PHARMACOTHERAPY OF HYPERTENSION



PHARMACOTHERAPY OF HYPERTENSIONVictor NadlerReferenceWhelton, PK et al., 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults, hyper..This report from the American College of Cardiology and the American Heart Association evaluates all the available data on the etiology, adverse consequences, diagnosis, and treatment of hypertension and provides a new evidence-based set of clinical practice guidelines. It updates the previous guidelines issued by the NHLBI in 2003 and reconciles the three somewhat conflicting sets of guidelines for pharmacotherapy issued by different professional organizations early in 2014.HypertensionHigh blood pressure is the leading cause of death and disability-adjusted life years worldwide. In the United States, hypertension accounts for more deaths from cardiovascular disease than any other modifiable risk factor and is second only to smoking as a preventable cause of death for any reason. Most deaths from cardiovascular disease and stroke occur in persons who are hypertensive. The percentage of cardiovascular events attributable to hypertension is greater in women (32%) than in men (19%) and in African-Americans (36%) than in white Americans (21%). Hypertension also accounts for 34% of end-stage renal disease and is the second leading cause after diabetes.The 2017 therapeutic guidelines redefined hypertension as a functional pathology characterized in an adult by a blood pressure of ≥130 mm Hg systolic or ≥80 mm Hg diastolic. Because cardiovascular risk is a continuous function of blood pressure, any such definition must be somewhat arbitrary. In fact, cardiovascular disease risk increases in a log-linear fashion from systolic blood pressure <115 mm Hg to >180 mm Hg and from diastolic blood pressure <75 mm Hg to >105 mm Hg. A 20 mm Hg higher systolic blood pressure and a 10 mm Hg higher diastolic blood pressure double the number of deaths from cardiovascular disease.The redefinition of hypertension from a threshold of ≥140/90 mm Hg to ≥130/80 mm Hg was motivated in large part by results of the SPRINT trial reported in 2015 (NEJM, 373, 2103-2116). In this large-scale randomized controlled study, persons with systolic blood pressure ≥130 mm Hg and increased risk of cardiovascular disease (but not diabetic) were assigned to either standard therapy (goal systolic blood pressure <140 mm Hg) or intensive therapy (goal systolic blood pressure <120 mm Hg). On average, one additional antihypertensive drug was required for intensive vs standard therapy. The trial was stopped early because it was already evident that the intensive therapy group experienced significantly less progression to symptomatic cardiovascular disease and lower all-cause mortality. At the same time, however, rates of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or kidney failure were higher in this same group. Based on these and other findings, it was decided that a diagnostic threshold of ≥130/80 mm Hg offered the optimal balance of benefit vs risk.CategorySystolic (mm Hg)Diastolic (mm Hg)Normal<120and<80Elevated120-129and<80Hypertension Stage 1130-139or80-89 Stage 2≥140or≥90The hazard ratio for coronary heart disease and stroke is 1.1-1.5 for elevated vs normal blood pressure and 1.5-2.0 for Stage 1 hypertension vs elevated blood pressure. Progression to symptomatic cardiovascular disease is influenced by modifiable and relatively fixed risk factors. Modifiable risk factors include smoking, diabetes, dyslipidemia, overweight/obesity, physical inactivity, unhealthy diet. Relatively fixed risk factors include chronic kidney disease, family history, low socioeconomic/educational status, male gender, obstructive sleep apnea, psychosocial stress.EtiologyEssential hypertension (hypertension of unknown cause) accounts for more than 85% of all cases. This appears to be a polygenic and multifactorial disorder in which the interaction of several genes with each other and with the environment is important. Secondary hypertension is rare; nevertheless, examination should seek to eliminate this possibility. Physical findings suggestive of secondary hypertension include: abdominal or flank masses (polycystic kidneys), abdominal bruits, particularly those that lateralize or have a diastolic component (renovascular disease), delayed or absent femoral arterial pulses or decreased blood pressure in lower extremities (aortic coarctation), truncal obesity with pigmented striae (Cushing’s syndrome), tachycardia, orthostatic hypotension, sweating, and pallor (pheochromocytoma). Among the most important and best studied drivers of essential hypertension are age, obesity, salt sensitivity, and African-American ethnicity.Overall, 46% of American adults are hypertensive by the current definition (32% by the former definition of ≥140/90 mm Hg). Of those 65-74 years of age, 77% of men and 75% of women are hypertensive compared with 30% of men and 19% of women 20-44 years of age. This trend toward higher blood pressure with age applies to all ethnicities. For example, of all 45 year olds who are normotensive, 93% of African-Americans, 92% of Hispanic-Americans, 86% of white Americans, and 84% of Chinese-Americans will eventually attain a blood pressure ≥140/90 mm Hg. Individuals who are normotensive at 55 years of age have a 90% lifetime risk for developing hypertension. The age-related increase is usually in systolic blood pressure, with little change or even some decrease in diastolic blood pressure. This condition, referred to as isolated systolic hypertension, is therefore characterized by increased pulse pressure (systolic – diastolic). Indeed, in persons older than 50 years, systolic blood pressure of more than 140 mm Hg is a much more important cardiovascular disease risk factor than diastolic blood pressure.Obesity (BMI >30 kg/m2) accounts for at least 40% of hypertension. Obesity increases the relative risk of being or becoming hypertensive by a factor of 2.7; achieving normal weight reverses this risk completely. There is an almost linear relationship between blood pressure and BMI. The relationship between blood pressure and waist-to-hip ratio or central fat distribution is even stronger.In an unselected human population, the effect of sodium on blood pressure is normally distributed. Some individuals respond to high salt with a 10-20 mm Hg increase in systolic blood pressure and to low salt with a similarly large reduction. These individuals are said to be salt-sensitive or to have salt-sensitive blood pressure (SSBP). Other individuals evidence little or no change in blood pressure with changes in salt intake. These individuals are said to be salt-resistant or to have salt-resistant blood pressure (SRBP). These distinct responses to dietary sodium are thought to result from differences in the efficiency of normal sodium handling mechanisms (renal transport, aldosterone, natriuretic peptides, renal eicosanoids, etc). In salt-sensitive persons, one or more of these mechanisms is thought to be impaired. Thus poor sodium regulation by the normal mechanisms requires elimination of a salt load by pressure natriuresis. Conversely, sodium homeostasis in the face of low intake requires a blood pressure reduction. Salt sensitivity is accompanied by several other abnormalities that include a blunted response of the renin-angiotensin system to changes in sodium, impairment of both the production and action of NO increasing oxidative stress, hyperactivity of the sympathetic nervous system, and hyperinsulinemia. The last three of these contribute to cardiovascular pathology. It is important to distinguish between hypertension and salt sensitivity; the one does not necessarily imply the other. Most hypertensive persons are not salt-sensitive. Conversely, although salt sensitivity is a major risk factor for the development of hypertension, not all salt-sensitive individuals are hypertensive. Low-to-moderate sodium intake and/or high sodium loss (e.g., through perspiration or diarrheal disease) can prevent the rise in blood pressure.Salt sensitivity is especially common in African-Americans, the elderly, those with higher blood pressure, and those with certain comorbidities including chronic kidney disease, diabetes, and metabolic syndrome. Although environmental factors do influence sodium handling, salt sensitivity is largely driven by genetics (estimated at 75% in African-Americans, about double the estimated genetic involvement in hypertension). Uncovering the genetic bases for salt sensitivity is an active area of research. These efforts are important because salt sensitivity is an independent risk factor for cardiovascular disease. That is to say, salt-sensitive persons are at increased risk of developing symptomatic cardiovascular disease even if they are not hypertensive.Hypertension is arguably the greatest risk to the cardiovascular health of African-Americans, as well as the greatest area of opportunity for the prevention of disease if effectively managed and prevented. The prevalence of hypertension in African-American adults (men: 59%; women: 56%) is among the highest of any population in the world. Hypertensive African-Americans are actually somewhat more likely than other Americans to be diagnosed and treated. However, a lower percentage of African-Americans achieve blood pressure control. Treatment failures have significant implications for mortality. For example, the same elevation in blood pressure increases the risk of stroke three times more in African-Americans than in white Americans. These disparities have a number of causes. Two of the best established causes are obesity and salt sensitivity. African-Americans are more likely to be obese than white Americans, especially African-American women. The latest available figures are: African-American women – 58%, African-American men – 38%, white men – 34%, white women – 33%. In addition, the prevalence of severe obesity (BMI ≥40 kg/m2) is double that for any other American population. Clinical studies indicate that ~70% of African-Americans with hypertension are salt-sensitive, a considerably higher percentage than other American populations. Both obesity and salt sensitivity individually, and the combination especially, contribute substantially to the higher average blood pressure in hypertensive African-Americans compared to blood pressure in other hypertensive American populations. This higher blood pressure requires more aggressive therapy to achieve the treatment goal. As one might expect then, African-Americans are more likely than others to develop resistant hypertension (see below).DiagnosisDiagnosis is based on the average of two or more blood pressure measurements separated by 1-2 min repeated at two or more visits. The patient must be seated in a comfortable chair for at least 5 min before and during the measurement. At the first visit, blood pressure is recorded in both arms; use the arm that gives the higher reading for all subsequent measurements. Out of office blood pressure measurements are recommended to confirm the diagnosis of hypertension and for titration of medication. These additional measurements are needed to exclude the possibilities of “white coat hypertension” (20/10 mm Hg higher in the office than at home) and “masked hypertension” (20/10 mm Hg less in the office than at home).Goal of Antihypertensive TherapyThe goal of prevention and management of hypertension is to reduce morbidity and mortality by the least intrusive means possible. The morbid consequences of chronic hypertension include congestive heart failure, stroke, renal failure, peripheral arterial disease, and retinopathy. Any blood pressure reduction appears to reduce the risk of developing these complications and also reduces all-cause mortality. These results have been obtained in patients in various countries regardless of sex, age, ethnic background, blood pressure level, or socioeconomic status.Treatment GuidelinesCategoryRecommended TreatmentNormal blood pressureReassess in one yearElevated blood pressureLifestyle modifications; reassess in 3-6 monthsStage 1 hypertension with 10-year risk <10%Lifestyle modifications; reassess in 3-6 monthsStage 1 hypertension with 10-year risk ≥10%Lifestyle modificationsMedicationStage 1 hypertension with symptomatic CVDLifestyle modificationsMedicationStage 2 hypertension, blood pressure <150/90 mm HgLifestyle modificationsMedicationStage 2 hypertension, blood pressure ≥150/90 mm HgLifestyle modificationsTwo first-line medications from different classesThe target blood pressure for adults with confirmed hypertension and symptomatic cardiovascular disease or a 10-year risk of ischemic cardiovascular disease ≥10% is 130/80 mm Hg.For adults with confirmed hypertension, but without additional risk, a target blood pressure of <130/80 mm Hg may be reasonable. The few studies that have been done on these persons provide little guidance.Patients whose 10-year risk is ≥10% should return for followup and adjustment of medications at monthly intervals until the blood pressure goal is achieved. Otherwise, reassess blood pressure status every 3-6 months. Serum potassium and creatinine should be monitored once or twice a year.Recommended Lifestyle ModificationsThe lifestyle modifications listed below are recommended for all persons diagnosed with either elevated blood pressure or hypertension. There is not a recommended set period of time to try lifestyle modifications alone before initiating pharmacotherapy. The physician must decide on a case-by-case basis whether lifestyle modification alone can achieve the goal blood pressure and, if the decision is that it can, when attempted lifestyle modifications have been tried for a sufficiently long period without achieving the goal.ModificationRecommendationExpected Reduction in Systolic BPWeight reductionMaintain normal body weight (BMI of 18.5-24.9)1 mm Hg for each kg lostAdopt the DASH dietConsume diet rich in fruits, vegetables, and low-fat dairy products with reduced saturated and total fatup to 11 mm HgDietary sodium reductionReduce intake to no more than 1500 mg NaCl per dayvariable (see discussion of salt sensitivity above)Increase dietary potassiumOptimal intake is 3500-5000 mg per day, preferably through healthy diet4-5 mm Hg (possibly double this in persons who eat a high sodium diet)Physical activityEngage in aerobic physical activity (e.g., brisk walking) for at least 150 minutes per week5-8 mm HgModeration of alcohol consumptionNo more than 2 standard drinks per day for most men and no more than 1 for women2-4 mm HgStop smoking!An example of the improvement in blood pressure that can be achieved with dietary measures alone was provided by the outcome of a multicenter clinical trial of the “DASH” (Dietary Approaches to Stop Hypertension) diet. The DASH diet substitutes low-fat dairy products for much of the meat and sweets in the normal diet and includes twice the national average consumption of fruits and vegetables. Strict adherence to this diet reduced systolic blood pressure by an average of 11 mm Hg, about the same as can be achieved by treatment with a single first-line antihypertensive drug. The inclusion of low-fat dairy products in the diet was crucial to its success; simply increasing fruits and vegetables did not work. The mechanism of the blood pressure reduction remains unknown. The DASH diet is enriched in potassium, calcium, magnesium, and fiber, and these properties may play a role. Adherence to the DASH diet has been shown to reduce the incidence of stroke and coronary heart disease and to improve insulin sensitivity. However, the DASH diet is rather bland and only ~20% of hypertensive persons adhere to it long-term. Some other diets can also reduce blood pressure, but there is less evidence behind them. The success of dietary measures requires taking personal preferences, cultural traditions, economic circumstances, and other considerations into account. The standard DASH diet is neutral with regard to calories and sodium. If weight loss or reduced sodium intake is desired, then a low-calorie or low-sodium version of the DASH diet must be followed.The largest effects of dietary sodium reduction are obtained in persons who follow the DASH diet, achieve significant weight loss, and/or are salt sensitive. Thus elderly and African-American patients benefit disproportionally. A low sodium diet is difficult to maintain. Most dietary sodium comes from additions during food processing or during commercial food preparation. Patients may have to prepare their own food from the raw ingredients.Higher potassium intake appears to blunt the effect of excess sodium. The sodium/potassium ratio may be more important than either alone. Foods high in potassium include fruits, vegetables, low-fat dairy, nuts, soy, and some fish and meats.The recommendation for alcohol consumption is a compromise between risk and benefit. Systolic blood pressure increases in most men when alcohol consumption exceeds 3 standard drinks per day (less for women). However, moderate alcohol consumption is associated with a lower incidence of coronary heart disease. MedicationFirst-Line DrugsThe first-line agents are thiazide diuretics, calcium channel blockers, and angiotensin converting enzyme inhibitors (ACEI)/angiotensin receptor (AT1) blockers (ARBs). Know the points about antihypertensive drugs indicated by asterisks.Thiazide Diuretics See handout on Diuretics.MechanismShort-term – reduction in extracellular fluid, therefore reduced cardiac outputLong-term – reduction in peripheral resistance from opening of potassium channels in vascular smooth muscle, increased NO production and action, and ?*NotesThiazide diuretics reduce blood pressure about equally in all population groups.*Chlorthalidone is preferred for monotherapy* because (1) it was shown in the ALLHAT trial that it reduces progression to symptomatic cardiovascular disease more effectively than lisinopril (ACE inhibitor) or amlodipine (vascular-specific calcium channel blocker) and subsequent trials demonstrated superiority to hydrochlorothiazide, (2) it has a longer duration of action than hydrochlorothiazide, ensuring maximal effect throughout the entire 24-hr dosing interval, and (3) it more effectively opens potassium channels in vascular smooth muscle.When combining antihypertensive drugs, the use of fixed-dose tablets can improve adherence. However, the great majority of thiazide-containing combinations utilize hydrochlorothiazide. Only a few utilize chlorthalidone.Thiazide diuretics reduce blood pressure about as effectively as loop diuretics, but loop diuretics are more difficult to manage; they are more prone to produce electrolyte abnormalities, dehydration, and/or hyponatremia. Use a loop diuretic only if it is needed to treat congestive heart failure or chronic renal disease.*ACE InhibitorsMolecular MechanismCompetitive inhibition of angiotensin converting enzyme (kininase II)*Physiological MechanismsBlock of angiotensin II-mediated vasoconstriction*Reduced norepinephrine release by block of angiotensin II-mediated enhancementReduced sympathetic outflow from the brain stemIncreased bradykinin-mediated vasodilationSlightly reduced aldosterone secretion*Block of angiotensin II-mediated arterial and left ventricular remodeling*Other ActionsDry cough (partly caused by increased bradykinin)*Rapid swelling of nose, throat, mouth, tongue (angioedema; partly caused by bradykinin)*Teratogenesis in the second and third trimesters*Hyperkalemia (especially in the absence of diuretic)*NotesAll generic drug names end in –pril.*These drugs are less effective than thiazide diuretics and calcium channel blockers in reducing blood pressure and preventing stroke. In African-Americans they are also less effective in preventing heart failure.These drugs are less effective in salt-sensitive individuals, because such individuals have a blunted renin-angiotensin system.*However, the combination of ACE inhibitor and thiazide diuretic reduces blood pressure equally well in all populations.*If cough is intolerable or angioedema develops, switch to an ARB or just use an ARB instead.*ACE inhibitor or ARB should be used in persons with congestive heart failure, chronic kidney disease, and/or who are post-MI.*Endocrinology societies recommend using an ACE inhibitor or ARB in persons with diabetes. The AHA/ACC guidelines recognize that all first-line agents have been shown to benefit persons with both hypertension and diabetes. They do not call specifically for an ACE inhibitor or ARB.Do not combine an ACE inhibitor with an ARB or aliskerin. There is no benefit to doing so and these combinations are potentially harmful. Also there is no rationale for substituting an ACE inhibitor for an ARB.* Angiotensin IIARBsMolecular MechanismCompetitive antagonism of angiotensin II at the AT1 receptor*Physiological MechanismsBlock of angiotensin II-mediated vasoconstriction*Reduced norepinephrine release by block of angiotensin II-mediated enhancementReduced sympathetic outflow from the brain stemSlightly reduced aldosterone secretion*Block of angiotensin II-mediated arterial and left ventricular remodeling*NotesAll generic drug names end in –artan.*Efficacy is equivalent to that of ACE inhibitors.*No change in bradykinin levels. Thus much lower risk of dry cough and angioedema than with ACE inhibitors*Useful as a replacement for ACE inhibitor, especially in patients who cannot tolerate ACE inhibitorsAs teratogenic as ACE inhibitors*Hyperkalemia (in the absence of diuretic)*Same as ACE inhibitors with respect to limited efficacy, combination with thiazide diuretics, and use in patients with specific comorbidities.*Do not combine an ARB with an ACE inhibitor. There is no benefit to doing so and these combinations are potentially harmful.*Calcium Channel Blockers (amlodipine and other vascular-specific blockers are first line; verapamil and diltiazem are used mostly in special circumstances)Molecular MechanismsReversible block of L-type Ca2+ channels in vascular smooth muscle cells*Reversible block of L-type Ca2+ channels in cardiac muscle cells* (verapamil, diltiazem only) Physiological MechanismsReduced sympathetically-mediated vasoconstriction due to block of Ca2+ action potentials and Ca2+-mediated Ca2+ release from sarcoplasmic reticulum*Reduced inotropy, cardiac output* (verapamil, diltiazem only)Other ActionsReflex tachycardia (risk in ischemic heart disease; avoid using rapidly-acting calcium channel blockers)*Reduced inotropy and chronotropy (verapamil, diltiazem only)*Edema from precapillary dilatation with reflex postcapillary constriction (all)Reflux due to relaxation of the lower esophageal sphincter (all)NotesAll generic names of vascular-specific calcium-channel blockers end in -dipine.*Calcium channel blockers reduce blood pressure about equally well in all population groups.*Verapamil or diltiazem should be used in preference to a vascular-specific drug to treat hypertension in persons with diastolic congestive heart failure, stable/unstable angina, or supraventricular arrhythmia.*Second-Line DrugsThese agents reduce progression to symptomatic cardiovascular disease less well than the first-line agents. They should be considered only when they are required anyway for treating the comorbidities discussed below or sometimes for patients who are inadequately treated with a combination of three first-line drugs.Beta BlockersMolecular MechanismsMajor importanceCompetitive antagonism of β1 adrenergic receptors (atenolol, metoprolol)*Competitive antagonism of β1, β2, α1 adrenergic receptors, anti-oxidant and anti-apoptotic effects (carvedilol)*Competitive antagonism of β1 adrenergic receptors, increased availability of NO (nebivolol)*Lesser importance+ intrinsic sympathomimetic activity (acebutolol)+ β2 agonist activity (celiprolol)+ β2 antagonist activity (propranolol)+ CNS depression (propranolol)Physiological Mechanisms (note: other mechanisms may be important when the same drug is used to treat other cardiovascular problems)MajorReduced myocardial contractility (reduced cardiac output)*OthersVasodilation (Carvedilol [by α1 antagonism], Nebivolol [by increasing NO])*Reduced renin secretionReduced norepinephrine release by block of positive β2 feedbackReduced sympathetic outflow from the brain stemOther ActionsReduced inotropy and chronotropy* (mainly β1 antagonism)Bronchoconstriction (β2 antagonism). Use only β1-selective blockers in persons with asthma and then only with caution.*Block of epinephrine-mediated vasodilation of skeletal muscle beds (β2 antagonism)Reduced glycogenolysis and reduced blood glucose (β2 antagonism) Increased plasma triglycerides and reduced HDL (β2/β3 antagonism)Combined β2/α1 block (carvedilol) or selective β1 block greatly reduces the potentially unfavorable metabolic effectsExercise intolerance* (β1- and β2-mediated); Carvedilol and nebivolol produce less. This reflects inability to upregulate those aspects of sympathetic function that operate through β receptors. Although block of β1 receptors in the heart has much to do with this, block of β2 receptor-mediated effects in the periphery (reduced vasodilation in the skeletal muscles and glucose utilization) and the brain (centrally-mediated fatigue) also play a role.Sexual dysfunction; Nebivolol produces lessNotesBeta blockers should be used in persons with congestive heart failure, stable/unstable angina, supraventricular arrhythmia and/or who are post-MI.Agents that block 1 receptors and have vasodilatory properties (e.g., carvedilol, nebivolol) are particularly useful in heart failure patients and in patients with hyperlipidemia or prostatic hyperplasia. Carvedilol may be the most efficacious beta blocker for the pharmacotherapy of congestive heart failure and arguably the most useful drug in this class overall. Its superiority relates to (1) its greater affinity for the β1 receptor, (2) its anti-oxidant activity, (3) its anti-apoptotic activity, which has been attributed to its almost unique ability to stimulate β1 receptor-mediated, G protein-independent beta-arrestin signalling.Alpha BlockersMolecular MechanismCompetitive antagonism of 1 adrenergic receptors*Physiological mechanismDirect postsynaptic blockade of sympathetically-mediated vasoconstriction*Other ActionsTransient reflex increase in heart rate, cardiac output, plasma renin* (risk in ischemic heart disease)Depression of the baroreceptor reflex, leading to orthostatic hypotension*Edema (similar to Ca2+ channel blockers)Reduced total and LDL cholesterol, increased HDL cholesterolNotesExtreme orthostatic hypotension may develop in response to the first dose, but tolerance to this side effect usually develops rapidly.Alpha blockers are most useful in patients with prostatic hyperplasia who may be receiving a drug of this type anyway.*Antihypertensive drugs may improve cardiovascular morbidity and mortality by mechanisms independent of blood pressure control. Large retrospective studies have indicated that some of the protective effect of first-line antihypertensive drugs against stroke and congestive heart failure is obtained even if the drug has little or no effect on systemic blood pressure. Thus the first-line antihypertensive drugs seem to confer some health benefits that are independent of their antihypertensive action. This additional benefit probably results from inhibition or reversal of cardiovascular remodeling. Arteriosclerosis, remodeling of the arteries, is the pathologic basis for age-related hypertension and is impacted favorably by drugs and dietary/lifestyle measures that reduce the effect of catecholamines, angiotensin II, aldosterone, excessive extracellular Na+, oxidative stress, plasma glucose, and other drivers of the underlying pathology.Major Antihypertensive Drugs to KnowA.DIURETICSHydrochlorothiazide (generic)Thiazide diureticChlorthalidone (generic)Thiazide diureticB.INTERFERE WITH SYMPATHETIC FUNCTIONCarvedilol(generic)?1, 1, and 2 antagonist, anti-oxidant, anti-apoptoticNebivolol(Bystolic?)β??antagonist, increases NO availabilityAtenolol(generic)1 antagonist, eliminated by kidneyMetoprolol(generic)1 antagonist, eliminated by liver metabolismPrazosin(generic)?1 antagonistC.CALCIUM CHANNEL BLOCKERSAmlodipine(generic)Vascular-selectiveVerapamil(generic)Blocks both cardiac and vascular channelsDiltiazem(generic)Blocks both cardiac and vascular channelsD.INTERFERE WITH RENIN-ANGIOTENSIN SYSTEMLisinopril(generic)ACE inhibitorCandesartan(generic)ARBResistant HypertensionResistant hypertension is defined as blood pressure that remains above goal despite the concurrent use of three first-line antihypertensive drugs from different classes, including a diuretic. Patients whose blood pressure is controlled with four or more medications are considered to have resistant hypertension. Before concluding that a patient truly has resistant hypertension, check the technique for measuring blood pressure, the possibility of a secondary cause, the choice of drugs and dosing regimen, adherence, and associated comorbidities.Most cases of resistant hypertension are thought to arise from occult expansion of extracellular fluid volume and/or from increased production or action of aldosterone. Salt sensitivity and higher blood pressures are major risk factors. Thus patients with resistant hypertension should be encouraged to reduce their dietary sodium intake as much as possible. The preferred fourth drug is a potassium-sparing diuretic (spironolactone, eplerenone, triamterene, amiloride). These drugs increase diuretic action to eliminate excess fluid and, importantly, also combat the action of aldosterone.Hypertensive Crisis (Emergency)Hypertensive emergencies are those situations in which blood pressure must be lowered within one hour. Examples include hypertensive encephalopathy, intracranial hemorrhage, acute left ventricular failure with pulmonary edema, dissecting aortic aneurysm, eclampsia or severe hypertension associated with pregnancy, head trauma, extensive burns, unstable angina pectoris, and acute myocardial infarction.Sodium nitroprusside (IV) is the most effective remedy. Its onset of action is immediate and it has a very short half-life. Nitroprusside, like other organic nitrates, is a source of NO, which causes vasodilation by increasing cGMP in vascular smooth muscle cells. However, mitochondrial aldehyde dehydrogenase is not required. Nitroprusside binds to oxyhemoglobin to release cyanide, methemoglobin, and NO. This reaction takes place in the circulation and is very rapid. Due to its cyanogenic nature, nitroprusside overdose can be dangerous.Add a diuretic for prolonged control. Otherwise the patient may retain sodium and water, resulting in “tolerance.” ................
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