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Hypertension

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  1. Hypertension Pharm.D Balsam Alhasan

  2. DEFINITION • Hypertension is defined by persistent elevation of arterial blood pressure (BP). • Patients with diastolic blood pressure (DBP) values <90 mm Hg and systolic blood pressure (SBP) values ≥140 mm Hg have isolated systolic hypertension.

  3. A hypertensive crisis (BP >180/120 mm Hg) may be categorized as either a hypertensive emergency (extreme BP elevation with acute or progressing target organ damage) or a hypertensive urgency (severe BP elevation without acute or progressing target organ injury).

  4. PATHOPHYSIOLOGY • Hypertension is a heterogeneous disorder that may result either from a specific cause (secondary hypertension) or from an underlying pathophysiologic mechanism of unknown etiology (primary or essential hypertension). • Secondary hypertension accounts for fewer than 10% of cases, and most of these are caused by chronic kidney disease or renovasculardisease. • Also note that some diseases or drugs can cause elevation of BP.

  5. Factors contributing to the development of primary hypertension • Humoralabnormalities involving the renin-angiotensin-aldosterone system, natriuretic hormone, or hyperinsulinemia; • A pathologic disturbance in the CNS, autonomic nerve fibers, adrenergic receptors, or baroreceptors; • Abnormalities in either the renal or tissue autoregulatory processes for sodium excretion, plasma volume, and arteriolar constriction;

  6. A deficiency in the local synthesis of vasodilating substances in the vascular endothelium, or an increase in production of vasoconstricting substances. • A high sodium intake and increased circulating natriuretic hormone inhibition of intracellular sodium transport, resulting in increased vascular reactivity and a rise in BP; and • Increased intracellular concentration of calcium, leading to altered vascular smooth muscle function and increased peripheral vascular resistance.

  7. Mortality: • The main causes of death in hypertensive subjects are cerebrovascular accidents, cardiovascular (CV) events, and renal failure. The probability of premature death correlates with the severity of BP elevation.

  8. Clinical Presentation • Patients with uncomplicated primary hypertension are usually asymptomatic initially. • Patients with secondary hypertension may complain of symptoms suggestive of the underlying disorder. Patients with pheochromocytomamay have a history of paroxysmal headaches, sweating, tachycardia, palpitations, and orthostatic hypotension.

  9. Clinical Presentation • In primary aldosteronism, hypokalemic symptoms of muscle cramps and weakness may be present. Patients with hypertension secondary to Cushing’s syndrome may complain of weight gain, polyuria, edema, menstrual irregularities, recurrent acne, or muscular weakness.

  10. Diagnosis: • Frequently, the only sign of primary hypertension on physical examination is elevated BP. The diagnosis of hypertension should be based on the average of two or more readings taken at each of two or more clinical encounters. • As hypertension progresses, signs of end-organ damage begin to appear, chiefly related to pathologic changes in the eye, brain, heart, kidneys, and peripheral blood vessels.

  11. Cardiopulmonary examination may reveal an abnormal heart rate or rhythm, left ventricular (LV) hypertrophy, precordial heave, third and fourth heart sounds, and rales. • Peripheral vascular examination can detect evidence of atherosclerosis, which may present as aortic or abdominal bruits, distended veins, diminished or absent peripheral pulses, or lower extremity edema.

  12. Patients with renal artery stenosis may have an abdominal systolic-diastolic bruit. • Patients with Cushing’s syndrome may have the classic physical features of moon face, buffalo hump, hirsutism, and abdominal striae. • Baseline hypokalemia may suggest mineralocorticoid-induced hypertension. The presence of protein, blood cells, and casts in the urine may indicate renovascular disease.

  13. Laboratory tests that should be obtained in all patients prior to initiating drug therapy include urinalysis, complete blood cell count, serum chemistries (sodium, potassium, creatinine, fasting glucose, fasting lipid panel), and a 12-lead electrocardiogram (ECG). These tests are used to assess other risk factors and to develop baseline data for monitoring drug-induced metabolic changes. • More specific laboratory tests are used to diagnose secondary hypertension.

  14. Desired Outcome • Reduce morbidity and mortality by the least intrusive means possible. • Goal BP values are <140/90 for most patients, but <130/80 for patients with diabetes mellitus, significant chronic kidney disease, known coronary artery disease, non-coronary atherosclerotic vascular disease. • Patients with LV dysfunction have a BP goal of <120/80 mmHg. • SBP is a better predictor of CV risk than DBP and must be used as the primary clinical marker of disease control in hypertension.

  15. TREATMENT

  16. Nonpharmacologic Therapy • All patients with prehypertension and hypertension should be prescribed lifestyle modifications, including: • Weight reduction if overweight, • Adoptionof the Dietary Approaches to Stop Hypertension eating plan, • Dietarysodium restriction ideally to 1.5 g/day (3.8 g/day sodium chloride), • Regularaerobic physical activity, • Moderate alcohol consumption (two or fewer drinks per day), • Smoking cessation.

  17. Nonpharmacologic Therapy • Lifestyle modification alone is appropriate therapy for patients with prehypertension. • Patients diagnosed with stage 1 or 2 hypertension should be placed on lifestyle modifications and drug therapy concurrently.

  18. Pharmacologic Therapy: • Initial drug selection depends on the degree of BP elevation and the presence of compelling indications for selected drugs. • Most patients with stage 1 hypertension should be treated initially with a thiazide diuretic, angiotensin-converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB), or calcium channel blocker (CCB) • Combination therapy is recommended for patients with stage 2 disease, with one of the agents being a thiazide-type diuretic unless contraindications exist.

  19. There are six compelling indications where specific antihypertensive drug classes have shown evidence of unique benefits; those indications will be discussed later on.

  20. Class Selection: • Diuretics, ACE inhibitors, ARBs, and CCBs are primary agents acceptable as first-line options based on outcome data demonstrating CV risk reduction benefits (Dosing and subtypes in Table 10-2in Handbook). • β-Blockers may be used either to treat a specific compelling indication or as combination therapy with a primary antihypertensive agent for patients without a compelling indication.

  21. Class Selection: • α1-Blockers, direct renin inhibitors, central α2-agonists, peripheral adrenergic antagonists, and direct arterial vasodilators are alternatives that may be used in select patients after primary agents. (Dosing and subtypes in Table 10-3 in Handbook).

  22. Diuretics:

  23. Classes: • Thiazides are the preferred type of diuretic for treating hypertension, and all are equally effective in lowering BP. • Potassium-sparing diuretics are weak antihypertensiveswhen used alone but provide an additive hypotensive effect when combined with thiazide or loop diuretics. Moreover, they counteract the potassium- and magnesium losing properties and perhaps glucose intolerance caused by other diuretics. • Aldosterone antagonists (spironolactone, eplerenone) are also potassium- sparing diuretics but are more potent antihypertensives with a slow onset of action (up to 6 weeks with spironolactone).

  24. MOA: • Acutely, diuretics lower BP by causing diuresis. The reduction in plasma volume and stroke volume associated with diuresis decreases cardiac output and, consequently, BP. The initial drop in cardiac output causes a compensatory increase in peripheral vascular resistance.

  25. MOA: • With chronic diuretic therapy, the extracellular fluid volume and plasma volume return almost to pretreatment levels, and peripheral vascular resistance falls below its pretreatment baseline. The reduction in peripheral vascular resistance is responsible for the long-term hypotensive effects. Thiazides lower BP by mobilizing sodium and water from arteriolar walls, which may contribute to decreased peripheral vascular resistance.

  26. When diuretics are combined with other antihypertensive agents, an additive hypotensive effect is usually observed because of independent mechanisms of action. Furthermore, many non-diuretic antihypertensive agents induce salt and water retention, which is counteracted by concurrent diuretic use. • Side effects of thiazides include: hypokalemia, hypomagnesemia, hypercalcemia, hyperuricemia, hyperglycemia, hyperlipidemia, and sexual dysfunction. Loop diuretics have less effect on serum lipids and glucose, but hypocalcemiamay occur.

  27. Hypokalemia and hypomagnesemia may cause muscle fatigue or cramps. • Serious cardiac arrhythmias may occur, especially in patients receiving digitalis therapy, patients with LV hypertrophy, and those with ischemic heart disease. Low-dose therapy (e.g., 25 mg hydrochlorothiazide or 12.5 mg chlorthalidonedaily) rarely causes significant electrolyte disturbances.

  28. Potassium-sparing diuretics may cause hyperkalemia, especially in patients with chronic kidney disease or diabetes, and in patients receiving concurrent treatment with an ACE inhibitor, ARB, NSAID, or potassium supplement. • Eplerenonehas an increased risk for hyperkalemia and is contraindicated in patients with impaired renal function or type 2 diabetes with proteinuria. • Spironolactone may cause gynecomastia in up to 10% of patients, but this effect occurs rarely with eplerenone.

  29. Angiotensin-Converting Enzyme Inhibitors (ACEI)

  30. Angiotensin-Converting Enzyme Inhibitors • ACE facilitates production of angiotensin II, which has a major role in regulating arterial BP. ACE is distributed in many tissues and is present in several different cell types, but its principal location is in endothelial cells. • Therefore, the major site for angiotensin II production is in the blood vessels, not the kidney. • ACE inhibitors block the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor and stimulator of aldosterone secretion.

  31. Angiotensin-Converting Enzyme Inhibitors • ACE inhibitors also block the degradation of bradykinin and stimulate the synthesis of other vasodilating substances including prostaglandin E2 and prostacyclin. The fact that ACE inhibitors lower BP in patients with normal plasma renin activity suggests that bradykinin and perhaps tissue production of ACE are important in hypertension.

  32. Treatment with ACEI: • Starting doses of ACE inhibitors should be low with slow dose titration. • Acute hypotension may occur at the onset of ACE inhibitor therapy, especially in patients who are sodium- or volume-depleted, in heart failure exacerbation, very elderly, or on concurrent vasodilators or diuretics. • Patients with these risk factors should start with half the normal dose followed by slow dose titration (e.g., 6-week intervals).

  33. Treatment with ACEI: • All ACE can be dosed once daily for hypertension except captopril, which is usually dosed two or three times daily. The absorption of captopril (but not enalapril or lisinopril) is reduced by 30% to 40% when given with food.

  34. Side Effects and Precautions: • ACE inhibitors decrease aldosterone and can increase serum potassium concentrations. Hyperkalemia occurs primarily in patients with chronic kidney disease or diabetes and in those also taking ARBs, NSAIDs, potassium supplements, or potassium-sparing diuretics.

  35. Side Effects and Precautions: • Acute renal failure is a rare but serious side effect of ACE inhibitors; preexisting kidney disease increases the risk. • Bilateral renal artery stenosis or unilateral stenosis of a solitary functioning kidney renders patients dependent on the vasoconstrictive effect of angiotensin II on efferent arterioles, making these patients particularly susceptible to acute renal failure.

  36. Side Effects and Precautions: • The GFR decreases in patients receiving ACE inhibitors because of inhibition of angiotensin II vasoconstriction on efferent arterioles. Serum creatinine concentrations often increase, but modest elevations (e.g., absolute increases of less than 1 mg/dL) do not warrant changes. • BUT Therapy should be stopped or the dose reduced if larger increases occur.

  37. Side Effects and Precautions: • Angioedema is a serious potential complication that occurs in less than 1% of patients. It may be manifested as lip and tongue swelling and possibly difficulty breathing. Drug withdrawal is necessary for all patients with angioedema, and some patients may also require drug treatment and/or emergent intubation. Cross-reactivity between ACE inhibitors and ARBs has been reported.

  38. Side Effects and Precautions: • A persistent dry cough occurs in up to 20% of patients and is thought to be due to inhibition of bradykinin breakdown. • ACE inhibitors are absolutely contraindicated in pregnancy because of possible major congenital malformations associated with exposure in the firsttrimester and serious neonatal problems, including renal failure and death in the infant, from exposure during the second and third trimesters.

  39. Angiotensin II Receptor Blockers (ARBs)

  40. Angiotensin II Receptor Blockers: • Angiotensin II is generated by the renin-angiotensin pathway (which involves ACE) and an alternative pathway that uses other enzymes such as chymases. ACE inhibitors block only the renin-angiotensin pathway, whereas ARBs antagonize angiotensin II generated by either pathway.

  41. The ARBs directly block the angiotensin type 1 receptor that mediates the known effects of angiotensin II (vasoconstriction, aldosterone release, sympathetic activation, antidiuretic hormone release, and constriction of the efferent arterioles of the glomerulus).

  42. Effects & Side Effects: • Unlike ACE inhibitors, ARBs do not block the breakdown of bradykinin. While this accounts for the lack of cough as a side effect, there may be negative consequences because some of the antihypertensive effect of ACE inhibitors may be due to increased levels of bradykinin. Bradykininmay also be important for regression of myocyte hypertrophy and fibrosis, and increased levels of tissue plasminogen activator.

  43. All drugs in this class have similar antihypertensive efficacy and fairly flat dose-response curves. The addition of low doses of a thiazide diuretic can increase efficacy significantly. • In patients with type 2 diabetes and nephropathy, ARB therapy has been shown to significantly reduce progression of nephropathy. For patients with LV dysfunction, ARB therapy has also been shown to reduce the risk of CV events when added to a stable regimen of a diuretic, ACE inhibitor, and β-blocker or as alternative therapy in ACEinhibitor-intolerant patients.

  44. Effects & Side Effects: • ARBs appear to have the lowest incidence of side effects compared with other antihypertensive agents. Because they do not affect bradykinin, they do not cause a dry cough like ACE inhibitors. Like ACE inhibitors, they may cause renal insufficiency, hyperkalemia, and orthostatic hypotension. Angioedema is less likely to occur than with ACE inhibitors, but cross-reactivity has been reported. ARBs should not be used in pregnancy.

  45. Calcium Channel Blockers (CCBs)

  46. Calcium Channel Blockers • CCBs cause relaxation of cardiac and smooth muscle by blocking voltage sensitive calcium channels, thereby reducing the entry of extracellular calcium into cells. Vascular smooth muscle relaxation leads to vasodilation and a corresponding reduction in BP.

  47. Dihydropyridine calcium channel antagonists may cause reflex sympathetic activation, and all agents (except amlodipine and felodipine) may demonstrate negative inotropic effects.