Antihypertensive agents Hypertension : BP SYSTOLIC DIASTOLIC Normal < 120 < 80 Pre- hypertension 120 - 139 80 - 89 Stage 1 hypertension 140 - 159 90 - 99 Stage 2 hypertension 160 - higher 100 - higher

Antihypertensive agents - Rationale Long-term goal of antihypertensive therapy: Reduce mortality due to hypertension-induced disease Stroke Congestive heart failure Coronary artery disease Nephropathy Peripheral artery disease Retinopathy

Typical Diurnal Blood Pressure Rhythm in a "Dipper"                                                                                       

Paradigms of Antihypertensive Therapy A endothelin receptor antagonist (ERA) is a drug that blocks endothelin receptors. Three main kinds of ERAs exist: selective ERAs (sitaxentan, ambrisentan, atrasentan), which affect endothelin A receptors. dual ERAs (bosentan, tezosentan), which affect both endothelin A and B receptors selective endothelin receptor antibodies which affect endothelin B receptors (sarafotoxin B) are used in research but have not yet reached the clinical trial stage. Sitaxentan, ambrisentan and bosentan are mainly used for the treatment of pulmonary arterial hypertension, while atrasentan is an experimental anti-cancer drug.

Antihypertensive agents Classification of antihypertensives : ACE inhibitors : Captopril, Enalapril. Angiotensin receptor blockers: Losartan Renin inhibitors: Aliskiren Beta adrenergic blockers : Propranolol Calcium channel blockers : Amlodipine Alpha adrenergic blockers : Prazosin Central alpha-2 agonist: Clonidine, Methyldopa Diuretics: Chlorothiazides, Furosemide Vasodilators -Arterial (hydralazine, minoxidil, fenoldopam) -Arterial and venous (Nitroprusside)

Antihypertensive agents Diuretics : Thiazides or thiazides like: Chlorothiazides, Indapamide, Metolazone These are the most effective diuretics to reduce blood pressure in patients with normal renal function!!! High ceiling diuretics : Furesomide, Torsemide, Bumetanide Potassium sparing diuretics : Spironolactone, Amiloride

Diuretics Thiazides or thiazides like diuretics: These are the first line of treatment in uncomplicated hypertension especially in elderly and African-American populations. Potassium sparing diuretics are only used in combination with diuretics in hypertension to counteract hypokalemia. Thiazides can improve the hypotensive effects of many antihypertensive agents like ACE inhibitors and ARBs. Mechanism of action is not clear and could be due to Depletion of body Na+ stores leads to a fall in smooth muscle [Na+]. This in turn decreases intracellular [Ca ++] by activating the Ca/Na exchanger. Induction of renal prostaglandin biosynthesis Loop diuretics are preferable to thiazides only in some well recognized clinical situations such as malignant hypertension, concomitant chronic kidney disease etc.

Antihypertensive agents Angiotensin Converting Enzyme (ACE) Inhibitors: Captopril, Lisinopril, Enalapril, Ramipril, Benazepril, Fosinopril Reduction in arterial resistance (after load) Reduction in venous tension (preload) Reduction in aldosterone secretion

Antihypertensive agents

Antihypertensive agents Indications for ACE inhibitors includes: Congestive heart failure (CHF) Post-myocardial infarction Hypertension Hypertensive emergencies – enalaprilat. Prevention of nephropathy in diabetes mellitus increased glomerular pressure induces glomerular injury and ace inhibitors reduces this parameter both by decreasing the bp and dilating efferent arterioles. Ace inhibitors increase the selective permeability of the filtering membrane, thereby diminishes exposure of mesangium to proteninaceous factors that may stimulate mesangial cell proliferation and matrix production, the two processess that contribute to expansion of mesangium in diabetic nephropathy.

ACE Inhibitors ACE Inhibitors: Avoid in Bilateral renal artery stenosis In bilateral renal artery stenosis and renovascular hypertension, glomerular filtration pressures are maintained by vasoconstriction of the efferent areteiole (post-glomerular arterioles), an effect mediated by angiotensin II. Chemokines play an important role in the pathogenesis of diabetic nephropathy. Angiotensin II induces several fibrogenic chemokines, namely monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor-β. The progression of diabetic nephropathy can be retarded by ACE inhibitors (ACEIs) in patients with type 1 and type 2 diabetes. Blockade of the renin-angiotensin system in type 2 diabetic patients with diabetic nephropathy reduces uMCP-1 levels and improves renal function. Because MCP-1 induces monocyte immigration and differentiation to macrophages, which augment extracellular matrix production and tubulointerstitial fibrosis, pharmacological reduction of angiotensin II may also exert its beneficial effects in diabetic nephropathy by downregulation of renal MCP-1.

ACE INHIBITORS

Antihypertensive agents ANGIOTENSIN RECEPTOR BLOCKERS ARBs (AT 1 BLOCKERS): Losartan, Erbesartan, Candesartan Competitive antagonists of Angiotensin II No inhibition of ACE or breakdown of bradykinin

Antihypertensives agents agents

Antihypertensive agents RENIN INHIBITORS: Aliskiren: Aliskiren inhibits the activity of renin and thus prevents the conversion of angiotensinogen to angiotensin-I Aliskiren may have renoprotective effects that are independent of its blood pressure lowering effect in patients with hypertension and type 2 diabetes Aliskiren is also available as combination therapy with hydrochlorothiazide. Adverse effects includes stroke, angioedema, hyperkalemia and hypotension In December 2011, Novartis had to halt a clinical trial of the drug after discovering increased incidence of non-fatal stroke, renal complications, hyperkalemia and hypotension in patients with diabetes and renal impairment. The following recommendations are being added to the drug labels for aliskiren-containing products as of 4/20/12: I) A new contraindication against the use of aliskiren with ARBs or ACEIs in patients with diabetes because of the risk of renal impairment, hypotension, and hyperkalemia. II) A warning to avoid use of aliskiren with ARBs or ACEIs in patients with moderate to severe renal impairment (i.e., where glomerular filtration rate [GFR] < 60 mL/min).

Antihypertensive agents BETA BLOCKERS: Mechanism of action: Atenolol, Propranolol Decrease in cardiac output (blockade of cardiac beta1 receptors) Inhibition of renin release (blockade of beta1 receptors on juxtaglomerular cells) Inhibition of NE release from presynaptic adrenergic terminals (blockade of presynaptic beta receptors) Reduction of central adrenergic tone

Antihypertensive agents Guidelines for the use of Beta-Blockers in Hypertension Patients benefit the most from a beta-blocker drug therapy are those who have: a) hyperkinetic essential hypertension (associated high levels of catecholamines) b) hypertrophic obstructive cardiomyopathy. c) exertional angina. c) post myocardial infarction. d) hypertensive emergency (labetalol).

Antihypertensive agents BETA BLOCKERS: Adverse effects: Bradycardia is the most common adverse cardiac effect of beta-receptor blocking drugs. Sometimes, patients find cooling effect in hands and feet. Beta-receptor blockade with nonselective agents commonly causes worsening of preexisting asthma and other forms of airway obstruction without having these consequences in normal individuals.

Antihypertensive agents REDUCING SYMPATHETIC OUTFLOW FROM CNS: Alpha2 receptor agonists: Clonidine, Methyldopa Activation of α-2 receptors in NTS and in RVLM. Clonidine can cause hypertensive crisis after abrupt withdrawal leading to tachycardia, tremors and anxiety and may be life-threatening. Methyldopa is often preferred for the treatment of gestational hypertension. Methyldopa causes hepatic injury and hemolytic anemia (Coombs’ test positive) Activate alpha2 receptors in the Nucleus of Tractus Solitarius and in rostral ventrolateral medulla (main mechanism) Methyldopa: Taken up by adrenergic neurons and converted to methylNE and acts as an alpha2 receptor agonist. It acts by inhibiting DOPA decarboxylase Central Sympatholytic Drugs Key Points (Journal of Clinical Hypertensions. 2011;13:658–661). • Central sympatholytic drugs reduce blood pressure mainly by stimulating central a2-adrenergic receptors in the brainstem centers, thereby reducing sympathetic nerve activity and neuronal release of norepinephrine to the heart and peripheral circulation. • This class of drugs, however, is currently used mainly as fourth-line (or beyond) drug therapy for hypertension because of side effects of drowsiness, fatigue, and dry mouth. • Rebound hypertension is also another major concern with clonidine, particularly in patients who are non-adherent to the regimen. Adverse effects of Alpha 2 agonists: Xerostomia (mostly with clonidine; methyldopa also) Methyldopa: positive Coombs’ test (long-term therapy). Hemolytic anemia (rare). Methyldopa can cause hepatic injury (resolves when drug discontinued). Rarely methyldopa can cause hyperprolactinemia (inhibition of dopaminergic transmission in the hypothalamus). Medications that cause a positive direct Coombs test include high doses of penicillin, methyldopa and quinidine.

Antihypertensive agents CALCIUM CHANNELS BLOCKERS : CCB Types of calcium channels : L, N, T Calcium channel blockers mainly block L TYPE : SAN, AVN and smooth muscles Amlodipine, Nifedipine, Diltiazem, Verapamil Verapamil and diltiazem block Ca++channels both in the heart and in the vessels Dihydropyridines (DHP) like Nifedipine block calcium channels in the vessels only.

Clinical uses of calcium channel - blocking drugs Indication Amlodipine Angina, hypertension Felodipine Hypertension, Raynaud’s disease Nicardipine Nifedipine Angina, hypertension, Raynaud’s disease Nimodipine Subarachnoid hemorrhage Diltiazem Angina, hypertension and Supraventricular arrhythmia Verapamil Angina, hypertension, Supraventricular arrhythmias, Migraine

Adverse effects of calcium channel blockers Headache, dizziness, flushing and peripheral edema (DHP like nifedipine and amlodipine) Tachycardia, palpitations and aggravation of myocardial ischemia (nifedipine) Gingival hyperplasia (nifedipine) A-V block, bradycardia, arrhythmias (ver, dil) Constipation (verapamil) Verapamil can double the plasma concentration of digoxin

Vasodilators Used in the Treatment of hypertension Drug Site of action Mechanism of action Sodium nitroprusside Arterioles and veins Production of nitric oxide Hydralazine Arterioles Stimulation of NO release, Inhibition of Ca++ release from SR Minoxidil K+ channel opening Diazoxide Fenoldopam D1-receptor activation Direct Acting Vasoldilators Key Points and Practical Recommendations. Journal of Clinical Hypertension. 2011;13:690–692. • Hydralazine and minoxidil act by dilating resistance arterioles, thus reducing peripheral resistance, with no dilating effect on the venous side of the circulation. • There is a baroreflex-mediated venoconstriction, resulting in an increase in venous return to the heart, along with a direct catecholamine-mediated positive inotropic and chronotropic stimulation of the heart. • Hydralazine therapy is usually combined with a sympathetic inhibitor to prevent expression of this reflex, as well as with a diuretic agent to prevent sodium retention caused by reduction in renal perfusion pressure. • Hydralazine is indicated in the long-term therapy of essential hypertension, in the short-term therapy of pregnancy-induced hypertension and eclampsia, and in the therapy of hypertensive crisis. • Adverse effects include the anticipated tachycardia, fluid retention, and headache, caused by the vasodilation, especially in the early days of therapy, but may frequently be prevented by the concomitant use of a beta blocker. • As with other drugs that are N-acetylated, there is a low risk of lupus-like syndrome with high doses and long-term use. • Because of the severity of adverse effects with minoxidil, its usage is limited to persons with severe hypertension unresponsive to other treatments. • Hirsutism, a common side effect of minoxidil, is particularly bothersome in women and reverses in a few months after discontinuation. • Sodium nitroprusside is used in the intensive care setting to lower pressure in hypertensive crisis or to treat severe left ventricular failure, particularly valuable when elevated pressure or severe left ventricular failure threatens the patient’s survival. • Although nitrates have not achieved widespread use as antihypertensive agents, they are effective in producing sustained blood pressure (BP) reductions when added to other antihypertensive regimens.

Antihypertensive agents Sodium nitroprusside (SNP): Sodium nitroprusside (SNP) has potent vasodilating effects in arterioles and venules. SNP breaks down in circulation to release nitric oxide (NO). Sodium nitroprusside is metabolized to release cyanide ions which is further converted by liver rhodanase to thiocyanate for excretion in urine. Toxic accumulation of cyanide can cause severe lactic acidosis. S/S of thiocyanate toxicity includes nausea, disorientation and psychosis. (arterioles more than venules). Sodium nitroprusside slowly breaks down to release 5 cyanide ions, especially upon exposure to UV light. Despite the toxic potential of cyanide, nitroprusside remains an effective drug in certain clinical circumstances such as malignant hypertension or for rapid control of blood pressure during vascular surgery and neurosurgery. The cyanide can be detoxified by reaction with a sulfur-donor such as thiosulfate, catalysed by the enzymerhodanese. In the absence of sufficient thiosulfate, cyanide ions can quickly reach toxic levels.[7] The half-life of nitroprusside is 1–2 minutes, but the metabolite thiocyanate has an excretion half-life of several days.

Antihypertensive agents Sodium nitroprusside: It is administered intravenously in cases of hypertensive emergencies. It is also used in control of blood pressure in vascular and neurosurgery. Concomitant administration of sodium thiosulfate or hydroxocobalamin (Hydroxocobalamin combines with cyanide to form the nontoxic cyanocobalamin) can prevent cyanide accumulation in patients receiving more than usual dose of nitroprusside. The limiting factor in the metabolism of cyanide is sulfur containing substrates like thiosulfates.

Antihypertensive agents Hydralazine : Direct arteriolar vasodilator. Release of nitric oxide from vascular endothelium cause the vasodilation of the arteries. Reflex tachycardia due to sympathetic stimulation may precipitate angina/MI in CAD patients. Hydralazine is not used as a primary drug for treating hypertension because it elicits a reflex sympathetic stimulation of the heart (the baroreceptor reflex). The sympathetic stimulation may increase heart rate and cardiac output, and in patients with coronary artery disease may cause angina pectoris or myocardial infarction.[1] Hydralazine may also increase plasma renin concentration, resulting in fluid retention. In order to prevent these undesirable side-effects, hydralazine is usually prescribed in combination with a beta-blocker (e.g., propranolol) and a diuretic.[1] Hydralazine is used to treat severe hypertension, but again, it is not a first-line therapy for essential hypertension. However, hydralazine is the first-line therapy for hypertension in pregnancy, with methyldopa.

Antihypertensive agents Hydralazine : Adverse effects Tolerance due to salt and water retention and to baroreceptor-mediated activation of the SNS. Throbbing headache, palpitations. SLE – in slow acetylators or on prolonged use at a higher dose.

Antihypertensive agents Hydralazine : Uses Hypertension not controlled by first line of antihypertensives agents. Can be used in hypertension of pregnancy Hypertensive emergencies. Heart failure (combined with isosorbide dinitrate in African-American patients) Hydralazine is usually prescribed in combination with a beta-blocker (e.g., propranolol) and a diuretic to counteract its undesirable effects.

Antihypertensive agents Minoxidil : Arteriolar vasodilator - K channel activator Used in severe hypertension with renal failure and not responding to other agents (given with diuretic and beta blocker). Hypertrichosis on chronic therapy – excess growth of hair on face, back and arms. Topical minoxidil (ROGAINE) is marketed over the counter for the treatment of male pattern baldness, hair loss and thinning in women.

Effects of Minoxidil

Rationale for use of 1. Diuretics and 2 Rationale for use of 1. Diuretics and 2. Beta blockers along with vasodilators.

Antihypertensive agents Diazoxide: It is a rapidly acting and long acting arterial dilator that is occasionally used to treat hypertensive emergencies. It acts by opening of potassium channels leading to relaxation of arteries. The most significant toxicity from diazoxide is excessive hypotension that can cause stroke and myocardial infarction. Other adverse effects includes hyperglycemia (inhibits insulin secretion)

Antihypertensive agents Fenoldopam is used as an antihypertensive agent postoperatively, and also to treat hypertensive crisis. It acts as a selective peripheral dopamine D1 receptor weak partial agonist. The drug is administered by continuous intravenous infusion. The major toxicities are reflex tachycardia, headache and flushing.

Antihypertensive agents Hypertensive emergencies : Sodium Nitroprusside Nitroglycerine Labetolol Enalaprilat Nicardipine Esmolol Diazoxide Hydralazine Sodium nitroprusside (SNP) has potent vasodilating effects in arterioles and venules (arterioles more than venules). It is administered intravenously in cases of acute hypertensive emergency. SNP breaks down in circulation to release nitric oxide (NO). NO activates guanylate cyclase in vascular smooth muscle and increases intracellular production of cGMP. cGMP stimulates calcium movement from the cytoplasm to the endoplasmic reticulum and reduces calcium available to bind with calmodulin. Vascular smooth muscle relaxes and vessels dilate. In the human heart, nitric oxide reduces both total peripheral resistance as well as venous return, thus decreasing both preload and afterload. For this reason, it can be used in severe cardiogenic heart failure where this combination of effects can act to increase cardiac output. In situations where cardiac output is normal, the effect is to reduce blood pressure.

Antihypertensive drug   THE CHOICE OF THE ANTIHYPERTENSIVE IN PATIENTS WITH CONCOMITANT DISEASES. Concomitant disease Antihypertensive drug Diuretics ß-block. Ca-block. ACE-inhibitor Diabetes C.I AVOID OK INDI CATED Gout Dyslipidemia Angina pectoris --   I I Cardiac failure judicious Pregnancy Cautious C.I – Contraindicated I- Indicated OK – can be used.

Pulmonary Hypertension Endothelin receptor antagonists – Bosentan, Sitaxentan Phosphodiesterase type 5 inhibitors - Sildenafil Prostacyclin derivatives – Epoprostenol (PGI2), Iloprost (PGI2)

Antihypertensives agents Diuretics often considered first choice to use in mild uncomplicated HTN. ACE inhibitors are the best choice in patients with hypertension and diabetes mellitus. Beta blockers are the best choice in hypertensive patient with history of CAD. Calcium channel blockers are suited for HTN with history of bronchial asthma. Methyldopa is often preferred for treatment of HTN in pregnancy.