Antihypertensive Drugs Dr. Kaukab Azim. MBBS, PhD

Inhibitors and antagonists of the renin-angiotensin system Drug List * Diuretics Sympathoplegic drugs Vasodilators Inhibitors and antagonists of the renin-angiotensin system ACE inhibitors ARBs Renin inhibitors Hydrochloro-thiazide Clonidine Hydralazine Captopril Losartan Aliskiren Indapamide Methyldopa Nitroprusside Enalapril Furosemide Prazosin Minoxidil Enalaprilat Spironolactone Propranolol Diazoxide Labetalol Fenoldopam Esmolol CCBs * More drugs have been mentioned in other slides

Hypertension Epidemiology It is estimated that, in industrialized countries, some kind of hypertension (HTN) affects 25 % of subjects over 20. HTN is a main risk factor for stroke, coronary and renal diseases, heart failure and sudden death. In about 95% of cases, the etiology of HP is unknown (essential or primary hypertension) but is thought to be multifactorial. Heredity is a predisposing factorial. Environmental factors (i.e. dietary Na+, obesity, stress) seem to act only in genetically susceptible persons. In most cases the disease lacks subjective symptoms. The medical treatment of HP is usually long-lasting (often for life). It is estimated that today 50% of hypertensive patients lacks an effective treatment.

Other definitions Isolated systolic hypertension is defined as a systolic blood pressure of greater than 140 mm Hg and a diastolic pressure of < 90 mm Hg and staged appropriately (e.g. 170/85 mm Hg is defined as stage 2 isolated systolic pressure). Hypertensive crisis can be defined as a severe elevation in blood pressure (diastolic BP >120 mm Hg), and is classified further as hypertensive emergency (immediately life-threatening, with end-organ damage) hypertensive urgency (non immediately life-threatening, without end-organ damage) The terms accelerated hypertension or malignant hypertension are used to define a severe hypertension accompanied by end organ damage.

Pathophysiology of HTN 1) Disorder of sodium metabolism (likely the main factor) The extracellular fluid volume increases in hypertensive patients when exposed to high dietary sodium intake, in spite of the expected natriuretic response 2) Imbalance of the renin-angiotensin system 20 % have lower than normal renin values 20 % have higher than normal renin values 60 % have normal renin values 3) Sympathetic overactivity (hyperdynamic state). Increased sympathetic activity leads to increases in cardiac output, heart rate, plasma renin concentration and peripheral vascular resistance. [all the above mentioned mechanisms are probably secondary to a genetic predisposition] 4) Mosaic theory: Multiple factors sustain hypertension even though aberration of only one could be initially responsible.

Classification of Antihypertensive Drugs 1) Diuretics Thiazides and congeners. Loop diuretics. Potassium-sparing diuretics. 2) Sympatholytic drugs Centrally acting antiadrenergic agents. Alpha adrenergic blockers. Beta adrenergic blockers. Alpha-beta adrenergic blockers. 3) Vasodilators Nitric oxide releasers. Potassium channel openers. Calcium channel blockers D1-dopamine receptor agonists. 4) Angiotensin inhibitors and antagonists Angiotensin Converting Enzyme (ACE) inhibitors. Angiotensin receptor antagonists.

Diuretics Diuretics lower blood pressure but there is no strict correlation between diuretic efficacy and antihypertensive efficacy. The fact points out that diuretics do not reduce blood pressure only by increasing diuresis. The initial hypotensive effects of diuretics is associated with a reduction in plasma volume and cardiac output. Peripheral vascular resistance is usually unaffected (or sometimes increased). After 4-8 weeks of continuous therapy intravascular volume and cardiac output return towards normal while peripheral vascular resistance decreases, due to arteriolar vasodilation.

Diuretics Mechanisms of this vasodilation are still poorly understood, but are probably related to: a) Depletion of body Na+ stores (likely the main mechanism) which leads to a fall in smooth muscle Na+ concentration. This in turn decreases intracellular Ca++ concentration by activating the Ca/Na exchanger. b) Induction of renal prostaglandin biosynthesis. c) Opening of K channels.

Diuretics Thiazides and thiazide-like drugs are first choice antihypertensive agents. They are the most effective diuretics to reduce blood pressure in patients with normal renal function. The antihypertensive doses are lower that those required for diuretic effect. Loop diuretics are preferable to thiazides only in some well recognized clinical situations (malignant hypertension, concomitant chronic kidney disease etc.) Potassium sparing diuretics are only used in combination with thiazides to counteract hypokalemia. Spironolactone is used in hypertension due to hyperaldosteronism. Diuretics can enhance the hypotensive effects of many antihypertensive agents.

Drugs that alter sympathetic nervous system function

Centrally acting sympathoplegic Drugs Alpha-2 receptor agonists: clonidine Indirect acting adrenergic drugs: methyldopa Mechanisms of antihypertensive action a) Alpha-2 receptor agonists: Activation of alpha-2 receptors in Nucleus Tractus Solitarius and in rostral ventrolateral medulla (the main mechanism). Activation of peripheral alpha-2 receptors (after high doses). b) Indirect acting adrenergic drugs: Methyldopa acts as a false neurotransmitter. It is taken up by the adrenergic neurons where it is transformed into methylnorepinephrine, the alpha-2 receptor agonist, which acts as described above. The final effect common to all these drugs is a decreased firing of the reticulospinal tract, that is a decrease of central adrenergic tone

Therapeutic uses in hypertension Clonidine and methyldopa (usually given together with a diuretic) are second choice drugs for therapy of hypertension. Methyldopa is often preferred for the treatment of hypertension in pregnancy (long experience has shown that it is not harmful to the fetus).

Toxicity of centrally acting sympathoplegic drugs Central Nervous Ssytem Sedation and drowsiness (up to 50%), mental clouding. Weakness, headache, dizziness, nightmares (up to 15%) Risk for depression Cardiovascular system Clonidine (and rarely methyldopa) can cause a hypertensive crisis, when the drug is suddenly withdrawn. Bradycardia, A-V block (in risk patients). Gastrointestinal system Xerostomia (clonidine up to 50%, methyldopa up to 10%) (the effect is centrally mediated). Other systems Sexual dysfunction (up to 20%). Skin eruption (up to 20% with clonidine, when given transdermally). Methyldopa can cause positive Coombs’ test (up to 30%, after longterm therapy).

Alpha Blockers Drugs Prazosin, doxazosin, etc. Mechanism of action Selective blockade of alpha-1 receptors. (They reduce blood pressure by dilating both resistance and capacitance vessels) Adverse effects 1) Cardiovascular system Postural hypotension, mainly after the first dose (the so called "first-dose phenomenon"). It can lead to myocardial and cerebral ischemia (syncope). The mechanism is uncertain. Tachycardia, palpitations (.5%). Nasal stuffiness Peripheral edema, after chronic treatment (due to sodium and water retention).

2) Central nervous system Fatigue, dizziness, vertigo, drowsiness (up to 10%) 3) Other systems Urinary frequency, urinary incontinence. Sexual dysfunction (up to 20%, it includes priapism and inhibition of ejaculation). - (second choice drugs), often associated with other antihypertensive drugs.

Beta-blockers (the “olols”) Proposed mechanisms of action (the mechanisms are listed in order of decreasing importance) Decrease in cardiac output (blockade of cardiac beta-1 receptors) Inhibition of renin release (blockade of beta-1 receptors of juxtaglomerular cells) Inhibition of norepinephrine release from presynaptic adrenergic terminals (blockade of presynaptic beta receptors) Reduction of central adrenergic tone (blockade of hypothalamic and bulbar beta receptors?)

Classes of Beta Blockers Non-selective Selective (at Beta 1) Propranolol Carteolol Penbutolol Pindolol Timolol Acebutolol Atenolol Betaxolol Bisoprolol Metoprolol

Hemodynamic actions Beta-blockers (Propranolol) Alpha-beta blockers (Labetalol) Heart rate: decreased. Cardiac output: decreased. Venous tone: unchanged. Postural hypotension: negligible. Renal blood flow: decreased (early) normal (late). Efficacy of antihypertensive effect: good. Peripheral vascular resistance: increased (early), decreased (late)mainly in hypertensive patients (the mechanism of this decrease is uncertain). Heart rate: unchanged. Cardiac output: unchanged or decreased. Venous tone: decreased. Postural hypotension: evident. Renal blood flow: unchanged. Efficacy of antihypertensive effect: high. Peripheral vascular resistance: decreased.

Guidelines for use of Beta-blockers Patients most likely to benefit from a beta-blocker drug therapy are those who have: young age. supraventricular arrhythmias. hypertrophic obstructive cardiomyopathy. exertional angina. post myocardial infarction. hypertensive emergency (labetalol).

Points to remember about BBs All beta-blockers give equivalent results in the treatment of hypertension. The choice is therefore mainly dictated by the tolerability of the treatment. In this regard it is worth remembering that: Compounds which are partial agonists appear to depress heart function less than other beta-blockers. Selective compounds increase airway resistance less than nonselective compounds. Nonselective compounds devoid of partial agonist activity are most prone to cause peripheral vascular disturbances (because of a decreased cardiac output associated with a blockade of vasodilation in skeletal muscle).

Adverse Effects CVS: Bradycardia, hypotension, rebound hypertension when withdrawn abruptly Respiratory: Bronchoconstriction CNS: Insomia, depression, nightmares, constipation Hepatic: Impaired ability of the liver for gluconeogenesis and glycogenolysis causing hypoglycemia Sexual dysfunction

Vasodilators used in treatment of hypertension Drug Site of action Mechanism of action Nitropursside Arterioles and veins Production of nitric oxide Hydralazine Arterioles Uncertain (Perhaps inhibition of Ca++ release from sarcoplasmic reticulum, and stimulation of NO release) Minodoxil Diazoxide K+ channel opening Fenoldopam D1- receptor activation

Nitroprusside Pharmacology Pharmacokinetics Rapidly metabolized by red blood cells with liberation of cyanide, which in turn is metabolized to thiocyanate. The half life is about 2 minutes, so the drug must be given by continuous infusion to be effective. Adverse effects Excessive vasodilation, rebound hypertension, palpitations Nausea and vomiting, substernal pain Accumulation of: a) cyanide (with too high doses) b) thiocyanate (over prolonged administration) Contraindications and precautions Impaired cerebral circulation Compensatory hypertension (i.e., stenosis of aorta) Therapeutic uses Hypertensive emergencies. Severe heart failure (cardiac output can increase owing to afterload reduction). To induce a controlled hypotension, during surgery.

Hydralazine Pharmacology Adverse effects a) Due to extension of pharmacological effects: Asthenia, headache, nausea, dizziness. Palpitations, sweating and flushing. Myocardial ischemia, angina (in risk patients) b) Due to immunological reactions Lupoid syndrome (up to 20% incidence, with very high doses). Fever, serum sickness, hemolytic anemia, vasculitis. Contraindications and precautions Coronary artery disease Cerebrovascular disease Collagen disease Therapeutic uses Hypertension (second choice drug). Heart failure (combined with isosorbide mononitrate in African-American patients)

Minodoxil Pharmacology Pharmacokinetics and administration Minoxidil is a prodrug which is transformed by the liver into the active molecule. The half life is about 4 hours but the duration of action is 24-48 hours probably because of the formation of the active metabolite. Administration: oral. Adverse effects Salt and water retention (can be pronounced) (7%). Tachycardia, palpitations, flushing, nasal stuffiness angina. Cardiac failure (mainly in patients with left ventricular hypertrophy and diastolic dysfunction, who respond poorly to volume overload) Hypertrichosis (Hair growth > 95% of patients, if used for more than a month). Therapeutic uses (Not very commonly used because of its toxicity) Severe hypertension that responds poorly to other antihypertensive medications. Locally used to treat baldness.

Diazoxide Pharmacology Chemistry The drug is similar to thiazide diuretics, but it does not cause diuresis Adverse effects Salt and water retention, edema. Hyperglycemia (50% of patients) Excessive hypotension (may lead to stroke, angina and myocardial infarction) Flushing and headache (all vasodilators cause this) Hypertrichosis (Hair growth in 20% of patients). Contraindication and precautions Compensatory hypertension (i.e., stenosis of aorta) Impaired cerebral circulation Coronary disease Sulfa drug hypersensitivity (a sulfur atom is present in diazoxide molecule) Diabetes mellitus Therapeutic uses Hypertensive emergencies. To treat hypoglycemia secondary to insulinoma.

Dopamine D1-Receptor Agonist Fenoldopam is the only drug on the market. Pharmacodynamics Vasodilation, mainly in renal and mesenteric vascular beds. Increased natriuresis (activation of D1 receptors causes an inhibition of NA+ reabsorption in the proximal tubule) Pharmacokinetics Half-life: about 10 minutes. Administration: IV infusion Adverse effects Reflex tachycardia, flushing Dose-dependent increase in intraocular pressure Decrease in serum potassium levels (likely due to natriuresis-induced aldosterone release). Contraindications Angina (tachycardia can trigger an anginal attack) Glaucoma. Hypokalemic states. Therapeutic uses Hypertensive emergencies. To induce a controlled hypotension, during surgery.

Calcium Channel Blockers as Antihypertensives Drugs All calcium channel blockers (verapamil, diltiazem, dihydropyridines) are equally effective in lowering blood pressure. Hemodynamic actions Heart rate: increased (dihydropyridines); unchanged or decreased (verapamil, diltiazem) Cardiac output: increased (dihydropyridines); unchanged (verapamil, diltiazem) Venous tone: unchanged. Peripheral vascular resistance: decreased. Postural hypotension: negligible. Renal blood flow: unchanged or increased. Efficacy of antihypertensive effect: moderate. Duration of antihypertensive effect: variable (nifedipine . 2-6 hours; amlodipine 24-36 hours)

Calcium Channel blockers Uses in hypertension Hypertension (first choice drugs, more effective in African patients). Hypertensive emergencies (nicardipine). Long term epidemiological studies have reported an increased risk of mortality when short-acting nifedipine is used in hypertension. Slow release formulations apparently do not increase this risk. While there is still debate about causation, it seems that the sudden decrease in blood pressure causes a pronounced reflex tachycardia which can precipitate a myocardial infarction in patients at risk].

Renin Inhibitors Drugs Aliskiren is the only drug on the market Mechanism of action Competitive inhibition of renin, the enzyme that converts angiotensinogen into angiotensin I (the rate limiting step in angiotensin II biosynthesis). The inhibition of renin activity causes a decrease of angiotensin I, II, and aldosterone and an increase (up to 10 fold) of plasma renin. Pharmacodynamics Dose-dependent decrease in blood pressure. Pharmacokinetics Oral bioavailability: . 2.5% Mainly eliminated unmetabolized by biliary excretion. Half-life: 24 hours.

Renin Inhibitors Adverse effects (usually well tolerated) Dizziness, fatigue Diarrhea (up to 10%, dose-related ) Hyperkalemia (when given with ACE inhibitors or angiotensin antagonists) Severe hypotension (rare) Angioedema (rare) Contraindications Pregnancy (because of the known teratogenic effects from blocking the renin-angiotensin-aldosterone system) Therapeutic uses Hypertension (second choice drugs)

ACE inhibitors Drugs Captopril, lisinopril and enalaprilat are active drugs. All other compound (enalapril, benazepril, fosinopril, etc.) are prodrugs. Mechanism of action The converting enzyme peptidyl dipeptidase hydrolyzes angiotensin one to angiotensin II and inactivates bradykinin. By inhibiting this enzyme, ACE-inhibitors lead to: 1) inhibition of the renin-angiotensin system 2) increased plasma levels of bradykinin Both actions lead to a relaxation of vascular smooth muscle, but the first action is the most important. All drugs of this class have the same actions and similar patterns of adverse effects. (i.e. by inhibiting angiotensin II formation ACE inhibitors decrease the negative feed-back so causing an increase in renin release. This may attenuate the antihypertensive effect of these drugs).

ACE inhibitors Pharmacokinetics Oral bioavailability: variable (enalapril 95%, benazepril 40%) Distribution in peripheral tissues (most compounds do not cross the blood-brain barrier) All compounds that are prodrugs are transformed by the liver into active metabolites. Half-lives are variable (captopril . 2 hours: benazepril . 20 hours) All compounds, except enalaprilat, are administered by oral route only .

ACE inhibitors: Adverse effects Cardiovascular system Hypotension and postural hypotension (mainly after the initial doses, in 3-5% of patients who are salt and water depleted, or who have congestive heart failure). Respiratory system Dry and disturbing cough (up to 20%) (it may be mediated by accumulation in the lungs of bradykinin and prostaglandins or, more likely, substance P). Urinary system Renal insufficiency (in patients with bilateral renal artery stenosis or with stenosis of the renal artery of a solitary kidney)

Other systems Hyperkalemia (mainly when given in conjunction with other drugs or diseases that alter K+ homeostasis). Angioneurotic edema. It is rare (up to 0.3%), but may be fatal (inhibition of bradykinin metabolism can be involved). Prenatal effects ACE inhibitors are pregnancy categoty D

ACE inhibitors: Therapeutic uses Hypertension (first choice drugs) (thiazide diuretics can increase substantially the antihypertensive effect) Hypertensive emergencies (enalaprilat IV) Myocardial infarction (overall mortality is reduced when treatment is begun during periinfarction period). Chronic congestive heart failure (they decrease the progression of heart failure, the incidence of sudden death and myocardial infarction, and they improve the quality of life) Diabetic glomerulopathy, hypertensive nephroangiosclerosis (they decrease the progression of the disease by preventing the angiotensin II induced vasoconstriction on the efferent glomerular arteriole). Primary or secondary hyperaldosteronism (when resistant to conventional therapy).

Angiotensin II Receptor antagonists Drugs Losartan, eprosartan, irbesartan, etc. Mechanism of action Competitive antagonism at angiotensin II receptors (these drugs selectively block AT1 receptors) Pharmacodynamics They can prevent and reverse most known actions of angiotensin II, including: Rapid and slow hypertensive responses Stimulant effect on the peripheral sympathetic nervous system. All CNS effects (thirst, vasopressin release, etc.) Release of adrenal catecholamines Secretion of aldosterone All direct and indirect effects of angiotensin II on the kidney All growth-promoting actions They exert a more complete inhibition of angiotensin actions compared with ACE inhibitors (enzymes other than ACE are capable of generating angiotensin II) They have no effect on bradykinin and leukotriene metabolism. Main actions are: a) Vasodilation b) Increased salt and water secretion

Angiotensin II Receptor antagonists Pharmacokinetics Losartan: - Oral bioavailability:. 33%. Half-life: . 2 hours. All compounds are administered by oral route only. Adverse effects [all adverse effects that result from inhibiting angiotensin II related functions should be expected] Hypotension (mainly in patients in whom hypertension is highly dependent on angiotensin II) Hyperkalemia (in conjunction with other factors that alter K+ homeostasis) Main Contraindications Bilateral renal artery stenosis, severe stenosis of abdominal aorta. Pregnancy [these drugs are classified by FDA in the pregnancy risk category D because of their substantial teratogenic risk]. Therapeutic uses Hypertension (first choice drugs)(thiazide diuretics can increase substantially the antihypertensive effect)

Algorithm for the treatment of hypertension Algorithm for the treatment of hypertension.[From The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (2004).Bethesda, MD: National Heart, Lung &Blood Institute, National Institutes of Health. Available at: http://www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.htm] Step 1:Lifestyle modifications are instituted •Weight reduction•Smoking cessation •Moderation of alcohol intake•Reduction of salt in diet •Increase in physical activity Step 2:Inadequate response Continue lifestyle modifications. If measures in step 1 are notsufficient to lower blood pressure to an acceptable level,thendrug therapy is added:•Diuretic (decreases serum sodium levels and blood volume) •Beta-blocker (leads to a decrease in heart rate and strength ofcontraction,as well as vasodilation)•ACE inhibitor (blocks the conversion of angiotensin I toangiotensin II)•Calcium channel blocker (which relaxes muscle contraction)or other autonomic blockers•Angiotensin II–receptor blocker (blocks the effects ofangiotensin on the blood vessel) Step 3:Inadequate response Consider change in drug dose or class,or addition of anotherdrug for combined effect. (Note:Fixed-combination drugsshould only be used when the patient has been stabilized oneach drug separately; see Box 43.3.) Step 4:Inadequate response •All of the above measures are continued.•A second or third agent or diuretic is added if not alreadyprescribed.