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Malformations of the Genitourinary System: Hypospadias & Epispadias

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I. HYPOSPADIAS

Definition

Embryology

Incidence

• Approximately 1 in 200–300 male births (one of the most common congenital penile anomalies)
• Higher incidence in first-degree relatives

Classification

Clinical Features

• Abnormal urinary stream (deflected downward/ventral)
• Chordee — ventral curvature of the penis (more common in proximal types)
• Dorsal hooded prepuce (incomplete foreskin ventrally)
• Difficulty with micturition in proximal types
• Psychosocial / sexual dysfunction if untreated

Associations

• Cryptorchidism (~10%)
• Inguinal hernia
• In severe cases: disorders of sex development (DSD) should be excluded

Management

1. Timing: Ideally before 18 months of age
2. Distal hypospadias:
   • Often repaired for cosmetic and functional reasons
   • Technique of choice: Tubularised Incised Plate (TIP) urethroplasty (Snodgrass procedure)
3. Proximal hypospadias with chordee: Two-stage repair
   • Stage 1: Correct penile curvature (chordee release ± skin grafting)
   • Stage 2: Urethral reconstruction (urethroplasty using preputial or buccal mucosa)
4. Circumcision should be avoided prior to repair — preputial skin is valuable tissue for reconstruction

Complications of Surgery

• Urethrocutaneous fistula (most common)
• Meatal stenosis
• Urethral stricture
• Wound dehiscence
• Persistent/recurrent chordee

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II. EPISPADIAS

Definition

A useful conceptual mnemonic: if hypospadias results from a ventral opening (scissors blade into the urethra, cutting ventrally), epispadias is the dorsal counterpart — cutting dorsally through the penis and pubis into the bladder.

Incidence

• Much rarer than hypospadias: ~1 in 117,000 males, ~1 in 484,000 females

Embryology

Classification (Males)

Epispadias–Exstrophy Complex

Clinical Features

• Dorsal urethral opening on the penis
• Dorsal chordee (upward penile curvature)
• Urinary incontinence — common, especially in penopubic type (incompetent bladder neck)
• Widened pubic symphysis (diastasis) in exstrophy
• Fertility issues — retrograde ejaculation, epididymo-orchitis risk

In Females

• Short, wide urethra with cleft clitoris
• Incontinence is the predominant symptom
• Bifid clitoris

Management

1. Penile/bladder neck reconstruction — restore continence
2. Urethral reconstruction — tubularize the dorsal urethral plate
3. Pelvic osteotomy — for bladder exstrophy (to close the pubic diastasis)
4. Bladder augmentation / urinary diversion — in severe exstrophy

• Boys with epispadias and a functioning bladder neck may achieve continence with reconstructive surgery alone (Bailey & Love's, p. 300)

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III. COMPARISON: Hypospadias vs. Epispadias

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Treatment Differences: Male vs. Female

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HYPOSPADIAS

Males

• Distal types: Tubularised Incised Plate (TIP) urethroplasty — the urethral plate is incised and tubularised to bring the meatus to the glans tip
• Proximal types with chordee: Two-stage repair
  • Stage 1 — chordee release ± skin/buccal mucosa graft
  • Stage 2 — urethroplasty (urethral tube construction)
• Circumcision avoided pre-operatively (preputial skin needed for repair)
• Goal: functional meatus at glans tip, straight penis, normal voiding stream

Females

• A urethral diverticulum (causing recurrent UTIs, post-void dribbling) — treated by surgical excision
• A urethral caruncle (minor mucosal prolapse) — usually requires no treatment (Bailey & Love's, p. 1471)
• Rarely, a low-opening urethra as part of a disorder of sex development (DSD) — managed by a multidisciplinary team

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EPISPADIAS

Males

• Boys with a functioning bladder neck may achieve continence with urethral repair alone (Bailey & Love's, p. 300)
• Boys with bladder exstrophy require staged neonatal closure of the bladder plate as the first priority

Females

• Bladder neck reconstruction is the primary surgical priority (since virtually all females with epispadias are incontinent)
• Urethral lengthening — the female urethra is reconstructed/lengthened to restore resistance
• Clitoroplasty — repair of the bifid clitoris for cosmesis
• Vaginal/pelvic floor repair if associated exstrophy is present
• Pelvic osteotomy — when pubic diastasis is present (bladder exstrophy cases)

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Summary Table

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Antimicrobial Drugs — Short Notes for Pharmacology

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I. ANTIBACTERIAL DRUGS

A. β-LACTAMS

1. Penicillins

• MOA: Inhibit bacterial cell wall synthesis by binding Penicillin-Binding Proteins (PBPs) → block transpeptidation (cross-linking of peptidoglycan) → cell lysis. Bactericidal, time-dependent.
• Resistance: β-lactamase production (most S. aureus); reduced PBP affinity (MRSA)

2. Cephalosporins

• MOA: Same as penicillins (PBP binding)
• Generations:

3. Carbapenems

• Drugs: Imipenem, Meropenem, Ertapenem
• MOA: Broadest β-lactam spectrum — G+, G−, anaerobes
• Use: Serious/polymicrobial infections, ESBL-producing organisms
• Note: Imipenem given with cilastatin (prevents renal degradation); can cause seizures

4. Monobactams

• Drug: Aztreonam
• Spectrum: G− only (including Pseudomonas); safe in penicillin allergy

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B. GLYCOPEPTIDES

• Drugs: Vancomycin, Teicoplanin
• MOA: Bind D-Ala-D-Ala terminus of peptidoglycan precursors → inhibit cell wall synthesis. Bactericidal.
• Use: MRSA, C. difficile (oral vancomycin), serious G+ infections
• ADRs: "Red man syndrome" (rapid infusion), nephrotoxicity, ototoxicity

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C. PROTEIN SYNTHESIS INHIBITORS

• 30S inhibitors: "Aminoglycosides Tetracyclines" → AT 30
• 50S inhibitors: "CELL" → Chloramphenicol, Erythromycin (macrolides), Linezolid, cLindamycin

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D. FLUOROQUINOLONES

• Drugs: Ciprofloxacin, Levofloxacin, Moxifloxacin, Norfloxacin
• MOA: Inhibit DNA gyrase (topoisomerase II) and topoisomerase IV → prevent DNA supercoiling/separation → bactericidal
• Spectrum: Broad G+, G−, atypicals (Mycoplasma, Chlamydia), mycobacteria
• ADRs: Tendon rupture (Achilles), QT prolongation, cartilage damage (avoid in children/pregnancy), photosensitivity

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E. SULFONAMIDES & TRIMETHOPRIM

• MOA:
  • Sulfonamides (Sulfamethoxazole): inhibit dihydropteroate synthase → block folate synthesis
  • Trimethoprim: inhibits dihydrofolate reductase → block THF production
  • Together (Co-trimoxazole/TMP-SMX): sequential blockade of folate pathway → bactericidal synergy
• Use: UTIs, Pneumocystis jirovecii pneumonia (PCP), Nocardia, Toxoplasma

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F. OTHER ANTIBACTERIALS

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II. ANTIFUNGAL DRUGS

A. POLYENES

• Drugs: Amphotericin B, Nystatin
• MOA: Bind ergosterol in fungal cell membrane → form pores → ion leakage → cell death. Fungicidal.
• Amphotericin B: IV; broad spectrum (Candida, Aspergillus, Cryptococcus, endemic fungi)
  • ADRs: Nephrotoxicity (dose-limiting), infusion reactions (fever, rigors), hypokalemia, hypomagnesemia; use liposomal form to reduce toxicity
• Nystatin: Topical/oral only (too toxic for systemic use); oral/vaginal Candida

B. AZOLES

• MOA: Inhibit 14α-demethylase (CYP450 enzyme) → block lanosterol → ergosterol conversion → membrane dysfunction. Fungistatic (mostly).

• ADRs: Hepatotoxicity, CYP450 inhibition (drug interactions), teratogenic

C. ECHINOCANDINS

• Drugs: Caspofungin, Micafungin, Anidulafungin
• MOA: Inhibit β-(1,3)-D-glucan synthase → disrupt fungal cell wall synthesis. Fungicidal against Candida.
• Use: Invasive Candida (including azole-resistant), Aspergillus (2nd line)
• ADRs: Generally well tolerated; mild hepatotoxicity, histamine release

D. ALLYLAMINES

• Drugs: Terbinafine, Naftifine
• MOA: Inhibit squalene epoxidase → block ergosterol synthesis → squalene accumulates (toxic to fungi)
• Use: Dermatophytes (tinea unguium/nail fungus, tinea pedis) — oral/topical

E. OTHER ANTIFUNGALS

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III. ANTIVIRAL DRUGS

A. ANTI-HERPESVIRUS AGENTS

• MOA: Nucleoside analogues → phosphorylated by viral thymidine kinase → incorporated into viral DNA → chain termination

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B. ANTI-INFLUENZA AGENTS

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C. ANTIRETROVIRALS (HIV)

• HAART/ART: Combination therapy — typically 2 NRTIs + 1 NNRTI or INSTI

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D. ANTI-HEPATITIS AGENTS

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E. MISCELLANEOUS ANTIVIRALS

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QUICK SUMMARY TABLE

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Antiallergic Drugs — Short Notes for Pharmacology

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BACKGROUND: HISTAMINE & ALLERGY

• Histamine is synthesized by decarboxylation of L-histidine (enzyme: histidine decarboxylase)
• Stored in mast cell & basophil granules, ECL cells of stomach, neurons
• Released by: IgE-mediated degranulation (allergy/anaphylaxis), cold, trauma, venoms, drugs
• Mediates: immediate allergic reactions (urticaria, rhinitis, anaphylaxis), gastric acid secretion, neurotransmission

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I. H1 ANTIHISTAMINES (Main Antiallergic Drugs)

MOA

• Inverse agonists at H1 receptors (not simple competitive antagonists)
• Stabilize the inactive form of H1 receptor → reduce histamine-driven allergic response
• Block: bronchoconstriction, itch, urticaria, vascular permeability, rhinorrhea

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Generation 1 (Sedating / Classical)

• Sedation, drowsiness (major)
• Anticholinergic: dry mouth, blurred vision, urinary retention, constipation, tachycardia
• Paradoxical CNS stimulation in children

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Generation 2 (Non-Sedating / Modern)

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Clinical Uses of H1 Antihistamines

• Allergic rhinitis
• Urticaria / angioedema
• Allergic conjunctivitis
• Motion sickness (1st gen)
• Insomnia / sedation (1st gen)
• Pruritus (itching)
• Anaphylaxis (adjunct — NOT first-line; epinephrine is first-line)

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II. H2 ANTIHISTAMINES

• MOA: Block H2 receptors on gastric parietal cells → ↓ gastric acid secretion
• Primary use: Peptic ulcer, GERD, Zollinger-Ellison (largely replaced by PPIs)
• Also used as adjunct in anaphylaxis (with H1 blockers + epinephrine)

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III. MAST CELL STABILIZERS

• MOA: Prevent degranulation of mast cells → block release of histamine, leukotrienes, and other mediators
• Act prophylactically — must be used before allergen exposure; not effective once reaction has started

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IV. LEUKOTRIENE RECEPTOR ANTAGONISTS (LTRAs)

• MOA: Block cysteinyl leukotriene (CysLT1) receptors → prevent bronchoconstriction, mucus secretion, and eosinophil recruitment triggered by leukotrienes (LTC4, LTD4, LTE4)
• Leukotrienes are major mediators in asthma and allergic rhinitis

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V. CORTICOSTEROIDS

• MOA: Broad anti-inflammatory effect — suppress release of histamine, leukotrienes, prostaglandins, cytokines; reduce mast cell and eosinophil numbers

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VI. EPINEPHRINE (ADRENALINE) — First-Line in Anaphylaxis

• MOA: α1 → vasoconstriction (reverses hypotension); β1 → ↑HR/cardiac output; β2 → bronchodilation; also inhibits further mast cell degranulation
• Route: IM (anterolateral thigh) — preferred; IV in cardiac arrest
• Device: EpiPen (auto-injector 0.3 mg for adults, 0.15 mg for children)
• Indications: Anaphylaxis, severe angioedema, laryngeal edema

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VII. IMMUNOTHERAPY (Desensitization)

• MOA: Repeated allergen exposure → shift from Th2 → Th1 response; induces IgG4 "blocking" antibodies; reduces IgE production and mast cell sensitivity
• Routes: Subcutaneous (SCIT) or sublingual (SLIT)
• Use: Allergic rhinitis, bee venom allergy, food allergy (peanut — Palforzia)
• Only treatment that modifies the underlying allergic disease

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VIII. BIOLOGICS (Newer Antiallergic Agents)

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QUICK SUMMARY TABLE

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MNEMONIC: 1st vs. 2nd Gen H1 Blockers