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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)

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Urinary Tract Infection (UTI): Complete Clinical Guide

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1. DEFINITION

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2. TYPES / CLASSIFICATION

A. By Anatomical Location

B. By Complexity

C. By Course

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3. CAUSES AND RISK FACTORS

Causative Organisms

Risk Factors

• Short urethra (anatomical - opens near vulva and perirectal area)
• Sexual activity, new sexual partner
• Spermicide use (disrupts vaginal flora, promotes E. coli colonisation)
• Prior UTI; family history of UTI (possible inherited urethral anatomy)
• Postmenopausal status (oestrogen deficiency → loss of Lactobacillus protection)
• Pregnancy (physiological urinary stasis; dilated ureters; progesterone smooth muscle relaxation)
• Diabetes mellitus
• High postvoid residual (incomplete emptying)

• Urological abnormalities (BPH, urethral stricture)
• Unretracted foreskin
• Male homosexuality (rectal E. coli)
• Lack of circumcision

• Urinary tract obstruction (calculi, stricture, tumour, BPH)
• Urinary instrumentation (catheterisation, cystoscopy)
• Vesicoureteral reflux
• Neurogenic bladder
• Immunosuppression (HIV, steroids, transplant)
• Hospital/nursing home setting
• Diabetes mellitus

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4. PATHOPHYSIOLOGY AND PATHOLOGY

Route of Infection

1. Colonisation of periurethral/perirectal area by enteric/vaginal flora (predominantly E. coli)
2. Colonisation of urethra → bladder ascent (facilitated by short female urethra; sexual intercourse; instrumentation)
3. Bladder infection (cystitis) → may ascend ureters to renal pelvis → pyelonephritis
4. The most common mechanism in pregnancy is ascending infection from perineal bacteria with fimbriated E. coli attaching to uroepithelial cells

Virulence Factors of Uropathogens (E. coli)

Host Defence Mechanisms (and their Failure)

• Urine flow (mechanical flushing) - impaired by obstruction, incomplete voiding
• Urinary pH, osmolality, organic acids
• Tamm-Horsfall protein (uromodulin) - binds bacteria; first-line defence
• Urothelial tight junctions - barrier
• Secretory IgA in urine
• Vaginal Lactobacillus flora in women - maintains acidic pH, produces H₂O₂

Pathology

• Mucosal erythema, oedema, petechiae
• Superficial infection of bladder mucosa - hence no systemic fever
• Microscopy: epithelial cell vacuolation, submucosa oedema, neutrophilic infiltrate

• Gross: kidney swollen, focal yellow-white abscesses on cortex (wedge-shaped)
• Micro: suppurative (neutrophilic) infiltrate in interstitium, tubules, collecting ducts; tubular necrosis; glomeruli relatively spared; pus-filled tubules
• Cortical abscesses when severe → renal carbuncle
• Complications: perinephric abscess, emphysematous pyelonephritis (gas-forming organisms in diabetics - life-threatening)

• Gross: coarse irregular corticomedullary scars; deformed calyces
• Micro: interstitial fibrosis, tubular atrophy, mononuclear infiltrate; "thyroidisation" (colloid casts in atrophic tubules resembling thyroid tissue)
• Occurs with vesicoureteric reflux (reflux nephropathy) or obstruction

• Xanthogranulomatous pyelonephritis: Lipid-laden macrophages (foam cells) replace renal parenchyma; associated with Proteus or E. coli + obstructing calculus; can mimic renal carcinoma
• Malacoplakia: Soft yellowish plaques of macrophages containing Michaelis-Gutmann bodies (calcified bacterial remnants); rare
• Emphysematous cystitis/pyelonephritis: Gas in bladder wall or renal parenchyma by glucose-fermenting organisms (E. coli, Klebsiella); mainly diabetics

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5. CLINICAL FEATURES

Uncomplicated Cystitis (Lower UTI)

• Dysuria (burning/stinging on micturition) - single most reliable symptom
• Urinary frequency (voiding small amounts frequently)
• Urgency (sudden, compelling desire to void)
• Suprapubic pain or pressure
• Haematuria (visible or microscopic)
• Nocturia
• Foul-smelling or cloudy urine (non-specific)
• NO fever, chills, or systemic symptoms
• Combination of dysuria + frequency predicts UTI in >90% of cases (in absence of vaginal discharge)

Acute Pyelonephritis (Upper UTI)

• Fever (≥38°C) - often high-spiking with rigors
• Flank/loin pain (unilateral or bilateral)
• Costovertebral angle tenderness (CVAT) on examination
• Nausea, vomiting
• Lower urinary tract symptoms (dysuria, frequency) - may precede or accompany
• Systemic toxaemia: malaise, myalgia, headache
• In pregnancy: right-sided predominance (right ureter more dilated)
• May progress to urosepsis → septic shock (10-20% mortality)

Prostatitis

• Acute bacterial prostatitis: Fever, chills, perineal/pelvic pain, dysuria, urinary retention, tender boggy prostate on PR (do NOT massage - bacteraemia risk)
• Chronic bacterial prostatitis: Voiding symptoms, low back and perineal pain, myalgias; recurrent UTIs in men

Asymptomatic Bacteriuria (ASB)

• No symptoms; detected on routine screening
• Treat in: Pregnant women, immunosuppressed, prior to urological procedures
• Do NOT treat in: Elderly, catheterised patients, diabetics (unless symptomatic) - treatment increases resistant organisms without clinical benefit

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6. DIAGNOSTIC APPROACH

Step 1: History

• Symptoms (onset, duration, character)
• Previous UTIs, recurrence pattern
• Sexual activity, spermicide use
• Pregnancy status
• Prior urological procedures, catheterisation
• Antibiotic use history (resistance risk)
• Comorbidities: DM, immunosuppression, renal disease

Step 2: Physical Examination

• Temperature (fever → upper UTI)
• Abdominal palpation - suprapubic tenderness
• CVA tenderness (CVAT) - hallmark of pyelonephritis
• PR examination in men (prostate tenderness/size)
• Pelvic examination in women (to exclude vaginitis, cervicitis)

Step 3: Urinalysis (Primary Diagnostic Test)

• Pyuria: ≥10 WBCs/mm³ (haemocytometer) - present in nearly all UTIs from coliforms
• Bacteria on microscopy: Most reliable test; Gram stain may identify organism class
• WBC casts: Highly specific for pyelonephritis (casts formed in renal tubules)
• RBC casts: Glomerulonephritis (distinguish from UTI)

• Positive culture: ≥10⁵ CFU/mL (conventional); ≥10³ CFU/mL acceptable with classic symptoms
• Identifies organism and antibiotic sensitivities (C&S)
• When to send culture:
  • Pyelonephritis
  • Complicated UTI
  • Recurrent or relapsing UTI
  • Pregnant women
  • Suspected multidrug-resistant organism
  • Men with UTI
  • No improvement after 48-72 hours of treatment
  • NOT required for uncomplicated cystitis in young women with typical symptoms

• Mid-stream clean catch (MSCC) urine - most common
• Catheter specimen (for inpatients/catheterised patients)
• Suprapubic aspiration (gold standard for infants and equivocal cases - any growth significant)

Step 4: Blood Tests (for Pyelonephritis/Complicated UTI)

Step 5: Imaging

• Previous urinary trauma/surgery
• Previous bladder/renal calculi
• Gross haematuria after resolution of infection
• Obstructive symptoms; high PVR
• Urea-splitting organisms on culture
• Immunocompromise/DM
• Repeated pyelonephritis
• Bacterial persistence despite sensitivity-based therapy

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7. MANAGEMENT

General Measures (All UTIs)

• Increased fluid intake (2-3 L/day) - dilutes urine, flushes bacteria
• Urinary analgesic: Phenazopyridine (bladder-specific local anaesthetic) for dysuria symptom relief (colours urine orange; max 2 days)
• Complete the full antibiotic course
• Treat underlying risk factors (calculi, obstruction, DM control)
• Remove/change urinary catheters where possible
• Follow-up culture (test of cure) for pregnant women, recurrent UTI, pyelonephritis

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8. PHARMACOLOGY

A. Treatment of Uncomplicated Cystitis (Lower UTI)

1. Nitrofurantoin (Macrobid, Macrodantin)

• Mechanism: Complex mechanism not fully understood; rapidly reduced intracellularly by bacterial nitroreductases to highly reactive intermediates → damage bacterial DNA, ribosomes, and multiple enzyme systems; both bacteriostatic and bactericidal (concentration-dependent)
• Spectrum: Gram-negatives (E. coli, Klebsiella, Enterobacteriaceae), Enterococci; NOT effective against Proteus, Pseudomonas, or Serratia
• Dose: Nitrofurantoin macrocrystals (Macrobid): 100 mg BD × 5 days (uncomplicated cystitis)
• ADME: Rapidly absorbed; concentrates only in urine (not in serum or tissues) → NOT suitable for upper UTI, pyelonephritis, bacteraemia, or systemic infections
• Advantages: Minimal effects on bowel or vaginal flora; exceedingly low acquired resistance in E. coli; inexpensive
• Adverse Effects: GI upset (take with food); pulmonary reactions (acute hypersensitivity pneumonitis or chronic pulmonary fibrosis - with prolonged use); peripheral neuropathy (long-term); hepatotoxicity (rare); haemolytic anaemia in G6PD deficiency
• Contraindications: eGFR <30 mL/min (inadequate urinary concentrations; accumulation of toxic metabolites); pregnancy at term (≥38 weeks) and first trimester when alternatives available; G6PD deficiency
• Avoid in: Pyelonephritis (does NOT achieve adequate tissue levels)

2. Trimethoprim-Sulfamethoxazole (TMP-SMX / Co-trimoxazole)

• Mechanism:
  • Sulfamethoxazole: Structural analogue of PABA → competitively inhibits dihydropteroate synthase → blocks dihydrofolic acid synthesis
  • Trimethoprim: Inhibits dihydrofolate reductase → blocks conversion of dihydrofolate to tetrahydrofolate (active form)
  • Sequential blockade of the same folate pathway = synergistic bactericidal effect (50:1 ratio in SMX:TMP in co-trimoxazole)
  • Human cells unaffected because they use dietary preformed folate
• Dose: 160/800 mg (one DS tablet) BD × 3 days (uncomplicated cystitis)
• Spectrum: E. coli, Klebsiella, Enterobacteriaceae; Staphylococci; Listeria; Pneumocystis
• Adverse Effects: GI upset; Stevens-Johnson syndrome (severe - rare); bone marrow suppression; hyperkalaemia (trimethoprim blocks renal K⁺ secretion); crystalluria; megaloblastic anaemia (folate deficiency with prolonged use)
• Contraindications: Pregnancy (first trimester - sulfonamides may cause foetal haemolysis and hyperbilirubinaemia; third trimester - risk of kernicterus); G6PD deficiency; severe renal failure
• Note: Rising resistance (up to 20-30% in some regions); check local antibiogram before empirical use

3. Fosfomycin Trometamol (Monurol)

• Mechanism: Inhibits MurA (UDP-N-acetylglucosamine enolpyruvyl transferase) → blocks the first step in peptidoglycan cell wall synthesis; bactericidal
• Dose: 3 g sachet as a SINGLE ORAL DOSE (uncomplicated cystitis); single dose is highly effective and improves compliance
• Spectrum: E. coli, Enterococcus faecalis; active against some ESBL-producers and VRE
• ADME: Well absorbed; concentrates in urine; urinary concentrations maintained for 24-48 hours after single dose
• Advantages: Single-dose therapy; active against multidrug-resistant organisms; safe in pregnancy
• Adverse Effects: Diarrhoea, nausea; headache
• Not effective for: Pyelonephritis (inadequate tissue levels)

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B. Treatment of Uncomplicated Pyelonephritis (Upper UTI - Outpatient)

4. Fluoroquinolones (First-Line for Outpatient Pyelonephritis)

Ciprofloxacin

• Mechanism: Inhibits bacterial DNA gyrase (topoisomerase II) and topoisomerase IV → prevents DNA supercoiling, replication, and repair → stabilises DNA-enzyme complex → lethal double-strand DNA breaks; bactericidal
• Dose: Ciprofloxacin XR 500-1000 mg OD × 7 days (pyelonephritis); or Ciprofloxacin 500 mg BD × 7 days
• Spectrum: Excellent against gram-negatives (E. coli, Klebsiella, Proteus, Pseudomonas); Staphylococci
• Advantages: Excellent tissue penetration including prostate (first-line for prostatitis); excellent urinary concentrations
• Adverse Effects: GI disturbances; CNS effects (dizziness, headache, seizures - rare); tendinopathy/tendon rupture (especially Achilles; risk with age >60, steroids); peripheral neuropathy; prolonged QT interval; photosensitivity; cartilage damage (avoid in children and pregnancy); Clostridioides difficile
• Resistance: Chromosomal mutations in DNA gyrase/topoisomerase IV; plasmid-mediated PMQR genes; up to 20-30% resistance in some regions; 80% resistance in transplant units using prophylactic fluoroquinolones
• Contraindications: Pregnancy, children, myasthenia gravis; caution with QT-prolonging drugs

Levofloxacin

• Third-generation fluoroquinolone; enhanced gram-positive activity vs. ciprofloxacin
• Dose: 250-500 mg OD × 7-10 days (uncomplicated pyelonephritis); 750 mg OD × 5 days (complicated)

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C. Treatment of Complicated UTI / Severe Pyelonephritis (Inpatient IV Therapy)

5. Third/Fourth-Generation Cephalosporins

Ceftriaxone

• Mechanism: Beta-lactam; binds Penicillin-Binding Proteins (PBPs) → inhibits transpeptidation step in peptidoglycan cross-linking → cell wall synthesis blocked → osmotic lysis
• Dose: 1-2 g IV once daily (pyelonephritis, urosepsis); first IV dose for severe pyelonephritis requiring admission
• Spectrum: Excellent gram-negative coverage (E. coli, Klebsiella, Proteus); limited Pseudomonas; Staphylococci (not MRSA)
• Adverse Effects: Hypersensitivity; GI disturbance; biliary sludge; cholecystitis (with high doses or prolonged use)

Cefepime (4th gen)

• Extended gram-negative coverage including Pseudomonas
• Dose: 1-2 g IV every 8-12 hours
• Used for complicated UTI/pyelonephritis

6. Aminoglycosides

Gentamicin / Amikacin

• Mechanism: Binds irreversibly to 30S ribosomal subunit → inhibits protein synthesis → causes mRNA misreading → insertion of wrong amino acids → dysfunctional proteins; also disrupts cell membrane
• Dose: Gentamicin 3-5 mg/kg/day IV (once-daily dosing preferred; monitor trough levels); Amikacin 15 mg/kg/day
• Advantages: Excellent urinary concentrations; bactericidal; active against Pseudomonas
• Adverse Effects: Nephrotoxicity (tubular necrosis; monitor creatinine); ototoxicity (vestibular > cochlear); avoid in pre-existing renal failure
• Use: Second-line; complicated UTI; hospital-acquired UTI

7. Piperacillin-Tazobactam

• Mechanism: Piperacillin (anti-pseudomonal penicillin) + tazobactam (beta-lactamase inhibitor) → protects from enzymatic inactivation
• Dose: 4.5 g IV every 6-8 hours
• Spectrum: Broad gram-negative including Pseudomonas; gram-positive; anaerobes
• Use: Complicated/hospital UTI; Pseudomonas UTI; ESBL-producing organisms (some strains)

8. Carbapenems

Meropenem / Imipenem-Cilastatin / Ertapenem

• Mechanism: Beta-lactam with broadest spectrum; stable to most beta-lactamases including ESBLs; binds PBPs → cell wall synthesis inhibition
• Use: Multidrug-resistant UTI (ESBL producers, carbapenem-sensitive Klebsiella); last resort for complicated UTI
• Dose: Meropenem 500 mg-1 g IV every 8 hours; Ertapenem 1 g IV once daily

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D. Treatment of Specific UTI Types

Trimethoprim (alone - used in UK)

• Mechanism: Inhibits dihydrofolate reductase alone
• Dose: 200 mg BD × 3 days (uncomplicated cystitis); or 100 mg ON for prophylaxis
• Commonly used in the UK as first-line for uncomplicated UTI

Nitrofurantoin vs Trimethoprim for Uncomplicated Cystitis (Efficacy)

• Both have ~85-90% clinical cure rates for uncomplicated cystitis
• Nitrofurantoin preferred when TMP-SMX resistance is >20% locally

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E. Antibiotic Selection by UTI Type - Treatment Summary

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F. Drugs for Recurrent UTI Prophylaxis

---

G. Non-Antibiotic Approaches for Recurrent UTI Prevention

---

9. SPECIAL POPULATIONS

---

• Rosen's Emergency Medicine - Chapter 85 (UTI in adults and pregnancy; drug tables; diagnostic approach)
• Campbell-Walsh-Wein Urology 3-Volume Set - Chapter 55 (Nitrofurantoin, fluoroquinolone pharmacology; antimicrobial formulary; recurrent UTI management)
• Comprehensive Clinical Nephrology 7th Ed - Chapter definitions, pathogenesis, pregnancy UTI
• Harrison's Principles of Internal Medicine 22E - Antibiotic mechanisms (nitrofurantoin, quinolones)
• Goldman-Cecil Medicine - Complicated UTI, Pseudomonas UTI management

---

Lithiasis (Urolithiasis / Nephrolithiasis): Complete Clinical Guide

---

1. DEFINITION

• Prevalence in the United States: 8.8% (NHANES 2007-2010); increasing over decades
• Annual economic burden: >$2.1 billion (2000 estimate, 50% increase from 1994)
• Recurrence rate: ~50% within 5-7 years if untreated
• Male > Female (3:1), though the gender gap is narrowing
• Peak incidence: 4th-6th decade of life
• Most stones pass spontaneously if <5 mm; those >7 mm rarely pass without intervention

---

2. TYPES OF URINARY CALCULI

Distribution in a Typical U.S. Population:

A. Calcium Stones (~75-80% of all stones)

1. Calcium Oxalate (Most Common - ~60-70%)

• Monohydrate (whewellite): Dumbbell or oval shape; harder; more dense; worse fragmentation with ESWL
• Dihydrate (weddellite): Envelope shape; more amenable to ESWL
• Radiopaque on plain X-ray
• Associated with: Hypercalciuria, hyperoxaluria, hypocitraturia, hyperuricosuria, low urine volume
• Urine pH: Usually acidic to neutral (5.5-6.5)

2. Calcium Phosphate (~10-20%)

• Brushite (calcium hydrogen phosphate dihydrate): More common in younger patients; resistant to ESWL
• Hydroxyapatite: Component of struvite and other mixed stones
• Radiopaque
• Associated with: Distal renal tubular acidosis (Type 1 RTA), primary hyperparathyroidism, alkaline urine
• Urine pH: Alkaline (>6.5)

B. Struvite Stones (Infection/Triple Phosphate Stones - ~15-20%)

• Composition: Magnesium Ammonium Phosphate (MAP) + calcium carbonate apatite
• Also called "triple phosphate" (magnesium + ammonium + phosphate) or "infection stones"
• Form staghorn calculi (fill the renal pelvis and calyces)
• Require urease-producing bacteria (most commonly Proteus mirabilis, also Klebsiella, Pseudomonas, Staphylococcus aureus - see Section 3)
• Urine pH: Persistently alkaline (>7.0-7.2)
• Radiopaque (often visible even on plain X-ray)
• More common in women (higher UTI prevalence); also in patients with neurogenic bladder, spinal cord injury, indwelling catheters
• Sometimes called "stone cancer" due to significant morbidity from recurrent infection and renal damage

C. Uric Acid Stones (~5-10%)

• Radiolucent on plain X-ray (visible on CT and ultrasound; filling defects on IVU)
• Associated with: Acidic urine (pH <5.5), hyperuricosuria, low urine volume
• Found in: Gout patients, metabolic syndrome, diabetes mellitus (insulin resistance → impaired ammoniagenesis → acidic urine), high purine diet, myeloproliferative disorders, Lesch-Nyhan syndrome, tumour lysis syndrome
• Uric acid stones in Mediterranean and Middle Eastern countries: up to 75% of all stones
• Amenable to dissolution (chemolysis) by alkalinising the urine to pH 6.5-7.0 with potassium citrate

D. Cystine Stones (~1-2%)

• Due to cystinuria - autosomal recessive (or dominant with incomplete penetrance) disorder of dibasic amino acid transport in proximal tubule and jejunum
• Defective tubular reabsorption of Cystine, Ornithine, Lysine, Arginine (mnemonic: COLA)
• Yellow-brown; moderately radiopaque (high sulfur content); waxy appearance
• First present in 2nd-3rd decade of life
• Urine: hexagonal cystine crystals (pathognomonic)
• Poor fragmentation with ESWL
• Treatment: high fluid intake, alkalinisation, penicillamine or tiopronin (thiol chelators)

E. Drug-Induced Stones

F. Other/Rare Stones

• Xanthine stones: Xanthinuria (congenital) or allopurinol therapy (xanthine oxidase inhibition)
• 2,8-dihydroxyadenine: Adenine phosphoribosyltransferase (APRT) deficiency
• Ammonium acid urate: Malabsorptive states, laxative abuse
• Silica (very rare): Related to silica antacids

---

3. CAUSES AND RISK FACTORS

Common Metabolic Risk Factors

Non-Metabolic Risk Factors

• Anatomic: Horseshoe kidney, medullary sponge kidney, calyceal diverticulum, ureteropelvic junction (UPJ) obstruction, vesicoureteric reflux - all cause urine stasis
• Infection: Urease-producing organisms (Proteus, Klebsiella, Pseudomonas, S. aureus, Ureaplasma urealyticum)
• Dietary: High animal protein (↑ calcium and uric acid excretion, ↓ citrate), high sodium (↑ calciuria), high oxalate foods, low calcium diet paradoxically increases stone risk (free oxalate in gut)
• Genetic: Cystinuria, primary hyperoxaluria (types I/II/III), Dent disease, APRT deficiency
• Medications: As listed above
• Systemic disease: Primary hyperparathyroidism, sarcoidosis, malignancy, inflammatory bowel disease, gout, type 1 RTA, diabetes mellitus, metabolic syndrome
• Lifestyle: Obesity (↑ uric acid, ↓ urine pH), sedentary lifestyle, hot climate, dehydration, global warming

---

4. PATHOPHYSIOLOGY

Core Concept: Supersaturation and Crystallisation

PATHOPHYSIOLOGY FLOWCHART
═══════════════════════════════════════════════════════════════

PREDISPOSING FACTORS
  ├── ↑ Lithogenic solutes (↑Ca²⁺, ↑Oxalate, ↑Urate, ↑Cystine)
  ├── ↓ Urine volume (dehydration, low fluid intake)
  ├── ↓ Inhibitors (↓Citrate, ↓Magnesium, ↓Pyrophosphate, ↓Tamm-Horsfall)
  ├── Abnormal urine pH (acidic → uric acid; alkaline → CaPO₄, struvite)
  └── Structural abnormality (stasis) / Infection (urease bacteria)
                    │
                    ▼
        URINARY SUPERSATURATION
   (Free ion activity product > Equilibrium solubility product)
                    │
                    ▼
         NUCLEATION
   ┌─────────────────────────────────────────────────────────┐
   │  Homogeneous: same ions join (Ca²⁺ + Ox²⁻ → CaOx crystal)│
   │  Heterogeneous: crystal grows on existing surface        │
   │  (e.g., CaOx nucleates on uric acid crystals,            │
   │   on sloughed epithelial cells, or on Randall plaques)   │
   └─────────────────────────────────────────────────────────┘
                    │
                    ▼
          CRYSTAL GROWTH
   (Rate increases with supersaturation)
                    │
                    ▼
         CRYSTAL AGGREGATION
   (Small crystals clump → larger particles)
                    │
                    ▼
       CRYSTAL RETENTION / ANCHORING
   ┌──────────────────────────────────────────────────────────┐
   │ Calcium oxalate crystals anchor to RANDALL PLAQUES       │
   │ (calcium phosphate deposits in renal papillae originating│
   │ around thin loop of Henle → erode through papillary      │
   │ epithelium → exposed to pelvic urine → CaOx deposits)    │
   │                                                          │
   │ OR: Collecting duct plugs (Bellini duct plugs) form from │
   │ supersaturated tubular fluid → crystal retention         │
   └──────────────────────────────────────────────────────────┘
                    │
                    ▼
         STONE GROWTH → CLINICALLY APPARENT CALCULUS
   (Continued deposition → growth → detachment → migration)
                    │
                    ▼
        STONE MIGRATION INTO URETER
                    │
        ┌───────────┴────────────┐
        │                        │
   OBSTRUCTION              STONE PASSES
   (Pain, hydronephrosis,    spontaneously
   AKI if bilateral)          in urine
        │
        ▼
   URETERAL COLIC → RENAL COLIC (pain)
   └── Peristaltic contractions against obstruction
   └── Ureteral smooth muscle spasm
   └── Distension of collecting system → prostaglandin release
       → stimulate pain receptors → severe, colicky loin-to-groin pain

═══════════════════════════════════════════════════════════════

Stone-Specific Pathophysiology

Calcium Oxalate Stone Pathophysiology

Increased dietary oxalate / malabsorption (fatty acids bind Ca²⁺ in gut)
            ↓
Unbound free oxalate → absorbed by colon → hyperoxaluria (urinary oxalate ↑)
            +
Hypercalciuria (absorptive / resorptive / renal leak)
            +
Hypocitraturia (citrate normally chelates Ca²⁺ → reduces free [Ca²⁺])
            ↓
CaOx supersaturation → Randall plaque nucleation site → CaOx stone

• Citrate: (1) Chelates Ca²⁺ → reduces free ionic Ca; (2) directly inhibits CaOx precipitation; (3) prevents crystal aggregation; (4) prevents heterogeneous nucleation of CaOx by urate
• Magnesium: Complexes oxalate → reduces ionic [Ox]; reduces Ca-Ox contact time
• Pyrophosphate: Inhibits crystal nucleation and growth (25-50% of inhibitory activity)
• Tamm-Horsfall protein (uromodulin): Binds crystal components; prevents aggregation
• Glycosaminoglycans (chondroitin sulfate): Bond with crystal surface Ca²⁺ ions → inhibit nucleation and growth
• Osteopontin: Inhibits crystal adhesion to urothelium

Struvite Stone Pathophysiology

Urease-producing bacteria (Proteus mirabilis, Klebsiella, etc.)
            ↓
Urease enzyme: Urea (CO(NH₂)₂) → NH₃ + CO₂
            ↓
NH₃ + H₂O → NH₄⁺ + OH⁻ → ALKALINE URINE (pH >7.2)
            ↓
CO₂ → Carbonate → combines with Ca²⁺ + PO₄³⁻ → Calcium carbonate apatite
            +
NH₄⁺ + Mg²⁺ + PO₄³⁻ + H₂O → Magnesium Ammonium Phosphate (Struvite)
            ↓
Rapidly growing → fills renal pelvis and calyces → STAGHORN CALCULUS

Uric Acid Stone Pathophysiology

↑ Purine intake / cell turnover / gout / metabolic syndrome
            ↓
↑ Uric acid production → hyperuricaemia + hyperuricosuria
            +
Acidic urine (pH <5.5) → uric acid poorly soluble (pKa = 5.35)
    [In metabolic syndrome/DM: insulin resistance → impaired NH₃ production → 
    reduced urinary buffering → acidic urine even without hyperuricosuria]
            ↓
Uric acid supersaturation → crystallisation → uric acid stone

Cystine Stone Pathophysiology

Genetic mutation (SLC3A1 or SLC7A9 genes) 
→ Defective apical amino acid transporter in proximal tubule + jejunum
→ Failure to reabsorb dibasic amino acids: Cystine, Ornithine, Lysine, Arginine
→ Cystinuria: Cystine >250 mg/day
→ Cystine insoluble at normal urine pH → crystallises → forms waxy yellow-brown stones
(Cystine solubility: ~250 mg/L at pH 7; increases markedly at pH >7.5)

---

5. CLINICAL FEATURES

Acute Renal Colic (Most Dramatic Presentation)

• Abrupt onset, severe, colicky flank pain radiating anteriorly and downward:
  • Ureteropelvic junction stone: Loin/flank pain
  • Mid-ureteral stone: Pain radiates to iliac fossa and groin
  • Lower ureteral stone: Pain radiates to testis/labia majora, inner thigh, suprapubic area
  • Vesicoureteric junction stone: Lower urinary tract symptoms (urgency, frequency, dysuria)
• Pain is colicky (waves every 20-60 min as ureter peristalses) but typically not completely resolving between episodes
• Patient writhes and cannot find comfortable position (distinguishes from peritonitis where patient lies still)
• Nausea, vomiting (renal and GI neural connections)
• Haematuria (visible ~30% of cases; microscopic ~90%)
• Fever + rigors: Suggests infected obstructed kidney (urological emergency - urosepsis)

Other Presentations

---

6. DIAGNOSTIC APPROACH

DIAGNOSTIC FLOWCHART

PATIENT PRESENTS WITH
Acute loin/flank pain ± haematuria ± urinary symptoms
                    │
                    ▼
        CLINICAL ASSESSMENT
    History: Pain character, radiation, prior stones, fever, medications,
             diet, family history, systemic disease (gout, IBD, hyperPTH)
    Exam: CVA tenderness, abdominal palpation, temperature
                    │
                    ▼
    INITIAL INVESTIGATIONS (ALL CASES)
    ┌─────────────────────────────────────────────────────┐
    │  1. Urine dipstick + microscopy (haematuria? pyuria?)│
    │  2. Urine culture (if fever, pyuria)                 │
    │  3. Serum: FBC, CRP, U&E/Cr, Ca, Uric acid, PO₄    │
    │  4. Blood glucose                                    │
    │  5. Pregnancy test (women of childbearing age)       │
    └─────────────────────────────────────────────────────┘
                    │
                    ▼
         PRIMARY IMAGING
    ┌─────────────────────────────────────────────────────┐
    │  NON-CONTRAST CT KUB (NCCT) ← GOLD STANDARD        │
    │  Sensitivity 98%, Specificity 97%                   │
    │  Detects all stone types including radiolucent      │
    │  Provides: Stone size, location, density (HU),     │
    │  hydronephrosis, alternative diagnoses              │
    │                                                     │
    │  OR Ultrasound (first-line in pregnancy, children)  │
    │  - No radiation; detects stones, hydronephrosis     │
    │  - Lower sensitivity for small/ureteral stones      │
    └─────────────────────────────────────────────────────┘
                    │
                    ▼
         STONE CONFIRMED?
    ┌─────┴──────────────────────────────────┐
    YES                                      NO
     │                                        │
     ▼                                        ▼
  ASSESS:                              Consider alternative:
  • Stone size and location              AAA, ectopic pregnancy,
  • Degree of obstruction                appendicitis, ovarian torsion,
  • Signs of infection                   pancreatitis, muscle strain,
  • Single/solitary kidney               pulmonary embolism
                    │
                    ▼
    ┌─────────────────────────────────────────────────────┐
    │  STONE ANALYSIS (when stone passed/retrieved)       │
    │  - MANDATORY for recurrent stone formers            │
    │  - Infra-red spectroscopy or X-ray crystallography  │
    └─────────────────────────────────────────────────────┘
                    │
                    ▼
    FOR RECURRENT/METABOLICALLY ACTIVE STONES:
    24-HOUR URINE COLLECTION (see Table below)
    ┌─────────────────────────────────────────────────────┐
    │  Parameters: Volume, Ca, Oxalate, Uric acid,        │
    │  Citrate, Na, PO₄, pH, Creatinine (adequacy check) │
    │  Target values: See Table 60.2                      │
    └─────────────────────────────────────────────────────┘

Investigations in Detail

A. Urinalysis

B. Blood Tests

C. Imaging

D. Urine Culture

• Mandatory when fever, pyuria, or struvite stone suspected
• Specify "identify organism even if <10⁵ CFU/mL" to detect Ureaplasma urealyticum

E. 24-Hour Urine Collection (for recurrent stone formers, metabolically active stones, all children)

F. Indications for Further Investigation in Recurrent UTI/Stone Disease

• Previous urinary trauma or surgery
• Bladder or renal calculi
• Gross haematuria after resolution of infection
• Obstructive symptoms, low uroflowmetry, high postvoid residual
• Urea-splitting bacteria on culture
• Prior abdominopelvic malignancy
• Bacterial persistence despite sensitivity-guided therapy
• Diabetes or immune compromise

---

7. MANAGEMENT

MANAGEMENT FLOWCHART

STONE CONFIRMED ON IMAGING
                │
                ▼
    EMERGENCY ASSESSMENT
    Fever + obstruction?   ─── YES ──► UROSEPSIS/PYONEPHROSIS
                │                      Immediate: IV antibiotics +
                │                      Emergency drainage (DJ stent or PCN)
               NO                      IV fluids, ICU if septic shock
                │
                ▼
    Pain control adequate?  ─── NO ──► Escalate analgesia (see below)
                │
                ▼
    STONE SIZE ASSESSMENT
    ┌────────────────────────────────────────────────────┐
    │  <5 mm: 90-95% pass spontaneously                 │
    │  5-7 mm: ~50% pass spontaneously                  │
    │  >7-10 mm: <29% pass without intervention         │
    │  >10 mm: Very unlikely to pass; intervention needed│
    └────────────────────────────────────────────────────┘
                │
                ▼
    ┌───────────────────────────────────────────────────────────┐
    │               CONSERVATIVE MANAGEMENT                    │
    │  (Stones ≤7 mm with controlled pain + no complications)  │
    │  - High fluid intake (2-3 L/day) → "flush" stone         │
    │  - Analgesia (NSAIDs first-line; opioids if needed)      │
    │  - Strain urine (collect stone for analysis)             │
    │  - Medical Expulsive Therapy (MET): tamsulosin 400 μg OD │
    │    (α-blocker for distal ureteral stones ≤10 mm)         │
    │  - Follow-up imaging to confirm passage                  │
    └───────────────────────────────────────────────────────────┘
                │
      Stone passes? ─── YES ──► Stone analysis + metabolic evaluation
                │                → Prevention therapy (see pharmacology)
               NO
                │
     Indications for intervention:
     • Pain persistent >72h despite analgesia
     • Stone >7-10 mm unlikely to pass
     • Obstruction with impaired renal function (single kidney, bilateral)
     • Urinary sepsis + obstruction
     • Recurrent/intractable vomiting
     • Complete obstruction
                │
                ▼
    ┌────────────────────────────────────────────────────────────┐
    │                SURGICAL INTERVENTION                      │
    │  Select modality based on stone size, location, type:     │
    │                                                           │
    │  ESWL (Extracorporeal Shock Wave Lithotripsy)             │
    │  • Stones ≤2 cm in kidney; distal ureteral stones         │
    │  • Focused high-energy shock waves → stone fragmentation  │
    │  • Non-invasive; general or IV sedation                   │
    │  • NOT for: cystine, brushite (hard); BMI >30;            │
    │    aortic aneurysm; coagulopathy; pregnancy; pacemaker   │
    │  • Passage of fragments over days-weeks after procedure  │
    │                                                           │
    │  URETEROSCOPY (URS) + Laser Lithotripsy                   │
    │  • All ureteral stones; renal stones ≤2 cm                │
    │  • Rigid (lower ureter) or flexible (upper ureter/kidney) │
    │  • Holmium:YAG laser fragments stone → basket extraction  │
    │  • Avoid in children <5 years                             │
    │  • DJ (double-J) stent placed post-procedure if needed    │
    │                                                           │
    │  PERCUTANEOUS NEPHROLITHOTOMY (PCNL)                      │
    │  • Renal stones >2 cm, staghorn calculi                   │
    │  • ESWL-refractory stones <2 cm                           │
    │  • Multiple stones, cystine stones (poor ESWL response)   │
    │  • Percutaneous tract dilated → nephroscope + lithotripsy │
    │  • Most invasive; highest stone-free rate for large stones │
    │  • Mini/micro/ultra-PCNL: smaller tracts, less morbidity  │
    │                                                           │
    │  OPEN SURGERY (Pyelolithotomy, Ureterolithotomy)          │
    │  • Rare: only when all minimally invasive options fail     │
    │  • Anatomic abnormalities precluding endoscopic access    │
    │                                                           │
    │  LAPAROSCOPIC / ROBOTIC SURGERY                           │
    │  • Intermediate option; UPJ obstruction + stone           │
    │                                                           │
    │  CHEMOLYSIS                                               │
    │  • Oral alkalinisation: URIC ACID stones dissolve at      │
    │    pH >6.5 with potassium citrate                         │
    │  • Direct irrigation: struvite stones with Renacidin     │
    └────────────────────────────────────────────────────────────┘

Surgical Approach Summary Table

---

8. PHARMACOLOGY

A. Analgesia for Acute Renal Colic

1. NSAIDs - FIRST-LINE ANALGESICS

Diclofenac / Ketorolac / Ibuprofen

• Mechanism: Inhibit COX-1 and COX-2 (cyclooxygenase enzymes) → block prostaglandin (PGE₂) synthesis → reduces ureteral smooth muscle spasm; reduces inflammation and pain; reduces glomerular filtration → decreases urine flow proximal to obstruction (reduces distension pressure)
• Dose: Diclofenac 75 mg IM/IV; Ketorolac 30 mg IV/IM; Ibuprofen 400-600 mg PO
• Advantages: Superior to opioids for renal colic in multiple RCTs; reduces spasm AND pain; antiemetic effect via prostaglandin reduction
• Contraindications: Renal impairment (use with caution; AKI risk); GI ulceration; coagulopathy; pregnancy; allergy; solitary obstructed kidney (may precipitate acute renal failure)

2. Opioid Analgesics (Second-Line / Adjunct)

Morphine / Tramadol / Pethidine (Meperidine)

• Mechanism: Bind μ-opioid receptors → inhibit pain transmission; raise pain threshold; central and peripheral analgesia
• Dose: Morphine 2.5-5 mg IV/IM; Tramadol 50-100 mg IV/IM/PO; Pethidine 50-100 mg IM
• Use: When NSAIDs contraindicated or inadequate; combined with NSAIDs for severe colic
• Adverse Effects: Nausea/vomiting (add antiemetic); sedation; respiratory depression; constipation; pethidine has toxic metabolite (norpethidine) - avoid in renal failure

3. Antiemetics

• Metoclopramide 10 mg IV/IM; Ondansetron 4-8 mg IV - for nausea/vomiting associated with colic and opioids

4. Antispasmodics (Limited evidence for colic)

• Hyoscine butylbromide (Buscopan) 20 mg IM/IV - smooth muscle relaxant; may reduce ureteral spasm

---

B. Medical Expulsive Therapy (MET) - To Facilitate Stone Passage

5. Tamsulosin (Alpha-1A Blocker)

• Mechanism: Selective antagonist of α₁A and α₁D adrenoceptors in ureteral smooth muscle (particularly the distal ureter) and trigone → relaxes ureteral smooth muscle → reduces baseline tone and intrinsic ureteral peristalsis → ↓ resistance to stone passage → facilitates spontaneous expulsion; preserves propulsive peristalsis
• Dose: 0.4 mg (400 μg) once daily until stone passes (up to 4 weeks)
• Evidence: Most guidelines recommend for distal ureteral stones <10 mm; data mixed from large RCTs (UK SUSPEND trial showed no benefit; multiple meta-analyses show benefit); used in most urology guidelines
• Adverse Effects: Orthostatic hypotension, dizziness, retrograde ejaculation, rhinitis
• Contraindications: Hypotension; caution with phosphodiesterase-5 inhibitors (severe hypotension risk)

6. Nifedipine (Calcium Channel Blocker - Alternative MET)

• Mechanism: Blocks L-type voltage-gated calcium channels in ureteral smooth muscle → ↓ intracellular Ca²⁺ → smooth muscle relaxation → facilitates stone passage
• Dose: 30 mg once daily (extended-release)
• Less favoured than tamsulosin; more systemic vasodilation

---

C. Long-Term Prevention Pharmacology

7. Potassium Citrate (First-Line Prevention Drug)

• Mechanism (Multiple Actions):
  1. Citrate supplementation: Directly raises urinary citrate → citrate chelates Ca²⁺ → reduces free [Ca²⁺] for crystal formation; inhibits crystal nucleation, aggregation, and growth
  2. Alkalinises urine: Citrate metabolised to bicarbonate → raises urine pH → dissolves uric acid stones; increases cystine solubility; reduces CaOx supersaturation
  3. Potassium (not sodium) minimises calciuria (sodium supplements increase urinary calcium)
• Dose: 15-25 mmol (1-2 tablets) 2-3 times daily with meals
• Indications: Hypocitraturia (citrate <320 mg/24h); uric acid stones; distal RTA; post-intestinal surgery (hyperoxaluria); recurrent calcium oxalate stones; ADPKD-associated stones; cystine stones (in combination)
• Adverse Effects: GI intolerance (take with food); hyperkalemia (monitor K⁺ in renal failure); tablets preferred over liquid (less GI upset)
• Monitoring: Serum K⁺ especially if eGFR <60 mL/min

8. Thiazide Diuretics (Hypercalciuria Treatment)

Hydrochlorothiazide / Chlorthalidone / Indapamide

• Mechanism: Block Na⁺-Cl⁻ co-transporter (NCC) in distal convoluted tubule → ↓ intracellular Na⁺ → activates basolateral Na⁺/Ca²⁺ exchanger → ↑ tubular calcium reabsorption → ↓ urinary calcium excretion (hypocalciuric effect) → reduces calcium oxalate/phosphate supersaturation → prevents stone formation
• Dose: Hydrochlorothiazide 25-50 mg/day; Chlorthalidone 25-50 mg/day; Indapamide 1.25-2.5 mg/day
• Indication: Idiopathic hypercalciuria (absorptive or renal leak); recurrent calcium stones with urinary calcium >300 mg/24h
• Adverse Effects: Hypokalaemia (supplement K⁺; will also worsen hypocitraturia); hyponatraemia; hyperuricaemia; glucose intolerance; impotence; volume depletion
• Note: Combine with potassium citrate to correct thiazide-induced hypokalaemia (hypokalaemia → ↓ citrate excretion → worsens stone risk)

9. Allopurinol (Uric Acid Stone and Hyperuricosuric Calcium Oxalate Stones)

• Mechanism: Structural analogue of hypoxanthine; competitive inhibitor of xanthine oxidase → blocks conversion of hypoxanthine → xanthine → uric acid → ↓ serum and urinary uric acid levels → ↓ urate crystal nucleation of calcium oxalate; prevents uric acid stone formation
• Dose: 100-300 mg/day (start low; titrate); taken after meals
• Indications:
  • Uric acid nephrolithiasis with hyperuricosuria or hyperuricaemia
  • Hyperuricosuric calcium oxalate nephrolithiasis
  • Gout with renal stones
  • Tumour lysis prophylaxis
• Adverse Effects: Hypersensitivity rash (can progress to SJS/TEN - discontinue immediately); GI upset; hepatotoxicity; DRESS syndrome; drug interactions (azathioprine - life-threatening; warfarin - increased INR); febuxostat is alternative in allopurinol intolerance
• Monitoring: Liver function, uric acid levels, renal function

10. Penicillamine / Tiopronin (Cystine Stones)

• Mechanism: Thiol chelation - sulfhydryl group of drug forms mixed disulfide with cysteine → converts poorly soluble cystine to soluble cysteine-drug complex → increases urinary cystine solubility (up to 5x)
  • Penicillamine: D-penicillamine + cysteine → D-penicillamine-cysteine mixed disulfide
  • Tiopronin: More tolerated alternative with same mechanism
• Dose: Penicillamine 250 mg QDS; Tiopronin 100-300 mg TDS (titrate to urinary cystine <250 mg/day)
• Adverse Effects (Penicillamine): Severe - thrombocytopenia, proteinuria, nephrotic syndrome, SLE-like reaction, myasthenia, rash; tiopronin has better tolerability
• Combination: Always with high fluid intake (>3L/day) AND urinary alkalinisation (potassium citrate to pH >7.5)

11. Acetohydroxamic Acid (AHA) - Struvite Stone Prevention

• Mechanism: Irreversible inhibitor of urease enzyme → blocks bacterial urea hydrolysis → prevents alkaline urine and ammonia production → inhibits struvite crystal formation
• Dose: 250 mg three to four times daily
• Use: Struvite (infection) stone prevention; adjunct to antibiotics
• Adverse Effects: Teratogenic (contraindicated in pregnancy); haemolytic anaemia; deep vein thrombosis; tremor; headache; rash
• Limitation: Significant side-effect profile limits widespread use; requires kidney function (Cr <2.5 mg/dL)

12. Antibiotics (Struvite Stones)

• Rationale: Complete stone removal is necessary to cure struvite stones; ongoing antibiotics prevent regrowth from bacteria sequestered in stone interstices
• After PCNL for struvite: Stone fragments cultured → culture-specific antibiotics continued; urine sterilised ~2 weeks post-initiation; dose halved when sterile; monthly urine cultures for 3+ months
• Prophylaxis: Long-term suppressive antibiotics (fluoroquinolone or TMP-SMX based on sensitivities) to prevent reinfection and stone regrowth

---

D. Stone-Type Prevention Summary

---

E. Pharmacology of Key Urological Drugs - Quick Reference

---

9. SPECIAL SITUATIONS

---

• Comprehensive Clinical Nephrology 7th Ed - Chapter 60 (Stone pathogenesis, types, metabolic evaluation, medical management, inhibitors, 24h urine targets) and Chapter 63 (Surgical management, imaging)
• Campbell-Walsh-Wein Urology 3-Volume Set - Chapter 92 (Infection calculi, struvite pathophysiology, urease-producing organisms) and Chapter 50 (Inhibitors and promoters, crystal formation mechanisms)
• Schwartz's Principles of Surgery 11th Ed - Chapter 40 (Stone epidemiology, types, diagnostic approach, surgical management)
• National Kidney Foundation Primer on Kidney Diseases 8th Ed - Chapter 45 (Pathophysiology, supersaturation, urinary risk factors, calcium stone formation)
• Bailey and Love's Short Practice of Surgery 28th Ed - Urolithiasis in children (ESWL, URS, PCNL sizing criteria)
• Rosen's Emergency Medicine - Acute renal colic diagnosis and emergency managementHere is your complete comprehensive guide on Lithiasis (Urolithiasis). Here is a summary of what was covered:

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What This Guide Covers

1. Definition

2. Types of Stones (with distribution pie chart)

• Calcium oxalate (~60-70%) - most common; radiopaque; monohydrate (dumbbell) and dihydrate (envelope) crystal forms
• Calcium phosphate (~10-20%) - includes brushite; alkaline urine; associated with RTA and hyperparathyroidism
• Struvite (~15-20%) - infection stones; magnesium ammonium phosphate; form staghorn calculi; need urease-producing bacteria
• Uric acid (~5-10%) - radiolucent; acidic urine; dissolvable with alkalinisation
• Cystine (~2%) - autosomal recessive; hexagonal crystals; COLA amino acids
• Drug-induced - indinavir, triamterene, topiramate, acyclovir, loop diuretics

3. Causes and Risk Factors

4. Pathophysiology + Flowcharts

• Master flowchart: Predisposing factors → Supersaturation → Nucleation (homogeneous/heterogeneous) → Crystal growth → Aggregation → Randall plaque anchoring → Stone growth → Ureteral migration → Colic
• Stone-specific pathways: CaOx (enteric hyperoxaluria), Struvite (urease cascade: urea → NH₃ → alkaline urine → MgNH₄PO₄), Uric acid (acidic urine + hyperuricosuria), Cystine (genetic transporter defect)
• Key inhibitors: citrate, magnesium, pyrophosphate, Tamm-Horsfall protein, glycosaminoglycans

5. Clinical Features

• Acute renal colic: abrupt onset severe colicky flank pain with location-dependent radiation (loin → groin → testis/labia); haematuria; nausea/vomiting; patient writhes
• Other presentations: asymptomatic, recurrent UTI, chronic loin pain, AKI, urosepsis

6. Diagnostic Approach (with flowchart)

• Urinalysis: pH, crystals (hexagonal = cystine pathognomonic; coffin-lid = struvite; envelope = CaOx)
• Blood: Ca, PTH, uric acid, eGFR, FBC/CRP
• NCCT (gold standard): 98%/97% sensitivity/specificity; all stone types; low-dose CT preferred
• Radiopacity table: uric acid is radiolucent; drug stones may be invisible even on CT
• 24-hour urine collection targets table for recurrent stone formers

7. Management (with flowchart)

• Emergency: Infected obstructed kidney → immediate decompression (DJ stent or PCN) + IV antibiotics
• Conservative: Stones ≤7 mm with controlled pain; hydration, analgesia, MET, strain urine
• Surgical: ESWL (≤2 cm, non-cystine); URS + laser lithotripsy (all ureteral stones, renal ≤2 cm); PCNL (>2 cm, staghorn); open surgery (last resort)
• Chemolysis: uric acid stones dissolve with urinary alkalinisation

8. Pharmacology

• Analgesia: NSAIDs first-line (diclofenac - COX inhibition → ↓PGE₂ → ↓ureteral spasm); opioids second-line
• MET: Tamsulosin 0.4 mg OD (α₁A-blocker → relax distal ureteral smooth muscle); Nifedipine (CCB) as alternative
• Prevention: Potassium citrate (↑citrate, alkalinise); Thiazides (↑distal tubular Ca reabsorption → ↓calciuria); Allopurinol (xanthine oxidase inhibitor → ↓uric acid); Penicillamine/Tiopronin (thiol chelators for cystine); Acetohydroxamic acid (urease inhibitor for struvite); Antibiotics for struvite eradication