(a) Define poison and classify it. Describe the treatment of venomous snakebite. Write a note on 'designer drug'. 15 marks (b)…

(a) Poison, snakebite treatment and designer drugs

A poison is a substance that, when introduced into or brought into contact with the living body, causes ill-health or death through its physical or chemical action.

Classification: by origin (animal, vegetable, mineral); or by action (corrosives, irritants, neurotics acting on brain, spinal cord or peripheral nerves, cardiac poisons, asphyxiants and miscellaneous).

Treatment of venomous snakebite:

• First aid: reassure, immobilise the limb, remove rings and tight items and shift quickly to hospital. Do not cut, suck, apply tourniquets or wash the bite. A pressure-immobilisation bandage is used only for neurotoxic bites when hospital is 30 minutes to 3 hours away.
• Hospital: check airway, breathing and circulation; do the 20-minute whole blood clotting test (repeat hourly for 3 hours, then 4-hourly) and watch for ptosis and respiratory weakness.
• Polyvalent anti-snake venom (ASV) as an infusion over 30–60 minutes (about 10 vials initially); repeat as per national protocol if clotting stays abnormal or neurological signs progress.
• Anaphylaxis: stop infusion, adrenaline 0.5 mg intramuscular, antihistamine and steroid; restart slowly. Late serum sickness: antihistamine or prednisolone.
• Neurotoxic bites: atropine followed by neostigmine (1.5 mg, then repeat doses) and ventilation if needed. Renal failure: dialysis. Fresh frozen plasma or blood for bleeding; wound care and tetanus prophylaxis.

Designer drugs: synthetic psychoactive substances made by modifying the chemical structure of controlled drugs to avoid legal control while retaining the effect, for example synthetic cannabinoids, synthetic cathinones (mephedrone), amphetamine derivatives (ecstasy) and fentanyl analogues. Unpredictable potency makes overdose, psychosis, seizures and death common; they are not detected by routine drug screens, and are controlled under the NDPS Act, 1985.

(b)(i) Oral cancer

Predisposing conditions: tobacco (smoked and smokeless), areca nut and betel quid, alcohol, high-risk HPV (mainly oropharynx), poor oral hygiene and chronic irritation from sharp teeth, immunosuppression, and precursor lesions: leukoplakia, erythroplakia, oral submucous fibrosis, Plummer–Vinson syndrome.

Pathogenesis and molecular basis: carcinogens produce field cancerisation, with stepwise genetic damage from hyperplasia to dysplasia to carcinoma in situ and invasive carcinoma. Common changes are TP53 and CDKN2A (p16) inactivation, EGFR overexpression, cyclin D1 amplification, PIK3CA and NOTCH1 mutations; HRAS mutations are frequent in Indian gingivobuccal cancers. HPV-related cancers show E6 and E7 oncoprotein action (p53 and Rb degradation) with p16 overexpression.

Morphology: early lesion is a white or red patch; later an exophytic or ulcerative, indurated mass with raised everted edges. Microscopically most are squamous cell carcinoma with nests of atypical cells, intercellular bridges, keratin pearls, mitoses and pleomorphism, graded well, moderately or poorly differentiated; verrucous carcinoma is a low-grade variant.

(b)(ii) Glomerular injury and glomerulonephritis

Pathologic responses: hypercellularity (mesangial or endothelial proliferation, leucocyte infiltration, parietal cell crescents); basement membrane thickening (immune deposits or increased matrix); hyalinosis (plasma proteins deposited, with glomerular sclerosis); and sclerosis (collagenous scarring that obliterates capillary loops).

Pathogenesis: most primary glomerulonephritis is immune-mediated.

• In situ immune complex formation: antibody binds fixed glomerular antigen (anti-GBM disease; PLA2R in membranous nephropathy).
• Deposition of circulating immune complexes (post-streptococcal GN, lupus).
• Cytotoxic antibodies to glomerular cell components, and ANCA-mediated or T-cell-mediated injury.
• Alternative complement pathway dysregulation (C3 glomerulopathy).

Complement activation (C5a, membrane attack complex), neutrophils, macrophages, platelets and mediators such as oxygen radicals, proteases and cytokines then damage the capillary wall and cause proteinuria, haematuria and reduced GFR.

(c)(i) Mechanisms of antimicrobial resistance

Resistance may be intrinsic or acquired (by mutation or horizontal gene transfer).

• Drug inactivation: beta-lactamases, ESBLs, carbapenemases (NDM-1, KPC, OXA-48), aminoglycoside-modifying enzymes.
• Target alteration: PBP2a (mecA) in MRSA, D-Ala–D-Lac (vanA) in VRE, gyrase or topoisomerase mutations (quinolones), rpoB (rifampicin), ribosomal methylation (macrolides).
• Reduced uptake: loss or reduced expression of porins (OprD in Pseudomonas).
• Active efflux pumps: tetracycline, macrolide and multidrug pumps such as AcrAB–TolC.
• Bypass pathways: alternative drug-insensitive enzymes (e.g. altered dihydropteroate synthase in sulphonamide resistance).
• Biofilm formation limiting drug penetration.
• Spread: conjugation (plasmids), transformation, transduction, transposons and integrons. Misuse of antibiotics selects resistant strains.

(c)(ii) Third and fourth generation cephalosporins

Third generation: cefotaxime, ceftriaxone, ceftazidime, cefoperazone, ceftizoxime; oral cefixime, cefpodoxime, cefdinir. Fourth generation: cefepime and cefpirome.

Indications: bacterial meningitis (ceftriaxone, cefotaxime); typhoid fever and gonorrhoea (ceftriaxone, cefixime); septicaemia and hospital-acquired Gram-negative infections; Pseudomonas infections (ceftazidime, cefoperazone, cefepime); febrile neutropenia (cefepime, ceftazidime); pneumonia, pyelonephritis and biliary sepsis.