Antihypertensive Agents Dr S. O. Olayemi

HYPERTENSION Chronically persistent elevated blood pressure>/=140 mm Hg systolic blood pressure and or diastolic >/= 90 mmHg in individual above 18 years of age Controlled BP SBP <140mmHg and DBP<90mmHG

Expert Committee on non Communicable diseases One third of Nigerian adults above 15 years of age are hypertensives, from this one third are aware of the hypertensive status, and one third are on treatment. One third of Nigerian adults above 15 years of age are hypertensives, from this one third are aware of the hypertensive status, and one third are on treatment. Control definition?Complex?compliance/cost etc Control definition?Complex?compliance/cost etc

TREATMENT GOAL Prevent morbidity and mortality associated with high blood pressure. Achieving control through least intrusive means possible Control other modifiable cardiovascular risk factors.

Ace Inhibitors: Captopril (Capoten) 12.5 – 150mg daily Captopril (Capoten) 12.5 – 150mg daily Enalapril (Vasotec) 5 – 40 mg daily Enalapril (Vasotec) 5 – 40 mg daily Lisinopril (Zestril) 5 – 40mg daily Lisinopril (Zestril) 5 – 40mg daily Ramipril (Tritace) 2.5 – 10mg daily Ramipril (Tritace) 2.5 – 10mg daily Perindopril (Aceon) 4 – 16 mg daily Perindopril (Aceon) 4 – 16 mg daily Fosinopril (Monopril) 5 – 40mg daily Fosinopril (Monopril) 5 – 40mg daily

Action: ACEI block conversion of Angiotensin 1 to Angiotensin 11 thereby blocking stimulation of aldosterone. Action: ACEI block conversion of Angiotensin 1 to Angiotensin 11 thereby blocking stimulation of aldosterone. Major site of Angiotensin II production – Vessels and not the kidneys. Major site of Angiotensin II production – Vessels and not the kidneys. reduce peripheral resistance and salt and water retention. reduce peripheral resistance and salt and water retention. Side Effect: Cough, Rashes, Leukopenia, Hyperkalaemia, Angio- Odema Side Effect: Cough, Rashes, Leukopenia, Hyperkalaemia, Angio- Odema

ACE inhibitors Reduce dose in volume depleted pt, elderly(hypotension) Reduce dose in volume depleted pt, elderly(hypotension) May be combined with diuretics May be combined with diuretics Hyperkalaemia – CKD pts, potassium sparing diuretics and angiotensin receptor blockers. Hyperkalaemia – CKD pts, potassium sparing diuretics and angiotensin receptor blockers. ARF- renal artery stenosis ARF- renal artery stenosis Contraindicated in pregnancy and pt with hx of angioodema. Contraindicated in pregnancy and pt with hx of angioodema.

ANGIOTENSIN II RECEPTOR ANTAGONISTS Losartan (Cozaar) 50 – 100 mg daily Losartan (Cozaar) 50 – 100 mg daily Valsartan (Diovan) 80 – 320 mg daily Valsartan (Diovan) 80 – 320 mg daily Temilsartan (Micardis) 20 – 80 mg daily Temilsartan (Micardis) 20 – 80 mg daily Irbesartan (Avapro) 150 –300mg daily Irbesartan (Avapro) 150 –300mg daily Olmesartan (Benicar) 20 – 40 mg daily Olmesartan (Benicar) 20 – 40 mg daily Candesartan (Atacand) 8 – 32 mg daily Candesartan (Atacand) 8 – 32 mg daily

ANGIOTENSIN II RECEPTOR ANTAGONISTS: ARBs Action: They directly block the angiotensin II type 1 (AT1) receptors – vasoconstriction, aldosterone release, sympathetic activation, ADH release, constriction of efferent renal arterioles Action: They directly block the angiotensin II type 1 (AT1) receptors – vasoconstriction, aldosterone release, sympathetic activation, ADH release, constriction of efferent renal arterioles Beneficial AT2-vasodilation,tissue repair and inhibition of cellular growth in blood vessels Beneficial AT2-vasodilation,tissue repair and inhibition of cellular growth in blood vessels (reduce peripheral resistance and salt/water retention) (reduce peripheral resistance and salt/water retention) Side Effects: Rashes, Leukopenia,Hyperkalaemia but no cough Side Effects: Rashes, Leukopenia,Hyperkalaemia but no cough

ARBs Reduce dose in volume depleted pt, elderly(hypotension) Reduce dose in volume depleted pt, elderly(hypotension) May be combined with diuretics May be combined with diuretics Hyperkalaemia – CKD pts, potassium sparing diuretics and angiotensin receptor blockers. Hyperkalaemia – CKD pts, potassium sparing diuretics and angiotensin receptor blockers. ARF- renal artery stenosis ARF- renal artery stenosis Contraindicated in pregnancy Contraindicated in pregnancy Do not induce cough as in ACEIs Do not induce cough as in ACEIs

VASODILATORS ; Hydralazine (Apresoline 20 – 100 mg daily, Minoxidil (Loniten) 10 – 40mg daily, Action: They decrease peripheral resistance by dilating arteries/arterioles. Action: They decrease peripheral resistance by dilating arteries/arterioles. Combined with diuretic/B blockers –diminish fluid retention/reflex tarchycardia. Combined with diuretic/B blockers –diminish fluid retention/reflex tarchycardia. Side Effect: Hydralazine (Headache, lupus-like syndrome), Side Effect: Hydralazine (Headache, lupus-like syndrome), Minoxidil (Orthostasis, facial hirsutism), Minoxidil (Orthostasis, facial hirsutism), Diazoxide (Hyperglycaemia. Diazoxide (Hyperglycaemia.

CALCIUM CHANNEL BLOCKERS Dihydropyridines : Dihydropyridines : Nifedipine (Adalat/ProcardiA) 20 – 90 mg dly, I, Felodipine (Plendil) 5 – 20 mg dly, Nifedipine (Adalat/ProcardiA) 20 – 90 mg dly, I, Felodipine (Plendil) 5 – 20 mg dly, Amlodipine (Norvasc) 2.5 – 10 mg dly Amlodipine (Norvasc) 2.5 – 10 mg dly Nicardipine (Cardene) 60 – 120 mg dly Nicardipine (Cardene) 60 – 120 mg dly Phenylakylamine: Verapamil 100 – 400 mg dly Phenylakylamine: Verapamil 100 – 400 mg dly Benzothiazepine: Diltiazem 120 – 480 mg dly. Benzothiazepine: Diltiazem 120 – 480 mg dly. Action: Reduce smooth muscle tone and cause vasodilation: may reduce cardiac output. Action: Reduce smooth muscle tone and cause vasodilation: may reduce cardiac output. Verapamil/diltiazem: decrease HR/delay A-V nodal conduction – Supra ventricular tachycardia Verapamil/diltiazem: decrease HR/delay A-V nodal conduction – Supra ventricular tachycardia

Calcium channel blockers Avoid immediate release nifedipines etc Avoid immediate release nifedipines etc Dihydropyridines are more potent peripheral vasodilators compared to non-dihydropyridines. Dihydropyridines are more potent peripheral vasodilators compared to non-dihydropyridines. Side effect: Dihydropyridines – reflex sympathetic discharge (tarchycardia) Headache, flushing, peripheral oedema. Side effect: Dihydropyridines – reflex sympathetic discharge (tarchycardia) Headache, flushing, peripheral oedema. Non dihyropyridines – variable heart block Non dihyropyridines – variable heart block

DIURETICS Loop diuretics – Frusemide (Lasix) 20mg – 1 g, Bumetanide (Bumex) mg Torsemide (Demadex) – 5mg dly. Loop diuretics – Frusemide (Lasix) 20mg – 1 g, Bumetanide (Bumex) mg Torsemide (Demadex) – 5mg dly. Site of Action: Loop of Henle, Reduce Na+/K+/Cl- cotransporter: reduce urine concentration; Increase calcium excretion. Site of Action: Loop of Henle, Reduce Na+/K+/Cl- cotransporter: reduce urine concentration; Increase calcium excretion. Preferrably morning/afternoon (avoid nocturnal diuresis) Preferrably morning/afternoon (avoid nocturnal diuresis) Higher doses in patients with CKD. Higher doses in patients with CKD. Side effect: Ototoxicity, Hypokalaemia, Hypotension, Gout. Side effect: Ototoxicity, Hypokalaemia, Hypotension, Gout.

DIURETICS: Thiazides: Chlorthalidone (Hygroton) 6.25 – 25mg dly, Hydrochlorothiazides (Esidrix) 12.5 – 50mg dly Bendrofluazide 2.5 – 5mg dly Thiazides: Chlorthalidone (Hygroton) 6.25 – 25mg dly, Hydrochlorothiazides (Esidrix) 12.5 – 50mg dly Bendrofluazide 2.5 – 5mg dly Site of Action: Early distal tubule, they reduce NaCl reabsorption thereby reducing the diluting capacity of nephron. Decrease Calcium excretion. Site of Action: Early distal tubule, they reduce NaCl reabsorption thereby reducing the diluting capacity of nephron. Decrease Calcium excretion. Dose in Morning (avoid noctunal diuresis) Dose in Morning (avoid noctunal diuresis) More effective antihypertensives than loops except in CKD (GFR <30ml/min More effective antihypertensives than loops except in CKD (GFR <30ml/min Side effects: Hypokalaemia, Hyponatreamia, Hypercalcemia, Hyperglyceamia, Hyperlipidaemia, Hyperuricaemia (Problematic in gout), Side effects: Hypokalaemia, Hyponatreamia, Hypercalcemia, Hyperglyceamia, Hyperlipidaemia, Hyperuricaemia (Problematic in gout),

Potassium sparing diuretics Aldosterone antagonist: Spironolactone (Aldactone) 25 –50 mg dly, Epleronone (Inspra) 50 – 100 mg dly Aldosterone antagonist: Spironolactone (Aldactone) 25 –50 mg dly, Epleronone (Inspra) 50 – 100 mg dly Site of Action: Cortical collecting tubule, They block Na+ channels Site of Action: Cortical collecting tubule, They block Na+ channels Side effects: Hyperkalemia, Sexual dysfunction Side effects: Hyperkalemia, Sexual dysfunction Potassium Sparing: Amiloride/hydrothiaz- Moduretic 5 – 10/50 –100 mg dly, Potassium Sparing: Amiloride/hydrothiaz- Moduretic 5 – 10/50 –100 mg dly, Triamterene/hydrothiaz 37.5 – 75/25 50 mg dly Triamterene/hydrothiaz 37.5 – 75/25 50 mg dly Aldosterone antagonist : Gynaecomastia. Aldosterone antagonist : Gynaecomastia. Action: Reduce extracellular fluid volume and thereby reduce vascular resistance Action: Reduce extracellular fluid volume and thereby reduce vascular resistance

CENTRALLY ACTING DRUGS: Methyl dopa (Aldomet) 250mg – 1g dly, Clonidine (Catapres) mg dly, Action:They inhibit Sympathetic Nervous System via Central Alpha 2 Adrenergic Receptors. Action:They inhibit Sympathetic Nervous System via Central Alpha 2 Adrenergic Receptors. Clonidine withdrawal –Rebound BP elevation Clonidine withdrawal –Rebound BP elevation Side Effects : Somnolence, Orthostasis, Impotence, Rebound Hypertension Side Effects : Somnolence, Orthostasis, Impotence, Rebound Hypertension RESERPINE ( mg) dly- RESERPINE ( mg) dly- Combined with diuretics-reduce fluid retention Combined with diuretics-reduce fluid retention

BETA BLOCKERS Selective Cardioselective: Atenolol (Tenormin) 25 – 100 mg dly, Metropolol (Lopressor) 50 – 200mg dly, Bisprolol (Zebetal) mg dly Bexalolol (Kerlone) mg dly. Selective Cardioselective: Atenolol (Tenormin) 25 – 100 mg dly, Metropolol (Lopressor) 50 – 200mg dly, Bisprolol (Zebetal) mg dly Bexalolol (Kerlone) mg dly. Non Selective: Propranolol (Inderal) mg dly, Nadolol(Corgard) 40 – 120mg dly, Timolol Blocaden) 10 – 40 mg dly. Non Selective: Propranolol (Inderal) mg dly, Nadolol(Corgard) 40 – 120mg dly, Timolol Blocaden) 10 – 40 mg dly. Intrinsic Sympathomimetic activity: Pindolol (Visken) 10 – 60mg dly, Penbutolol(Levatol) 10 – 40mg dly, Acebutolol (Sectral) 200 – 800 mg dly. Intrinsic Sympathomimetic activity: Pindolol (Visken) 10 – 60mg dly, Penbutolol(Levatol) 10 – 40mg dly, Acebutolol (Sectral) 200 – 800 mg dly. Alpha and Beta Blockers: Labetalol (Trandate Alpha and Beta Blockers: Labetalol (Trandate mg dly, Carvedilol (Coreg) 12.5 – 50mg dly) mg dly, Carvedilol (Coreg) 12.5 – 50mg dly).

Beta Blockers Actions: They reduce cardiac contractility and Rennin release. Actions: They reduce cardiac contractility and Rennin release. Additional benefit- Tarchyarrythmias,essential tremor, migraine headache and thyrotoxicosis Additional benefit- Tarchyarrythmias,essential tremor, migraine headache and thyrotoxicosis Side Effect: Bronchospasm ( in severe asthma), bradycardia (A-V Block), Congestive Heart Failure exacerbation, impotence, fatigue, depression. Side Effect: Bronchospasm ( in severe asthma), bradycardia (A-V Block), Congestive Heart Failure exacerbation, impotence, fatigue, depression. Abrupt withdrawal-rebound hypertension. Abrupt withdrawal-rebound hypertension.

Antihypertensive Medications indicated in specific Patient Population Diabetes with proteinuria Diabetes with proteinuria Ace Inhibitors (ACEI) Ace Inhibitors (ACEI) Congestive Heart Failure ACEI, Diuretics +/-Beta Blockers Congestive Heart Failure ACEI, Diuretics +/-Beta Blockers Isolated systolic Hypertension Isolated systolic Hypertension Diuretics preferred: long acting dihyropyridine calcium channel blockers Diuretics preferred: long acting dihyropyridine calcium channel blockers

CONTD MIBeta Blockers without intrinsic sympathomimetic activity, ACEI MIBeta Blockers without intrinsic sympathomimetic activity, ACEI OsteoporosisThiazide diuretics OsteoporosisThiazide diuretics BPHAlpha antagonists BPHAlpha antagonists PregnancyMethyldopa, Beta blockers, Labetalol, Hydralazine +/-calcium antagonists PregnancyMethyldopa, Beta blockers, Labetalol, Hydralazine +/-calcium antagonists

Antihypertensives in pregnancy Methyldopa-preferred based on safety data Methyldopa-preferred based on safety data B Blockers- Safe, but IUGR reported B Blockers- Safe, but IUGR reported Labetalol-preffered over methyldopa because of fewer side effects Labetalol-preffered over methyldopa because of fewer side effects Clonidine- Limited data available Clonidine- Limited data available CCBs-Limited data available, no teratogenicity with exposure CCBs-Limited data available, no teratogenicity with exposure Diuretics-not first line agents but probably safe in low doses Diuretics-not first line agents but probably safe in low doses ACEIs/ARBs- major teratogenicity on exposure ACEIs/ARBs- major teratogenicity on exposure

JNC 7 MANAGEMENT OF HYPERTENSION Prehypertension / Life style modification. Prehypertension / Life style modification. Stage /90-99-Thiazides, may consider ACEI,ARB, B Blockers Calcium blockers or a combination Stage /90-99-Thiazides, may consider ACEI,ARB, B Blockers Calcium blockers or a combination Stage 2 >160/>100 – Two drug combination (usually a thiazide diuretic+an ACEI, an ARB, a B blocker, or calcium blocker Stage 2 >160/>100 – Two drug combination (usually a thiazide diuretic+an ACEI, an ARB, a B blocker, or calcium blocker

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