Hypertension Lecture Notes PDF

2024/08/05 HYPERTENSION Dr Sarentha Chetty BPharm, MSc, PhD CONTENT BP Pathophysiology of HT Drugs used in the treat HT Mechanisms of action Adverse Effects Drug interactions Clinical applications ...

2024/08/05 HYPERTENSION Dr Sarentha Chetty BPharm, MSc, PhD CONTENT BP Pathophysiology of HT Drugs used in the treat HT Mechanisms of action Adverse Effects Drug interactions Clinical applications  2024/08/05 INTRODUCTION Persistent arterial HT →damage - blood vessels in kidney, heart, brain ↑ risk of end organ damage - renal failure, coronary disease, HF, stroke, dementia Diagnosis - repeated measurements - elevated blood pressure Risks: genetic factors, psychological stress, environmental and dietary factors (increased salt and decreased potassium or calcium intake), alcohol consumption, and obesity Additional risk factors e.g. established cardiovascular disease (e.g. angina, previous stroke or myocardial infarction), established target organ damage, smoking, hyperlipidaemia and diabetes – require lower targets for intervention Lifestyle modifications: healthy diet (moderation of alcohol and salt intake) exercise ↓es BP Smoking cessation ↓es concurrent cardiovascular risk No specific cause of HT can be found → essential or primary HT Where there is specific etiology - secondary HT Genetic/inherited essential hypertension ± 30% Appears to be polygenic Functional variations of genes: angiotensinogen, angiotensin converting enzyme (ACE), angiotensin II receptor, β2 adrenoceptor, α-adducin (a cytoskeletal protein), uromodulin (modulator of renal electrolyte transport), and others  2024/08/05 BLOOD PRESSURE IN ADULTS Blood Pressure Systolic [mm Hg]/Diastolic [mm Hg] Low 70–90/40–60 Normal 90–120/60–80 Elevated 120–129/80 Hypertension Stage I 130–139/80–90 Stage II >140/>90 REGULATION OF NORMAL BP BP - directly proportionate to the product of the blood flow (cardiac output) and the resistance to passage of blood through pre-capillary arterioles (peripheral vascular resistance) BP = CO × PVR  2024/08/05 A. POSTURAL BAROREFLEX Baroreflexes -responsible for rapid adjustments in BP e.g. reclining to an upright posture Carotid baroreceptors – stimulated by stretch of the vessel walls (arterial BP). Baroreceptor activation inhibits central sympathetic discharge Transition to upright posture →baroreceptors sense the reduction in arterial pressure that results from pooling of blood in the veins below the level of the heart as reduced wall stretch, and sympathetic discharge is disinhibited The reflex increase in sympathetic outflow increases peripheral vascular resistance (constriction of arterioles) and cardiac output (direct stimulation of the heart and constriction of capacitance vessels, which increases venous return to the heart), thereby restoring normal BP. B. RENAL RESPONSE TO DECREASED BLOOD PRESSURE The kidney controls blood volume - affects long-term BP control ↓ renal perfusion pressure →intrarenal redistribution of blood flow and ↑reabsorption of salt and water ↓pressure in renal arterioles as well as sympathetic neural activity (via β- adrenoceptors) stimulates production of renin which ↑Angiotensin II Angiotensin II causes : (1) direct constriction of resistance vessels (2) stimulation of aldosterone synthesis in the adrenal cortex, which ↑ renal sodium absorption and intravascular blood volume Vasopressin released -posterior pituitary gland also plays a role in maintenance of BP through its ability to regulate water reabsorption by the kidney  2024/08/05 ANTIHYPERTENSIVE AGENTS 1. Diuretics- Depletes sodium and ↓ blood volume 2. Agents that block production/action of renin or angiotensin - ↓peripheral vascular resistance and (potentially) blood volume 3. Direct vasodilators - Relaxes vascular smooth muscle →dilating resistance vessels To varying degrees – also ↑capacitance 4. Sympathoplegic agents - ↓ peripheral vascular resistance and ↑venous pooling in capacitance vessels thereby reducing cardiac output Sites of action of the major classes of antihypertensive drugs. Citation: Chapter 11 Antihypertensive Agents, Vanderah TW. Katzung’s Basic & Clinical Pharmacology, 16th Edition; 2024. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=3382&sectionid=281748109 Accessed: May 20, 2024 Copyright © 2024 McGraw-Hill Education. All rights reserved  2024/08/05 DRUGS THAT ALTER SODIUM & WATER BALANCE Mechanisms of Action & Hemodynamic Effects of Diuretics: Act mainly by depleting sodium stores Initially ↓ BP by ↓ blood volume, venous return and CO Peripheral vascular resistance may increase After 6–8 weeks, CO returns to normal but the hypotensive effect remains because the peripheral resistance ↓es Na+ ↑vascular resistance by ↑ vessel stiffness and neural reactivity, through sodium-calcium exchange with a resultant ↑ intracellular calcium These effects are reversed by diuretics or dietary sodium restriction. Vasodilatation by diuretics associated with a small but persistent reduction in body Na+ One possible mechanism ↓smooth muscle Na+ causes a secondary ↓intracellular Ca2+ so muscle becomes less responsive to endogenous vasoconstrictors. Diuretics – lower BP by 10–15 mm Hg in most patients Diuretics alone – mild or moderate essential HT More severe HT - combined with sympathoplegic and vasodilator drugs to control the tendency toward Na+ retention Vascular responsiveness diminished by sympathoplegic and vasodilator drugs, so that the vasculature behaves like an inflexible tube BP becomes highly sensitive to blood volume  2024/08/05 USE OF DIURETICS Thiazides: Bendroflumethiazide, hydrochlorothiazide Mild or moderate HT with normal renal and cardiac function Lower doses exert as much antihypertensive effect as do higher doses ‘thiazide-like diuretics’ - Chlortalidone, indapamide, Loop diuretics: Act on the loop of Henle Furosemide, bumetanide, and torsemide Severe HT Used when multiple drugs with Na+ retaining properties are used in renal insufficiency When GFR < 30–40 mL/min Cardiac failure or cirrhosis, in which sodium retention is high Potassium sparing diuretics: Aldosterone, spironolactone Avoids excessive potassium depletion and to enhance the natriuretic effects of other diuretics ↑Dose - ↑therapeutic effect  2024/08/05 DIURETIC: ADVERSE EFFECTS Potassium depletion →Hypokalemia Dangerous – patients on digoxin, chronic arrhythmia, acute myocardial infarction or left ventricular dysfunction Magnesium depletion Impair glucose tolerance especially thiazides ↑serum lipid concentrations ↑ uric acid concentrations and may precipitate gout Low doses minimizes these adverse metabolic effects Potassium sparing diuretics - hyperkalemia, particularly in patients with renal insufficiency, or on ACE inhibitors or angiotensin receptor blockers Spironolactone associated with gynecomastia. INHIBITORS OF ANGIOTENSIN ↓ renal arterial pressure, sympathetic neural stimulation, ↓ sodium delivery or increased sodium concentration at the distal renal tubule ↑es Renin release Renin acts on angiotensinogen → angiotensin I ACE converts Angiotensin I to angiotensin II Ang II is converted in the adrenal gland to angiotensin III Angiotensin II – potent vasoconstrictor and sodium retaining activity Angiotensin II and III - stimulate aldosterone release Angiotensin may contribute to maintaining high vascular resistance in hypertensive states associated with high plasma renin activity e.g. renal arterial stenosis, some types of intrinsic renal disease, malignant HT, as well as in essential HT after treatment with sodium restriction, diuretics, or vasodilators  2024/08/05 ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS Inhibition of Ang II synthesis → ↓vasoconstrictor tone and peripheral resistance & lowers BP E.g. Captopril, Enalapril, perindopril Enalapril: oral prodrug →converted by hydrolysis to active form enalaprilat *Enalaprilat itself is available only for IV use, primarily for hypertensive emergencies Lisinopril is a lysine derivative of enalaprilat Benazepril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril - long acting members of the class. All except lisinopril are prodrugs- converted to active agents by hydrolysis mainly in the liver. Useful - in treating patients with chronic kidney disease because they diminish proteinuria and stabilize renal function (even in the absence of lowering of blood pressure) Effect is particularly valuable in diabetes - renoprotective These drugs - now recommended in diabetes even in the absence of hypertension These benefits probably result from improved intrarenal hemodynamics, with ↓ glomerular efferent arteriolar resistance and a resulting ↓ of intra-glomerular capillary pressure ACEI -useful in heart failure and as treatment after myocardial infarction ACEIs reduce the incidence of diabetes in patients with high cardiovascular risk  2024/08/05 ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS: ADVERSE EFFECTS ACE also metabolizes bradykinin Common adverse effect - dry cough - may be caused by ↑ bradykinin Bradykinin and substance P seem to be responsible for the cough and angioedema Rare, but serious, adverse effects – angio-oedema, proteinuria and neutropenia Angio-oedema more common in Black patients CI: History of angio-odema First dose may cause steep fall in BP, for e.g. in patients on diuretics (because they are Na+ depleted) why titrate up. May cause acute renal failure in patients with bilateral renal artery stenosis. In bilateral renal artery stenosis, angiotensin II is required to constrict post-glomerular arterioles and maintain adequate glomerular filtration ACEI contraindicated – 2nd and 3rd trimesters of pregnancy Risk of fetal hypotension, anuria, and renal failure, sometimes associated with fetal malformations or death First trimester - ↑risk - teratogenicity Captopril - patients with renal insufficiency, may cause neutropenia or proteinuria Minor toxic effects: altered sense of taste, allergic skin rashes, drug fever  2024/08/05 Aldosterone ↑ Na+ reabsorption and K+excretion Inhibiting angiotensin II formation ↓es aldosterone secretion → excessive K+ retention in patients on potassium supplements/potassium-sparing diuretics NSAIDs may impair the hypotensive effects of ACEI by blocking bradykinin mediated vasodilation ANGIOTENSIN RECEPTOR BLOCKERS (ARBS) Block angiotensin II type 1 (AT1) receptor E.g. Losartan, valsartan, azilsartan, candesartan, eprosartan, irbesartan, olmesartan, and telmisartan No effect on bradykinin metabolism Potential for increased inhibition of angiotensin action compared with ACEI because there are enzymes other than ACE that are capable of generating angiotensin II Angiotensin receptor blockers provide benefits similar to those of ACEIs in patients with heart failure and chronic kidney disease Adverse effects: similar to those described for ACEIs, including CI in pregnancy. Cough and Angio-oedema can occur but are uncommon.  2024/08/05 VASODILATORS Oral vasodilators: hydralazine and minoxidil - for long-term outpatient therapy of HT Parenteral vasodilators: nitroprusside and fenoldopam - hypertensive emergencies Calcium channel blockers: both Nitrates used mainly - ischemic heart disease, sometimes hypertensive emergencies ↓ arterial resistance, ↓mean arterial BP causes compensatory responses, mediated by baroreceptors and the sympathetic nervous system and ↑ renin, angiotensin, and aldosterone Because sympathetic reflexes are intact, vasodilator therapy does not cause orthostatic hypotension or sexual dysfunction. Vasodilators work best in combination with other antihypertensive drugs that oppose the compensatory cardiovascular responses  2024/08/05 VASODILATORS: MECHANISM OF ACTION HYDRALAZINE Hydrazine derivative - dilates arterioles but not veins Tachyphylaxis to its antihypertensive effects developes rapidly Benefits if in combination therapy Hydralazine may be used particularly in severe HT Combination of hydralazine with nitrates: Effective in heart failure and should be considered in patients with both hypertension and heart failure, especially in patients who are intolerant to angiotensin inhibiting drugs  2024/08/05 Well absorbed and undergoes first pass metabolism. Bioavailability is low (±25%) and variable among individuals Metabolized in part by acetylation Rapid acetylators → greater first pass metabolism, lower blood levels, and less anti-hypertensive benefit than slow acetylators Half-life (1.5 to 3 hours), but vascular effects persist longer than do blood concentrations, possibly due to strong binding to vascular tissue. HYDRALAZINE: ADVERSE EFFECTS Most common: headache, nausea, anorexia, palpitations, sweating, flushing In patients with ischemic heart disease - reflex tachycardia and sympathetic stimulation may provoke angina or ischemic arrhythmias With dosages ≥ 200 mg/d and in slow acetylators (10–20% incidence) → syndrome characterized by arthralgia, myalgia, skin rashes, and fever that resembles lupus erythematosus This syndrome is not associated with renal damage and is reversed by discontinuance of hydralazine Uncommon adverse effects: Peripheral neuropathy and drug fever  2024/08/05 MINOXIDIL Orally active vasodilator MOA: Opening of potassium channels in smooth muscle membranes by active metabolite minoxidil sulfate ↑potassium permeability stabilizes the membrane at its resting potential and makes contraction less likely Dilates arterioles but not veins Because of its greater potential antihypertensive effect, minoxidil should replace hydralazine when maximal doses of the latter are not effective or in patients with renal failure and severe HT, who do not respond well to hydralazine. Associated with reflex sympathetic stimulation and sodium and fluid retention Must be used in combination with a β blocker and a diuretic. MINOXIDIL: ADVERSE EFFECTS Tachycardia, palpitations, angina, and edema Why? co-administration with β-blockers and diuretics Headache, sweating, and hypertrichosis Topical minoxidil (as Regaine®) is used as a stimulant to hair growth for correction of baldness.  2024/08/05 SODIUM NITROPRUSSIDE Powerful parenteral vasodilator → hypertensive emergencies, severe heart failure Dilates both arterial and venous vessels, resulting in ↓peripheral vascular resistance and venous return Activates guanylyl cyclase via nitric oxide release or by direct stimulation → increased intracellular cGMP, which relaxes vascular smooth muscle In the absence of heart failure, ↓ BP due to decreased vascular resistance, whereas cardiac output does not change or ↓ slightly In patients with heart failure and low cardiac output, output often increases owing to afterload reduction Is a complex of iron, cyanide groups, and a nitroso moiety Rapidly metabolized by uptake into RBCs with release of nitric oxide and cyanide Cyanide- metabolized by mitochondrial enzyme rhodanese to thiocyanate Thiocyanate slowly eliminated by the kidney Nitroprusside rapidly ↓ BP Its effects disappear within 1–10 min after discontinuation Is an aqueous solution, IV infusion, sensitive to light Dosage typically begins at 0.5 mcg/kg/min - may be ↑ up to 10 mcg/kg/min to control blood pressure. Higher rates of infusion, if continued for > 1hr, may result in toxicity. Because of its efficacy and rapid onset of effect arterial BP continuously monitored  2024/08/05 SODIUM NITROPRUSSIDE: ADVERSE EFFECTS Accumulation of cyanide; metabolic acidosis, arrhythmias, excessive hypotension, and death Sodium thiosulfate as a sulfur donor facilitates metabolism of cyanide Hydroxocobalamin combines with cyanide → non-toxic cyanocobalamin Both used for prophylaxis or treatment of cyanide poisoning during nitroprusside infusion Thiocyanate may accumulate over the course of prolonged administration particularly renal insufficiency Thiocyanate toxicity - weakness, disorientation, psychosis, muscle spasms, and convulsions Rarely, delayed hypothyroidism, owing to thiocyanate inhibition of iodide uptake by the thyroid Methemoglobinemia during infusion of nitroprusside also been reported DIAZOXIDE Potassium channel opener-causes hyperpolarization in smooth muscle and pancreatic β cells. Rarely used now - hypertensive emergencies Rapid fall in systemic vascular resistance and mean arterial BP Also inhibits insulin release from the pancreas (by opening potassium channels in the beta cell membrane) and is used to treat hypoglycemia caused by hyperinsulinism secondary to insulinoma. Excessive hypotension - resulted in stroke and myocardial infarction Reflex sympathetic response can provoke angina, ischemia, and cardiac failure in patients with ischemic heart disease Diazoxide should be avoided in this situation Occasionally, hyperglycemia particularly in persons with renal insufficiency. Causes renal salt and water retention  2024/08/05 FENOLDOPAM Peripheral arteriolar dilator for hypertensive emergencies and postoperative HT MOA: Agonist of dopamine D1 receptors, resulting in dilation of peripheral arteries and natriuresis Racemic mixture with the (R)isomer mediating the pharmacologic activity. Rapidly metabolized, primarily by conjugation, half-life (10 min) Administered by continuous IV infusion. Major toxicities: reflex tachycardia, headache, and flushing ↑ intraocular pressure - Avoid in glaucoma CALCIUM CHANNEL BLOCKERS Anti-anginal, anti-arrhythmic effects, ↓peripheral resistance and BP Inhibits calcium influx into arterial smooth muscle cells. Verapamil, diltiazem, and the dihydropyridine family (amlodipine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, nimodipine, and nitrendipine Clevidipine is formulated for intravenous use only. Amlodipine and the other dihydropyridine agents are more selective as vasodilators and have less cardiac depressant effect than verapamil and diltiazem Reflex sympathetic activation with slight tachycardia maintains or increases cardiac output in most patients given dihydropyridines.  2024/08/05 Verapamil - greatest depressant effect on the heart and may ↓ heart rate and cardiac output Diltiazem has intermediate actions Some epidemiologic studies reported an increased risk of myocardial infarction or mortality in patients receiving short-acting nifedipine for HT Sustained release calcium blockers or calcium blockers with long half-lives →chronic HT Oral short-acting nifedipine has been used in emergency management of severe HT DRUGS THAT ALTER SYMPATHETIC NERVOUS SYSTEM FUNCTION Classified according to the site of action Drugs ↓ BP by actions on CNS → sedation and mental depression and may produce disturbances of sleep, including nightmares By ↓ release of norepinephrine from sympathetic nerve endings cause effects - inhibition of ejaculation, and postural hypotension and after exercise. Drugs – that block post-synaptic adrenoceptors produce - more selective spectrum of effects All agents that lower BP by altering sympathetic function can cause compensatory effects thus, the antihypertensive effect of any of these agents used alone may be limited by retention of sodium by the kidney and expansion of blood volume Sympathoplegic antihypertensive drugs are most effective when used with a diuretic.  2024/08/05 CENTRALLY ACTING SYMPATHOPLEGIC DRUGS METHYLDOPA Methyldopa - converted to α-methyldopamine and α-methylnorepinephrine α-methylnorepinephrine – replaces norepinephrine - interacts with postsynaptic adrenoceptors The false transmitter is not responsible for methyldopa’s antihypertensive effect α-methylnorepinephrine - agonist at α2-receptors in the medulla and ↓sympathetic outflow Used primarily - HT during pregnancy ↓ BP chiefly by ↓ peripheral vascular resistance, with a variable reduction in heart rate and cardiac output. Most cardiovascular reflexes remain intact after administration of methyldopa, and BP reduction is not markedly dependent on posture. Postural (orthostatic) hypotension sometimes occurs, particularly in volume depleted patients Methyldopa also causes reduction in renal vascular resistance.  2024/08/05 METHYLDOPA: ADVERSE EFFECTS Sedation is common, particularly at the onset of treatment Long-term - Persistent mental lassitude and impaired mental concentration Infrequent - Nightmares, mental depression, vertigo, and extrapyramidal signs may occur Lactation due to ↑ prolactin secretion - occurs both in men and in women Due to inhibition of dopaminergic mechanisms in the hypothalamus Development of positive Coombs test (10–20% in therapy >12 months) - makes cross-matching blood for transfusion difficult. Rarely is associated with hemolytic anemia, as well as hepatitis and drug fever Discontinuation - reversal of these abnormalities. CLONIDINE Partial agonist at α receptors Stimulates the pre-synaptic α-2-adrenoceptors →decreasing noradrenaline release from both central and peripheral sympathetic nerve terminals Alternatively may act on postsynaptic α-2 adrenoceptors to inhibit activity Also binds to - imidazoline receptor, may also mediate anti-HT effects BP lowering effect - ↓cardiac output due to ↓ heart rate, relaxation of capacitance vessels, ↓ in peripheral vascular resistance. ↓ in arterial BP - accompanied by ↓ed renal vascular resistance and maintenance of renal blood flow Lipid soluble and rapidly enters the brain from the circulation Relatively short half-life given twice a day  2024/08/05 CLONIDINE: ADVERSE EFFECTS Common- Dry mouth and sedation Both effects are centrally mediated and dose-dependent Should not be given to patients who are at risk for mental depression and should be withdrawn if depression occurs during therapy. Concomitant treatment with tricyclic antidepressants may block the antihypertensive effect of clonidine The interaction is believed to be due to α-adrenoceptor– blocking actions of the tricyclics Rare - postural hypotension Sudden withdrawal of clonidine after protracted use → threatening hypertensive crisis HT Crises: ↑ sympathetic nervous activity Nervousness, tachycardia, headache, and sweating after omitting one or two doses of the drug Stopping the drug must be gradual GANGLION BLOCKING AGENTS Historically among the first agents used Competitively block nicotinic cholinoceptors on postganglionic neurons in both sympathetic and parasympathetic ganglia May also directly block the nicotinic acetylcholine channel Adverse effects include both sympathoplegia (excessive orthostatic hypotension and sexual dysfunction) and parasympathoplegia (constipation, urinary retention, precipitation of glaucoma, blurred vision, dry mouth, etc) These severe toxicities - major reason for discontinuing ganglion blockers for the therapy of HT  2024/08/05 ADRENERGIC NEURON BLOCKING AGENTS Lower BP by preventing normal physiologic release of norepinephrine from postganglionic sympathetic neurons Significant toxicity and are now rarely used. Guanethidine can produce profound sympathoplegia (marked postural hypotension, diarrhea, and impaired ejaculation) Is too polar to enter CNS therefore has none of the central effects seen with many of the other antihypertensive agents Guanadrel is a guanethidine like drug that is no longer used Bethanidine and debrisoquin, antihypertensive agents not available for clinical use RESERPINE An alkaloid extracted from the roots of an Indian plant, Rauwolfia serpentine Now rarely used - 4th line treatment for HT in SA MOA: Blocks the ability of aminergic transmitter vesicles to take up and store biogenic amines, probably by interfering with the vesicular membrane associated transporter (VMAT) Effect occurs throughout body →depletion of norepinephrine, dopamine, and serotonin in both central and peripheral neurons Depletion of peripheral amines - beneficial antihypertensive effect but a central component cannot be ruled out Lowers BP by a combination of ↓ cardiac output and ↓ peripheral vascular resistance.  2024/08/05 RESERPINE: ADVERSE EFFECTS Low doses produces little postural hypotension High doses → sedation, lassitude, nightmares, and severe mental depression Occasionally occur even in patients receiving low doses Less frequently, low doses cause extrapyramidal effects probably as a result of dopamine depletion in the corpus striatum. Patients with a history of mental depression should not take, and the drug should be stopped if depression appears. Reserpine produces mild diarrhea and gastrointestinal cramps and ↑ gastric acid secretion Should not be given to patients with a history of peptic ulcer. ADRENOCEPTOR ANTAGONISTS  2024/08/05 BETA-ADRENOCEPTOR–BLOCKING AGENTS Propranolol First β-blocker shown to be effective in hypertension and ischemic heart disease Largely replaced by cardioselective β-blockers All β-adrenoceptor–blocking agents- ↓BP in mild to moderate HT Severe HT, β-blockers are especially useful in preventing the reflex tachycardia that often results from treatment with direct vasodilators β-blockers - shown to reduce mortality after a myocardial infarction and some also ↓ mortality in patients with heart failure Propranolol - ↓BP primarily as a result of ↓ in cardiac output Other β blockers may ↓ cardiac output or ↓ peripheral vascular resistance to various degrees, depending on cardioselectivity and partial agonist activities Inhibits the stimulation of renin production by catecholamines (mediated by β1-receptors) Antihypertensive effect partly due to depression of the renin- angiotensin-aldosterone system Beta blockers might also act on peripheral presynaptic β-adrenoceptors to reduce sympathetic vasoconstrictor nerve activity. In mild to moderate HT, propranolol produces a significant reduction in blood pressure without prominent postural hypotension Can be administered twice daily, and slow-release once daily  2024/08/05 PROPRANOLOL: ADVERSE EFFECTS β1-blocking action affects patients with bradycardia or cardiac conduction disease β2-blocking action affects patients with asthma, peripheral vascular insufficiency, and diabetes When β-blockers are discontinued after prolonged regular use, some patients experience a withdrawal syndrome Symptoms: nervousness, tachycardia, increased intensity of angina, and ↑BP Myocardial infarction - been reported in a few patients Although the incidence of these complications is probably low, β blockers should not be discontinued abruptly The withdrawal syndrome may involve upregulation or supersensitivity of β-adrenoceptors METOPROLOL & ATENOLOL Cardioselective - most widely used β-blockers - treatment of HT Metoprolol approximately equipotent to propranolol in inhibiting β1- adrenoceptors e.g. heart but 50 to 100 fold less potent than propranolol in blocking β2-receptors Relative cardioselectivity is advantageous in treating HT in patients who have diabetes, or peripheral vascular disease All B-blockers even the cardioselective ones – should not be used in asthmatics Metoprolol is extensively metabolized by CYP2D6 with high first-pass metabolism Relatively short half-life (4–6 hrs), but extended release preparation -once daily Sustained release metoprolol is effective in reducing mortality from heart failure and is particularly useful in patients with HT and heart failure.  2024/08/05 Atenolol Not extensively metabolized and is excreted primarily renally Half-life (6hrs) - usually dosed once daily Found to be less effective than metoprolol in preventing the complications of HT A possible reason for this difference is that once daily dosing does not maintain adequate blood levels of atenolol Patients with reduced renal function should receive lower doses. NADOLOL, CARTEOLOL, BETAXOLOL, & BISOPROLOL Nadolol and carteolol Non-selective β-receptor antagonists Not highly metabolized and excreted largely in the urine Reduce doses in reduced renal function Betaxolol and bisoprolol β1selective blockers that are primarily metabolized in the liver Long half-lives - can be administered once daily.  2024/08/05 PINDOLOL, ACEBUTOLOL, & PENBUTOLOL Pindolol, acebutolol, and penbutolol Partial agonists β-blockers with some intrinsic sympathomimetic activity Lower BP but are rarely used in HT Labetalol, Carvedilol, & Nebivolol Both β-blocking and vasodilating effects Labetalol - formulated as a racemic mixture of four isomers Two of these isomers—the (S,S)and (R,S)isomers—are relatively inactive, a third (S,R) is a potent α blocker, and the last (R,R) is a potent β blocker Labetalol has a 3:1 ratio of β:α antagonism after oral dosing BP is lowered by reduction of systemic vascular resistance (via α blockade) without significant alteration in heart rate or cardiac output Because of its combined α and β-blocking activity - is useful in treating the HT of pheochromocytoma and hypertensive emergencies  2024/08/05 Carvedilol: Administered as a racemic mixture The S(-) isomer is a non-selective β-adrenoceptor blocker Both S(-) and R(+) isomers have approximately equal α1-blocking potency The isomers are stereoselectively metabolized in the liver, which means that their elimination half-lives may differ The average half-life ( 7–10 hours) Reduces mortality in patients with heart failure and is particularly useful in patients with both heart failure and hypertension Nebivolol: β1selective blocker with vasodilating properties The drug is marketed as a racemic mixture L-isomer causes vasodilation Vasodilating effect may be due to ↑endothelial release of nitric oxide via induction of endothelial nitric oxide synthase. The hemodynamic effects of nebivolol differs from those of pure β- blockers in that peripheral vascular resistance is acutely lowered (by nebivolol) as opposed to increased acutely (by the older agents) Nebivolol - extensively metabolized and has active metabolites The half-life (10–12 hours), but the drug can be given once daily Efficacy of nebivolol - similar to that of other antihypertensive agents, but several studies report fewer adverse effects.  2024/08/05 Esmolol β1selective blocker Rapidly metabolized via hydrolysis by RBC esterases Short half-life (9–10 minutes) and is administered by IV infusion Esmolol - used for management of intra-operative and post- operative HT Sometimes for hypertensive emergencies, particularly when hypertension is associated with tachycardia or when there is concern about toxicity such as aggravation of severe heart failure as the drug with a short duration of action that can be discontinued quickly ALPHA-1 BLOCKERS Prazosin, terazosin, and doxazosin: Selectively block α1 receptors in arterioles and venules Less reflex tachycardia when lowering BP than non-selective α-antagonists such as phentolamine. Alpha-1receptor selectivity allows norepinephrine to exert unopposed negative feedback (mediated by presynaptic α2 receptors) on its own release Alpha blockers reduce arterial pressure by dilating both resistance and capacitance vessels  2024/08/05 BP is reduced more in the upright than in the supine position Retention of salt and water occurs when these drugs are administered without a diuretic. The drugs are more effective when used in combination with other agents, such as a β blocker and a diuretic Beneficial effects in males with prostatic hyperplasia and bladder obstruction symptoms, these drugs are used primarily in men with concurrent hypertension and benign prostatic hyperplasia Terazosin - extensively metabolized but undergoes very little first- pass metabolism. Has a half-life (12 hrs). Terazosin can often be given once daily Doxazosin Has an intermediate bioavailability and a half-life (22 hrs). Usually given once daily ADVERSE EFFECTS Although long-term treatment with these α-blockers causes relatively little postural hypotension, a high drop in standing BP develops in some patients shortly after the first dose is absorbed. Why first dose should be small and administered at bedtime. Although the mechanism of this first-dose phenomenon is not clear, it occurs more commonly in patients who are salt and volume depleted. Other adverse effects: Dizziness, palpitations, headache, and lassitude Some patients develop a positive test for antinuclear factor in serum while on prazosin therapy, but this has not been associated with rheumatic symptoms  2024/08/05 OTHER ALPHA-ADRENOCEPTOR– BLOCKING AGENTS Phentolamine blocks both presynaptic and postsynaptic α- receptors Reflex activation of sympathetic neurons produces greater release of transmitter onto β-receptors ↑cardiac rate Phentolamine and phenoxybenzamine Non-selective Useful in diagnosis and treatment of pheochromocytoma & Other clinical situations associated with exaggerated release of catecholamines (eg, phentolamine may be combined with a β- blocker to treat the clonidine withdrawal syndrome) CLINICAL PHARMACOLOGY  2024/08/05 CLINICAL PHARMACOLOGY OF ANTIHYPERTENSIVE AGENTS HT – chronic disease that causes few symptoms until the advanced stage Establish with certainty- persistent HT and requires treatment Exclude secondary causes BP values, age, severity of organ damage (if any) due to high BP, and the cardiovascular risk factors must be considered Treat with medications: BP ≥ 140/90 mm Hg if 10year cardiovascular disease risk < 10% BP ≥130/80 if 10year risk ≥ 10% Assess renal function and the presence of proteinuria guide drug selection Drug selection deoends on level of blood pressure, the presence and severity of end organ damage, and the presence of other diseases Obesity should be treated Drugs that ↑ BP (sympathomimetic decongestants, non-steroidal anti-inflammatory drugs, estrogen-containing oral contraceptives, stimulant drug abuse, and some herbal medications) should be eliminated if possible Frequent follow-up visits Patient education Other factors that may improve compliance Simplifying dosing regimens Patient monitor BP at home.  2024/08/05 OUTPATIENT THERAPY OF HYPERTENSION First step may be non-pharmacologic Sodium restriction may be effective treatment for some patients with mild HT Weight reduction- shown to normalize BP in up to 75% of overweight patients with mild to moderate HT Diet rich in fruits, vegetables, and low fat dairy products with a reduced content of saturated and total fat Moderation of alcohol intake (no more than two drinks per day) also lower blood pressure. Both the DASH (Dietary Approach to Stop Hypertension) and more recently the Chinese HeartHealthy Diet have been demonstrated to reduce blood pressure Using salt that substitutes potassium for sodium ↓ BP and risk of future cardiovascular events Regular exercise Mild HT – Tx with a single drug Becoming more common to see the use of low dose combination pharmacotherapy to improve effectiveness and reduce adverse effects Most patients with moderate to severe HT require two or more antihypertensive medications Thiazide diuretics, ACE inhibitors, angiotensin receptor blockers, and calcium channel blockers have all been shown to reduce complications of HT and may be used for initial drug therapy Beta blockers are less effective in reducing cardiovascular events and are currently not recommended as first-line treatment for uncomplicated hypertension.  2024/08/05 CHOICE OF BP MEDICATION Presence of concomitant disease should influence selection of antihypertensive drugs because two diseases may benefit from a single drug E.g: Drugs that inhibit the renin-angiotensin system are particularly useful in patients with diabetes or evidence of chronic kidney disease with proteinuria Beta blockers or calcium channel blockers are useful in patients who also have angina Diuretics, ACE inhibitors, angiotensin receptor blockers, β blockers, hydralazine combined with nitrates in patients who also have heart failure α1 blockers in men who have benign prostatic hyperplasia Race may also affect drug selection: African Americans respond better on average to diuretics and calcium channel blockers than to β-blockers and ACE inhibitors Chinese patients are more sensitive to the effects of β-blockers and may require lower doses. Drugs with different sites of action can be combined to effectively lower blood pressure while minimizing toxicity If three drugs are required, combining a diuretic, an ACE inhibitor or angiotensin receptor blocker, and a calcium channel blocker is often effective. If a fourth drug is needed, a sympathoplegic agent such as a β- blocker or clonidine should be considered  2024/08/05 BP TO AIM FOR The Systolic Blood Pressure Intervention Trial (SPRINT) and several meta-analyses suggest a target systolic blood pressure of 120 mm Hg for patients at high cardiovascular risk Systolic hypertension (>150 mm Hg in the presence of normal diastolic blood pressure) is a strong cardiovascular risk factor in people older than 60 years of age and should be treated TREATMENT FAILURE Non-compliance with medication Failure to respond to drug therapy include excessive sodium intake and inadequate diuretic therapy with excessive blood volume Drugs that can interfere with actions of some antihypertensive drugs or directly raise blood pressure: Tricyclic antidepressants Non-steroidal anti-inflammatory drugs Over the counter sympathomimetics Abuse of stimulants (amphetamine or cocaine) Excessive doses of caffeine Oral contraceptives  2024/08/05 MANAGEMENT OF HYPERTENSIVE EMERGENCIES Hypertensive emergencies are relatively rare Marked or sudden elevation of blood pressure may be life- threatening Hypertensive emergencies occur in patients whose HT is severe and poorly controlled and in those who suddenly discontinue antihypertensive medications. Clinical Presentation & Pathophysiology Hypertensive emergencies include: HT associated with vascular damage (malignant hypertension) HT associated with hemodynamic complications such as heart failure, stroke, or dissecting aortic aneurysm The underlying pathologic process in malignant hypertension is a progressive arteriopathy with inflammation and necrosis of arterioles. Vascular lesions occur in the kidney, which releases renin, which in turn Stimulates production of angiotensin and aldosterone, which further increase BP Hypertensive encephalopathy is a classic feature of malignant hypertension Presents as severe headache, mental confusion, and apprehension. Blurred vision, nausea and vomiting, and focal neurologic deficits are common. If untreated, the syndrome may progress over a period of 12–48 hours to convulsions, stupor, coma, and even death.  2024/08/05 TREATMENT OF HYPERTENSIVE EMERGENCIES Monitoring the patient in the ICU with continuous recording of arterial BP Fluid intake and output- carefully monitored Body weight measured daily as an indicator of total body fluid volume during the course of therapy. Parenteral antihypertensive medications are used to lower BP rapidly (within a few hours) As soon as reasonable BP control switch to oral The goal of treatment in the first few hours or days is not complete normalization of BP because chronic HT is associated with autoregulatory changes in cerebral blood flow Thus, rapid normalization of blood pressure may lead to cerebral hypoperfusion and brain injury. Rather, BP should be lowered by about 25%, maintaining diastolic blood pressure at no less than 100–110 mm Hg Subsequently, blood pressure can be reduced to normal using oral medications over several weeks Parenteral drugs used to treat hypertensive emergencies include sodium nitroprusside, nitroglycerin, labetalol, calcium channel blockers, fenoldopam, and hydralazine. Esmolol is often used to manage intra-operative and postoperative hypertension Diuretics e.g. furosemide are administered to prevent the volume expansion that typically occurs during administration of powerful vasodilators.  2024/08/05 RESISTANT HYPERTENSION ± 40% - respond inadequately even to two agents - “resistant hypertension” Reasons: Some - treatable secondary HT was missed Most HT drugs cause compensatory regulatory mechanisms for maintaining blood pressure - may limit their effect e.g. vasodilators (hydralazine) cause significant ↓peripheral vascular resistance, but cause a strong compensatory tachycardia and salt and water retention that may almost completely reverse their effect Addition of β-blocker prevents the tachycardia and addition of a diuretic prevents the salt and water retention All three drugs ↑sensitivity of the CVS to each other’s actions. Compensatory responses to vasodilators; basis for combination therapy with β blockers and diuretics. Effect blocked by diuretics. Effect blocked by β blockers. Citation: Chapter 11 Antihypertensive Agents, Vanderah TW. Katzung’s Basic & Clinical Pharmacology, 16th Edition; 2024. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=3382&sectionid=281748109 Accessed: May 20, 2024 Copyright © 2024 McGraw-Hill Education. All rights reserved  2024/08/05 Some drugs have only modest maximum efficacy but reduction of long-term morbidity requires use. Studies on ACEI report - maximal lowering BP 160/100 mm Hg), this is inadequate to prevent all the sequelae of hypertension, but ACE inhibitors have important long-term benefits in preventing or reducing renal disease in diabetic persons and in reduction of heart failure The toxicity of some effective drugs prevents their use at maximally effective doses. TWO APPROACHES TO TREATING HYPERTENSION CAN BE CONSIDERED: Start with monotherapy If HT does not respond, a second drug from a different class with a different mechanism of action and different pattern of toxicity is added. If the response is still inadequate and good compliance, a third drug should be added.  2024/08/05 Second Approach - use small doses of drugs two or three dugs (for example a diuretic, ACE inhibitor, or angiotensin reception blocker and/or a calcium channel blocker) If three drugs (usually including a diuretic) are inadequate, other causes of resistant hypertension such as excessive dietary sodium intake, use of non-steroidal anti-inflammatory or stimulant drugs, or the presence of secondary hypertension should be considered In some instances, an additional drug may be necessary, and mineralocorticoid antagonists, such as spironolactone, have been found to be particularly useful. Occasionally patients are resistant to four or more drugs, and non- pharmacologic approaches have been considered  2024/08/05 CASE STUDY A 35 year old male presents with a blood pressure of 140/90 mm Hg. He has been generally healthy, is sedentary, drinks several cocktails per day, and does not smoke cigarettes. He has a family history of hypertension, and his father died of a myocardial infarction at age 55. Physical examination is remarkable only for moderate obesity. Total cholesterol is 220, and high density lipoprotein (HDL) cholesterol level is 40 mg/dL. Fasting glucose is 105 mg/dL. Chest Xray is normal. Electrocardiogram shows left ventricular hypertrophy. How would you treat this patient? REFERENCES NEAL, M.J. - MEDICAL PHARMACOLOGY AT A GLANCE. Katzung – Basic and Clinical Pharmacology Goodman and Gilman - The Pharmacological Basis of Therapeutics