anti hypertensive agents for mbbs and bds lecture.pptx

for mbbs bds lectures

1. HTN IN ADULTS: PHARMACOLOGICAL MANAGEMENT DR SANDIP GURAGAIN

2. Epidemiology: Hypertension is the most common cardiovascular disease. Elevated arterial pressure causes hypertrophy of the left ventricle and pathological changes in the vasculature. As a consequence, hypertension is the principal cause of stroke; a major risk factor for CAD and its attendant complications , MI and sudden cardiac death; and a major contributor to heart failure, renal insufficiency, and dissecting aneurysm of the aorta. The prevalence of hypertension increases with age; for example, about 50 % of people between the ages of 60 and 69 years old have hypertension, and the prevalence further increases beyond age 70. According to a survey in the U.S., 81.5% of those with hypertension are aware they have it , 74.9% are being treated, yet only 52.5% are considered controlled ( Go et al., 2014).

3. Defination : Hypertension is defined as a sustained increase in blood pressure of 140/90 mmHg or higher, a criterion that characterizes a group of patients whose risk of hypertension-related cardiovascular disease is high enough to merit medical attention. Actually , the risk of both fatal and nonfatal cardiovascular disease in adults is lowest with systolic blood pressures of less than 120 mmHg and diastolic blood pressures less than 80 mmHg; These risks increase incrementally as systolic and diastolic blood pressures rise .

4. Progressive elevations of systolic pressure are predictive of adverse cardiovascular events; at every level of diastolic pressure. Risks are greater with higher levels of systolic blood pressure. Indeed , in patients more than 50 years old, systolic blood pressures predict adverse outcomes better than do diastolic pressures.

5. The presence of pathological changes in certain target organs heralds a worse prognosis than the same level of blood pressure in a patient lacking these findings. The risk of cardiovascular disease, disability, and death in hypertensive patients also is increased markedly by concomitant cigarette smoking, diabetes , or elevated LDL; The coexistence of hypertension with these risk factors increases cardiovascular morbidity and mortality to a degree that is compounded by each additional risk factor. The purpose of treating hypertension is to decrease cardiovascular risk; thus , other dietary and pharmacological interventions may be required to treat these additional risk factors. Effective pharmacological treatment of patients with hypertension decreases morbidity and mortality from cardiovascular disease, reducing the risk of strokes, heart failure, and CAD ( Rosendorff et al., 2015). The reduction in risk of MI may be less significant .

6. Isolated systolic hypertension (sometimes defined as systolic blood pressure greater than 140–160 mmHg with diastolic blood pressure less than 90 mmHg) is largely confined to people older than 60 years.

7. Pharmacologic antihypertensive therapy produces a nearly 50 percent relative risk reduction in the incidence of heart failure, a 30 to 40 percent relative risk reduction in stroke, and a 20 to 25 percent relative risk reduction in myocardial infarction. Thus , 100 patients must be treated for four to five years to prevent an adverse cardiovascular event in two patients.

8. Dx of HTN in Adults:

9. Classification of anti hypertensives: Diuretics: Thiazides and related agents: Chlorothiazide , Chlorthalidone , Hydrochlorothiazide, Indapamide Loop diuretics: Bumetanide, Furosemide, Torsemide K +-sparing diuretics: Amiloride , Triamterene, MRA Spironolactone Sympatholytic drugs β Blockers: Atenolol, Bisoprolol , Esmolol , Metoprolol, Nadolol,nebivolol , Propranolol, Timolol α Blockers: Prazosin, Terazosin, Doxazosin, Phenoxybenzamine α/β blockers : Labetalol, Carvedilol Centrally acting sympatholytic agents: Clonidine, Guanabenz , Guanfacine , Methyldopa, Moxonidine , Reserpine Ca2 + channel blockers: Amlodipine, Clevidipine , Diltiazem, Felodipine , Isradipine , Lercanidipine , Nicardipine , Nifedipine,a Nisoldipine , Verapamil Renin-angiotensin antagonists Angiotensin-converting enzyme inhibitors : Benazepril, Captopril, Enalapril , Fosinopril , Lisinopril, Moexipril , Perindopril, Quinapril, Ramipril, Trandolapril AngII receptor blockers: Candesartan, Eprosartan , Irbesartan , Losartan, Olmesartan , Telmisartan , Valsartan Direct renin inhibitor : Aliskiren Vasodilators: • Arterial: Diazoxide , Fenoldopam , Hydralazine, Minoxidil Arterial And Venous: Nitroprusside

10. Principles of blood pressure regulation and its modification by drugs.

11. HEMODYNAMIC EFFECTS OF LONG-TERM ADMINISTRATION OF ANTIHYPERTENSIVE AGENTS

12. Diuretics: The exact mechanism for reduction of arterial blood pressure by diuretics is not certain. The initial action of thiazide diuretics decreases extracellular volume by interacting with a thiazide-sensitive NCC ( SLC12A3) expressed in the distal convoluted tubule in the kidney, enhancing Na+ excretion in the urine, and leading to a decrease in cardiac output. However, the hypotensive effect is maintained during long-term therapy due to decreased vascular resistance; cardiac output returns to pretreatment values , and extracellular volume returns to almost normal due to compensatory responses such as activation of the RAS. Hydrochlorothiazide may open Ca2+-activated K+ channels, leading to hyperpolarization of vascular smooth muscle cells, which leads in turn to closing of L-type Ca2+ channels and lower probability of opening, resulting in decreased Ca2+ entry and reduced vasoconstriction . Also inhibits vascular carbonic anhydrase, which, hypothetically, could alter smooth muscle cell systolic pH and thereby cause opening of Ca2+-activated K+ channels with the consequences noted previously.

13. Regimen for Administration of the Thiazide-Class Diuretics in Hypertension Though members of the thiazide class have similar pharmacological effects; the pharmacokinetics and pharmacodynamics of these drugs differ, so they may not necessarily have the same clinical efficacy in treating hypertension. The antihypertensive efficacy of chlorthalidone was greater than that of hydrochlorothiazide, particularly during the night (Ernst et al ., 2006 ), suggesting the much longer t 1/2 of chlorthalidone (>24 h) compared to hydrochlorothiazide (several hours) gave more stable blood pressure reductions. Antihypertensive effects can be achieved in many patients with as little as 12.5 mg daily of chlorthalidone or hydrochlorothiazide. Furthermore, when used as monotherapy, the maximal daily dose of thiazide-class diuretics usually should not exceed 25 mg of hydrochlorothiazide or chlorthalidone (or equivalent)

14. Low doses of either thiazide reduce the risk of adverse effects such as K+ wasting and inhibition of uric acid excretion, indicating an improved risk-to-benefit ratio at low doses of a thiazide. However, other studies suggested that low doses of hydrochlorothiazide have inadequate effects on blood pressure when monitored in a detailed manner ( Lacourciere et al., 1995 ). A case-control study found a dose-dependent increase in the occurrence of sudden death at doses of hydrochlorothiazide greater than 25 mg daily ( Siscovick et al ., 1994 ), supporting the hypothesis that higher diuretic doses are associated with increased cardiovascular mortality as long as hypokalemia is not corrected. Thus , if adequate blood pressure reduction is not achieved with the 25-mg daily dose of hydrochlorothiazide or chlorthalidone , the addition of a second drug is indicated rather than an increase in the dose of diuretic.

15. ACE inhibitors and ARBs will attenuate diuretic-induced loss of K+ to some degree, and this is a consideration if a second drug is required to achieve further blood pressure reduction beyond that attained with the diuretic alone. Because the diuretic and hypotensive effects of these drugs are greatly enhanced when they are given in combination, care should be taken to initiate combination therapy with low doses of each of these drugs ( Vlasses et al ., 1983). Indeed , hypertensive patients may become refractory to drugs that block the sympathetic nervous system or to vasodilator drugs, because these drugs engender a state in which the blood pressure is very volume dependent. Therefore , it is appropriate to consider the use of thiazide-class diuretics in doses of 50 mg of daily hydrochlorothiazide equivalent when treatment with appropriate combinations and doses of three or more drugs fails to yield adequate control of the blood pressure. Alternatively, there may be a need to use higher-capacity diuretics such as furosemide , especially if renal function is not normal.

16. The effectiveness of thiazides as diuretics or antihypertensive agents is progressively diminished when the glomerular filtration rate fall below 30 mL/min. One exception is metolazone , which retains efficacy in patients with this degree of renal insufficiency. Most patients will respond to thiazide diuretics with a reduction in blood pressure within about 4–6 weeks. Therefore, doses should not be increased more often than every 4–6 weeks. There is no way to predict the antihypertensive response from the duration or severity of the hypertensionin a given patient, although diuretics are unlikely to be effective as sole therapy in patients with stage 2 hypertension. Diuretics also have the advantage of minimizing the retention of salt and water that is commonly caused by vasodilators and some sympatholytic drugs. Omitting or underutilizing a diuretic is a frequent cause of “ resistant hypertension .”

17. Adverse Effects and Precautions The K+ depletion produced by thiazide-class diuretics is dose dependent and variable among individuals, such that a subset of patients may become substantially K+ depleted on diuretic drugs. Given chronically, even small doses lead to some K+ depletion, which is a well-known risk factor for ventricular arrhythmias by reducing cardiac repolarization reserve. Hypokalemia directly reduces repolarization reserve by decreasing several K+ conductances (inward rectifier IK1, delayed rectifier IKr , and the transient outward current Ito) and increases the binding activity of IKr -inhibiting drugs such as dofetilide (Yang and Roden , 1996). Hypokalemia reduces the activity of the Na+,K +-ATPase (the Na+ pump), causing intracellular accumulation of Na+ and Ca2+, further increasing the risk of afterdepolarizations ( Pezhouman et al., 2015). There is a positive correlation between diuretic dose and sudden cardiac death and an inverse correlation between the use of adjunctive K+-sparing agents and sudden cardiac death ( Siscovick et al., 1994). Thus , hypokalemia needs to be avoided by, for example, combining a thiazide with inhibitors of the RAS or with a K+-sparing diuretic.

18. Reduced Na+ reabsorption in the proximal tubule & increased presentation of Na+ at the macula densa leads to a reduced glomerular filtration rate via tubuloglomerular feedback. While this effect is clinically not meaningful in patients with normal renal function, it reduces diuretic effectiveness and may gain importance in patients with reduced kidney function. Erectile dysfunction is a troublesome adverse effect of the thiazide-class diuretics, Gout may be a consequence of the hyperuricemia induced by these diuretics. However, precipitation of acute gout is relatively uncommon with low doses of diuretics . Hydrochlorothiazide may cause rapidly developing, severe hyponatremia in some patients. Thiazides inhibit renal Ca2+ excretion, occasionally leading to hypercalcemia; although generally mild, this can be more severe in patients subject to hypercalcemia, such as those with primary hyperparathyroidism. The thiazide-induced decreased Ca2+ excretion may be used therapeutically in patients with osteoporosis or hypercalciuria .

19. Thiazide diuretics have also been associated with changes in plasma lipids and glucose tolerance that have led to some concern. The clinical significance of the changes has been disputed because the clinical studies demonstrated comparable efficacy of the thiazide diuretic chlortalidone in reducing cardiovascular risk (ALLHAT Officers, 2002). All thiazide-like drugs cross the placenta. While they have no direct adverse effects on the fetus, administration of a thiazide during pregnancy increases a risk of transient volume depletion that may result in placental hypoperfusion . Because the thiazides appear in breast milk, they should be avoided by nursing mothers.

20. Other Diuretic Antihypertensive Agents The thiazide diuretics are more effective antihypertensive agents than are the loop diuretics, such as furosemide and bumetanide, in patients who have normal renal function. This differential effect is most likely related to the short duration of action of loop diuretics. In fact, a single daily dose of loop diuretics does not cause a significant net loss of Na+ for an entire 24-h period because the strong initial diuretic effect is followed by a rebound mediated by activation of the RAS. Unfortunately , loop diuretics are frequently and inappropriately prescribed as a once-a-day medication in the treatment not only of hypertension, but also of congestive heart failure and ascites. The high efficacy of loop diuretics to produce a rapid and profound natriuresis can be detrimental for the treatment of hypertension. When a loop diuretic is given twice daily, the acute diuresis can be excessive and lead to more side effects than occur with a slower-acting, milder thiazide diuretic. Loop diuretics may be particularly useful in patients with azotemia or with severe edema associated with a vasodilator such as minoxidil .

21. K+-Sparing Diuretics Amiloride and triamterene are K+-sparing diuretics that have little valueas antihypertensive monotherapy but are important in combination with thiazides to antagonize urinary K+ loss and the concomitant risk of ventricular arrhythmias . They act by reversibly inhibiting the ENaC in the DCT membrane. In contrast to the immediate and short-term inhibition of ENaC by amiloride and triamterene, the action of MRAs is delayed for about 3 days and is long lasting because MRAs regulate the density of the channel protein in the tubule membrane . All K+-sparing diuretics should be used cautiously, with frequent measurements of plasma K+ concentrations in patients predisposed to hyperkalemia . Patients should be cautioned regarding the possibility that concurrent use of K+-containing salt substitutes could produce hyperkalemia. Renal insufficiency is a relative contraindication to the use of K +-sparing diuretics. Concomitant use of an ACE inhibitor or an ARB magnifies the risk of hyperkalemia with these agents.

22. Diuretic-Associated Drug Interactions Because the antihypertensive effects of diuretics are additive with those of other antihypertensive agents, a diuretic commonly is used in combination with other drugs. The K+- and Mg2+-depleting effects of the thiazides and loop diuretics can potentiate arrhythmias that arise from digitalis toxicity . Corticosteroids can amplify the hypokalemia produced by the diuretics. NSAIDs inhibit the synthesis of prostaglandins & reduce the antihypertensive effects of diuretics and all other antihypertensives . The renal effects of selective COX-2 inhibitors are similar to those of the traditional NSAIDs . NSAIDs and RAS inhibitors reduce plasma concentrations of aldosterone and can potentiate the hyperkalemic effects of a K+-sparing diuretic. All diuretics can decrease the clearance of Li+, resulting in increased plasma concentrations of Li+ and potential toxicity

23. Sympatholytic Agents 1. β Blockers Antagonism of β adrenergic receptors affects the regulation of the circulation through a number of mechanisms, including a reduction in myocardial contractility and heart rate (i.e., cardiac output). Antagonism of β1 receptors of the juxtaglomerular complex reduces renin secretion and RAS activity  likely contributes to the antihypertensive action . Some members of this large, heterogeneous class of drugs have additional effects unrelated to their capacity to bind to β adrenergic receptors . For example, labetalol and carvedilol are also α1 blockers, and nebivolol promotes endothelial cell–dependent vasodilation via activation of NO production (Pedersen and Cockcroft, 2006)

24. Pharmacodynamic Differences The β blockers vary in their selectivity for the β1 receptor subtype, presence of partial agonist or intrinsic sympathomimetic activity, and vasodilating capacity . While all of the β blockers are effective as antihypertensive agents , these differences influence the clinical pharmacology and spectrum of adverse effects of the various drugs. The antihypertensive effect resides in antagonism of the β1 receptor, while major unwanted effects result from antagonism of β2 receptors (e.g., peripheral vasoconstriction, bronchoconstriction , hypoglycemia). Standard therapies are β1 blockers without intrinsic sympathomimetic activity (e.g., atenolol, bisoprolol , metoprolol ). They produce an initial reduction in cardiac output (mainly β1) and a reflex-induced rise in peripheral resistance, with little or no acute change in arterial pressure. In patients who respond with a reduction in blood pressure, peripheral resistance gradually returns to pretreatment values or less. Generally , persistently reduced cardiac output and possibly decreased peripheral resistance account for the reduction in arterial pressure .

25. Pharmacodynamic Differences Nonselective β blockers (e.g., propranolol) have stronger adverse effects on peripheral vascular resistance by also blocking β2 receptors that normally mediate vasodilation. Vasodilating β blockers (e.g., carvedilol, nebivolol ) may be preferred in patients with peripheral artery disease. Drugs with intrinsic sympathomimetic activity (e.g., pindolol , xamoterol ) are not recommended for the treatment of hypertension or any other cardiovascular disease because they actually increase nighttime mean heart rate due to their direct partial agonistic activity.

26. Pharmacokinetic Differences Lipophilic β blockers (metoprolol, bisoprolol , carvedilol, propranolol) appear to have more antiarrhythmic efficacy than the hydrophilic compounds (atenolol , nadolol , labetalol), possibly related to a central mode of action. Many β blockers have relatively short plasma half-lives and require more than once-daily dosing (metoprolol, propranolol, carvedilol ), a significant disadvantage in the treatment of hypertension. They should generally be prescribed in sustained-release forms. Bisoprolol and nebivolol have t1/2 values of 10–12 h and thus achieve sufficient trough levels at once-daily dosing. Hepatic metabolism of metoprolol, carvedilol, and nebivolol is CYP2D6 dependent. The relevance is probably greatest in case of metoprolol, for which CYP2D6 poor metabolizers (~7% of the Caucasian population) show 5-fold higher drug exposure and 2-fold higher heart rate decreases than the majority of extensive metabolizers (Rau et al., 2009).

27. Effectiveness in Hypertension Meta-analyses have suggested that β blockers reduce the incidence of MI similar to other antihypertensives but are only be about half as effective in preventing stroke ( Lindholm et al., 2005). This has led to downgrading of this class of drugs in certain national guidelines; however, many of the studies supporting this conclusion were conducted with atenolol, which may not be the ideal β blocker. Atenolol may not lower central (aortic) blood pressure as effectively as it appears when conventionally measured in the brachial artery using a standard arm cuff (Williams et al., 2006). Indeed , atenolol, in contrast to bisoprolol , carvedilol, metoprolol, or nebivolol , has not been positively tested in heart failure trials. Prospective studies of hypertensive agents have not compared different β blockers head to head; therefore, the clinical relevance of pharmacological differences in this heterogeneous drug class remains unclear. Results of a detailed meta-analysis of 147 randomized trials of blood pressure reduction showed that, regardless of blood pressure before treatment, lowering systolic blood pressure by 10 mmHg or diastolic blood pressure by 5 mmHg using any of the main classes of antihypertensive drugs significantly reduced coronary events and stroke without an increase in nonvascular mortality (Law et al., 2009).

28. Adverse Effects and Precautions These drugs should be avoided in patients with reactive airway disease (e.g., asthma) or with SA or AV nodal dysfunction or in combination with other drug that inhibit AV conduction, such as verapamil. The risk of hypoglycemic reactions may be increased in diabetics taking insulin, but type 2 diabetes is not a contraindication. β Blockers increase concentrations of triglycerides in plasma and lower those of HDL cholesterol without changing total cholesterol concentrations. The long-term consequences of these effects are unknown. Sudden discontinuation of β blockers can produce a withdrawal syndrome that is likely due to upregulation of β receptors during blockade, causing enhanced tissue sensitivity to endogenous catecholamines — potentially exacerbating the symptoms of CAD & rebound hypertension. Thus , β blockers should not be discontinued abruptly, except under close observation; dosage should be tapered gradually over 10–14 days prior to discontinuation.

29. Therapeutic Uses The β blockers provide effective therapy for all grades of hypertension. Marked differences in their pharmacokinetic properties should be considered; once-daily dosing is preferred for better compliance. Populations that tend to have a lesser antihypertensive response to β blockers include the elderly and African Americans. The β blockers usually do not cause retention of salt and water, and administration of a diuretic is not necessary to avoid edema or the development of tolerance. However , diuretics do have additive antihypertensive effects when combined with β blockers. The combination of a β blocker, a diuretic, and a vasodilator is effective for patients who require a third antihypertensive drug. β Blockers (i.e., bisoprolol , carvedilol, metoprolol or nebivolol ) are highly preferred drugs for hypertensive patients with conditions such as MI, ischemic heart disease, or congestive heart failure. May be preferred for younger patients with signs of increase sympathetic drive. However , for other hypertensive patients, particularly older patients with a high risk for stroke, enthusiasm for their early use in treatment has diminished.

30. α1 Blockers Initially, α1 blockers reduce arteriolar resistance and increase venous capacitance ; this causes a sympathetically mediated reflex increase in heart rate and plasma renin activity. During long-term therapy, vasodilation persists , but cardiac output, heart rate, and plasma renin activity return to normal. Renal blood flow is unchanged during therapy with an α1 blocker. The α1 blockers cause a variable amount of postural hypotension, depending on the plasma volume. Retention of salt and water occurs in many patients during continued administration, and this attenuates the postural hypotension. The α1 blockers reduce plasma concentrations of triglycerides and total LDL cholesterol and increase HDL cholesterol. These potentially favorable effects on lipids persist when a thiazide-type diuretic is given concurrently. The long-term consequences of these small, drug-induced changes in lipids are unknown.

31. Therapeutic effets : α1 Blockers are not recommended as monotherapy for hypertensive patients , Consequently , they are used primarily in conjunction with diuretics, β blockers, and other antihypertensive agents. β Blockers enhance the efficacy of α1 blockers. α1 Blockers are not the drugs of choice in patients with pheochromocytoma because a vasoconstrictor response to epinephrine can still result from activation of unblocked vascular α2 adrenergic receptors. α1 Blockers are attractive drugs for hypertensive patients with benign prostatic hyperplasia because they also improve urinary symptoms.

32. Adverse effects: The use of doxazosin as monotherapy for hypertension increases the risk for developing congestive heart failure (ALLHAT Officers, 2002). This may be a class effect that represents an adverse effect of all of the α1 blockers and has led to recommendations not to use this class of drugs in patients with heart failure. Interpretation of the outcome of the ALLHAT study is controversial, but the commonly held belief that the higher rate of apparent heart failure development in the groups of patients treated with a nondiuretic was caused by withdrawal of prestudy diuretics has not been substantiated (Davis et al., 2006). A major precaution regarding the use of the α1 blockers for hypertension is the so-called first-dose phenomenon, in which symptomatic orthostatic hypotension occurs within 30–90 min (or longer) of the initial dose of the drug or after a dosage increase. This effect may occur in up to 50% of patients , especially in patients who are already receiving a diuretic. After the first few doses, patients develop a tolerance to this marked hypotensive

33. Combined α1 and β Blockers 1.carvedilol: Carvedilol is a nonselective β blocker with α1-antagonist activity . Carvedilol is approved for the treatment of hypertension and symptomatic heart failure. The ratio of α1- to β-antagonist potency for carvedilol is approximately 1:10. The drug dissociates slowly from its receptor , explaining why the duration of action is longer than the short t1/2 (2.2 h) and why its effect can hardly be overcome by catecholamines . Carvedilol undergoes oxidative metabolism and glucuronidation in the liver ; the oxidative metabolism occurs via CYP2D6. As with labetalol, the long-term efficacy and side effects of carvedilol in hypertension are predictable based on its properties as a β and α1 blocker. Carvedilol reduces mortality in patients with congestive heart failure. Due to the vasodilating effect, it is a β blocker of choice in patients with peripheral artery disease.

34. 2.labetalol: Labetalol) is an equimolar mixture of four stereoisomers. One isomer is an α1 blocker, another is a nonselective β blocker with partial agonist activity, and the other two isomers are inactive. Labetalol has efficacy and adverse effects that would be expected with any combination of an α1 and a β blocker. It has the disadvantages that are inherent in fixed-dose combination products: The extent of α1- to β-blockade is somewhat unpredictable and varies from patient to patient. Labetalol is FDA-approved for eclampsia, preeclampsia, hypertension, and hypertensive emergencies . The main indication for labetalol is hypertension in pregnancy , for which it is one of the few compounds known to be safe (Magee et al., 2016).

35. Centrally Acting Sympatholytic Drugs 1. Methyldopa Methyldopa, a centrally acting antihypertensive agent, is a prodrug that exerts its antihypertensive action via an active metabolite. Methyldopa’s adverse effect profile limits its current use largely to treatment of hypertension in pregnancy , where it has a record for safety. Methyldopa ( α- methyl-3,4-dihydroxy-l-phenylalanine), an analogue of DOPA, is metabolized by the l-aromatic amino acid decarboxylase in adrenergic neurons to α- methyldopamine ,  α- methylnorepinephrine , the pharmacologically active metabolite. α- Methylnorepinephrine is stored in the secretory vesicles of adrenergic neurons , substituting for NE, such that the stimulated adrenergic neuron now discharges α- methylnorepinephrine instead of NE. α- Methylnorepinephrine acts in the CNS to inhibit adrenergic neuronal outflow from the brainstem, probably via acting as an agonist at presynaptic α2 adrenergic receptors in the brainstem ,  attenuating NE release  reducing the output of vasoconstrictor adrenergic signals to the peripheral sympathetic nervous system.

36. ADME(abs/ dist / metabol /excretion) The drug is eliminated with a t1/2 of about 2 h . Methyldopa is excreted in the urine primarily as the sulfate conjugate (50%–70%) and as the parent drug (25%). Other minor metabolites include methyldopamine , methylnorepinephrine , and their O-methylated products. Despite its rapid absorption and short t1/2, the peak effect of methyldopa is delayed for 6–8 h, even after intravenous administration, and the duration of action of a single dose is usually about 24 h; this permits once- o twice-daily dosing. The t1/2 of methyldopa is prolonged to 4–6 h in patients with renal failure . Patients with renal failure are more sensitive to the antihypertensive effect of methyldopa, but it is not known if this is due to alteration in excretion of the drug or to an increase in transport into the CNS.

37. Therapeutic Uses: Methyldopa is a preferred drug for treatment of hypertension during pregnancy based on its effectiveness and safety for both mother and fetus (Magee et al., 2016). The usual initial dose of methyldopa is 250 mg twice daily; there is little additional effect with doses greater than 2 g/d. Administration of a single daily dose of methyldopa at bedtime minimizes sedative effects, but administration twice daily is required for some patients.

38. Adverse Effects and Precautions: Methyldopa produces sedation that is largely transient. A diminution in psychic energy may persist in some patients , and depression occurs occasionally. Methyldopa may produce dryness of the mouth. Other adverse effects include diminished libido, parkinsonian signs, and hyperprolactinemia that may become sufficiently pronounced to cause gynecomastia and galactorrhea. Methyldopa may precipitate severe bradycardia and sinus arrest. Hepatotoxicity , sometimes associated with fever, is an uncommon but potentially serious toxic effect of methyldopa . At least 20% of patients who receive methyldopa for a year develop a positive Coombs test ( antiglobulin test) The development of a positive Coombs test is not necessarily an indication to stop treatment with methyldopa; The Coombs test may remain positive for as long as a year after discontinuation of methyldopa, but the hemolytic anemia usually resolves within a matter of weeks. Severe hemolysis may be attenuated by treatment with glucocorticoids . Adverse effects that are even rarer include leukopenia, thrombocytopenia , red cell aplasia, lupus erythematosus–like syndrome, lichenoid and granulomatous skin eruptions, myocarditis, retroperitoneal fibrosis , pancreatitis, diarrhea, and malabsorption.

39. Clonidine and Moxonidine These drugs stimulate α2A adrenergic receptors in the brainstem, resulting in a reduction in sympathetic outflow from the CNS (MacMillan et al., 1996). The hypotensive effect correlates directly with the decrease in plasma concentrations of NE. Patients who have had a spinal cord transection above the level of the sympathetic outflow tracts do not display a hypotensive response to clonidine. At doses higher than those required to stimulate central α2A receptors, these drugs can activate α2B receptors on vascular smooth muscle cells ( MacMillan et al., 1996). This effect accounts for the initial vasoconstriction that is seen when overdoses of these drugs are taken and may be responsible for the loss of therapeutic effect that is observed with high doses. A major limitation in the use of these drugs is the paucity of information about their efficacy in reducing the risk of cardiovascular consequences of hypertension.

40. Pharmacological Effects. The α2 adrenergic agonists lower arterial pressure by effects on both cardiac output and peripheral resistance. In thesupine position, when the sympathetic tone to the vasculature is low, the major effect is a reduction in heart rate and stroke volume; However,in the upright position, when sympathetic outflow to the vasculature is normally increased, these drugs reduce vascular resistance  may lead to postural hypotension. The decrease in cardiac sympathetic tone leads to a reduction in myocardial contractility and heart rate that promote congestive heart failure in susceptible patients.

41. Therapeutic Uses. The CNS effects are such that this class of drugs is not a leading option for monotherapy of hypertension. Indeed , there is no fixed place for these drugs in the treatment of hypertension. They effectively lower blood pressure in some patients who have not responded adequately to combinations of other agents. A recent study with moxonidine in patients with hypertension and paroxysmal atrial fibrillation indicated that the drug reduced the incidence of atrial fibrillation (Giannopoulos et al., 2014). Clonidine may be effective in reducing early morning hypertension in patients treated with standard anti hypertensives . Overall , enthusiasm for α2 receptor antagonists is diminished by the relative absence of evidence demonstrating reduction in risk of adverse cardiovascular events. Clonidine has been used in hypertensive patients for the diagnosis of pheochromocytoma . The failure of clonidine to suppress the plasma concentration of NE to less than 500 pg /mL 3 h after an oral dose of 0.3 mg of clonidine suggests the presence of such a tumor. A modification of this test, wherein overnight urinary excretion of NE and epinephrine is measured after administration of a 0.3-mg dose of clonidine at bedtime, may be useful when results based on plasma NE concentrations are equivocal.

42. Adverse Effects and Precautions. Sedation and xerostomia, dry nasal mucosa, dry eyes, and swelling and pain of the parotid gland . Postural hypotension and erectile dysfunction may be prominent in some patients. Moxonidine has additional activity at central imidazoline receptors and may produce less sedation than clonidine. sleep disturbances with vivid dreams or nightmares, restlessness, and depression. Symptomatic bradycardia and sinus arrest in patients with dysfunction of the SA node and AV block in patients with AV nodal disease or in patients taking other drugs that depress AV conduction . Some 15 %–20% of patients who receive transdermal clonidine may develop contact dermatitis. Sudden discontinuation of clonidine and related α2 adrenergic agonists may cause a withdrawal syndrome consisting of headache, apprehension, tremors , abdominal pain, sweating, and tachycardia. Arterial blood pressure may rise to levels above those present prior to treatment, but the withdrawal syndrome may occur in the absence of an overshoot in pressure. Symptoms typically occur 18–36 h after the drug is stopped and are associated with increased sympathetic discharge, as evidenced by elevated plasma and urine concentrations of catecholamines and metabolites. The frequency of occurrence of the withdrawal syndrome is not known, but withdrawal symptoms are likely dose related and more dangerous in patients with poorly controlled hypertension. Rebound hypertension also has been seen after discontinuation of transdermal administration of clonidine (Metz et al., 1987)

43. Reserpine is an alkaloid extracted from the root of Rauwolfia serpentina , Ancient Hindu Ayurvedic writings describe medicinal uses of the plant; Mechanism of Action: Reserpine binds tightly to adrenergic storage vesicles in central and peripheral adrenergic neurons and remains bound for prolonged periods of time. The interaction inhibits the vesicular catecholamine transporter VMAT2, so that nerve endings lose their capacity to concentrate and store NE and dopamine  Catecholamines leak into the cytoplasm , where they are metabolized  little or no active transmitter is released from nerve endings,  pharmacological sympathectomy . Recovery of sympathetic function requires synthesis of new storage vesicles, which takes days to weeks after discontinuation of the drug. Because reserpine depletes amines in the CNS as well as in the peripheral adrenergic neuron, it is probable that its antihypertensive effects are related to both central and peripheral actions . Both cardiac output and peripheral vascular resistance are reduced during long-term therapy with reserpine. Reserpine

44. Toxicity and Precautions: Sedation and inability to concentrate or perform complex tasks are the most common adverse effects. More serious is the occasional psychotic depression that can lead to suicide . Depression usually appears insidiously over many weeks or months and may not be attributed to the drug because of the delayed and gradual onset of symptoms. Reserpine must be discontinued at the first sign of depression. Reserpine-induced depression may last several months after the drug is discontinued. The risk of depression is likely dose related. Other adverse effects include nasal stuffiness and exacerbation of peptic ulcer disease, which is uncommon with small oral doses. Therapeutic Uses: Reserpine at low doses, in combination with diuretics, is effective in the treatment of hypertension, especially in the elderly. Several weeks are necessary to achieve maximum effect. In elderly patients with isolated systolic hypertension, reserpine (at 0.05 mg/d) was used as an alternative to atenolol together with a diuretic (Perry et al., 2000;SHEP Cooperative Research Group, 1991). The use of reserpine has largely diminished, and it is no longer recommended for the treatment of hypertension ( Mancia et al., 2013).

45. Calcium channel blocker: The basis for their use in hypertension comes from the understanding that hypertension generally is the result of increased peripheral vascular resistance. Because contraction of vascular smooth muscle is dependent on the free intracellular concentration of Ca2+, inhibition of transmembrane movement of Ca2+ through voltage- sensitive Ca2+ channels can decrease the total amount of Ca2+ that reaches intracellular sites. Indeed , all of the Ca2+ channel blockers lower blood pressure by relaxing arteriolar smooth muscle and decreasing peripheral vascular resistance. As a consequence of a decrease in peripheral vascular resistance, the Ca2+ channel blockers evoke a baroreceptor reflex–mediated sympathetic discharge, tachycardia may occur . Tachycardia is typically minimal or absent with verapamil and diltiazem because of the direct negative chronotropic effect of these two drugs . Indeed, the concurrent use of a β blocker may magnify negative chronotropic effects of these drugs or cause heart block in susceptible patients. The Ca2+ channel blockers are among the preferred drugs for the treatment of hypertension, both as monotherapy and in combination with other antihypertensives , because they have a well-documented effect on cardiovascular end points and total mortality. The combination of amlodipine and the ACE inhibitors perindopril proved superior to the combination of the β blocker atenolol and hydrochlorothiazide ( Dahlof et al., 2005 ), and amlodipine was superior to hydrochlorothiazide as the combination partner for the ACEI benazepril ( Jamerson et al., 2008).

46. The Ca2+ channel blockers most studied and used for the treatment of hypertension are long-acting dihydropyridines with sufficient 24-h efficacy at once-daily dosing (e.g., amlodipine, felodipine , lercanidipine , and sustained-release formulations of others). Peripheral edema ( ankle edema ) are the main unwanted effects. Fewer patients appear to experience this harmless, but possibly distracting, side effect with newer compounds such as lercanidipine ( Makarounas-Kirchmann et al., 2009 ), but the commonly used combination with RAS inhibitors has the same effect ( Messerli et al., 2000). Immediate-release nifedipine and other short-acting dihydropyridines have no place in the treatment of hypertension. Verapamil and diltiazem also have short half-lives, more cardiac side effects, and a high drug interaction potential (verapamil > diltiazem) and are therefore not first-line antihypertensives . Compared with other classes of antihypertensive agents, there may be a greater frequency of achieving blood pressure control with Ca2+ channel blockers as monotherapy in elderly subjects and in African Americans, population groups in which the low renin status is more prevalent. Ca2 + channel blockers are effective in lowering blood pressure and decreasing cardiovascular events in the elderly with isolated systolic hypertension ( Staessen et al., 1997) and may be a preferred treatment in these patients.

47. Inhibitors of the Renin-Angiotensin System

48. Angiotensin-Converting Enzyme Inhibitors The ACE inhibitors appear to confer a special advantage in the treatment of patients with diabetes, slowing the development and progression of diabetic glomerulopathy . They also are effective in slowing the progression of other forms of chronic renal disease, such as glomerulosclerosis, which coexists with hypertension in many patients. Patients with hypertension and ischemic heart disease are candidates for treatment with ACE inhibitors. Administration of ACE inhibitors in the immediate post-MI period has been shown to improve ventricular function and reduce morbidity and mortality ACE inhibitors blunt the rise in aldosterone concentrations in response to Na+ loss  natriuresis is increased  ACE inhibitors tend to enhance the efficacy of diuretic drugs. This means that even very small doses of diuretics may substantially improve antihypertensive efficacy of ACE inhibitors ; conversely , the use of high doses of diuretics together with ACE inhibitors may lead to excessive reduction in blood pressure and to Na+ loss in some patients.

49. Substantial retention of K+ can occur in some patients with renal insufficiency & the potential for developing hyperkalemia should be considered when ACE inhibitors are used with other drugs that can cause K+ retention, including the K+- sparing diuretics, NSAIDs, K+ supplements, and β blockers. Cough is a common (~5%) adverse effect and Angioedema is a rare but serious and potentially fatal adverse effect of the ACE inhibitors. Patients starting treatment with these drugs should be explicitly warned to discontinue their use with the advent of any signs of angioedema. ACE inhibitors are contraindicated during pregnancy. In most patients, there is little or no appreciable change in glomerular filtration rate following the administration of ACE inhibitors. In patients with bilateral renal artery stenosis or stenosis in a sole kidney, the administration of an ACE inhibitor will reduce the filtration fraction and cause a substantial reduction in glomerular filtration rate.

50. In some patients with preexisting renal disease , the glomerular filtration may decrease with an ACE inhibitor. It should be kept in mind that ACE inhibitors, while inhibiting the progression of chronic kidney disease, carry a risk of reversible drug-induced impairment of glomerular filtration. Serum creatinine levels and K+ should therefore be monitored in the first weeks after establishing therapy . Increases of serum creatinine of greater than 20% predict the presence of renal artery stenosis (van de Ven et al., 1998) and are a reason to discontinue the treatment with ACE inhibitors.

51. Following the initial dose of an ACE inhibitor, there may be a considerable fall in blood pressure in some patients; The potential for a large initial drop in blood pressure is the reason for using a low dose to initiate therapy, especially in patients who may have a very active RAS supporting blood pressure, such as patients with diuretic-induced volume contraction or congestive heart failure. With continuing treatment, there usually is a progressive fall in blood pressure that in most patients does not reach a maximum for several weeks . Young and middle-aged Caucasian patients have a higher probability of responding to ACE inhibitors; elderly African American patients as a group are more resistant to the hypotensive effect of these drugs. While most ACE inhibitors are approved for once-daily dosing for hypertension, a significant fraction of patients has a response that lasts less than 24 h and may require twice-daily dosing for adequate control of blood pressure (e.g., enalapril , ramipril ). Captopril, with its very short duration of action, is not a good choice in the treatment of hypertension.

52. AT1 Receptor Blockers By antagonizing the effects of AngII , these agents relax smooth muscle and thereby promote vasodilation, increase renal salt and water excretion, reduce plasma volume, and decrease cellular hypertrophy. AT1 receptor blockers have the same pharmacological profile as ACE inhibitors with one notable exception. AT1 receptor blockers do not inhibit the ACE-mediated degradation of bradykinin and substance P and thereby cause no cough . Because the AT1 receptor mediates feedback inhibition of renin release, renin and AngII concentrations are increased during AT1 receptor antagonism, leading to increased stimulation of uninhibited AT2 receptors . Despite considerable interest, not much evidence supports any extra benefit from AT1 blockade versus ACE inhibition, and attempts to show greater reductions in cardiovascular events by AT1 receptor blockers or by the combination of an AT1 receptor blocker plus an ACE inhibitor over ACE inhibitor alone failed . Telmisartan caused less cough and angioedema than ramipril but had identical efficacy. The combination, although not more efficacious, was associated with greater worsening of renal function (13.5% vs. 10.2%), hypotension, and syncope (Yusuf et al .,2008 ).

53. The AT1 receptor blockers have a sufficient 24-h effect at once-daily dosing (except losartan). The full effect of AT1 receptor blockers on blood pressure typically is not observed until about 4 weeks after the initiation of therapy. If blood pressure is not controlled by an AT1 receptor blocker alone , a second drug acting by a different mechanism (e.g., a diuretic or Ca2 + channel blocker) may be added. The combination of an ACE inhibitor and an AT1 receptor blocker is not recommended for the treatment of hypertension. Adverse effects of AT1 receptor blockers include hypotension, hyperkalemia, and reduced renal function, including that associated with bilateral renal artery stenosis and stenosis in the artery of a solitary kidney. Hypotension is most likely to occur in patients in whom the blood pressure is highly dependent on AngII , including those with volume depletion (e.g., with diuretics ), renovascular hypertension, cardiac failure, and cirrhosis; Hyperkalemia may occur in conjunction with other factors that alter K+ homeostasis, such as renal insufficiency, ingestion of excess K +, and the use of drugs that promote K+ retention. Cough and angioedema occur rarely. ACE inhibitors and AT1 receptor blockers should not be administered during pregnancy and should be discontinued as soon as pregnancy is detected.

54. Direct Renin Inhibitors Aliskiren , the first orally effective direct renin inhibitor is FDA-approved for the treatment of hypertension. A large study comparing a placebo or aliskiren added to a background of an ARB or an ACE inhibitor was stopped prematurely for a trend toward increased cardiovascular events in the aliskiren treatment group (McMurray et al., 2012). The combination also induced more renal worsening, hypotension , and hyperkalemia. This mirrors previous studies with ARB/ACE inhibitor combinations and indicates that complete blockade of the RAS system achieves more harm than benefit . Aliskiren is effective following oral administration; it directly and competitively inhibits the catalytic activity of renin, leading to diminished production of AngI , AngII , and aldosterone—with a resulting fall in blood pressure. Aliskiren inhibits renin activity, plasma renin activity does not increase as occurs with these other classes of drugs

55. Aliskiren is poorly absorbed, with an oral bioavailability of less than 3%. Elimination of the drug may be primarily through hepatobiliary excretion with limited metabolism via CYP3A4. Taking the drug with a high-fat meal may substantially decrease plasma concentrations. Aliskiren has an elimination t 1/2 of at least 24 h. The combination of aliskiren with other RAS inhibitors is contraindicated. Aliskiren is generally well tolerated. Diarrhea may occur, especially at higher-than-recommended doses. The incidence of cough may be higher than for placebo but substantially less than found with ACE inhibitors. Aliskiren has been associated with several cases of angioedema in clinical trials (Frampton and Curran, 2007). Drugs acting on the RAS may damage the fetus and should not be used in pregnant women.

56. Vasodilators 1.HYDRALAZINE Hydralazine directly relaxes arteriolar smooth muscle with little effect on venous smooth muscle. Potential mechanisms include inhibition of inositol trisphosphate–induced release of Ca2+ from intracellular storage sites, opening of high-conductance Ca2+-activated K+ channels in smooth muscle cells, and activation of an arachidonic acid, COX , and prostacyclin pathway ( Maille et al., 2016). Hydralazine-induced vasodilation is associated with powerful stimulation of the sympathetic nervous system, likely due to baroreceptor-mediated reflexes , resulting in increased heart rate and contractility, increased plasma renin activity, and fluid retention. These effects tend to counteract the antihypertensive effect of hydralazine.

57. Hydralazine is no longer a first-line drug in the treatment of hypertension on account of its relatively unfavorable adverse-effect profile. Can be part of evidence-based therapy in patients with congestive heart failure (in combination with nitrates for patients who cannot tolerate ACE inhibitors or AT1 receptor blockers ), May be useful in the treatment of hypertensive emergencies , especially preeclampsia, in pregnant women. Hydralazine should be used with great caution in elderly patients and in hypertensive patients with CAD because of the possibility of precipitating myocardial ischemia due to reflex tachycardia. The usual oral dosage of hydralazine is 25–100 mg twice daily. The maximum recommended dose of hydralazine is 200 mg/d to minimize the risk of drug-induced lupus syndrome.

58. Toxicity and Precautions Headache , nausea, flushing, hypotension, palpitations, tachycardia, dizziness, and angina pectoris Following parenteral administration to patients with CAD, the myocardial ischemia may be sufficiently severe and protracted to cause frank MI In addition, if the drug is used alone, there may be salt retention with development of high-output congestive heart failure. When combined with a β blocker and a diuretic, hydralazine is better tolerated, although adverse effects such as headache are still commonly described and may necessitate discontinuation of the drug. Drug-induced lupus syndrome is the most common that resembles serum sickness , hemolytic anemia, vasculitis, and rapidly progressive glomerulonephritis. The mechanism of these autoimmune reactions is unknown, although it may involve the drug’s capacity to inhibit DNA methylation (Arce et al., 2006). The drug-induced lupus syndrome usually occurs after at least 6 months of continuous treatment with hydralazine, and its incidenc is related to dose, gender, acetylator phenotype, and race. The incidence is four times higher in women than in men, and the syndrome is seen more commonly in Caucasians than in African Americans . Hydralazine also can produce a pyridoxine-responsive polyneuropathy

59. KATP Channel Openers: Minoxidil Minoxidil is not active in vitro but must be metabolized to minoxidil N-O sulfate . Minoxidil sulfate activates the ATP-modulated K+ channel permitting K+ efflux, and causes hyperpolarization and relaxation of smooth muscle . Systemic minoxidil is best reserved for the treatment of severe hypertensionthat responds poorly to other antihypertensive medications, especially in male patients with renal insufficiency. Minoxidil should never be used alone; it must be given concurrently with a diuretic to avoid fluid retention, with a sympatholytic drug (e.g ., β blocker) to control reflex cardiovascular effects and an inhibitor of the RAS to prevent remodeling effects on the heart . The drug usually is administered either once or twice a day, but some patients may require more frequent dosing for adequate control of blood pressure. The initial daily dose of minoxidil may be as little as 1.25 mg, which can be increased gradually to 40 mg in one or two daily doses . The adverse effects of minoxidil , which can be severe, fall into three major categories : fluid and salt retention, cardiovascular effects, and hypertrichosis . Other side effects of the drug are rare and include rashes, Stevens- Johnson syndrome, glucose intolerance, serosanguineous bullae, formation of antinuclear antibodies, and thrombocytopenia.

60. Sodium Nitroprusside: Nitroprusside is a nitrovasodilator that acts by releasing NO.  + the guanylyl cyclase–cyclic guanosine monophosphate–protein kinase G pathway ,  vasodilation Tolerance develops to nitroglycerin but not to nitroprusside. Nitroprusside dilates both arterioles and venules , and the hemodynamic response to its administration results from a combination of venous pooling and reduced arterial impedance. In subjects with normal left ventricular function , venous pooling affects cardiac output more than does the reduction of afterload; cardiac output tends to fall. In contrast, in patients with severely impaired left ventricular function and diastolic ventricular distention , the reduction of arterial impedance is the predominant effect, leading to a rise in cardiac output. In general, renal blood flow and glomerular filtration are maintained, and plasma renin activity increases . Unlike minoxidil , hydralazine, diazoxide , and other arteriolar vasodilators , sodium nitroprusside usually causes only a modest increase in heart rate and an overall reduction in myocardial O2 demand.

61. The drug must be protected from light and given by continuous intravenous infusion to be effective . Its onset of action is within 30 sec; the peak hypotensive effect occurs within 2 min, and when the infusion of the drug is stopped, the effect disappears within 3 min . The metabolism of nitroprusside by smooth muscle is initiated by its reduction , which is followed by the release of cyanide and then NO. Cyanide is further metabolized by hepatic rhodanase to form thiocyanate, which is eliminated almost entirely in the urine. The mean elimination t 1/2 for thiocyanate is 3 days in patients with normal renal function and much longer in patients with renal insufficiency.

62. Nitroprusside has been used to lower blood pressure during acute aortic dissection; to improve cardiac output in congestive heart failure, especially in hypertensive patients with pulmonary edema that does not respond to other treatment (see Chapter 29); and to decrease myocardial O2 demand after acute MI . In the treatment of acute aortic dissection, it is important to administer a β blocker with nitroprusside because reduction of blood pressure with nitroprusside alone can increase the rate of rise in pressure in the aorta as a result of increased myocardial contractility, thereby enhancing propagation of the dissection The short-term adverse effects of nitroprusside are due to excessive vasodilation, with hypotension and its consequences. Toxic accumulation of cyanide leading to severe lactic acidosis usually occurs when sodium nitroprusside is infused at a rate greater than 5 μg/kg/min but also can occur in some patients receiving doses on the order of 2 μg/kg/min for a prolonged period.

63. The concomitant administration of sodium thiosulfate can prevent accumulation of cyanide in patients who are receiving higher-than-usual doses of sodium nitroprusside; the efficacy of the drug is unchanged. The risk of thiocyanate toxicity increases when sodium nitroprusside is infused for more than 24–48 h, especially if renal function is impaired. Signs and symptoms of thiocyanate toxicity include anorexia, nausea, fatigue, disorientation, and toxic psychosis Nitroprusside can worsen arterial hypoxemia in patients with chronic obstructive pulmonary disease because the drug interferes with hypoxic pulmonary vasoconstriction and therefore promotes mismatching ofventilation with perfusion.

64. Who should be treated with pharmacologic therapy?   Patients with out-of-office daytime blood pressure ≥135 mmHg systolic or ≥85 mmHg diastolic (or an average office blood pressure ≥140 mmHg systolic or ≥90 mmHg diastolic if out-of-office readings are not available) Patients with an out-of-office blood pressure (mean home or daytime ambulatory) ≥130 mmHg systolic or ≥80 mmHg diastolic (or, if out-of-office readings are unavailable, the average of appropriately measured office readings ≥130 mmHg systolic or ≥80 mmHg diastolic) who have one or more of the following features: Established clinical cardiovascular disease ( eg , chronic coronary syndrome [stable ischemic heart disease], heart failure, carotid disease, previous stroke, or peripheral arterial disease) Type 2 diabetes mellitus Chronic kidney disease Age 65 years or older An estimated 10-year risk of atherosclerotic cardiovascular disease of at least 10 percent 

65. Considerations for individualizing antihypertensive therapy

66. Target BP:   A goal blood pressure of <130 mmHg systolic and <80 mmHg diastolic using out-of-office measurements A less aggressive goal blood pressure of <135 mmHg systolic and <85 mmHg diastolic (using out-of-office measurement) or <140 mmHg systolic and <90 mmHg diastolic (using an average of appropriately measured office readings) in the following groups of hypertensive patients: Patients with labile blood pressure or postural hypotension Patients with side effects to multiple antihypertensive medications Patients 75 years or older with a high burden of comorbidity or a diastolic blood pressure <55 mmHg In older adults with severe frailty, dementia, and/or a limited life expectancy, or in patients who are nonambulatory or institutionalized ( eg , reside in a skilled nursing facility), we individualize goals and share decision-making with the patient, relatives, and caretakers, rather than targeting one of the blood pressure goals mentioned above. After antihypertensive therapy is initiated, patients should be re-evaluated and therapy should be increased monthly until adequate blood pressure control is achieved [ 4 ]. Once blood pressure control is achieved, patients should be reevaluated every three to six months to ensure maintenance of control  

67. Approach to antihypertensive drug therapy: Patients without indications for a specific drug 

68. approach of resistant hypertension in adults

69. THANK YOU……………………….