4. Diuretics AEs: electrolyte imbalances- hypokalaemia, hyponatraemia, hypomagnesaemia, hypochloraemic alkalosis, hypercalcaemia; hyperuricaemia- precipitates gout hyperglycaemia, hyperlipidaemia, hypersensitivity, hypotension, weakness, GI disturbances CIs: severe renal or hepatic impairment, hypokalaemia, pre-existing hypercalcaemia, gout, pregnancy DIs: K+ depleting agents, NSAIDs, cholestyramine, antidiabetics, digoxin, probenecid, lithium Note: #HCTZ may be used in combination with other antihypertensives #Low dose in long term therapy #Effective in GFR > 30ml/min #Monitor electrolytes, especially K+ Thiazides; Hydroclorthiazide MoA: inhibit Na+ and Cl-reabsorption at distal tubules, hence increase Na+ and water excretion, reduction of blood volume and pressure. I: first line Rx for mild to moderate HT, uncomplicated, in patients with adequate renal function [heart failure (CHF), hypercalciuria, diabetes insipidus] PKs: oral admin, t½ up to 15 hrs; renal excretion, unchanged; Slow onset of action, 2 months for full expression of antihypertensive effect
5. AEs: electrolyte imbalances- hypokalaemia, hyponatraemia, hypomagnesaemia, hypochloraemic alkalosis, hypocalcaemia; hyperuricaemia- precipitates gout hyperglycaemia, hyperlipidaemia, hypersensitivity, dehydration, hypotension, hypovolaemic shock, ototoxicity (tinnitus,ear pain, vertigo, hearing loss), GI disturbances CIs: hypersensitivity, hypokalaemia DIs: thiazides, captopril, cephalosporins, aminoglycosides, antigout drugs, antidiabetic drugs, K+ depleting agents, NSAIDs, lithium Note: Take with meals to avoid GI effects Warn about symptoms of electrolyte disturbances- weakness, dizziness, paraesthesia, mental confusion. 2. Loop Diuretics (high-ceiling ), furosemide MoA: reduce reabsorption of Na+, K+, Cl- in the ascending loop of Henle; most efficacious of diuretics (natriuretic) I: mild to moderate HT in renal impairment; unresponsive to thiazides, [CHF, hypercalcaemia, oedema of hepatic or renal origin] PKs: oral, parenteral admin; high albumin binding (> 90%); t½ = 30-60min, prolonged to 20hrs in renal or hepatic impairment; onset of action = 20-60min orally, 5min IV; hepatic metabolism, renal and biliary excretion
6. 3.K+ sparring diuretics, spironolactone MoA: competitive inhibitor of aldosterone, inhibits Na+ reabsorption and K+ excretion I: HT in combination with thiazides or loop diuretics, HT due to primary hyperaldosteronism, [CHF; oedema of hepatic cirrhosis, nephrotic syndrome] PKs: complete absorption, orally; high protein binding (> 90%); induces Cyt P450; hepatic metabolism to active canrenone with t½ = 13-24 hrs; renal and biliary excretion AEs: hyperkalaemia, nausea, peptic ulcers; oestrogen-like effects: gynaecomastia, decreased libido, menstrual irregularities, erectile dysfunction (impotence), postmenopausal bleeding CIs: hyperkalaemia, impaired renal function DIs: NSAIDs, digoxin, other diuretics, ACE inhibitors, K+ supplements, salt substitutes Note: #Monitor electrolytes, especially K+ Avoid high doses (>50mg daily) in males
7. SYMPATHOLYTICS (1) α-Adrenergic receptor blockers: prazosin, doxazosin, terazosin MoA: Selective α1-adrenoceptor antagonists, relax arterial and venous smooth muscle, hence vasodilation, reduced PVR, lowered blood pressure Doxazosin PKs: oral admin, 98% protein binding; t½ = 19-22 hrs; extensive hepatic metabolism, renal excretion AEs: first dose hypotension, dizziness, vertigo, headache, fatigue Due to AEs on the heart- reflex tachycardia, increased risk of heart failure- they are rarely used for HT
8. SYMPATHOLYTICS (2) β-Adrenoceptor blockers (propranolol, atenolol,….) MoA: block β-receptors, reduce sympathetic stimulation of the heart; reduce cardiac output and blood pressure Cardioselective- atenolol, acebutolol, esmolol, metoprolol, …. Atenolol I: HT (in comb with HCTZ, ACE inhibitor and Ca2+ channel blocker) [angina, arrhythmia, acute MI] PKs: oral admin, t½= 6-9hrs, effect lasts for 24hrs, excreted renally unchanged, accumulates in renal failure Propranolol: non-selective β-blocker I: HT [angina, arrhythmia, hypertrophic cardiomyopathy, ……] PKs: oral admin, first pass metabolism, highly lipophillic, crosses BBB, t½= 3-6 hrs, extensive metabolism, renal excretion. CI: asthma, COPD, CHF, mental depression, myasthenia gravis, type 1 diabetes mellitus, peripheral vascular disease, severe liver disease AEs: bradycardia, CNS effects, GIT disturbances, sexual dysfunction, sleep disturbances
9. SYMPATHOLYTICS (3) Carvedilol I: HT; [CHF] PKs: extensive hepatic metabolism, lipophilic, 98% protein-bound Safety aspects = refer to propranolol DIs of β-blockers Cimetidine, chlorpromazine –decreases hepatic metabolism of β- blockers Hepatic enzyme inducers- increased elimination of β- blockers Digoxin,verapamil, diltiazem- additive cardiodepressant effects NSAIDs- decreased efficacy of β- blockers Insulin, other antidiabetic drugs- increased risk of hyperglycaemia, masking of hypoglycaemia α- β- receptor blockers Block α1, β1 and β2 receptors Labetalol I: HT, HT with angina or MI, HT in pregnancy (2nd half), hypertensive crisis, controlled hypotension during surgery PKs: extensive hepatic metabolism
10. Sympatholytics (4): Centrally acting drugs CI: liver disease, phaeochromocytoma, AEs: drowsiness, dry mouth, sodium and water retention (oedema), depression, nightmares, hallucinations, decreased libido, impotence DIs: iron(↓absorption of meth), MAO inhibitors (severe HT, headaches, hallucinations), NSAIDs and TCAs (↓ meth efficacy) Methyldopa, Clonidine Selective α2 receptor agonists, reduce sympathetic outflow from CNS, hence vasodilation, reduced BP Clonidine no longer used for HT Methyldopa I: specifically for HT in pregnancy (mild to moderate)
11. ANGIOTENSIN INHIBITORS (1) CI: pregnancy, bilateral renal artery stenosis, aortic valve stenosis, K+ supplements AEs: dry cough, taste disturbances, pruritic rash, hypotension, hyperkalaemia, angioedema (signs= painful swelling of lips, face and throat) DIs: Other antihypertensives- additional hypotensive effect K+ supplements, K+ sparring drugs – serious hyperkalaemia NSAIDs – reduced hypertensive effect Antacids –reduced ACEI bioavailability Increased levels of digoxin and lithium, therefore monitor Precautions: warn patients about signs of angioedema Angiotensin-Converting enzyme (ACE) inhibitors : captopril, enalapril, perindopril, lisinopril, quinapril…… MoA: Inhibit ACE, prevent formation of ATII, reduce vasoconstriction, reduce aldosterone secretion, hence less water and salt retention and vasodilation = low BP I: HT (alone or adjuncts), in combination with diuretics (black patients), HT in diabetics, renal disease, post MI, CHF. [CHF] PKs: all ACEI except captopril and lisinopril are converted to active metabolites. Enalapril converted to enalaprilat, t½ = 11hrs; renally and faecally excreted, unchanged Captopril –short t½= 3hrs; Lisinopril is water soluble, not hepaticallymetabolised
12. ANGIOTENSIN INHIBITORS (2) Angiotensin receptor antagonists (losartan, valsartan,…..) MoA: block AT1 receptors in vascular smooth muscle and adrenal cortex, hence vasodilation and reduced aldosterone secretion I: HT, alone or in combination with other antihypertensives PKs: Losartan- undergoes first pass effect, converted to active metabolite (t½- 9hrs), more active than losartan (t½-2,5hrs), effect attained after 3-6weeks of therapy. CI: same as ACEI AEs: dizziness, orthostatic hypotension, headache, skin rash, myalgia, GIT effects, taste disturbances, fatigue no cough or angioedema DIs: as for ACEI
13. VASODILATORS (1) Ca2+ channel blockers- Nifedipine, amlodipine: dihydropyridones Verapamil, diltiazem: non-dihydropyridines MoA: block Ca++ channels in vascular smooth muscle, relax the smooth muscle, cause vasodilation- reduced BP V and D have more effect on cardiac tissue, hence reduce CO and HR. I: HT, HT with asthma [angina pectoris, arrhythmias] PKs: nifedipine-only slow-release used for HT; high protein binding (98%), hepatic metabolism, renal excretion CI: hypotension, unstable angina, acute MI, CHF AEs: headache, flushing, dizziness, lightheadedness, ankle oedema DIs: hepatic enzyme inhibitors- inhibit metabolism of nifedipine hepatic enzyme inducers- reduced plasma levels of nifedipine V and D are preferrably used in angina, MI and arrhythmias
14. VASODILATORS (2) Sodium nitroprusside MoA: directly dilates both arteries and veins I: hypertensive emergencies PKs: IV infusion, immediate onset of action, 1-10 min; CI: pregnancy, hepatic disease DI: other antihypertensives- increased hypotensive effect Hydralazine MoA: directly dilates arteries and arterioles I: 4th line Rx of HT, low dose in combination with other antihypertensives (diuretic, b-blocker) [chronic CHF] PKs: hepatic metabolism , acetylation, CI: pregnancy, aortic stenosis AEs: headache, nausea, postural hypotension, palpitations Monotherapy causes reflex tachycardia- avoided by co-administration of a β-blocker
