(a) Enumerate various classes of antihypertensive drugs. Briefly discuss the role of calcium channel blockers in the treatment of…

(a) Classes of antihypertensive drugs and the role of calcium channel blockers

Classes: Diuretics: thiazides (hydrochlorothiazide, chlorthalidone), loop (furosemide) and potassium-sparing (spironolactone, amiloride). Angiotensin-converting enzyme inhibitors (enalapril, ramipril). Angiotensin receptor blockers (losartan, telmisartan). Calcium channel blockers (amlodipine, nifedipine, verapamil, diltiazem). Beta blockers (atenolol, metoprolol), and alpha-beta blockers (labetalol, carvedilol). Alpha-1 blockers (prazosin, doxazosin). Centrally acting drugs (clonidine, methyldopa). Direct vasodilators (hydralazine, minoxidil, sodium nitroprusside). Direct renin inhibitor (aliskiren).

Role of calcium channel blockers. They block L-type voltage-gated calcium channels, so less calcium enters vascular smooth muscle, the arterioles relax, total peripheral resistance falls and blood pressure goes down. Dihydropyridines (amlodipine, nifedipine, felodipine) act mainly on vessels and are first-line, especially in the elderly, isolated systolic hypertension, black patients, pregnancy (nifedipine) and when combined with an ACE inhibitor or ARB. Their adverse effects are ankle oedema, flushing, headache and gum hyperplasia; short-acting nifedipine causes reflex tachycardia and is avoided. Non-dihydropyridines (verapamil, diltiazem) also depress the SA and AV nodes and contractility, so they suit hypertension with angina or supraventricular tachycardia, but must not be combined with beta blockers or used in heart failure; they cause bradycardia, and verapamil causes constipation. Intravenous nicardipine and clevidipine are used in hypertensive emergencies.

(b)(i) Type IV hypersensitivity and the tuberculin test

Type IV (delayed-type) hypersensitivity is cell-mediated, with no antibody involvement. Mechanism: Sensitisation: antigen-presenting cells (Langerhans cells, macrophages) take up the antigen and present it on MHC class II to CD4⁺ T cells, which under IL-12 become Th1 memory cells. Re-exposure: memory Th1 cells recognise the antigen and release IFN-γ, TNF and IL-2. IFN-γ activates macrophages, which release tissue-damaging enzymes and reactive oxygen species and, if the antigen persists, form epithelioid cells, giant cells and granulomas. CD8⁺ cytotoxic cells add direct killing in contact dermatitis. The reaction needs 48 to 72 hours to peak because T cells and monocytes must accumulate.

Tuberculin (Mantoux) test. PPD is injected intradermally; sensitised T cells release cytokines and the site shows induration, read at 48 to 72 hours (diameter of induration, not redness). A positive test shows past sensitisation, from infection or BCG, and does not prove active disease. A false negative occurs in anergy (miliary TB, HIV, malnutrition, steroids, measles, sarcoidosis).

(b)(ii) Salmonella diseases and the Widal test

Typhoidal Salmonella (S. Typhi, S. Paratyphi A, B) cause enteric (typhoid and paratyphoid) fever with complications (intestinal perforation, haemorrhage, osteomyelitis) and chronic gallbladder carriage. Non-typhoidal Salmonella (S. Enteritidis, S. Typhimurium) cause gastroenteritis (food poisoning), bacteraemia in the immunocompromised, and osteomyelitis, particularly in sickle cell disease.

Widal test. It is a tube (or slide) agglutination test measuring antibodies to the O (somatic) and H (flagellar) antigens of S. Typhi and S. Paratyphi A and B, in serial dilutions of the patient's serum. Interpretation: the test is read from the second week. A rising titre, a fourfold or greater increase in paired sera 7 to 10 days apart, is diagnostic. In endemic areas a single titre of O 1:160 or more and H 1:160 or more supports the diagnosis. Rising O titres suggest recent infection (IgM); H titres persist after vaccination or past infection. False positives occur in other febrile illnesses and false negatives with early antibiotics, so blood culture remains the gold standard.

(c) Disturbances of growth and the mechanism of atrophy

Disturbances of growth, enumerated: hypertrophy (increased cell size), hyperplasia (increased cell number), atrophy (decreased cell size and function) and metaplasia (reversible change of one adult cell type to another); dysplasia, aplasia and hypoplasia are also growth disorders.

Mechanism of atrophy. Atrophy follows reduced workload, denervation, loss of blood supply, inadequate nutrition, loss of hormonal or trophic stimulation, pressure and ageing. The cell reduces its size by lowering protein synthesis (less mTOR and growth-factor signalling) and by raising protein breakdown. Proteins are tagged with ubiquitin and degraded by the proteasome, and autophagy removes organelles; undigested debris accumulates as lipofuscin (brown atrophy). Apoptosis can also reduce cell number. Examples are disuse atrophy of a limb in a plaster cast, denervation atrophy, and involution of the uterus and thymus.

(d)(i) Likely diagnosis

Tuberculous meningitis. The subacute fever, headache, vomiting, neck rigidity and altered sensorium, with CSF showing a cobweb clot, lymphocytosis, low glucose and high protein, fit it, and pyogenic meningitis is excluded by the lymphocytic picture.

(d)(ii) Special stain and finding

Ziehl-Neelsen (acid-fast) stain of the CSF deposit, especially the cobweb clot, shows red, slender, beaded acid-fast bacilli on a blue background. The yield is low, so large volumes, repeated samples, culture and CBNAAT or PCR are used for confirmation.

(d)(iii) Gross pathology of the brain and meninges

A thick, gelatinous, greyish-yellow exudate fills the basal cisterns and covers the base of the brain, the optic chiasm, the pons and interpeduncular fossa and the Sylvian fissures, and it surrounds the cranial nerves. Small grey tubercles lie along the meningeal vessels. The exudate blocks CSF flow and absorption, so communicating hydrocephalus follows. Other features are endarteritis with infarcts, cranial nerve palsies (III, VI, VII) and tuberculomas.

(e) Blood group systems used for identification and paternity testing

Systems used: ABO, Rh (Rhesus), MNSs, Kell, Duffy, Kidd, Lutheran and P; HLA typing and DNA profiling are used as well. Blood groups follow Mendelian inheritance, so they can exclude a man as the father but cannot prove paternity. Examples: a child of group B with a mother of group O must have inherited B from the father, so an alleged father of group O is excluded; an Rh-positive child of two Rh-negative parents excludes paternity; a child of type M excludes a father of type N. Because these systems exclude only a fraction of falsely accused men, HLA typing and especially DNA fingerprinting with short tandem repeats are the modern standard and give a probability of paternity above 99.99%.