Drugs for The Treatment of Hypertension (HT)

Hypertension: Definition & Overview BP ≥ 140 mm Hg Systolic &/or 90 mm Hg diastolic Very common, especially in older people Incidence rising worldwide Major cause of morbidity and mortality Main complications are stroke, ischemic heart disease, renal failure and congestive heart failure Effective treatment leads to significant reduction of complications, improve survival and quality of life

HT: Physics, Physiology, & Pathophysiology BP= Cardiac output (CO) x peripheral resistance (PR) CO= Heart rate (HR) x stroke volume (SV) SV α venous return (VR) & contractility VR α blood volume & venous tone PR α arteriolar tone

HT: Physics, Physiology, & Pathophysiology Regulation of BP: Baro-receptors: acute settings Renin-angiotensin-aldosterone system (RAAS): intermediate term settings Renal regulation of BP: long term

Baroreceptors Involved in rapid control of BP Mediated through stretch sensitive receptors in the carotid sinus and aortic arch BP leads to reduced stretching of the receptors… Fewer impulses to the vasomotor centers in the brainstem Reduced parasympathetic drive and increased sympathetic drive Peripheral vasoconstriction, tachycardia, increased LV contractility

Renin-Angiotensin-Aldosterone system (RAAS) Renin is released from the JG apparatus β1 sympathetic stimulation Reduced afferent arteriolar stretching (in hypotension) Reduced tubular Na+ and water load (macula densa) Activates angiotensinogen (AT) into AT I, which is activated to AT II by angiotensin-converting enz. (ACE) AT II has many actions that raise BP

Actions of AT II to Raise BP Central activation of the sympathetic NS Stimulates catecholamine release from the adrenal medulla Stimulates the degranulation of sympathetic nerve endings Direct vasoconstrictor action: arteriolar ( PR) & venous ( venous return) Stimulates the release of aldosterone from the adrenal cortex: enhance sodium reabsorption from DCT

Actions of AT II to Raise BP Direct constrictor effect on the efferent arteriole in the glomeruli: Increase filtration pressure and filtration fraction Reduce hydrostatic pressure and increase oncotic pressure in the medullary arterioles Net increase of volume reabsorption, increased blood volume and BP

BP Manipulation Targeting the various components of the regulatory process of BP, i.e: Reducing plasma volume, venous return, CO, HR, LV contractility, PR

Pharmacological BP Manipulation Drugs modifying the sympathetic nervous system RAAS HR, contractility Peripheral resistance Venous tone and venous return Blood volume

Classes of Anti-HT Medications Diuretics β- adrenergic blockers Angiotensin converting enzyme inhibitors (ACE I) Angiotensin receptor blockers (ARBs) Calcium channel blockers α- receptor blockers Combined α- and β- blockers Centrally acting drugs Emergency treatment

Diuretics Thiazide diuretics Loop diuretics K+ sparing diuretics

Thiazide Diuretics Chlorthiazide, hydrochlorthiazide, chlorthalidone, metolazone Initial action: Diuresis: increase Na+ and water excretion in distal convoluted tubules Reduction of plasma volume Reduction of venous return Reduce cardiac output Reduction of renal blood flow Later on: restoration of plasma volume, but a hypotensive effect persists due to reduction of vasomotor tone & periph. resistance

Thiazide Diuretics: Side Effects (SE) Hypokalemia Hyperglycemia Hyperuricemia Fatigue Agranulocytosis NOT useful in renal failure (GFR ≤30 ml/min) except metolazone

Loop Diuretics Furosemide, bumetanide, ethacrynic acid, torsemide Most potent diuretic action: Block Na+ and water reabsorption in ascending limb of loop of Henle Increase renal blood flow (≠ thiazides) Usually used in combination with other drugs SE: K+, Ca++, Mg++; urine Ca++(≠ thiazides)

K+ Sparing Diuretics Aldosterone antagonists: Spironolactone, eplerinone DCT inhibitors: amiloride, triamterene Potentiate the effect of other classes of diuretics May cause hyperkalemia if used in combination with ACE I or ARBs

Classes of Anti-HT Medications Diuretics β- adrenergic blockers Angiotensin converting enzyme inhibitors (ACE I) Angiotensin receptor blockers (ARBs) Calcium channel blockers α- receptor blockers Combined α- and β- blockers Centrally acting drugs Emergency treatment

β- Adrenergic Blockers Non cardioselective: block β1 (heart, kidney) and β2 receptors (arteries, bronchi), e.g. propranolol, nadolol Cardioselective: only block β1 receptors: e.g. atenolol, metoprolol, bisoprolol: have little effect on bronchial and peripheral arterial tone Reduce BP by reducing C.O. and PR

β-Blockers: Pharmacokinetics Orally active: propranolol has individual variation of first pass liver metabolism, so effective dose can vary from patient to patient Intravenous preparations: propranolol, metoprolol, atenolol, and esmolol Most are metabolized in the liver Hydrophilic preparations (e.g. atenolol) are metabolized in the kidneys. They don’t cross the blood-brain barrier (no CNS S.E)

β-Blockers: Side Effects Brady cardia: avoided in patients with heart block Impaired LV contractility: avoided in patients with decompensated heart failure. However, some are the agents of choice in chronic heart failure Peripheral vasoconstriction: more with the non-selective agents. Should be avoided in critical limb ischemia Worsening of asthma: especially for non selective β blockers. Selective ones may be used cautiously in asthmatic patients

β-Blockers: Side Effects Other non cardiovascular SEs: insomnia with lipid soluble agents, nightmares, erectile dysfunction and reduced libido Disturbance of lipid metabolism: non cardioselective agents: HDL triglycerides

β-Blockers: Side Effects Abrupt withdrawal in patients with IHD may cause worsening of angina, precipitate acute MI, or even sudden death Therefore, should be withdrawn gradually (tapered) over a period of several weeks in patients with HT & IHD

Classes of Anti-HT Medications Diuretics β- adrenergic blockers Angiotensin converting enzyme inhibitors (ACE I) Angiotensin receptor blockers (ARBs) Calcium channel blockers α- receptor blockers Combined α- and β- blockers Centrally acting drugs Emergency treatment

Angiotensin Converting Enzyme Inhibitors (ACE Is) Captopril, enalapril, lisinopril, ramipril, fosinopril Reduce BP by inhibiting the activation of AT II Impair degradation of bradykinin, causing its level, NO and prostacyclin, which are vasodilators Lower aldosterone level, salt and water reabsorption from DCT Prevent efferent arteriolar constriction: intra-glomerular pressure Reduce vasomotor tone, afterload without CO

ACEI: Pharmacokinetics All ACEIs are orally bioavailable Captopril and lisinopril are active drugs. All other ACEIs are prodrugs, i.e. converted by the liver to an active metabolite Fosinopril is the only drug that is not excreted by the kidneys, so doesn’t need dose modification in CKD Enalaprilat is an intravenous preparation

ACEIs: Clinical Use HT, HT due to unilateral renal artery stenosis Drugs of choice in HT patients with renal impairment Reversal of LV hypertrophy (LVH) Control of proteinuria in diabetic nephropathy

ACEIs: Clinical Use Treatment of acute and chronic ischemic heart disease, & atherosclerosis Reversal of LV remodeling after acute myocardial infarction Standard therapy in all causes of systolic heart failure

ACEIs: SE Dry cough: bradykinin in the lung Skin rash Fever Altered taste Hyperkalemia: caution should be exercised when combining with K+ sparing diuretics or K+ supplements

ACEIs: SE Renal impairment: monitor S.K+ Contra-indicated in bilateral renal artery stenosis (why?) Angioedema: rare but serious: also due to high bradykinin levels Teratogenic effects: should be avoided in pregnancy!

Classes of Anti-HT Medications Diuretics β- adrenergic blockers Angiotensin converting enzyme inhibitors (ACE I) Angiotensin receptor blockers (ARBs) Calcium channel blockers α- receptor blockers Combined α- and β- blockers Centrally acting drugs Emergency treatment

Angiotensin Receptor Blockers (ARBs)

Angiotensin Receptor Blockers (ARBs) Losartan, valsartan, telmisartan, irbisartan, candisartan Block the AT receptor type 1 Same action as ACEIs: reduce sympathetic tone: vasodilatation reduce peripheral resistance Inhibit aldosterone release Renal efferent arteriolar dilatation ≠ ACEIs: they don’t inhibit bradykinin metabolism

Angiotensin Receptor Blockers (ARBs) SE: similar to ACEIs, except that cough is much less frequent (why?) Should not be combined with ACEIs: ineffective combination and more incidence of hyperkalemia Teratogenic effect: avoid in pregnancy!

Renin Antagonist Aliskerin Not widely used Equivalent anti-HT effect to ACEIs & ARBs May cause dry cough and angioedema (= ACEI) Other S.E: diarrhea

Classes of Anti-HT Medications Diuretics β- adrenergic blockers Angiotensin converting enzyme inhibitors (ACE I) Angiotensin receptor blockers (ARBs) Calcium channel blockers α- receptor blockers Combined α- and β- blockers Centrally acting drugs Emergency treatment

Calcium Channel Blockers (CCBs) Dihydropyridines: nifedipine, amlodipine, felodipine, nicardipine, isradipine Diphenylalkylamine group: verapamil Benzothiazipine group: diltiazem Generally divided into dihydropyridines and non- dihydropyridines Have different tissue affinity, different actions, and different SE profile

CCBs: Mechanism of Action Voltage sensitive Ca++ channels in excitable tissue (cardiac muscle and vascular smooth muscles) When stimulated, Ca++ influx into the cell causes augmented release of Ca++ from sarcoplasmic reticulum and mitochondria Ca++ release causes contraction of cardiac muscle ( contra- ctility) and vasoconstriction ( PR), i.e. increased BP CCBs inhibit this Ca++ mediated effect & lower BP

Not All CCBs Are Created Equal! Dihydropyridines (DHPs) act mainly on vascular SM cells: Relaxation and reduced vasomotor tone. Little effect on heart rate Non dihydropyridines act mainly on cardiac conductive system and myocardial cells: Bradycardia Negative inotropic state ( contractility) Group difference in SE profile

Pharmacokinetics of CCBs All have short plasma half life except amlodipine Therefore, sustained release preparations are used

SE of CCBs: Dihydropyridines Headache Flushing Edema Dizziness Gingival hypertrophy

SE of CCBs: Non-dihydropyridines Bradycardia Atrio-ventricular block Worsening of heart failure (contraindicated in any condition with impaired LV function, ≠ β- blockers) constipation

Classes of Anti-HT Medications Diuretics β- adrenergic blockers Angiotensin converting enzyme inhibitors (ACE I) Angiotensin receptor blockers (ARBs) Calcium channel blockers α- receptor blockers Combined α- and β- blockers Centrally acting drugs Emergency treatment

α- Adrenergic Blockers Prazocin, terazocin, doxazocin Block the α-1 receptors in arterial and venous smooth muscles Vasodilatation without alteration of CO or renal blood flow Initial effect: tachycardia and postural hypotension Later: SE disappear Low efficacy: so no longer used as standard therapy for HT, May be used for refractory cases with conjunction with other anti- HT drugs

Classes of Anti-HT Medications Diuretics β- adrenergic blockers Angiotensin converting enzyme inhibitors (ACE I) Angiotensin receptor blockers (ARBs) Calcium channel blockers α- receptor blockers Combined α- and β- blockers Centrally acting drugs Emergency treatment

Combined α- & β-Adrenergic Blockers Carvedilol, labetalol α, β1, and β2 receptor blockers Carvedilol: main use is in systolic HF, where it has been shown to improve outcome, preserve LV function and reduce mortality (other β blockers in this respect include bisoprolol and metoprolol) Labetalolo: main use is in gestational HT and hypertensive emergencies

Classes of Anti-HT Medications Diuretics β- adrenergic blockers Angiotensin converting enzyme inhibitors (ACE I) Angiotensin receptor blockers (ARBs) Calcium channel blockers α- receptor blockers Combined α- and β- blockers Centrally acting drugs Emergency treatment

Centrally Acting Antihypertensive Drugs Clonidine and α-methyl dopa Clonidine: acts by stimulating central α2 sympathetic receptors in the vasomotor centers in the CNS This stimulation results in inhibition of the peripheral sympathetic tone Reduction in PR without any effect on the kidneys Low efficacy drug: used as a adjunctive therapy if other drugs fail to control BP

Centrally Acting Antihypertensive Drugs: Clonidine Available in oral and transdermal forms Well absorbed via the oral route SE: sedation, constipation, and dry mouth Abrupt cessation leads to rebound increase of BP (sudden increase to more than pre-treatment levels) Rarely used clinically

Centrally Acting Antihypertensive Drugs: α-methyl dopa Central stimulation of sympathetic α-2 receptors Converted in the CNS into methylnorepinephrine Reduce central sympathetic flow Safe in pregnancy S.E: drowsiness, depression, SLE like syndrome Requires frequent dosing (2-3 times/day)

Peripheral Vasodilators Hydralazine, Minoxidil Direct arterial and arteriolar smooth muscle relaxation Reduce peripheral resistance Over-compensated by reflex tachycardia and enhanced LV contractility Increase myocardial oxygen consumption May precipitate angina, MI, and heart failure Also: increase plasma renin concentration (≠ DHPs): Na+ retention & edema

Peripheral Vasodilators: Hydralazine Used mainly in pregnancy-induced HT Injectable form used in HT emergencies Otherwise, used in combination therapy: Reflex tachycardia offset by a β-blocker Fluid retention counterbalanced by a diuretic S.E: headache, tachycardia, angina, nausea, sweating, arrhythmia, Also: SLE-like syndrome

Peripheral Vasodilators: Minoxidil No longer used due to low efficacy and cardiac S.E (Useful) SE: hirsutism Major current use: to stimulate hair growth in androgenic alopecia as a topical preparation(!)

Emergency Treatment of Hypertension Rarely effective or necessary Rapid lowering of BP may cause CNS catastrophes (stroke): The phenomenon of autoregulation Situations requiring rapid control of pressure, e.g. aortic dissection, unstable angina, STEMI, HT encephalopathy, toxemia of pregnancy

Emergency Treatment of Hypertension Intravenous forms Sodium nitroprusside: instantaneous titration of the drug according to BP SE: methemoglobinemia Glyceryl trinitrate: arterial and venous dilator Main use: Acute coronary syndrome (ACS) Isosorbide mononitrate: Arterial dilator

Emergency Treatment of Hypertension Labetalol: Combined α- & β- blocker Intravenous Ca++ blockers: nicardipine Hydralazine: i.v or i.m