

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Mechanism of Action (MOA)

┌─────────────────────────────────────────────────────────────┐
│              METOCLOPRAMIDE - DUAL MECHANISM                │
│                                                             │
│  PERIPHERAL (GI Tract)          CENTRAL (Brain)            │
│  ─────────────────────          ──────────────────          │
│  Blocks D2 receptors on    →    Blocks D2 receptors in      │
│  GI smooth muscle               Chemoreceptor Trigger Zone   │
│  (Dopamine normally             (CTZ / Area Postrema)        │
│   inhibits ACh release)                                     │
│         ↓                               ↓                   │
│  Uninhibited ACh release          Antiemetic effect          │
│  (Cholinergic stimulation)                                   │
│         ↓                                                    │
│  ↑ Esophageal peristalsis                                    │
│  ↑ Lower esophageal sphincter (LES) pressure                │
│  ↑ Gastric emptying rate                                     │
│  (No effect on small bowel or colon motility)               │
└─────────────────────────────────────────────────────────────┘

• Increases esophageal peristaltic amplitude
• Increases lower esophageal sphincter (LES) pressure
• Accelerates gastric emptying
• Potent antiemetic (via CTZ blockade)
• Does NOT affect small intestine or colonic motility

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Therapeutic Uses

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Adverse Effects

Precaution: Long-term use should be avoided unless absolutely necessary, especially in the elderly. Domperidone has fewer CNS/EPS effects because it does NOT cross the blood-brain barrier significantly.

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Contraindications

• Patients with pheochromocytoma (may cause hypertensive crisis)
• Bowel obstruction, perforation, or GI hemorrhage (where stimulation is dangerous)
• History of tardive dyskinesia or EPS
• Parkinson's disease (worsens motor symptoms)
• Prolactin-dependent tumors

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2. PROKINETIC AGENTS

Definition

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Classification with Examples

PROKINETIC AGENTS
│
├── 1. Dopamine D2 Receptor Antagonists
│       ├── Metoclopramide (crosses BBB)
│       └── Domperidone (does NOT cross BBB → fewer CNS side effects)
│
├── 2. Motilin Receptor Agonists (Macrolides)
│       └── Erythromycin (stimulates motilin receptors on GI smooth muscle)
│
├── 3. Serotonin (5-HT4) Receptor Agonists
│       └── Prucalopride (approved for chronic constipation)
│           (Cisapride, Tegaserod - withdrawn due to cardiovascular events)
│
└── 4. Acetylcholinesterase Inhibitors (less used)
        └── Neostigmine (for acute colonic pseudo-obstruction)

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Therapeutic Uses of Prokinetic Agents

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Adverse Effects Summary

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PART B: LAXATIVES AND PURGATIVES

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Classification of Laxatives

LAXATIVES AND PURGATIVES
│
├── 1. BULK-FORMING LAXATIVES
│       (Psyllium/Ispaghula, Methylcellulose, Polycarbophil, Bran)
│
├── 2. OSMOTIC LAXATIVES
│   │
│   ├── (a) Poorly Absorbed Ions (Saline Cathartics/Purgatives)
│   │       (Mg hydroxide, Mg sulfate, Mg citrate, Na phosphate)
│   │
│   └── (b) Poorly Absorbed Sugars
│               (Lactulose, Sorbitol, Mannitol, Polyethylene glycol/PEG)
│
├── 3. STIMULANT LAXATIVES (Cathartics)
│   ├── Anthraquinone derivatives: Senna, Cascara sagrada, Aloe
│   ├── Diphenylmethane derivatives: Bisacodyl, Sodium picosulfate
│   └── Ricinoleic acid: Castor oil
│
├── 4. STOOL SOFTENERS / SURFACTANT LAXATIVES
│       (Docusate sodium, Glycerin suppository)
│
├── 5. LUBRICANT LAXATIVES
│       (Liquid paraffin / Mineral oil)
│
└── 6. NEWER AGENTS (Secretagogues)
        (Lubiprostone, Linaclotide, Plecanatide)

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1. LACTULOSE

Nature

Mechanism of Action

┌───────────────────────────────────────────────────────┐
│               LACTULOSE - MOA                         │
│                                                       │
│  Oral Ingestion                                       │
│       ↓                                               │
│  NOT absorbed in small intestine (lactase-resistant)  │
│       ↓                                               │
│  Reaches colon INTACT                                  │
│       ↓                                               │
│  FERMENTATION by colonic bacteria                     │
│       ↓                                               │
│  Produces: Short-chain fatty acids (SCFAs)            │
│           + H2 gas + CO2                              │
│       ↓                                               │
│  Lowers intraluminal pH (acidic environment)          │
│       ↓                                               │
│  OSMOTIC EFFECT: draws water into lumen               │
│       ↓                                               │
│  Increased stool water content → Softened stool       │
│  Increased stool bulk → Stimulates peristalsis        │
│       ↓                                               │
│  LAXATIVE EFFECT (onset: 24-48 hours)                 │
│                                                       │
│  BONUS - Hepatic Encephalopathy:                      │
│  Acidic pH converts NH3 → NH4+ (non-absorbable)       │
│  NH4+ trapped in lumen → expelled in stool            │
│  ↓ Blood ammonia levels                               │
└───────────────────────────────────────────────────────┘

Therapeutic Uses of Lactulose

Adverse Effects

• Flatulence (gas), abdominal bloating, cramping (from fermentation)
• Nausea
• In hepatic encephalopathy: excessive use may cause diarrhea and electrolyte disturbances

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2. ISPAGHULA (PSYLLIUM) - BULK-FORMING LAXATIVE

Nature

Mechanism of Action

┌──────────────────────────────────────────────────────────┐
│              ISPAGHULA - BULK-FORMING MOA                │
│                                                          │
│  Ingested with WATER (essential)                         │
│       ↓                                                  │
│  Hydrophilic colloid - absorbs large amounts of water    │
│  in the intestinal lumen                                 │
│       ↓                                                  │
│  Forms a bulky, viscous, gel-like mass                   │
│       ↓                                                  │
│  TWO PARALLEL EFFECTS:                                   │
│  1. Distends the colon (mechanical stretch)              │
│     → Stimulates stretch receptors                       │
│     → Triggers peristaltic reflex                        │
│                                                          │
│  2. Softens stool consistency                            │
│     (water retained within gel)                         │
│       ↓                                                  │
│  Enhanced, easier defecation                             │
│                                                          │
│  Additional note:                                        │
│  Partial fermentation by colonic bacteria                │
│  → Produces gas (bloating possible side effect)          │
│  But largely INDIGESTIBLE → NOT fully fermented          │
└──────────────────────────────────────────────────────────┘

Properties

• Onset of action: 12-72 hours (not immediate)
• Increases stool weight and frequency
• Accelerates colonic transit time
• Also reduces LDL cholesterol (added benefit)

Uses

• Chronic constipation
• IBS (reduces loose stools AND constipation)
• Diverticular disease (increases fiber bulk)
• Hypercholesterolemia (adjunct)

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3. LAXATIVES - COMPREHENSIVE OVERVIEW

Therapeutic Uses / Indications

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Contraindications of Laxatives

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STIMULANT LAXATIVES - MOA in Detail

STIMULANT LAXATIVES (Cathartics)
│
├── Anthraquinones (Senna, Cascara, Aloe)
│   MOA: Poorly absorbed. Hydrolyzed in colon by bacteria.
│        → Direct stimulation of enteric (myenteric) nerve plexus
│        → ↑ intestinal peristalsis
│        → Inhibit electrolyte and water absorption from colon
│        → ↑ colonic secretion of water and electrolytes
│   Onset: 6-12 hours (oral), 2 hours (rectal)
│   Side effect: Melanosis coli (brown pigmentation of colon wall
│                from chronic use - macrophages phagocytosing
│                apoptotic epithelial cells)
│
└── Diphenylmethanes (Bisacodyl, Sodium picosulfate)
    MOA: Act on enteric nervous system
         → ↑ propulsive peristaltic contractions
         → Inhibit water and electrolyte absorption
         → Acts on both small intestine AND colon
    Onset: 6-10 hours (oral), 30-60 minutes (rectal/suppository)
    Uses: Constipation, bowel prep before colonoscopy

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OSMOTIC LAXATIVES - MOA in Detail

OSMOTIC LAXATIVES
│
│  Core principle: Colon cannot concentrate or dilute fecal fluid
│  (fecal water remains isotonic throughout colon)
│
├── Saline Cathartics (Mg salts, Phosphate salts)
│   MOA: Poorly absorbed ions → ↑ osmolarity in intestinal lumen
│        → Water drawn into lumen along osmotic gradient
│        → Increased stool liquidity + volume
│        → Mechanical distension → peristalsis
│   Onset: 1-3 hours (rapid)
│   Uses: Acute constipation, bowel prep, drug overdose (fast purge)
│   ADR: Hypermagnesemia (renal failure), phosphate nephropathy
│
└── Non-absorbable sugars (Lactulose, PEG)
    See above for lactulose MOA
    PEG: Large polymer → isoosmotic solution
         → No net fluid/electrolyte shifts
         → Safe for all patients including renal/cardiac
         → Less cramping than lactulose

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Indications Summary - At a Glance

Clinical Situation                  → Best Laxative Choice
──────────────────────────────────────────────────────────────
Chronic constipation (first-line)   → Bulk-forming (Ispaghula)
                                      + high fiber diet
Constipation in pregnancy           → Bulking agent / Stool softener
Post-MI / post-hemorrhoidectomy     → Stool softener (Docusate)
Hepatic encephalopathy              → Lactulose
Opioid-induced constipation         → Naloxegol / Methylnaltrexone
                                      (peripheral opioid antagonists)
Acute severe constipation           → Bisacodyl suppository / Senna
Bowel prep (colonoscopy/surgery)    → PEG electrolyte solution + Bisacodyl
Fecal impaction                     → Phosphate enema / Glycerin suppository
Elderly / bedridden patients        → Gentle stimulants (Senna) or PEG
Pediatric constipation              → PEG (preferred), Lactulose
IBS-C (constipation-predominant)    → Psyllium / Linaclotide / Lubiprostone
Drug/poison elimination             → Saline cathartic (Mg sulfate)

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Adverse Effects of Major Laxative Classes

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Quick Comparison: Laxative vs. Purgative

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KEY MEMORY AIDS

• Drowsiness/sedation
• Extrapyramidal effects (EPS)
• Prolactin elevation
• Tardive dyskinesia (long-term)

• Bulk-forming
• Osmotic
• Stimulant
• Stool softeners
• Lubricants

• Constipation
• Hepatic encephalopathy (main use)
• Encephalopathy (portal-systemic)
• Prevention of fecal impaction

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