Antihypertensives and diuretics

How blood pressure can be lowered

Blood pressure equals cardiac output times total peripheral resistance. Drugs lower it by reducing blood volume (diuretics), heart rate and contractility (β-blockers, rate-limiting calcium channel blockers), arteriolar tone (calcium channel blockers, α-blockers, hydralazine, minoxidil), angiotensin II and aldosterone (ACE inhibitors, ARBs, MRAs) or central sympathetic outflow (clonidine, methyldopa, moxonidine).

Diuretics by nephron site

• Why potassium falls with loop and thiazide diuretics: more sodium reaches the collecting duct, where its reabsorption through ENaC creates a lumen-negative potential that drives K+ secretion; volume loss also raises aldosterone.
• Why calcium differs: loop diuretics abolish the positive lumen potential that drives paracellular Ca2+ and Mg2+ reabsorption, so urinary calcium rises. Thiazides increase distal calcium reabsorption, so urinary calcium falls (useful in calcium stones; can cause hypercalcaemia).
• Thiazides decrease clearance of urate, calcium and lithium; volume contraction increases proximal reabsorption.
• Mannitol is filtered but not reabsorbed, so it holds water in the tubule. Given IV, it first draws water from cells into the circulation, expanding plasma volume before the diuresis begins. In heart failure (or anuria) this expansion precipitates pulmonary oedema.
• Acetazolamide lowers intraocular pressure by inhibiting carbonic anhydrase in the ciliary body, reducing aqueous humour production.
• Thiazides lose effect when GFR falls below about 30 mL/min: less drug is secreted into the tubule and the distal tubule handles only a small share of filtered sodium. Loop diuretics still work but need higher doses in CKD.
• Thiazide hyponatraemia typically appears in elderly women within weeks of starting (confusion with Na+ around 120 mmol/L); loop diuretics cause it less often because they impair urine concentration.
• IV furosemide relieves pulmonary oedema within minutes, before diuresis, through venodilatation that lowers preload; in a hypotensive patient this can drop BP further.
• Diuretic resistance: chronic loop diuretic use makes the distal tubule hypertrophy and reabsorb more sodium. Adding metolazone (thiazide-like) blocks this compensatory distal uptake (sequential nephron blockade), producing a large diuresis with profound hypokalaemia and hyponatraemia.
• Amiloride blocks ENaC directly, so it works in Liddle syndrome (gain-of-function ENaC with low aldosterone), where spironolactone fails.

Exam trap Thiazides reduce urinary calcium; loop diuretics increase it. Thiazide-induced hyponatraemia in a hypovolaemic elderly patient: stop the thiazide and give isotonic saline, correcting slowly.

Hyperkalaemia from antihypertensives

• ACE inhibitors, ARBs, spironolactone, amiloride and triamterene raise potassium, especially in diabetes (hyporeninaemic hypoaldosteronism), CKD, old age and with NSAIDs or potassium supplements. A collapse with K+ 6.7 mmol/L in such a patient is drug-induced until proved otherwise.

Renin–angiotensin system drugs

• ACE inhibitors (ramipril, lisinopril, enalapril, captopril) block conversion of angiotensin I to II and also block breakdown of bradykinin (ACE is kininase II).
• Dry cough (about 10%) and angioedema are caused by accumulated bradykinin; the usual substitute is an ARB (losartan, candesartan), which blocks the AT1 receptor without affecting bradykinin.
• Bilateral renal artery stenosis: with low perfusion pressure, GFR depends on angiotensin II constricting the efferent arteriole. Removing that efferent constriction drops glomerular pressure and causes acute kidney injury. Check creatinine and potassium before and 1–2 weeks after starting.
• First-dose hypotension: after vigorous diuresis, blood pressure is maintained by a high renin and angiotensin II level (angiotensin-dependent), so the first ACE inhibitor dose removes that support and BP collapses. Start low, at night, and pause diuretics if possible. A diabetic whose BP falls sharply after a new drug has often just started an ACE inhibitor.
• Creatinine rise up to about 30% (for example 88 to 106 µmol/L, 1.0 to 1.2 mg/dL) with normal potassium is expected from reduced intraglomerular pressure: continue and recheck. Stop if the rise is larger or potassium exceeds 6 mmol/L. Pause during vomiting or diarrhoea (sick-day rules).
• Angioedema (lips, tongue, no urticaria or itch) can appear even years after starting; it is bradykinin-mediated, so antihistamines and steroids help little.
• ACE inhibitors and ARBs are first choice in diabetes and proteinuric CKD (they lower intraglomerular pressure). Contraindicated in pregnancy (fetal renal damage, oligohydramnios): a woman who finds she is pregnant on lisinopril should stop it and switch to labetalol or nifedipine. Never combine an ACE inhibitor with an ARB.
• Losartan alone among ARBs is mildly uricosuric, useful in hypertension with gout.
• Sacubitril–valsartan (neprilysin inhibitor plus ARB) for heart failure; stop ACE inhibitors 36 hours before (angioedema). Aliskiren directly inhibits renin.

Calcium channel blockers

• Nifedipine (modified-release) is first-line drug treatment for Raynaud phenomenon.
• Nimodipine is a cerebroselective dihydropyridine given after subarachnoid haemorrhage to reduce delayed ischaemia from vasospasm.

β-blockers and centrally acting drugs

• β-blockers are not first line for uncomplicated hypertension. Propranolol is a poor choice in a diabetic (masks hypoglycaemia, worsens glucose tolerance) and adds bradycardia and fatigue in hypothyroidism; with such a profile it is the least appropriate option.
• Clonidine stimulates central α2 receptors to cut sympathetic outflow. Abrupt withdrawal releases suppressed sympathetic activity and upregulated receptors: sympathetic rebound with headache, sweating, tachycardia and severe hypertension. Restart clonidine or use α plus β blockade; taper when stopping.
• Methyldopa is converted to α-methylnoradrenaline, a false transmitter that stimulates central α2 receptors. It has the longest fetal safety record in chronic hypertension of pregnancy; switch it after delivery because it can cause postnatal depression.
• Cocaine chest pain: β-blockers are traditionally avoided at first because unopposed α stimulation worsens coronary vasospasm; use benzodiazepines and nitrates.

Vasodilators

• Hydralazine: arteriolar dilator; reflex tachycardia (blocked by β-blockers); drug-induced lupus in slow acetylators.
• Minoxidil: opens K-ATP channels; hirsutism, fluid retention.
• Sodium nitroprusside: arteriolar and venous dilator for emergencies; cyanide toxicity with prolonged use.

Hypercalcaemia of malignancy: why diuretics are second

• First rehydrate with IV saline, which restores GFR and calcium excretion. The most effective next step is an IV bisphosphonate (zoledronate or pamidronate), which blocks osteoclastic bone resorption over 2–4 days. Loop diuretics are used only for fluid overload after rehydration; thiazides are contraindicated.

Choosing treatment

• Hypertensive emergency (for example BP 230/135 with papilloedema and confusion): IV labetalol, nitroprusside, GTN or nicardipine; lower by about 25% in the first hour, because autoregulation has reset and a rapid fall causes cerebral ischaemia. Avoid sublingual nifedipine.
• Aortic dissection is the exception: lower pressure fast, β-blocker first, then a vasodilator such as nitroprusside. Giving the vasodilator first causes reflex tachycardia and a steeper pressure upstroke (dP/dt), raising aortic wall stress.
• Eplerenone is more selective for the mineralocorticoid receptor, so it keeps the survival benefit in heart failure without the anti-androgenic gynaecomastia of spironolactone. Hyperkalaemia remains the dangerous effect of both.

Remember ACE inhibitors cough through bradykinin and damage stenosed kidneys through the efferent arteriole.

How FCPS asks about this

• Dry cough on ramipril: bradykinin accumulation; switch to an ARB.
• AKI after ACE inhibitor in bilateral renal artery stenosis: loss of efferent arteriolar constriction.
• Rebound hypertension after stopping clonidine: sympathetic rebound.
• Painful gynaecomastia on spironolactone: switch to eplerenone.
• Verapamil versus nifedipine: verapamil acts mainly on the heart, nifedipine on vessels.
• Mannitol in heart failure: initial expansion of circulating volume causes pulmonary oedema.
• Acetazolamide: reduces aqueous production; causes normal anion gap metabolic acidosis.