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Antihypertensives (1).pptx

  1. Hypertension is a common condition that affects one in every three adults in the United States and is becoming increasingly prevalent among children. The 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines define hypertension in adults as a blood pressure of ≥ 130/80 mm Hg and the Eighth Joint National Committee (JNC 8) criteria specify ≥ 140/90 mm Hg. Hypertension can be classified as either primary (essential) or secondary. Primary hypertension accounts for ∼ 90% of cases of hypertension and has no detectable cause, whereas secondary hypertension is caused by a specific underlying condition. Typical underlying conditions include renal, endocrine, and vascular diseases (e.g., renal failure, primary hyperaldosteronism, coarctation of the aorta).
  2. Clinically, hypertension is usually asymptomatic until organ damage occurs, with the brain, heart, kidneys, and/or eyes (e.g., retinopathy, myocardial infarction, stroke) most commonly affected. If present, early symptoms of hypertension may include headache, dizziness, tinnitus, and chest discomfort. Hypertension is suspected if in-office blood pressure is persistently elevated on two or more separate measurements and is confirmed with out-of-office measurement. Further diagnostic measures include assessment of cardiovascular risk, evaluation of possible target organ damage (e.g., kidney function tests), and additional tests if an underlying disease is suspected. Treatment of primary hypertension includes lifestyle changes (e.g., diet, weight loss, exercise) and pharmacotherapy. Commonly prescribed antihypertensive medications include angiotensin- converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), thiazide diuretics, and calcium channel blockers (CCBs); pharmacological management of pediatric and pregnant patients differs, as some of these drugs are contraindicated in these patient populations. To treat secondary hypertension, the underlying cause needs to be addressed.
  3. •Hypertension in adults • 2017 ACC/AHA: persistent systolic blood pressure (SBP) ≥ 130 mm Hg and/or diastolic blood pressure (DBP) ≥ 80 mm Hg • 2020 International Society of Hypertension (ISH) and 2014 JNC 8: persistent SBP ≥ 140 mm Hg and/or DBP≥ 90 mm Hg •Primary hypertension: hypertension with no identifiable cause •Secondary hypertension: hypertension caused by an identifiable underlying condition •Resistant hypertension: hypertension that remains uncontrolled (≥ 130/80 mm Hg) despite treatment with ≥ 3antihypertensives OR requires ≥ 4 medications to be controlled
  4. The renin-angiotensin-aldosterone system (RAAS) •Drops in blood pressure reduce renal perfusion. •If the pressure in the renal artery falls by more than 10–15 mmHg, proteolytic renin is released from the juxtaglomerular apparatus → renin converts angiotensinogen to angiotensin I → ACE cleaves C-terminalpeptides on angiotensin I, converting it to angiotensin II → increases the blood pressure in two ways: vasoconstriction and stimulation of the release of aldosterone,
  5. Angiotensin-converting enzyme inhibitors (ACE inhibitors) •Drug names: enalapril, lisinopril, ramipril, captopril, benazepril •Indications • Arterial hypertension • Diabetes mellitus (type I and type II) with • Nephroprotective indications, such as: • Arterial hypertension • Microalbuminuria and proteinuria (especially ≥ 300 mg/g) • Coronary heart disease • Heart failure with reduced ejection fraction • Survival benefit (the exact mechanisms are poorly understood) • Any murmur that decreases with amyl nitrite has an etiology that is treatable with ACE inhibitors. • History of myocardial infarction • Nondiabetic chronic kidney disease with proteinuria • Scleroderma-associated hypertensive crisis (even if creatinine is elevated)
  6. ACE inhibitors •Mechanism of action: inhibition of ACE → ↓ conversion of angiotensin I to angiotensin II •Main effects • ↓ Angiotensin II • ↓ Vasoconstriction → ↓ blood pressure • ↓ Secretion of aldosterone → ↓ reabsorption of Na+ and water → ↓ blood pressure • Dilation of efferent arteriole → ↑ renal plasma flow → ↓ GFR → ↓ filtration fraction • ↑ Renin secretion (due to lack of feedback inhibition) → ↑ angiotensin I • ↓ Breakdown of bradykinin → ↑ production of arachidonic acid metabolites → ↑ vasodilation →↓ blood pressure •Other effects • ↓ Proteinuria and ↓ progression of proteinuric chronic kidney disease: ↓ intraglomerular hydrostatic pressure attenuates thickening and sclerosis of the GBM • ↓ Preload and afterload → ↓ cardiac remodeling after acute myocardial infarction or in chronic hypertensive disease
  7. ACE inhibitors •Increase in bradykinin concentration, which can lead to: • Dry cough (can be treated by discontinuing ACE inhibitor, consider switching to ARB) • Bradykinin-mediated angioedema due to increased vascular permeability and vasodilation •Hyperkalemia •↓ GFR (with ↑ creatinine): can cause acute kidney injury in patients with preexisting renal hypoperfusion (e.g., renal artery stenosis, hypovolemia, heart failure) •Hypotension •Proteinuria •Pemphigus vulgaris (unknown mechanism) •Teratogenicity: renal malformations •Leukopenia •Rash •Taste changes
  8. Angiotensin-receptor blocker (ARBs, sartans) •Drug names: valsartan, candesartan, losartan, irbesartan •Indications: same as ACE inhibitors, mostly used as second- line treatment if ACE inhibitors are not tolerated • Angioedema: can be tried under close surveillance if no adequate alternative is available • Non-life-threatening side effects (e.g., dry cough ): commonly used
  9. ARBs •Mechanism of action: inhibition of angiotensin II receptor type 1 (AT1 receptor) •Main effects • ↓ Vasoconstriction → ↓ blood pressure • ↓ Secretion of aldosterone → ↓ reabsorption of Na+ and water → ↓ blood pressure • ↑ Renin secretion (compensatory) → ↑ angiotensin I → ↑ angiotensin II •Other effects • ↓ Proteinuria and ↓ progression of proteinuric kidney disease • ↓ Cardiac remodeling after acute myocardial infarction or chronic hypertensive disease • No bradykinin elevation (opposed to ACE inhibitors)
  10. ARBs •Angioedema •Hyperkalemia •↓ GFR (with ↑ creatinine) •Hypotension •Teratogenicity •Leukopenia •Rash
  11. Contraindications for ACE inhibitors and ARBs •Absolute contraindications • Hypersensitivity • C1 esterase inhibitor deficiency (due to predisposition to angioedema) • Pregnancy: risk of harm to the fetus (e.g., renal impairment, renal malformations, oligohydramnios, placental insufficiency) [1] • Breastfeeding •Relative contraindications • Aortic stenosis • Renal dysfunction, consider altering dose if GFR < 60 mL/min [11][12] • Bilateral renal artery stenosis or a solitary kidney: GFR is already decreased and further reduction may lead to acute kidney injury. • Drug interactions: See “Interactions” below.
  12. ACE inhibitors and ARBs •Other antihypertensive drugs → ↑ hypotensive effect •NSAIDs → ↓ antihypertensive effect •Potassium-sparing diuretics or other drugs that increase potassium level: ↑ hyperkalemia •↑ Level of lithium due to ↓ renal elimination •Allopurinol: ↑ risk of immunological reactions or leukopenia [14][15] Interactions
  13. Thiazide diuretics Agents •Hydrochlorothiazide (HCTZ) •Chlorthalidone •Chlorothiazide •Metolazone Mechanism of action •Inhibition of Na+-Cl- cotransporters in the early distal convoluted tubule → ↑
  14. Indications •Hypertension •Chronic edema secondary to congestive heart failure, cirrhosis, and kidney disease •Prevention of calcium kidney stones, idiopathic hypercalciuria •Osteoporosis •Nephrogenic diabetes insipidus •Sequential nephron blockade
  15. Contraindications •Hypersensitivity (including hypersensitivity to any sulfonamide medications) •Gout •Anuria •Severe hypokalemia
  16. Interactions •Glucocorticoids: increased hypokalemia •Carbamazepine: increased hyponatremia •Lithium: increased hyponatremia •ACE inhibitors: hypotension (especially first-dose hypotension) •Propranolol: increased hyperlipidemia and hyperglycemia •NSAIDs: decreased diuretic effect •Increased effects of digitalis , methotrexate, and lithium
  17. Agents •Sulfonamides: furosemide, torsemide, bumetanide •Other: ethacrynic acid Mechanism of action •Blockage of Na+-K+-2Cl- cotransporter in the thick ascending loop of Henle • Diminishing concentration gradient between the (usually hypertonic) renal medulla and the cortex →concentration of urine is no longer possible → increased diuresis • Decreased reabsorption of Ca2+ and Mg2+ •Increased PGE release (can be inhibited by NSAIDs) • Dilation of renal afferent arterioles → diuresis • General venodilation (rapid venous pooling) → ↓ cardiac preload of alkalosis. Loop Diuretics
  18. Indications •Hypertension •Edema • Cardiac (acute and congestive heart failure, peripheral edema, lung edema) • Renal (nephrotic syndrome) • Hepatic (liver cirrhosis) •Renal failure (acute and chronic) •Hypercalcemia •Forced diuresis • Definition: massive diuresis for forced renal elimination of (toxic) substances • Implementation: IV administration of large amounts of fluids in combination with loop diuretics • Indications: hypercalcemic crisis, severe hyperkalemia, rhabdomyolysis, intoxication (e.g., lithium) •Sequential nephron blockade • Used to overcome resistance to diuretic treatment • Method: combination of loop diuretics and thiazides → restoration of diuretic effects
  19. Side effects •Metabolic imbalances • Hypokalemia, hypomagnesemia, hypocalcemia, hypochloremia, , hyponatremia (moderate) • Metabolic alkalosis • Hyperuricemia/gout • Hyperglycemia •Ototoxicity (potentially permanent hearing damage): especially high risk with ethacrynic acid •Dehydration/hypovolemia •Sulfonamide hypersensitivity (except ethacrynic acid, which can be used for diuresis in patients with allergies to sulfonamides) → rash, interstitial nephritis
  20. Potassium-sparing diuretics Agents •Aldosterone receptor antagonists: spironolactone, eplerenone •Epithelial sodium channel blockers: triamterene, amiloride
  21. Mechanism of action Although the molecular pathways differ, both types of potassium-sparing diuretics have very similar clinical effects. •Aldosterone receptor antagonists (spironolactone, eplerenone) • Competitively bind to aldosterone receptors in the late distal convoluted tubule and the collecting duct → inhibition of the effects of aldosterone → decreased Na+ reabsorption and K+ excretion → diuresis • Decreased H+ excretion → acidosis • Evolving hyperkalemia induces H+/K+-ATPases in all cells to counteract the increase in serum K+ → K+ enters cells in exchange for H+ → amplifies acidosis • Spironolactone also acts (nonspecifically) on sex hormone receptors → endocrine side effects • Epithelial sodium channel blockers (triamterene, amiloride): direct inhibition of the epithelial sodium channels(ENaC) in the distal convoluted tubule and the collecting duct → reduced Na+ reabsorption and reduced K+ secretion → diuresis
  22. Mechanism of action: potassium- sparing diuretics Aldosterone and the cytosolic mineralocorticoid receptor form an intracellular complex, acting as a transcription factor for several transport proteins that move potassium, sodium, and water. Potassium-sparing diuretics (e.g., spironolactone, eplerenone) are aldosterone antagonists that inhibit the expression of these transport proteins, as well as basolateral Na+/K+-ATPases, through competitive binding of the aldosterone receptor. This leads to increased retention of potassium and increased excretion of sodium and water.
  23. Indications •Hypertension (especially if hypokalemia is also present) •Ascites/edema due to congestive heart failure, nephrotic syndrome, or cirrhosis of the liver (mainly spironolactone) •Hyperaldosteronism (Conn syndrome) •Nephrogenic diabetes insipidus (amiloride) [20] •Hypokalemia •Hyperandrogenic states, e.g., polycystic ovary syndrome (spironolactone)
  24. Contraindications General •Anuria and/or renal insufficiency •Preexisting hyperkalemia •Addison disease •Combination with other potassium-sparing diuretics or potassium supplements Specific •Spironolactone: Use with caution in patients with CHF with either of the following: • GFR < 30 mL/min • Creatinine ≥ 2.5 mg/dL (men) or ≥ 2 mg/dL (women) •Eplerenone • Concomitant use of strong CYP3A4 inhibitors • Patients with hypertension with concomitant type II diabetes mellitus and microalbuminuria or with renal insufficiency (serum creatinine > 2.0 mg/dL for men or > or > 1.8 mg/dL for women; or creatinine clearance< 50 mL/min) • Creatinine clearance < 30 mL/min •Amiloride: diabetic nephropathy
  25. Calcium channel blockers (CCBs) are drugs that bind to and block L-type calcium channels, which are the predominant calcium channels in the myocardium and vascular smooth muscles. By blocking these channels, CCBs cause peripheral arterial vasodilation (leading to a drop in blood pressure) and myocardial depression (leading to negative chronotropic, inotropic, and dromotropic effects on the myocardium). CCBs are classified into two major groups according to the main site of action: Dihydropyridines (e.g., nifedipine, amlodipine) are potent vasodilators, and nondihydropyridines (e.g., verapamil) are potent myocardial depressants. Diltiazem, a common nondihydropyridine, has moderate vasodilatory and myocardial depressant effects. Nondihydropyridines are also categorized as class IV antiarrhythmic drugs and are used in the treatment of supraventricular arrhythmias. The most common indications for CCB use are arterial hypertension and stable angina. The main side effects of dihydropyridines are caused by vasodilation (e.g., headache, peripheral edema); those of nondihydropyridines are caused by myocardial depression (e.g., bradyarrhythmias, atrioventricular block). CCBs are contraindicated in patients with preexisting cardiac conduction disorders, symptomatic hypotension, and/or acute coronary syndrome.
  26. •CCBs bind to and block L-type calcium channels in cardiac and vascular smooth muscle cells → decreased frequency of Ca2+ channel opening in response to cell membrane depolarization → decreased transmembrane Ca2+ current •Effects of decreased Ca2+ influx • Vascular smooth muscle relaxation → vasodilation → decreased peripheral vascular resistance → decreased afterload → decreased blood pressure • Decreased cardiac muscle contractility (negative inotropic action) → decreased cardiac output → decreased blood pressure • Decreased SA node discharge rate (negative chronotropic action) → decreased heart rate (bradycardia) →decreased cardiac output → decreased blood pressure • Decreased AV node conduction (negative dromotropic action) → termination of supraventricular arrhythmias
  27. Dihydropyridine CCBs (nifedipine and amlodipine) primarily act on vascular smooth muscles. Nondihydropyridine CCBs (verapamil > diltiazem) primarily act on the heart. •Dihydropyridines act mainly on vascular smooth muscle. The order of potency is nifedipine/amlodipine followed by the nondihydropyridines verapamil and diltiaze m. •Nondihydropyridines act mainly on the heart. The order of potency is verapamil > diltiazem >amlodipine /nifedipine
  28. Indications All CCBs •Arterial hypertension (esp. amlodipine ) •Stable angina: for patients with contraindications for beta blockers or who are not responsive to beta blockers •Vasospastic angina (Prinzmetal angina) •Achalasia •Diffuse esophageal spasm
  29. Dihydropyridines •Raynaud phenomenon (e.g., nifedipine, felodipine) •Subarachnoid hemorrhage (e.g., nimodipine, nicardipine) to prevent secondary vasospasm •Tocolysis •Gestational hypertension •Hypertensive urgency/hypertensive emergency (e.g., nicardipine, clevidipine) •Thromboangiitis obliterans
  30. Nondihydropyridines •Supraventricular arrhythmias (verapamil and diltiazem ) • Supraventricular tachycardia • Atrial fibrillation, atrial flutter •Cardiomyopathy (hypertrophic obstructive cardiomyopathy, restrictive cardiomyopathy) •Migraine •Verapamil: cluster headache Short-acting CCBs (e.g., nifedipine) are not indicated for monotherapy of angina because they cause hypotension and secondary reflex tachycardia, which can worsen cardiac ischemia.
  31. Dihydropyridines •Effects due to vasodilation • Peripheral edema (esp. amlodipine) • Headaches, dizziness • Facial flushing, feeling of warmth • Reflex tachycardia: a condition of tachycardia secondary to a decrease in blood pressure (esp. nifedipine) • Vasodilation lowers the blood pressure, which stimulates baroreceptors of the sympathetic nervous system, resulting in reflex tachycardia. • May worsen symptoms of angina •Gingival hyperplasia
  32. Nondihydropyridines •Benzothiazepines: similar to those of the other CCB classes, but milder •Phenylalkylamines • Reduced contractility • Bradycardia • AV block • Gingival hyperplasia • Verapamil • Constipation • Hyperprolactinemia
  33. All CCBs •Allergy/hypersensitivity to CCBs •Symptomatic hypotension •Acute coronary syndrome Dihydropyridines •Hypertrophic obstructive cardiomyopathy (HOCM) •Severe stenotic heart valve defects Nondihydropyridines •Preexisting cardiac conduction disorders • Wolff-Parkinson-White syndrome • Sick sinus syndrome • Systolic dysfunction (in congestive heart failure) • Bradycardia • 2° AV block/3° AV block •Combination with beta blockers: risk of AV block, bradycardia, and/or decreased cardiac contractility
  34. Overdose/intoxication Clinical features Patients are usually symptomatic but those who present early or have only consumed a small quantity of CCBs may be asymptomatic. •Cardiovascular • Hypotension: may be profound, including cardiogenic shock • Cardiac arrhythmias • Cardiac arrest •Respiratory: respiratory depression (including apnea), pulmonary edema •Gastrointestinal: nausea and vomiting •Central nervous system: confusion, lethargy, and coma
  35. Diagnostics •Diagnosis is based on clinical observation and a thorough history • Determine the time of intake, type, amount, and preparation (extended-release vs. immediate-release) of the drug. • Assess for risk of self harm. •Any ingestion exceeding the maximum therapeutic dosage is usually clinically relevant. Laboratory tests •BMP: typically shows mild hyperglycemia and hyperkalemia •VBG/ABG: metabolic acidosis ECG May show any of the following associated arrhythmias: •AV block •AV dissociation •Junctional rhythm •Sinus bradycardia •Tachycardia
  36. Beta blockers are a group of drugs that inhibit the sympathetic activation of β- adrenergic receptors. Cardioselective blockers (e.g., atenolol, bisoprolol) primarily block β1 receptors in the heart, causing decreased heart rate, cardiac contractility, cardiac workload, and AVN conduction. Nonselective beta blockers (e.g., pindolol, propranolol) inhibit all β receptors and may cause bronchoconstriction, peripheral vasoconstriction, and metabolic imbalances (e.g., hypoglycemia and hyperglycemia, hypertriglyceridemia) in addition to cardiac effects. Cardioselective beta blockers have a lower side-effect profile and are preferred in the management of coronary heart disease, compensated heart failure, acute coronary syndrome, and certain types of arrhythmias. Propranolol, a nonselective beta blocker, is the first-line drug in the management of essential tremor, portal hypertension, migraine prophylaxis, and thyroid storm. Beta blockers are contraindicated in patients with symptomatic bradycardia, AV block, decompensated heart failure, and asthma. Initiation and cessation of beta-blocker therapy should always be gradual to avoid side effects or symptoms of withdrawal (e.g., rebound tachycardia, hypertension, acute cardiac death).
  37. Cardiovascular indications •Hypertension : beta blockers lower BP by ↓ cardiac output and ↓ renin secretion •Coronary artery disease • Acute myocardial infarction • Beta blockers should be initiated early in all patients (without contraindications) and continued long-term if tolerated. [33] • Beta blockers decrease the size of the infarct and also reduce early and delayed mortality rates in patients with acute MI. • Angina pectoris: first-line treatment for stable angina pectoris in addition to ACE
  38. Specific indications for propranolol •Essential tremor •Migraine prophylaxis •Portal hypertension •Hyperthyroidism and thyroid storm •Infantile hemangioma •Akathisia Miscellaneous •Hypertensive crises (e.g., malignant hypertension): IV labetalol (rapid onset of action) •Glaucoma: topical beta blockers (timolol, betaxolol) •Pregnancy-induced hypertension: Labetalol is the first-line drug.
  39. Beta-blocker overdose •Clinical features • Bradycardia/bradyarrhythmia • Cardiogenic shock (hypotension; cold, clammy extremities) • Hypoglycemia • Hyperkalemia • Wheezing (bronchoconstriction) • Neurological symptoms (seizure, delirium, coma) •Treatment • Secure the airways. • Correct cardiovascular decompensation (hypotension, bradycardia, and cardiogenic shock) via IV access:
  40. Sympatholytic agents inhibit the activity of the sympathetic nervous system, which is mediated by epinephrine and norepinephrine. They act primarily by blocking the postsynaptic adrenergic receptors (alpha and beta receptor antagonism) in target organs or by inhibiting the synthesis and storage of endogenous catecholamines (mainly norepinephrine). A sympatholytic effect can also be achieved via stimulation of the presynaptic alpha-2 receptor with an alpha-2 agonist, which inhibits the release of catecholamines. Sympatholytic drugs are most commonly used in the treatment of ischemic heart disease and hypertension but may also be used for urinary retention secondary to benign prostatic hyperplasia and for psychiatric conditions such as anxiety disorders and posttraumatic stress disorder.
  41. The thresholds for pharmacological treatment are controversial and vary depending on age; the following recommendations are based on the 2017 ACC/AHA guidelines. •Adults with SBP ≥ 130 mm Hg or DBP ≥ 80 mm Hg and ≥ 1 of the following: • Clinical ASCVD (e.g., ischemic heart disease, peripheral artery disease, or previous stroke) or congestive heart failure (CHF) • 10-year ASCVD risk ≥ 10% (includes age ≥ 65 years and diabetes mellitus) •All adults with SBP ≥ 140 mm Hg or DBP ≥ 90 mm Hg
  42. Choice of initial medication should be based on the following: •Patient's initial blood pressure [3][33] • SBP 130–139 mm Hg or DBP 80–89 mm Hg (stage 1 hypertension): Consider initial monotherapy. • SBP ≥ 140 mm Hg or DBP ≥ 90 mm Hg AND an average blood pressure > 20/10 mm Hg above target • Initiate combination therapy. • Commonly used combinations are an ACEI or ARBPLUS either a dihydropyridine CCB OR a thiazide-type diuretic. •Additional factors to consider • Major comorbidities • Major contraindications • Adverse effects that may be unacceptable to patients • Patient race: For Black patients (including individuals with diabetes) without CHF or CKD, initial antihypertensive therapy should include a thiazide- typediuretic or CCB.
  43. Long-term management and follow-up General principles Goals include evaluating medication adherence, monitoring treatment and relevant laboratory studies, and adjusting medication. •Patients on nonpharmacological treatment alone: Follow up after 3–6 months. • If blood pressure is uncontrolled: Initiate pharmacological treatment. •Most patients initiated on pharmacological treatment: Follow up after ∼ 1 month. • If blood pressure is uncontrolled: Continue to escalate therapy at one-month intervals. • Once blood pressure is controlled: Reassess after 3–6 months and annually thereafter if blood pressure remains stable. Laboratory studies [1][2][5] •Serum electrolytes • For most patients, check at the one-month follow-up visit. •Serum creatinine • Check within 2–4 weeks in patients with CKD who were started on an ACEI or ARB.