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Diarrhoea: Investigations and Management with Pharmacology

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Definition

• Acute diarrhoea: onset and duration <14 days (usually infectious)
• Persistent/chronic diarrhoea: >14 days (requires full evaluation)

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Pathophysiology (Types of Diarrhoea)

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INVESTIGATIONS

A. Bedside / Initial Screening Tests

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B. Stool Microbiological Studies

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C. Blood Investigations

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D. Special/Hormonal Tests (Secretory/Endocrine Causes)

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E. Imaging

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F. Endoscopy

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G. Functional Tests (Chronic Diarrhoea)

• Hydrogen breath test - lactose/fructose malabsorption, small intestinal bacterial overgrowth (SIBO)
• SeHCAT scan (75Se-taurocholate) - bile acid malabsorption
• Secretin stimulation test - pancreatic exocrine insufficiency
• Faecal elastase - pancreatic insufficiency (non-invasive)
• D-xylose absorption test - small intestinal mucosal disease vs. luminal maldigestion

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MANAGEMENT

Step 1: Assessment of Dehydration (WHO Classification)

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Step 2: Oral Rehydration Therapy (ORT) - Cornerstone

• Sodium: 75 mmol/L
• Chloride: 65 mmol/L
• Glucose (anhydrous): 75 mmol/L
• Potassium: 20 mmol/L
• Citrate: 10 mmol/L
• Osmolarity: 245 mOsm/L (reduced osmolarity)

• Mild (3-5% dehydration): 30-50 mL/kg over 4 hours
• Moderate (6-9%): 60-80 mL/kg over 4 hours
• Replace ongoing losses: 10 mL/kg per stool; 2 mL/kg per emesis

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Step 3: Dietary Management

• Continue feeding - do NOT withhold food; age-appropriate diet
• BRAT diet (Banana, Rice, Applesauce, Toast) or soft diet
• Avoid lactose-containing products temporarily in acute gastroenteritis
• Zinc supplementation (10-20 mg/day for 10-14 days) in children in developing countries - reduces duration and severity

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PHARMACOLOGY OF DIARRHOEA

1. Oral Rehydration Salts (ORS)

• Mechanism: Exploits intact Na⁺-glucose cotransport in small intestine enterocytes; water follows osmotically
• Remains effective even when electrogenic Na⁺ absorption is impaired

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2. Antimotility Agents

Loperamide (Imodium)

• Class: Opioid receptor agonist (MOR - mu opioid receptor)
• Mechanism:
  • Binds peripheral MOR on enteric neurons - reduces peristalsis
  • Increases small intestinal and mouth-to-caecum transit time
  • Increases anal sphincter tone
  • Has antisecretory activity against cholera toxin and E. coli toxin (counters adenylyl cyclase stimulation via G-linked receptors)
  • 40-50 times more potent than morphine as antidiarrhoeal; poorly crosses the BBB
• ADME: Oral (capsule/solution/chewable tablet); peak plasma at 3-5 hours; t½ ~11 hours; extensive hepatic metabolism
• Dose: Adults: 4 mg initially, then 2 mg after each loose stool; max 16 mg/day. Children: 2-5 yr: 3 mg/day max; 6-8 yr: 4 mg/day; 8-12 yr: 6 mg/day; not recommended <2 years
• Adverse effects: Constipation, abdominal bloating, nausea
• Contraindications: Bloody diarrhoea or suspected invasive bacterial diarrhoea (may mask infection, delay clearance, increase risk of systemic invasion); avoid in C. difficile colitis; caution in young children

Diphenoxylate + Atropine (Lomotil)

• Mechanism: Diphenoxylate is a synthetic opioid (MOR agonist); reduces GI motility. Atropine added in subtherapeutic dose to deter abuse
• Use: Acute/chronic non-inflammatory diarrhoea
• Penetrates CNS more than loperamide - more CNS side effects

Codeine phosphate

• Opioid with antidiarrhoeal and analgesic effects; used for refractory diarrhoea; risk of dependence

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3. Antisecretory Agents

Bismuth Subsalicylate (Pepto-Bismol)

• Mechanism: Antisecretory + anti-inflammatory + antimicrobial effects; in stomach low pH forms bismuth oxychloride; clay component may adsorb toxins; salicylate component has anti-inflammatory activity
• Uses: Traveller's diarrhoea (prevention and treatment), acute gastroenteritis, non-ulcer dyspepsia
• Dose: 30 mL or 2 tablets every 30-60 min, up to 8 times/day; each dose contains ~262 mg each of bismuth and salicylate
• Adverse effects: Black stools (bismuth sulfide - not melena), black tongue; salicylate absorbed - carries Reye's syndrome warning in children; tinnitus, CNS effects
• Note: 99% of bismuth unabsorbed; salicylate is absorbed

Racecadotril (Acetorphan)

• Mechanism: Prodrug - converted to thiorphan, an enkephalinase inhibitor (NEP inhibitor). Inhibits breakdown of enkephalins → increased enkephalin activity → reduced cAMP-driven intestinal secretion via delta opioid receptors (DOR). Pure antisecretory - does not affect motility
• Advantage: Does not cause rebound constipation; preferred in children
• Use: Acute secretory diarrhoea, especially in children

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4. Antibiotics (Empiric and Targeted)

• Moderate-to-severe traveller's diarrhoea
• Suspected bacterial dysentery (Shigella, Campylobacter)
• C. difficile colitis
• Giardia, Entamoeba histolytica
• Immunocompromised patients

• Enterohemorrhagic E. coli (EHEC/O157:H7) - risk of HUS
• Uncomplicated viral gastroenteritis
• Mild, self-limiting bacterial diarrhoea

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5. Probiotics

• Mechanism: Restore commensal microflora; compete with pathogens; modulate immune response
• Evidence-based strains:
  • Lactobacillus GG - effective in acute infectious diarrhoea, antibiotic-associated diarrhoea
  • Saccharomyces boulardii - effective in antibiotic-associated and infectious diarrhoea
• Uses: Antibiotic-associated diarrhoea, C. difficile (adjunct), acute gastroenteritis

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6. Drugs for Specific Syndromes

Diarrhoea-Predominant IBS (IBS-D)

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7. Anti-parasitic Drugs

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8. Zinc Supplementation

• WHO recommendation: 10 mg/day (<6 months); 20 mg/day (>6 months) for 10-14 days in children with acute diarrhoea
• Reduces severity, duration, and recurrence risk

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Summary Algorithm

Acute Diarrhoea (<14 days)
├── Mild/No dehydration → ORS + continue diet + zinc (children)
├── Bloody/fever/severe → Stool culture + antibiotics (targeted)
├── Traveller's diarrhoea → Fluoroquinolone or Azithromycin
├── Antibiotic-associated → Check C. difficile; vancomycin/fidaxomicin
└── Suspected viral → Supportive only; no antibiotics

Chronic Diarrhoea (>14 days)
├── Osmotic gap → check for osmotic cause (dietary, laxative)
├── Fecal leukocytes/calprotectin ↑ → Colonoscopy; consider IBD
├── Steatorrhea → Malabsorption workup (biopsy, ERCP, breath tests)
├── Secretory (hormonal) → Serum VIP, gastrin, 5-HIAA, calcitonin
└── IBS-D → Loperamide / Alosetron / Eluxadoline / Rifaximin

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• Henry's Clinical Diagnosis and Management by Laboratory Methods - Table 23.4 (Lab investigations)
• Harrison's Principles of Internal Medicine 22E - Chronic diarrhoea chapter
• Rosen's Emergency Medicine - Acute diarrhoea, dehydration management
• Goodman & Gilman's Pharmacological Basis of Therapeutics - Antidiarrheal pharmacology (loperamide, bismuth, racecadotril, alosetron, eluxadoline, antibiotics)
• Goldman-Cecil Medicine - Postoperative diarrhoea, C. difficile

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Dysentery: Complete Clinical Guide

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1. DEFINITION

• Stools are small in volume (not watery and large)
• Visible blood + mucus in stool
• Tenesmus - painful ineffectual urge to defecate
• Systemic features: fever, malaise, toxaemia

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2. TYPES / CLASSIFICATION

A. By Causative Agent

B. By Duration

C. By Severity

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3. CAUSES (Aetiology)

Bacterial

Parasitic

Other

• Clostridioides difficile - Antibiotic-associated pseudomembranous colitis
• Ulcerative colitis - Non-infectious inflammatory cause of bloody diarrhoea mimicking dysentery
• Ischaemic colitis - Particularly in elderly

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4. PATHOLOGY

A. Bacillary Dysentery (Shigella) - Detailed Pathogenesis

1. Entry via M cells: Shigella selectively adheres to and transcytoses through follicle-associated M cells (lack brush border) overlying mucosal lymphoid nodules
2. Macrophage apoptosis: Bacteria enter subepithelial macrophages, escape the phagosome, and activate caspase-1 via IpaB - inducing macrophage apoptosis (releases IL-18 and IL-1β)
3. Basolateral invasion of enterocytes: Released bacteria contact the basolateral surface of enterocytes; Type III secretion system injects IpaA, IpaB, IpaC, IpaD proteins into the host cell
4. Actin polymerization and intracellular spread: IcsA (VirG) protein on the bacterial surface recruits N-WASP to polymerize actin, propelling bacteria through cytoplasm and into neighbouring cells (cell-to-cell spread)
5. Massive inflammatory response: Infected epithelial cells release IL-8, massively recruiting PMNs, which further destabilize the epithelial barrier, exacerbating inflammation
6. NF-κB activation: Intracellular NLR (NOD-like receptor) activation + IL-1β drives NF-κB signalling → acute colitis

• Phase 1 (watery): Active secretion/abnormal water reabsorption in jejunum - due to enterotoxin ShET-1 and early mucosal inflammation
• Phase 2 (dysenteric): Colonic mucosal invasion - bloody, mucopurulent stools with tenesmus

• Acute purulent proctitis with multiple small shallow ulcers (bacillary dysentery - Bailey & Love)
• Edematous, hemorrhagic colonic mucosa
• Ulcerations with overlying exudates (pseudomembrane-like)
• Mainly affects distal colon and rectum

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B. Amoebic Dysentery - Pathology

1. Ingestion of cysts via contaminated water/food
2. Cysts excyst in small intestine → trophozoites in large intestine
3. Trophozoites invade colonic mucosa via proteolytic enzymes (cysteine proteases) and amoebapores (pore-forming peptides) → lysis of epithelial cells, goblet cells, and mucosal glands
4. Flask-shaped (bottleneck) ulcers: Trophozoites burrow through epithelium, creating ulcers with markedly undermined edges and a yellow necrotic floor with blood and pus
5. Trophozoites may be seen ingesting erythrocytes (erythrophagocytosis - pathognomonic)
6. Distribution: mainly distal sigmoid colon and rectum; can involve entire colon

• Hepatic amoebiasis (liver abscess) - most common extraintestinal complication
• Amoeboma: granulation tissue mass (mimics colonic carcinoma)
• Toxic megacolon (0.5% of cases)
• Haemorrhage, stricture formation, perforation
• Pericolitis with adhesions → intestinal obstruction
• Intussusception and necrotizing colitis (in children)

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5. CLINICAL FEATURES

Bacillary Dysentery (Shigellosis) - Four Phases:

• HUS (S. dysenteriae type 1): Microangiopathic haemolytic anaemia + thrombocytopenia + acute renal failure
• Toxic megacolon: Severe inflammation extending transmurally; colon dilatation
• Rectal prolapse - especially in malnourished children
• Hypoglycaemia, hyponatraemia (metabolic)
• Bacteraemia (rare; <5%; mainly malnourished/HIV patients)
• Ekiri syndrome (toxic encephalopathy in Japanese children)
• Reactive arthritis (post-dysentery HLA-B27 associated)
• Seizures, delirium, coma (children <5 years)

Amoebic Dysentery Features:

• Slower onset (3-4 weeks after infection) vs. bacterial (1-2 days)
• Lower fever or no fever (fever present in minority)
• Abdominal tenderness + increasingly severe diarrhoea
• Proctoscopy and sigmoidoscopy not painful (contrast to bacillary)
• More often chronic course with exacerbations after prolonged symptom-free periods

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6. DIAGNOSTIC APPROACH

Step 1: History

• Travel history, food/water source, contact history
• Antibiotic use (C. difficile)
• Duration, character of stool (blood, mucus, volume)
• Onset speed - bacterial: 1-2 days; amoebic: weeks

Step 2: Physical Examination

• Temperature, dehydration signs
• Abdominal tenderness (LIF/suprapubic)
• Rectal examination / proctoscopy / sigmoidoscopy

Step 3: Stool Investigations

• Shigellosis: Many PMNs per field; no trophozoites
• Amoebiasis: Erythrophagocytic trophozoites; very few PMNs

Step 4: Blood Investigations

Step 5: Endoscopy / Imaging

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7. MANAGEMENT

General / Supportive

1. Oral rehydration therapy (ORT) - WHO ORS (245 mOsm/L) is the mainstay; IV fluids only for severe dehydration/coma/shock
   • Shigellosis rarely causes significant dehydration - but remains important in endemic settings
2. Nutrition: Start as early as possible; malnutrition is the primary risk factor for death
3. Isolation: Source isolation; strict hand hygiene; sodium hypochlorite decontamination
4. Zinc supplementation (children): 10-20 mg/day × 10-14 days
5. AVOID antimotility agents (loperamide, diphenoxylate) in dysentery - risk of toxic megacolon, prolonged fever, increased HUS risk in EHEC

Management of Complications

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8. PHARMACOLOGY

A. Antibiotics for Bacillary Dysentery

IMPORTANT: As an invasive disease, shigellosis requires antibiotic treatment. However, multidrug resistance is now a dominant factor in treatment decisions.

First-Line: Fluoroquinolones

Alternative/Second-Line

Antibiotics by Organism (Goldman-Cecil Table 265-7)

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B. Treatment of Amoebic Dysentery

Step 1: Tissue Amoebiasis (Active Dysentery/Invasive Disease)

• Rapidly absorbed orally; t½ 8 hours; >50% hepatic metabolism; excreted in urine
• Adverse effects: Nausea, vomiting, diarrhoea, metallic taste (very common), headache, dizziness, vertigo, numbness
• Disulfiram-like reaction with alcohol (avoid alcohol during and 48h after course)
• Can cause peripheral neuropathy in high doses / prolonged use

• Longer half-life → shorter dosing regimen
• Less GI side effects
• Same alcohol warning (disulfiram-like reaction)

Step 2: Luminal Amoebiasis (Eradication of Cysts - MANDATORY after tissue therapy)

Neither metronidazole nor tinidazole reliably eradicates intraluminal cysts - therefore a luminal amoebiocide MUST always follow tissue therapy to prevent relapse.

1. Metronidazole or Tinidazole (tissue) THEN
2. Paromomycin or Diloxanide furoate (luminal cyst eradication)

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C. Treatment of Schistosomal Dysentery

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D. Treatment of C. difficile Colitis (Antibiotic-Associated Dysentery)

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E. Drugs to AVOID in Dysentery

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Summary: Bacillary vs. Amoebic Dysentery

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• Harrison's Principles of Internal Medicine 22E - Shigellosis chapter (Chapters 172, 230)
• Goldman-Cecil Medicine - Amebic Dysentery, Table 265-7
• Bailey and Love's Short Practice of Surgery 28th Ed - Bacillary and Amoebic dysentery pathology
• Sherris & Ryan's Medical Microbiology 8th Ed - Shigella pathogenesis
• Robbins & Kumar Basic Pathology - Infectious Enterocolitis
• Goodman & Gilman's Pharmacological Basis of Therapeutics - Metronidazole, antiprotozoal drugs

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Irritable Bowel Syndrome (IBS): Complete Clinical Guide

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1. DEFINITION

• Functional constipation (chronic idiopathic constipation)
• Functional diarrhoea
• Functional abdominal bloating/distension
• Functional dyspepsia

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2. EPIDEMIOLOGY

• Global prevalence: 4.1% (Rome IV criteria); up to 9% using older Rome III criteria
• More common in women (5.2%) than men (2.9%) - odds ratio ~1.7
• More prevalent in patients under 50 years and those with lower socioeconomic status
• Up to 50% of individuals with IBS symptoms do not seek healthcare
• Generates ~4.4 million annual physician visits in the US alone
• Associated with significant work absenteeism and impaired productivity
• IBS-D and IBS-M each account for 35-40% of cases; IBS-C ~25%; IBS-U <5%

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3. TYPES / SUBTYPES

• Women with IBS are more likely to have IBS-C (OR 2.38)
• Men with IBS are more likely to have IBS-D (OR 0.45 in women, i.e., men predominate)
• Women's symptoms can worsen premenstrually when oestrogen and progesterone decline

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4. CAUSES AND RISK FACTORS

A. Predisposing Factors

B. Precipitating Factors

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5. PATHOBIOLOGY (Pathophysiology)

A. Visceral Hypersensitivity (Central Mechanism)

• Patients have lowered pain thresholds to luminal distension (balloon distension studies show pain at lower volumes than healthy controls)
• Allodynia: Perception of pain with normally non-painful stimuli
• Central sensitization: Altered brain processing of visceral afferent signals
• Brain imaging shows activation of emotional arousal centres (amygdala, anterior cingulate cortex) during rectal distension rather than the pain inhibitory areas (prefrontal cortex) seen in controls
• Endogenous pain modulation is impaired: Reduced activation of descending inhibitory pathways; reduced activation of PFC during rectal distension
• Structural brain changes: Greater volume/cortical thickness of sensorimotor cortex correlating with symptom severity

B. Altered GI Motility

• Colonic transit is slower in IBS-C and faster in IBS-D
• Exaggerated colonic responses to meals (gastrocolic reflex), cholecystokinin (CCK), and mechanical stimuli
• Increased high-amplitude propagating contractions (HAPCs) in some patients

C. Mucosal Immune Activation

• Increased mast cells adjacent to sensory neurons in colonic mucosa
• Mast cells release histamine → activate afferent nerves → peripheral sensitization → increased abdominal pain
• Increased T lymphocytes in colonic mucosa
• Elevated mucosal colonic nerves expressing substance P, TRPV1 cannabinoid receptors, and protease-activated receptors

D. Increased Intestinal Permeability (Leaky Gut)

• Some patients have decreased tight junction protein expression in jejunum and colon
• Increased permeability linked to greater visceral hyperalgesia, abdominal pain severity, and altered bowel habits
• Likely mediated by immune activation (mast cells + T cells) and food allergens
• Also linked to non-classical food allergies and postprandial symptoms

E. Dysbiosis (Gut Microbiota Imbalance)

• IBS fecal microbiota shows:
  • Increased: Enterobacteriaceae, Lactobacillaceae, Bacteroides (produce organic acids, reduce mucosal glycoproteins)
  • Decreased: Clostridiales, Faecalibacterium prausnitzii, Bifidobacterium (produce butyrate - anti-inflammatory, epithelial energy source)
• ~25% of IBS patients have bile acid diarrhoea (BAD) due to impaired ileal bile acid reabsorption

F. Serotonin (5-HT) Dysregulation

• ~95% of body's serotonin is in enterochromaffin cells of the gut
• Serotonin regulates motility, secretion, and visceral sensation
• Altered serotonin transporter (SERT) expression in IBS:
  • Low SERT expression → excess 5-HT → IBS-D (increased secretion and motility)
  • High SERT expression → rapid 5-HT reuptake → IBS-C
• This forms the basis for 5-HT-targeted pharmacotherapy

G. Dysregulated Stress Response

• Hyperactivated hypothalamic-pituitary-adrenal (HPA) axis in IBS compared to controls
• Stress increases visceral sensitivity, gut motility, gut permeability, and mucosal immune responses
• Explains worsening of IBS during periods of psychological stress

H. Genetic/Epigenetic Factors

• Polymorphisms in 5-HTTLPR, CRF-1R, cannabinoid receptors, COMT
• Alterations in gene methylation and non-coding microRNA expression

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6. CLINICAL FEATURES

Core Symptoms (Required for Diagnosis)

• Recurrent abdominal pain: Crampy, lower abdominal, often related to defecation
• Altered bowel habits: Diarrhoea, constipation, or alternating
• Associated with defecation: Pain relieved or worsened by passing stool
• Bloating/abdominal distension: Very common; often worsens through the day

Supportive Symptoms

Extraintestinal Manifestations (Frequent Comorbidities)

• Functional: Functional dyspepsia, functional heartburn (coexist in ~1/3)
• Pain syndromes: Fibromyalgia, chronic pelvic pain, chronic fatigue syndrome
• Urological: Interstitial cystitis, painful bladder syndrome
• Neurological: Migraine headaches, temporomandibular joint disorder
• Gynaecological: Dysmenorrhoea
• Psychological: Anxiety, depression, somatization (major comorbidities)
• Sleep disturbances: Especially when GI symptoms are severe

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7. DIAGNOSTIC APPROACH

Rome IV Diagnostic Criteria (2016) - Gold Standard

1. Related to defecation
2. Associated with a change in frequency of stool
3. Associated with a change in form (appearance) of stool

IBS Diagnostic Algorithm (Goldman-Cecil, Fig. 123-1):

Alarm Features (Red Flags) - REQUIRE FURTHER INVESTIGATION

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Investigations

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8. MANAGEMENT

Step 1: Patient Education and Reassurance

• Explain the functional nature of IBS; reassure no malignancy
• Set realistic expectations - IBS is chronic but not progressive or life-threatening
• Address psychological concerns; validate symptoms

Step 2: Dietary Modification (First-Line)

Step 3: Psychological Therapies (Highly Effective)

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9. PHARMACOLOGY

A. Drugs for PAIN AND SPASM

1. Antispasmodics (First-Line for Abdominal Pain)

2. Peppermint Oil

• Mechanism: L-menthol - acts as calcium channel antagonist on gut smooth muscle → relaxation; also TRPV1 agonist → reduces visceral hypersensitivity; mild local anaesthetic effect
• Dose: ≥200 mg TDS (enteric-coated capsules to prevent lower oesophageal sphincter relaxation and heartburn)
• NNT: 4 (3-6) for abdominal pain and global IBS symptoms
• Recommended by: ACG, CAG, AGA, NICE
• Adverse effects: Heartburn/reflux (if non-enteric-coated), perianal burning

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B. Drugs for IBS-D (Diarrhoea-Predominant)

1. Loperamide

• Mechanism: Peripheral mu-opioid receptor (MOR) agonist → reduces intestinal motility + increases anal sphincter tone + antisecretory activity
• Dose: 2-4 mg as needed; max 16 mg/day
• Evidence: Reduces stool frequency and improves consistency; does NOT significantly reduce abdominal pain - used as an adjunct to other IBS-D therapies
• Caution: Do not use in IBS as monotherapy for pain

2. Alosetron (Lotronex) - 5-HT3 Antagonist

• Mechanism: Potent antagonist of 5-HT3 receptors on enteric neurons; reduces colonic contractility, decreases colonic transit, increases fluid and electrolyte absorption, reduces visceral hypersensitivity
• Dose: 0.5-1 mg BD; start at 0.5 mg BD × 4 weeks; max 1 mg BD
• Indication: FDA-approved for severe IBS-D in women who have failed conventional therapy
• Adverse effects: Ischaemic colitis (3/1000 patients - serious adverse effect), severe constipation, nausea, GI discomfort
• Restricted access: Requires physician certification and detailed patient consent/education protocol due to risk of ischaemic colitis (discontinued treatment required immediately if symptoms develop)

3. Eluxadoline (Viberzi) - Mixed Opioid Receptor Agent

• Mechanism: MOR agonist + DOR antagonist + KOR agonist - acts locally in enteric nervous system; reduces abdominal pain and diarrhoea without causing rebound constipation
• Dose: 100 mg BD with food (gallbladder intact); 75 mg BD (no gallbladder)
• Adverse effects: Pancreatitis (especially in patients without a gallbladder - sphincter of Oddi spasm), constipation, nausea, abdominal pain
• Contraindicated in: Biliary duct obstruction, sphincter of Oddi disease/dysfunction, pancreatitis history, absent gallbladder (relative), severe constipation, alcohol dependence

4. Rifaximin - Non-absorbable Antibiotic

• Mechanism: Non-absorbed rifamycin-class antibiotic; inhibits bacterial RNA polymerase β subunit → bactericidal effect within GI lumen without systemic absorption; reduces dysbiosis and SIBO
• Dose for IBS-D: 550 mg TDS × 14 days (may repeat up to 2 courses)
• Evidence: Reduces bloating, abdominal discomfort, and diarrhoea in non-constipating IBS; ~40% response rate
• Advantage: Minimal systemic side effects; low risk of Clostridium difficile
• ACG recommendation: Strong recommendation for non-constipating IBS

5. Bile Acid Sequestrants (for IBS-D with BAD)

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C. Drugs for IBS-C (Constipation-Predominant)

1. Osmotic Laxatives

• Polyethylene glycol (Macrogol/Movicol): Improves stool frequency and consistency but does NOT reduce abdominal pain; safe, OTC, inexpensive; side effects: bloating, abdominal pain, nausea

2. Lubiprostone (Amitiza)

• Mechanism: Chloride channel (ClC-2) activator on intestinal epithelium → increased luminal chloride secretion → fluid secretion into intestinal lumen → softens stool and increases motility
• Dose: 8 µg BD for IBS-C (lower dose than for chronic idiopathic constipation)
• Evidence: Improves constipation, stool consistency, straining, abdominal pain, bloating
• Adverse effects: Nausea (most common; reduced by taking with food), diarrhoea, dyspepsia
• Contraindicated in pregnancy (possible foetal harm - category C)

3. Linaclotide (Linzess)

• Mechanism: Guanylate cyclase-C (GC-C) receptor agonist on intestinal epithelium → increases intracellular cGMP → activates CFTR chloride channel → secretion of chloride and bicarbonate into intestinal lumen → increased fluid and motility. Also decreases firing of visceral sensory C-fibres via cGMP → reduces abdominal pain (dual action)
• Dose: 290 µg OD (30 min before first meal of day) for IBS-C
• Adverse effects: Diarrhoea (most common; dose-dependent), abdominal pain
• FDA approved for IBS-C and chronic idiopathic constipation

4. Plecanatide (Trulance)

• Mechanism: Structurally similar to uroguanylin; GC-C receptor agonist (same mechanism as linaclotide but pH-sensitive - greater activity in the alkaline small intestine)
• Dose: 3 mg OD
• Evidence: Similar benefits to linaclotide in IBS-C
• Adverse effects: Diarrhoea

5. Tenapanor (Ibsrela)

• Mechanism: Minimally absorbed inhibitor of Na⁺/H⁺ exchanger isoform 3 (NHE3) in the gut → blocks sodium (and therefore water) reabsorption → increased luminal fluid → softer stools and increased motility
• Dose: 50 mg BD for IBS-C
• Adverse effects: Diarrhoea

6. Prucalopride (Resolor)

• Mechanism: Selective, high-affinity 5-HT4 receptor agonist on enteric neurons → triggers prokinetic activity throughout the colon; stimulates peristaltic reflex
• Dose: 1-2 mg OD
• Primarily approved for chronic constipation; used off-label in IBS-C
• Adverse effects: Headache, nausea, diarrhoea, abdominal pain

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D. Brain-Gut Neuromodulators (for PAIN in ALL IBS subtypes)

1. Tricyclic Antidepressants (TCAs)

• Drugs: Amitriptyline, imipramine, doxepin, desipramine, nortriptyline
• Mechanism: Block serotonin and noradrenaline reuptake → enhance descending pain inhibition; also anticholinergic effects → slow gut transit (beneficial in IBS-D)
• Dose for IBS: Low doses, 10-25 mg at bedtime (sub-antidepressant doses for pain modulation); can titrate up to 75-100 mg
• Evidence: NNT = 4.5 (3.5-7) for global IBS symptoms; especially effective for abdominal pain
• Preferred agents: Desipramine or nortriptyline (less sedation, less constipation, less dry mouth than amitriptyline)
• Especially useful: IBS-D (anticholinergic slows transit); also for sleep disturbance
• Adverse effects: Dry mouth, sedation, constipation (problematic in IBS-C), blurred vision, urinary retention, weight gain, cardiac arrhythmia (at higher doses)
• Recommended by: ACG (1A), CAG (1A) - highest quality evidence

2. Selective Serotonin Reuptake Inhibitors (SSRIs)

• Drugs: Fluoxetine, sertraline, paroxetine, citalopram
• Mechanism: Block serotonin reuptake transporter (SERT) → increased synaptic serotonin → modulates gut motility (accelerates transit) and CNS pain processing; enhances descending inhibitory pathways
• Dose: 10-100 mg daily (standard antidepressant doses)
• Evidence: NNT = 5 (3-16.5) for global IBS symptoms; less effective than TCAs for abdominal pain reduction; may be useful in IBS-C (prokinetic effect); fewer side effects than TCAs
• Adverse effects: Nausea, insomnia, sexual dysfunction, GI side effects, serotonin syndrome (rare)
• Recommended by: ACG (2C), CAG (2C)

3. Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs)

• Drugs: Duloxetine, venlafaxine
• Mechanism: Dual reuptake inhibition of serotonin and noradrenaline → enhanced descending pain inhibition; especially effective for comorbid pain conditions (fibromyalgia, chronic pelvic pain)
• Use: Patients with IBS + chronic pain who cannot tolerate TCAs
• Adverse effects: Nausea, sweating, hypertension, serotonin syndrome risk

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E. Probiotics

• Mechanism: Restore commensal gut microbiota; improve dysbiosis; produce short-chain fatty acids (butyrate); modulate mucosal immune response; reduce visceral hypersensitivity
• Evidence: NNT = 7 (5-12) for global IBS symptoms (37 RCTs, n=4403); most useful for bloating
• Best-studied strains: Bifidobacterium infantis 35624, Lactobacillus plantarum, Lactobacillus GG, Saccharomyces boulardii
• Recommended by: ACG (2C), CAG (2C)
• Combination products may be more effective than single strains (NNT 19 for combinations, though CI wide)

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F. Summary Pharmacology by Subtype

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Summary: IBS at a Glance

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• Goldman-Cecil Medicine - Chapters 123 (IBS), including Rome IV criteria table and diagnostic algorithm
• Yamada's Textbook of Gastroenterology 7th Ed - Chapter 67 (comprehensive IBS pathobiology, treatment tables, NNT data)
• Sleisenger and Fordtran's Gastrointestinal and Liver Disease - Functional bowel disorders
• Goodman & Gilman's Pharmacological Basis of Therapeutics - Alosetron, eluxadoline, linaclotide, rifaximin, lubiprostone pharmacology

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Intestinal Worm Infestation (Intestinal Helminthiasis): Complete Clinical Guide

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1. DEFINITION

• Unlike protozoa, helminths are macroscopic multicellular organisms
• They cannot multiply within the human host (except Strongyloides and Capillaria) - disease severity is related to worm burden (intensity of infection)
• They produce eggs/larvae passed in faeces to continue the life cycle in soil or water
• Most infections are asymptomatic in low worm burdens; symptoms increase proportionately with worm load

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2. CLASSIFICATION / TYPES

A. By Organism Type

B. Common Intestinal Nematodes (Focus of This Guide)

C. Common Intestinal Cestodes (Tapeworms)

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3. CAUSES AND TRANSMISSION

Fecal-Oral Route (Most Common)

Skin Penetration Route

Meat Consumption

Special Routes

• Anisakiasis: Ingestion of raw saltwater fish (sushi/sashimi)
• Capillaria: Raw freshwater fish

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4. PATHOLOGY (Organ-by-Organ)

A. ASCARIS LUMBRICOIDES

1. Ingestion of embryonated eggs from contaminated soil/food
2. Larvae hatch in small intestine → penetrate intestinal mucosa → portal venules → liver → right heart → pulmonary capillaries
3. Too large for pulmonary capillaries → rupture into alveolar spaces → coughed up → swallowed → reach small intestine
4. Mature into adults in small intestine (2-3 months from ingestion to oviposition)
5. Adults live 1-2 years, survive by muscular swimming against intestinal flow (do NOT burrow into mucosa)

• Intestinal phase: Abdominal pain, nausea, vomiting; obstruction with heavy loads (bolus of worms in small intestine); malnutrition and growth stunting in children
• Larval migration phase (Loeffler's syndrome): Cough, wheezing, eosinophilia, transient pulmonary infiltrates on CXR
• Complications: Intestinal obstruction, biliary obstruction (worms migrating into bile duct/pancreatic duct), cholangitis, pancreatitis, perforation, volvulus, appendicitis
• Eosinophilia is prominent during larval migration phase

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B. TRICHURIS TRICHIURA (Whipworm)

1. Unembryonated eggs passed in stool → embryonate in soil (15-30 days)
2. Infective eggs ingested → hatch in small intestine → larvae mature and establish as adults in caecum and ascending colon
3. Anterior thin ends thread through and anchor in colonic mucosa; posterior ends remain free in lumen
4. Adults live ~1 year; females produce eggs 60-70 days after infection

• Light infections: Asymptomatic
• Moderate infections: Nausea, abdominal pain, diarrhoea, growth stunting
• Heavy infections (>800 worms): Entire colonic lumen parasitized → significant mucosal damage, blood loss, anaemia; "dysentery syndrome" with bloody diarrhoea mimicking Shigella; tenesmus; rectal prolapse (hallmark of heavy Trichuris load)
• Moderate eosinophilia in heavy infections (adults anchored in mucosa present antigens to GALT)

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C. ENTEROBIUS VERMICULARIS (Pinworm/Threadworm)

1. Eggs ingested (hand-to-mouth, fomites, bedding, inhalation) → hatch in small intestine → mature in large intestine
2. Female migrates nocturnally to perianal area to deposit 10,000-11,000 eggs in perianal skin folds
3. Eggs are immediately infective (no soil maturation required)
4. Reinfection: scratching → eggs under fingernails → fecal-oral transmission

• Perianal pruritus (especially nocturnal) - cardinal symptom
• Vulvovaginitis in girls (ectopic migration)
• Insomnia, irritability, restlessness
• Appendicitis (rare; ectopic worms in appendix)
• Light infections usually asymptomatic
• No eosinophilia (adults confined to intestinal lumen; no tissue invasion)

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D. HOOKWORM (Necator americanus and Ancylostoma duodenale)

1. Eggs passed in faeces → hatch in soil within 48 hours → rhabditiform larvae (free-living) → develop into infective filariform larvae within 1 week
2. Filariform larvae penetrate bare skin (usually feet)
3. Lymphohematogenous transport → right heart → lungs → rupture into alveoli → coughed up → swallowed → small intestine
4. Attach to small bowel mucosa using teeth/cutting plates; suck blood and villous tissue
5. Prepatent period: 6-8 weeks

• Ancylostoma duodenale: 0.2 mL/worm/day (more serious)
• Necator americanus: 0.03 mL/worm/day
• Additional blood loss from migration and old attachment sites

• Skin (ground itch): Pruritic maculopapular rash at larval entry site; serpiginous tracks
• Pulmonary (Loeffler's): Transient cough, eosinophilia, mild pneumonitis (less severe than Ascaris)
• Intestinal phase: Epigastric pain, nausea, bloating 1-2 months after heavy infection
• Chronic heavy infection: Iron-deficiency anaemia (hypochromic microcytic) - the major clinical consequence; hypoproteinaemia/hypoalbuminaemia with oedema (face, extremities, abdomen); fatigue, weakness, dyspnoea
• "Wakana disease" (Ancylostoma): Nausea, vomiting, dyspnoea after oral larval ingestion
• Eosinophilia peaks at 5-9 weeks (when adults appear in intestine)

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E. STRONGYLOIDES STERCORALIS

1. Filariform larvae penetrate skin → lungs → swallowed → embed in duodenojejunal mucosa
2. Parthenogenetic female worms (1-2 mm; no males in humans) produce eggs in mucosa → rhabditiform larvae pass in faeces OR
3. Autoinfection: Rhabditiform larvae → filariform larvae in bowel → penetrate colonic wall or perianal skin → re-enter circulation and repeat the cycle

• Uncomplicated strongyloidiasis: Often asymptomatic; cutaneous larva currens (serpiginous, erythematous, pruritic, moves up to 10 cm/h); midepigastric pain resembling peptic ulcer disease; nausea, diarrhoea, alternating constipation
• Hyperinfection syndrome (immunocompromised patients - steroids, HTLV-1, immunosuppression): Massive larval dissemination throughout body; gram-negative bacteraemia (larvae carry gut bacteria through intestinal wall); meningitis; hepatitis; can be fatal
• Eosinophilia characteristic; may be absent in hyperinfection

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F. TAPEWORMS (Cestodes)

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G. INTESTINAL FLUKES (Trematodes)

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5. CLINICAL FEATURES SUMMARY

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6. DIAGNOSTIC APPROACH

Step 1: History

• Geographic origin / travel history (tropical, endemic areas)
• Barefoot outdoor exposure (hookworm, Strongyloides)
• Dietary habits (raw fish, pork, beef, vegetables)
• Contact with soil / playing in dirt
• Household contacts with similar symptoms
• Perianal itch (Enterobius)
• Immunosuppression status (critical for Strongyloides hyperinfection)

Step 2: Clinical Examination

• Growth assessment in children (stunting, weight)
• Pallor (iron deficiency / B12 deficiency anaemia)
• Oedema (hypoalbuminaemia in hookworm)
• Abdominal tenderness
• Rectal prolapse (heavy Trichuris)
• Skin: perianal excoriation (Enterobius), ground itch, larva currens

Step 3: Stool Examination (Primary Diagnostic Tool)

Step 4: Special Tests by Organism

Step 5: Additional Investigations

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7. MANAGEMENT

General Principles

1. Anthelmintic therapy - mainstay
2. Nutritional rehabilitation - iron, protein, vitamins
3. Treat household contacts (Enterobius - all members simultaneously)
4. Sanitation and hygiene measures - prevent reinfection
5. Mass Drug Administration (MDA) programs in endemic areas - albendazole/mebendazole annually for school-aged children (WHO-recommended deworming)

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8. PHARMACOLOGY OF ANTHELMINTICS

A. BENZIMIDAZOLES

Albendazole (Albenza, Zentel) - Broad-spectrum, Drug of Choice

• Mechanism of Action:
  • Binds to β-tubulin of helminth → inhibits tubulin polymerization → disrupts microtubule assembly → impairs glucose uptake and transport → depletes glycogen stores → immobilization and death of worm
  • Also inhibits fumarate reductase (helminth mitochondrial enzyme) → impairs energy production
  • Absorbed systemically → reaches worm's head buried in gut wall (superior to mebendazole for Trichuris)
  • Active metabolite: Albendazole sulphoxide - pharmacologically active; penetrates blood-brain barrier (useful for cysticercosis)
• Spectrum and Doses (Goldman-Cecil Table 327-1):

• ADME: Well absorbed with fatty meals; extensive first-pass hepatic metabolism to albendazole sulphoxide (active); t½ 8-12 hours; biliary excretion
• Adverse Effects: Generally well tolerated; nausea, abdominal pain; elevated liver enzymes (monitor in prolonged courses); bone marrow suppression (rare, with prolonged use); teratogenic - contraindicated in pregnancy (Category D); alopecia

Mebendazole (Vermox)

• Mechanism: Same as albendazole - binds β-tubulin → inhibits microtubule polymerization → blocks glucose uptake
• Poorly absorbed from GI tract (acts locally in intestinal lumen) - therefore less effective when the worm's head is embedded in mucosa (e.g., Trichuris)
• Doses:
  • Ascaris: 500 mg single dose or 100 mg BD × 3 days
  • Hookworm: 500 mg OD or 100 mg BD × 3 days
  • Trichuris: 100 mg BD × 3 days (albendazole preferred)
  • Enterobius: 100 mg single dose, repeat in 2 weeks
• Adverse Effects: Generally well tolerated; mild GI upset; teratogenic (avoid in first trimester)

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B. MACROCYCLIC LACTONES

Ivermectin (Stromectol) - Drug of Choice for Strongyloides

• Mechanism of Action:
  • Binds to glutamate-gated chloride ion channels (invertebrate-specific) in nerve and muscle cells of helminths
  • Also potentiates GABA-gated chloride channels → hyperpolarization → paralysis → death of parasite
  • Does NOT cross the human blood-brain barrier at therapeutic doses (BBB excludes ivermectin via P-glycoprotein)
• Spectrum and Doses:

• ADME: Oral; peak concentration 4 hours; t½ ~18 hours; hepatic metabolism; fecal excretion
• Adverse Effects: Generally very well tolerated; Mazzotti reaction (fever, pruritus, rash, hypotension) in microfilaraemic patients with onchocerciasis; CNS toxicity if BBB compromised (avoid in meningitis, concurrent CNS disease, Loa loa co-infection with high microfilaraemia)
• Note: Contraindicated in pregnancy; caution in children <15 kg

Moxidectin

• Newer macrocyclic lactone; similar mechanism to ivermectin
• Ascaris: 8 mg single dose
• Trichuris: 8 mg OD × 3 days (in combination with albendazole)

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C. PYRANTEL PAMOATE (Combantrin)

• Mechanism: Depolarising neuromuscular blocking agent - acts as nicotinic acetylcholine receptor agonist → persistent activation → spastic paralysis of worm → expelled by normal intestinal peristalsis
• Poorly absorbed from GI tract - acts locally
• Doses:
  • Ascaris, Enterobius: 11 mg/kg single dose (max 1 g)
  • Hookworm (heavy burden): 11 mg/kg × 3 days
  • Trichostrongylus: 11 mg/kg single dose
  • Enterobius: Repeat after 2 weeks
• Adverse Effects: Mild nausea, vomiting, diarrhoea, headache; generally very safe
• Contraindication: Do NOT combine with piperazine (antagonistic - piperazine causes flaccid paralysis vs. pyrantel's spastic paralysis)

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D. PIPERAZINE

• Mechanism: GABA agonist → opens Cl⁻ channels → flaccid paralysis of worm musculature → worm expelled alive by peristalsis
• Used for Ascaris and Enterobius when other agents unavailable
• Largely replaced by safer agents

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E. PRAZIQUANTEL (Biltricide) - Drug of Choice for Cestodes and Trematodes

• Mechanism:
  • Increases Ca²⁺ permeability of parasite cell membrane → influx of calcium → tetanic spasm/paralysis of worm musculature
  • Also damages worm tegument → exposes worm surface to immune attack
• Doses:
  • Taenia (tapeworms): 5-10 mg/kg single dose
  • Intestinal flukes (Fasciolopsis, Heterophyes): 25 mg/kg TDS × 1 day
  • Schistosoma: 40 mg/kg in 2 divided doses (S. mansoni/haematobium); 60 mg/kg in 3 doses (S. japonicum)
  • Clonorchis/Opisthorchis: 25 mg/kg TDS × 1 day
• ADME: Well absorbed orally; extensive first-pass hepatic metabolism; t½ ~1.5 hours
• Adverse Effects: Nausea, headache, dizziness, abdominal pain (Mazzotti-like reactions); generally transient; caution in neurocysticercosis (may trigger inflammatory reaction around dying cysts - use corticosteroids)

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F. TRICLABENDAZOLE (Egaten)

• Mechanism: Benzimidazole that uniquely inhibits tubulin in Fasciola (not nematodes)
• Treats fascioliasis: 10 mg/kg × 2 doses on consecutive days
• Also used for paragonimiasis

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G. NICLOSAMIDE

• Mechanism: Inhibits mitochondrial ATP synthesis in tapeworms by uncoupling oxidative phosphorylation → kills worm scolex (head) → worm detaches
• Used for tapeworms (Taenia, D. latum, H. nana): 2 g single dose (chewed)
• Now largely replaced by praziquantel

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H. DILOXANIDE FUROATE (Luminal Amoebiocide - also used for some protozoa)

• Not for helminths; cross-referenced as it may appear in parasite tables

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I. TREATMENT SUMMARY TABLE (Goldman-Cecil, Table 327-1)

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J. Adjunct Pharmacological Treatments

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9. PREVENTION AND PUBLIC HEALTH

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• Harrison's Principles of Internal Medicine 22E - Chapters 236-240 (all intestinal helminths); Table 327-1 (treatment doses)
• Goldman-Cecil Medicine - Table 327-1 Oral Treatment of Intestinal Nematodes
• Sherris & Ryan Medical Microbiology 8th Ed - Chapter 54 (Ascaris, Trichuris, Enterobius, Hookworm, Strongyloides life cycles and pathogenesis)
• Yamada's Textbook of Gastroenterology 7th Ed - Chapter 147 (hookworm clinical manifestations, diagnosis, treatment)
• Goodman & Gilman's - Anthelmintic pharmacology (benzimidazoles, ivermectin, praziquantel, pyrantel pamoate)