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M HASANZADEH . MD, MUMS OCT 2009 2 Abbreviations ACE: angiotensin-converting enzyme ARB: angiotensin II receptor blocker AHA: American Heart Association BP: blood pressure CCB: calcium channel blocker CV: cardiovascular DBP: diastolic blood pressure GFR: glomerular filtration rate HF: heart failure ISA: intrinsic sympathomimetic activity JNC 7: Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure MI: myocardial infarction RAAS: renin-angiotensin aldosterone system SBP: systolic blood pressure 3 Overview Definition, classification of hypertension (HTN) Goals of therapy Compelling indications Lifestyle modifications Treatment Hypertensive crisis Monitoring antihypertensive drug therapy 4 Hypertension Persistent elevation of arterial blood pressure (BP) National Guideline 7th Report of the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) ~72 million Americans (31%) have BP > 140/90 mmHg Most patients asymptomatic Cardiovascular morbidity & mortality risk directly correlated with BP; antihypertensive drug therapy reduces cardiovascular & mortality risk Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–1252. 5 Guidelines in measuring BP Condition: -Posture (sitting,supine,standing) -Circumstances (no caffeine.no smoking) Equipment: -Cuff size -Manometer Technique: -number of readings -Performance -recordings Target-Organ Damage Brain: stroke, transient ischemic attack, dementia Eyes: retinopathy Heart: left ventricular hypertrophy, angina Kidney: chronic kidney disease Peripheral Vasculature: peripheral arterial disease 7 8 Etiology Essential hypertension: > 90% of cases hereditary component Secondary hypertension: < 10% of cases common causes: chronic kidney disease, renovascular disease other causes: Rx drugs, street drugs, natural products, food, industrial chemicals 9 Causes of 2˚ Hypertension Diseases chronic kidney disease Cushing's syndrome coarctation of the aorta obstructive sleep apnea parathyroid disease pheochromocytoma primary aldosteronism renovascular disease thyroid disease 10 Causes of 2˚ Hypertension Prescription drugs: prednisone, fludrocortisone, triamcinolone amphetamines/anorexiants: phendimetrazine, phentermine, sibutramine antivascular endothelin growth factor agents estrogens: usually oral contraceptives calcineurin inhibitors: cyclosporine, tacrolimus decongestants: phenylpropanolamine & analogs erythropoiesis stimulating agents: erythropoietin, darbepoietin 11 Causes of 2˚ Hypertension Prescription drugs: NSAIDs, COX-2 inhibitors venlafaxine bupropion bromocriptine buspirone carbamazepine clozapine ketamine metoclopramide 12 Causes of 2˚ Hypertension Situations: β-blocker or centrally acting α-agonists when abruptly discontinued β-blocker without α-blocker first when treating pheochromocytoma Food substances: sodium ethanol licorice 13 Causes of 2˚ Hypertension Street drugs, other natural products: cocaine anabolic steroids cocaine withdrawal narcotic withdrawal ephedra alkaloids methylphenidate (e.g., ma-huang) phencyclidine “herbal ecstasy” ketamine phenylpropanolamine ergot-containing herbal analogs products nicotine withdrawal St. John's wort 14 Arterial Pressure Determinants 15 Mechanisms of Pathogenesis Increased cardiac output (CO): increased preload: increased fluid volume excess sodium intake renal sodium retention venous constriction: excess RAAS stimulation sympathetic nervous system overactivity 16 Mechanisms of Pathogenesis Increased peripheral resistance (PR): functional vascular constriction: excess RAAS stimulation sympathetic nervous system overactivity genetic alterations of cell membranes endothelial-derived factors structural vascular hypertrophy: excess RAAS stimulation sympathetic nervous system overactivity genetic alterations of cell membranes endothelial-derived factors hyperinsulinemia due to obesity, metabolic syndrome 17 Arterial Blood Pressure Sphygmomanometry: indirect BP measurement MAP = 1/3 (SBP) + 2/3 (DBP) BP = CO x TPR MAP: Mean Arterial Pressure SBP: Systolic Blood Pressure DBP: Diastolic Blood Pressure BP: Blood Pressure CO: Cardiac Output TPR: Total Peripheral Resistance 18 Adult Classification Classification Normal Systolic Blood Pressure (mmHg) Diastolic Blood Pressure (mmHg) Less than 120 and Less than 80 Prehypertension 120-139 or 80-89 Stage 1 hypertension 140-159 or 90-99 Stage 2 hypertension > 160 or > 100 Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–1252. 19 SYSTEMIC HYPERTENSION CLASSIFICATION OPTIMAL <120 <80 NORMAL <130 <85 HIGH NORMAL 130-139 85-89 HYPERTENSION Clinical Controversy White coat hypertension: elevated BP in clinic followed by normal BP reading at home Aggressive treatment of white coat hypertension is controversial Patients with white coat hypertension may have increased CV risk compared to those without such BP changes 22 Classification for Adults Classification based on average of > 2 properly measured seated BP measurements from > 2 clinical encounters If systolic & diastolic blood pressure values give different classifications, classify by highest category > 130/80 mmHg: above goal for patients with diabetes mellitus or chronic kidney disease Prehypertension: patients likely to develop hypertension 23 Classification of blood pressure for adult JNC7 Normal JNC6 SBP and/or optimal <120 and Prehypertension ___ 120_139 ____ normal <130 ____ high-normal 130_139 Hypertension: hypertension: Stage 1 stage 1 140-159 stage 2 >/=160 _____ stage 2 160-179 _____ stage 3 >/=180 DBP <80 or and or 80_89 <85 85_89 or or or or 90-99 >/=100 100-109 >/=110 Clinical Controversy Ambulatory BP measurements may be more accurate & better predict target-organ damage than manual BP measurements using a sphygmomanometer in a clinic setting (gold standard) many patients may be misdiagnosed, misclassified poor technique, daily BP variability, white coat HTN Validated ambulatory BP monitoring: role in the routine HTN management unclear 25 26 Investigation of the New Hypertensive History and examination Exclude secondary Hypertension Urea and electrolytes FBS and ESR ECG Lipid profile Chest x-ray no longer routinely indicated LABORATORY TESTS FOR HTN BASIC TESTS FOR INITIAL EVALUATION: ALWAYS INCLUDED USUALL INCLUDED SPECIAL STUDIES LABORATORY TESTS FOR HTN ALWAYS INCLUDED TESTS: URINE FOR PROTEIN,BLOOD,GLUCOSE. MICROSCOPIC URINALYSIS. HEMATOCRIT. SERUM POTASSIUM. SERUM CREATININE OR BUN. FASTING GLUCOSE. TOTAL CHOLESTROL. EKG LABORATORY TESTS FOR HTN USUALLY INCLUDED TESTS: TSH WBC HDL,LDL,TG SERUM CALC& PHOS CHEST X RAY &ECHO LABORATORY TESTS FOR HTN SPECIAL STUDIES TO SCREEN FOR SECONDARY HTN: 1 . RENOVASCULAR DISEASE: ACE INHIBITOR RADIONUCLEIDE RENAL SCAN,RENAL DUPLEX DOPPLER FLOW STUDIES ,MRI ANGIOGRAPHY. 2 . PHEOCHROMOCYTOMA: 24-h URINE ASSAY FOR: CREATININE,METANEPHRINES,&CATHECH LABORATORY TESTS FOR HTN SPECIAL STUDIES TO SCREEN FOR SECONDARY HTN: 3 .CUSHING SYNDROME: OVERNIGHT DEXAMETHASONE SUPRESSION TEST. 24-h URINE CORTISOL & CREATININE. 4 .PRIMARY ALDOSTRONISM: PLASMA ALDOSTRONE:RENIN ACTIVITY RISK FACTORS FOR ADVERS PROGNOSIS IN HTN BLACK RACE EVIDENCE OF END YOUTH MALE GENDER SMOKING DM OBESITY ALCOHOL INTAKE HYPERCHOLESTROLEMIA ORGAN DAMAGE(LVH,LVSTRAIN, MI,CHF) RETINAL HEMORR&EXODATE PAPILLEDEMA RENAL:IMP REN FUN CVA HYPERTENSION EMERGENCY URGENCY ACCELERATED MALIGNANT Treatment Goals Reduce morbidity & mortality Select drug therapy based on evidence demonstrating risk reduction Patient Population Most patients Diabetes mellitus Chronic kidney disease Target Blood Pressure < 140/90 mmHg < 130/80 mmHg <130/80 mmHg Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–1252. 35 2007 AHA Recommendations More aggressive BP lowering for high risk patients Most patients for general prevention <140/90 mmHg Patients with diabetes (CAD risk equivalent), <130/80 mmHg significant CKD, known CAD (MI, stable angina, unstable angina), noncoronary atherosclerotic vascular disease (ischemic stroke, TIA, PAD, abdominal aortic aneurism [CAD risk equivalents]), Framingham risk score > 10% Patients with left ventricular dysfunction (HF) <120/80 mmHg Rosendorff C, Black HR, Cannon CP, et al. Treatment of hypertension in the prevention and management of ischemic heart disease: A scientific statement from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation 2007;115(21):2761–2788. 36 ALLHAT Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Primary endpoints fatal CHD nonfatal MI Secondary endpoints other hypertension-related complications HF stroke ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288(23):2981–2997. 37 ALLHAT Prospective, double-blind trial randomized patients to: chlorthalidone amlodipine doxazosin lisinopril-based therapy 42,418 patients: age > 55 yr with HTN + 1 additional CV risk factor (mean subject participation 4.9 years) Thiazide-type diuretics remain unsurpassed for reducing CV morbidity & mortality in most patients ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288(23):2981–2997. 38 JNC7 Recommendations Thiazide-like diuretics preferred 1st line therapy based on clinical trials showing morbidity & mortality reductions ALLHAT confirms 1st line role of thiazide diuretics Compelling indications: comorbid conditions where specific drug therapies provide unique long-term benefits based on clinical trials drug therapy recommendations are in combination with or in place of a thiazide diuretic Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and 39 Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–1252. Clinical Controversy Avoiding Cardiovascular Events through COMbination Therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) Endpoint: composite of death from CV causes, hospitalization for angina, nonfatal MI or stroke, coronary revascularization, & resuscitation after cardiac arrest Prospective, double-blind, industry sponsored trial randomized patients to benazepril + amodipdine or benazepril + HCTZ 11,506 patients with HTN & high CV risk Combination benazepril + amlodipine superior to benazepril + HCTZ for reducing CV events in high risk patients Jamerson KA, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension. N Engl J Med. 2009;359(23):2417-2428. 40 41 Compelling Indications Heart Failure Post Myocardial Infarction High Coronary Disease Risk Diabetes Mellitus Chronic Kidney Disease Recurrent Stroke Prevention 42 Recommendations & Evidence Strength of recommendations A: good, B: moderate, C: poor Quality of evidence 1: more than 1 properly randomized, controlled trial 2: at least 1 well-designed clinical trial with randomization; cohort or case-controlled analytic studies; dramatic results from uncontrolled experiments or subgroup analyses 3: opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert communities 43 ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker; CCB: calcium channel blocker; DBP: diastolic blood pressure; SBP: systolic blood pressure 44 4545 Lifestyle Modifications Modification Weight loss DASH-type dietary patterns Reduced salt intake Physical activity Moderation of alcohol intake Approximate Systolic Blood Recommendation Pressure Reduction (mm Hg)a Maintain normal body weight (body mass 5–20 per 10-kg weight loss 2 index 18.5–24.9 kg/m ) Consume a diet rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat Reduce daily dietary sodium intake as much as possible, ideally to 65 mmol/day (1.5 g/day sodium, or 3.8 g/day sodium chloride) Regular aerobic physical activity (at least 30 min/day, most days of the week) Limit consumption to 2 drinks/day in men and 1 drink/day in women and lighterweight persons 8–14 2–8 4–9 2–4 DASH, Dietary Approaches to Stop Hypertension. a Effects of implementing these modifications are time and dose dependent and could be greater for some patients. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/ 46 Clinical Controversy Prehypertension: patients do not have HTN but at risk for developing it Trial of Preventing Hypertension (TROPHY) showed treating prehypertension with candesartan decreased progression to stage 1 hypertension Unknown whether managing prehypertension with drug therapy and lifestyle modifications decreases CV events or if this approach is cost-effective Julius S, Nesbitt SD, Egan BM, et al. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med 2006;354(16):1685–1697. 47 Hypertension in Pregnancy Important to differentiate preeclampsia from chronic, transient, & gestational hypertension Preeclampsia: >140/90 mmHg after 20 weeks’ gestation with proteinuria restricted activity, bed rest, close monitoring beneficial definitive treatment: delivery Methyldopa: drug of choice 48 Chronic HTN in Pregnancy Drug/Class Comments Methyldopa Preferred based on long-term follow-up data supporting safety β-Blockers Generally safe, but intrauterine growth retardation reported Labetolol Increasingly preferred over methyldopa because of fewer side effects Clonidine Limited data Calcium channel blockers Limited data; no increase in major teratogenicity with exposure Diuretics Not first-line, probably safe in low doses ACE inhibitors, ARBs Pregnancy category C in 1st trimester, category D in 2nd & 3rd trimester. Major teratogenicity has been reported with exposure (fetal toxicity, death) DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/ 49 Diuretics Exact hypotensive mechanism unknown Initial BP drop caused by diuresis reduced plasma & stroke volume decreases CO and BP causes compensatory increase in peripheral vascular resistance Extracellular & plasma volume return to near pretreatment levels with chronic use peripheral vascular resistance becomes lower than pretreatment values results in chronic antihypertensive effects 50 Diuretics Thiazide chlorthalidone, hydrochlorothiazide (HCTZ), indapamide, metolazone Loop bumetanide, furosemide, torsemide Potassium-sparing amiloride, triamterene Aldosterone antagonists eplerenone, spironolactone 51 Thiazide Diuretics Dose in morning to avoid nocturnal diuresis Adverse effects: hypokalemia, hypomagnesemia, hypercalcemia, hyperuricemia, hyperuricemia, hyperglycemia, hyperlipidemia, sexual dysfunction lithium toxicity with concurrent administration More effective antihypertensives than loop diuretics unless CrCl < 30 mL/min Chlorthalidone 1.5 to 2 times as potent as HCTZ 5252 Loop Diuretics Dose in AM or afternoon to avoid nocturnal diuresis Higher doses may be needed for patients with severely decreased glomerular filtration rate or heart failure Adverse effects: hypokalemia, hypomagnesemia, hypocalcemia, hyperuricemia, hyperuricemia 53 Potassium-sparing Diuretics Dose in AM or afternoon to avoid nocturnal diuresis Generally reserved for diuretic-induced hypokalemia patients Weak diuretics, generally used in combination with thiazide diuretics to minimize hypokalemia Adverse effects: may cause hyperkalemia especially in combination with an ACE inhibitor, angiotensin-receptor blocker or potassium supplements avoid in patients with CKD or diabetes 54 Aldosterone antagonists Dose in AM or afternoon to avoid nocturnal diuresis Due to increased risk of hyperkalemia, eplerenone contraindicated in CrCl < 50 mL/min & patients with type 2 diabetes & proteinuria Adverse effects: may cause hyperkalemia especially in combination with ACE inhibitor, angiotensin-receptor blocker or potassium supplements avoid in CKD or DM patients Gynecomastia: up to 10% of patients taking spironolactone 55 ACE Inhibitors 2nd line to diuretics for most patients Block angiotensin I to angiotensin II conversion ACE (Angiotensin Converting Enzyme) distributed in many tissues primarily endothelial cells blood vessels: major site for angiotensin II production Block bradykinin degradation; stimulate synthesis of other vasodilating substances such as prostaglandin E2 & prostacyclin Prevent or regress left ventricular hypertrophy by reducing angiotensin II myocardial stimulation 56 5757 ACE Inhibitors Monitor serum K+ & SCr within 4 weeks of initiation or dose increase Adverse effects: cough up to 20% of patients due to increased bradykinin angioedema hyperkalemia: particularly in patients with CKD or DM neutropenia, agranulocytosis, proteinuria, glomerulonephritis, acute renal failure 58 ARBs Angiotensin II Receptor Blockers Angiotensin II generation renin-angiotensin-aldosterone pathway alternative pathway using other enzymes such as chymases Inhibit angiotensin II from all pathways directly block angiotensin II type 1 (AT1) receptor ACE inhibitors partially block effects of angiotensin II 59 ARBs Do not block bradykinin breakdown less cough than ACE Inhibitors Adverse effects: orthostatic hypotension renal insufficiency hyperkalemia 60 6161 ACE Inhibitor/ARB Warnings Reduce starting dose 50% in some patients due to hypotension risk patients also taking diuretic volume depletion elderly patients May cause hyperkalemia in: CKD patients patients on other K+ sparing medications K+ sparing diuretics aldosterone antagonists 62 ACE Inhibitor/ARB Warnings Can cause acute kidney failure in certain patients severe bilateral renal artery stenosis severe stenosis in artery to solitary kidney Pregnancy category C in 1st trimester Pregnancy category D in 2nd & 3rd trimester 63 64 Clinical Controversy CV events risk further reduced when ARB combined with an ACE inhibitor for patients with left ventricular dysfunction Data supports ACE/ARB combination therapy for patients with severe forms of nephrotic syndrome Combination ACE/ARB therapy not well studied as standard treatment for HTN Significantly higher risk of adverse effects such as hyperkalemia 65 Clinical Controversy ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) Endpoint: composite of death, dialysis, SCr doubling Prospective, randomized, multicenter, double-blind trial; patients randomized patients to ramipril, telmisartan, combination of both 25,620 patients > age 55 yr with diabetes & end-organ damage or established atherosclerotic vascular disease Combination therapy reduces proteinuria more than monotherapy but worsens major renal outcomes Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372:547-543. 66 Renin Inhibitor 1st agent FDA approved in 2007: aliskiren Inhibits angiotensinogen to angiotensin I conversion FDA approved as monotherapy & combination therapy with other antihypertensives Efficacy demonstrated with other antihypertensives including amlodipine, HCTZ, ACEIs/ARBs Does not block bradykinin breakdown less cough than ACE Inhibitors Adverse effects: orthostatic hypotension, hyperkalemia 67 68 68 β-Blockers Inhibit renin release weak association with antihypertensive effect Negative chronotropic & inotropic cardiac effects reduce CO β-blockers with intrinsic sympathomimetic activity (ISA) do not reduce CO lower BP decrease peripheral resistance Membrane-stabilizing action on cardiac cells at high enough doses 69 β-Blockers Adverse effects: bradycardia atrioventricular conduction abnormalities acute heart failure abrupt discontinuation may cause rebound hypertension or unstable angina, myocardial infarction, & death in patients with high coronary disease risk bronchospastic pulmonary disease exacerbation may aggravate intermittent claudication, Raynaud’s phenomenon 70 β-Receptors Distributed throughout the body concentrate differently in certain organs & tissues β1 receptors: heart, kidney stimulation increases HR, contractility, renin release β2 receptors: lungs, liver, pancreas, arteriolar smooth muscle stimulation causes bronchodilation & vasodilation mediate insulin secretion & glycogenolysis 71 Cardioselective β-Blockers Greater affinity for β1 than β2 receptors inhibit β1 receptors at low to moderate dose higher doses block β2 receptors Safer in patients with bronchospastic disease, peripheral arterial disease, diabetes may exacerbate bronchospastic disease when selectivity lost at high doses dose where selectivity lost varies from patient to patient Generally preferred β-blockers for HTN 72 β-Blockers Cardioselective atenolol, betaxolol, bisoprolol, metoprolol, nebivolol Nonselective nadolol, propranolol, timolol Intrinsic sympathomimetic activity acebutolol, carteolol, penbutolol, pindolol Mixed α- and β-blockers carvedilol, labetolol 73 Nonselective β-Blockers Inhibit β1 & β2 receptors at all doses Can exacerbate bronchospastic disease Additional benefits in: essential tremor migraine headache thyrotoxicosis 74 Intrinsic sympathomimetic activity Partial β-receptor agonists do not reduce resting HR, CO, peripheral blood flow No clear advantage except patients with bradycardia who must receive a β-blocker Contraindicated post-myocardial infarction & for patients at high risk for coronary disease May not be as cardioprotective as other β-blockers Rarely used 75 Clinical Controversy Meta-analyses suggest β-blocker based therapy may not reduce CV events as well as other agents Atenolol t½: 6 to 7 hrs yet it is often dosed once daily IR forms of carvedilol & metoprolol tartrate have 6- to 10- & 3- to 7-hour half-lives respectively: always dosed at least BID Findings may only apply to atenolol may be a result of using atenolol daily instead of BID 76 Mixed α- & β-blockers Carvedilol reduces mortality in patients with systolic HF treated with diuretic & ACE inhibitor Adverse effects: additional blockade produces more orthostatic hypotension 77 CCBs Calcium Channel Blockers Inhibit influx of Ca2+ across cardiac & smooth muscle cell membranes muscle contraction requires increased free intracellular Ca2+ concentration CCBs block high-voltage (L-type) Ca2+ channels resulting in coronary & peripheral vasodilation dihydropyridines vs non-dihydropyridines different pharmacologically similar antihypertensive efficacy 78 CCBs Dihydropyridines: amlodipine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, clevidipine Non-dihydropyridines: diltiazem, verapamil Adverse effects of non-dihydropyridines: bradycardia atrioventricular block systolic HF 79 CCBs Dihydropyridines: baroreceptor-mediated reflex tachycardia due to potent vasodilating effects do not alter conduction through atrioventricular node not effective in supraventricular tachyarrhythmias Non-dihydropyridines: decrease HR, slow atrioventricular nodal conduction may treat supraventricular tachyarrhythmias 80 Non-dihydropyridine CCBs ER products preferred for HTN Block cardiac SA & AV nodes: reduce HR May produce heart block Not AB rated as interchangeable/equipotent due to different release mechanisms & bioavailability Additional benefits in patients with atrial tachyarrhythmia 81 Dihydropyridine CCBs Avoid short-acting dihydropyridines particularly IR nifedipine, nicardipine Dihydropyridines more potent peripheral vasodilators than nondihydropyridines may cause more reflex sympathetic discharge: tachycardia, dizziness, headaches, flushing, peripheral edema Additional benefits in Raynaud’s syndrome Effective in older patients with isolated systolic HTN 82 α1-Blockers Not appropriate monotherapy for HTN Inhibit smooth muscle catecholamine uptake in peripheral vasculature: vasodilation & BP lowering Adverse effects: orthostatic hypotension 1st dose phenomenon: transient dizziness, faintness, palpitations, syncope within 1 to 3 hours of 1st dose lassitude, vivid dreams, depression priapism Na+/H2O retention 83 α1-Blockers 1st dose at bedtime Used with diuretics to minimize edema Caution in elderly patients Reduce benign prostatic hypertrophy symptoms block postsynaptic α1-adrenergic receptors on the prostate relaxation decreased urinary outflow resistance 84 Central α2-Agonists Stimulate α2-adrenergic receptors in the brain reduces sympathetic outflow from the brains vasomotor center increases vagal tone peripheral stimulation of presynaptic α2-receptors may further reduce sympathetic tone decrease HR, CO, TPR, plasma renin activity, baroreceptor activity 85 Central α2-Agonists Adverse effects: sodium/water retention abrupt discontinuation may cause rebound HTN depression orthostatic hypotension dizziness Clonidine: anticholinergic side effects Methyldopa: can cause hepatitis, hemolytic anemia (rare) 86 Central α2-Agonists Most effective if used with a diuretic minimizes fluid retention Use caution in elderly patients Clonidine transdermal patch: placed weekly may result in fewer adverse effects avoids high peak serum drug concentrations delayed onset: 2 to 3 days overlap with PO formulation at initiation/discontinuation 87 Direct Arterial Vasodilators Direct arterial smooth muscle relaxation causes antihypertensive effect (little or no venous vasodilation) reduce impedence to myocardial contractility potent reductions in perfusion pressure activate baroreceptor reflexes baroreceptor activation: compensatory increase in sympathetic outflow; tachyphylaxis can cause loss of antihypertensive effect counteract with concurrent β-blocker clonidine if β-blocker contraindicated 88 Direct Arterial Vasodilators Adverse effects: sodium/water retention angina Hydralazine can cause lupus-like syndrome Minoxidil can cause hypertrichosis 89 Reserpine Peripheral adrenergic antagonist depletes norephinephrine from sympathetic nerve endings; blocks norephinephrine transport into storage granules reduces norephinephrine release into synapse following nerve stimulation reduced sympathetic tone peripheral vascular resistance reduction decreased BP depletes catecholamines from brain & myocardium Maximum antihypertensive effect: 2 to 6 weeks 90 Reserpine Adverse effects: sedation depression decreased CO sodium/water retention increased gastric acid secretion diarrhea bradycardia Use with diuretic (preferably thiazide) to avoid fluid retention 91 Direct Arterial Vasodilators Use with diuretic (preferably thiazide) & β-blocker to reduce fluid retention & reflex tachycardia minoxidil more potent vasodilator hydralazine 92 Orthostatic Hypotension Decrease in SBP > 20 mmHg or DBP > 10 mmHg when changing from supine to standing position Older patients with isolated systolic hypertension at risk at initiation of drug therapy Prevalent with diuretics, ACE inhibitors, ARBs Treatment should remain the same with low initial doses & gradual dose titrations 93 Hypertensive Crisis BP > 180/120 mmHg reduce gradually Hypertensive urgency elevated BP no acute or progressing target-organ injury Hypertensive emergency acute or progressing target-organ damage encephalopathy, intracranial hemorrhage, acute left ventricular failure with pulmonary edema, dissecting aortic aneurysm, unstable angina, eclampsia 94 Hypertensive Emergency Drug Dose Onset (min) Sodium 0.25–10 mcg/kg/min Immediate nitroprusside intravenous infusion (requires special delivery system) Nicardipine 5–15 mg/h hydrochloride intravenous Clevidipine butyrate Fenoldopam mesylate 1-2 mg/h intravenous infusion; may double dose every 90 sec initially; maximum: 32 mg/h; typical maintenance dose: 4 to 6 mg/h 0.1–0.3 mcg/kg/min intravenous infusion 5–10 Duration Adverse Effects (min) 1–2 Nausea, vomiting, muscle twitching, sweating, thiocyanate and cyanide intoxication 15–30; may Tachycardia, headache, exceed 240 flushing, local phlebitis 2-4 5-15 <5 30 Headache, syncope, dyspnea, nausea, vomiting Tachycardia, headache, nausea, flushing Special Indications Most hypertensive emergencies; caution with high intracranial pressure, azotemia, or in chronic kidney disease Most hypertensive emergencies except acute heart failure; caution with coronary ischemia Most hypertensive emergencies except severe aortic stenosis; caution with heart failure Most hypertensive emergencies; caution with glaucoma DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/ 95 Hypertensive Emergency Drug Dose Onset (min) 2–5 Duration Adverse Effects (min) 5–10 Headache, vomiting, methemoglobinemia, tolerance with prolonged use Special Indications Coronary ischemia Nitroglycerin 5–100 mcg/min intravenous infusion Hydralazine hydrochloride 12–20 mg intravenous 10–50 mg intramuscular 10–20 20–30 60–240 Tachycardia, flushing, 240–360 headache vomiting, aggravation of angina Eclampsia Labetalol hydrochloride 20–80 mg intravenous bolus every 10 min; 0.5– 2.0 mg/min intravenous infusion 5–10 Esmolol hydrochloride 250–500 mcg/kg/min intravenous bolus, then 50–100 mcg/kg/min intravenous infusion; may repeat bolus after 5 min or increase infusion to 300 mcg/min 1–2 180–360 Vomiting, scalp tingling, bronchoconstriction, dizziness, nausea, heart block, orthostatic hypotension 10–20 Hypotension, nausea, asthma, first-degree heart block, heart failure Most hypertensive emergencies except acute heart failure Aortic dissection; perioperative DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/ 96 Monitoring Antihypertensives Class Parameters Diuretics blood pressure BUN/serum creatinine serum electrolytes (K+, Mg2+, Na+) uric acid (for thiazides) β-Blockers blood pressure heart rate Aldosterone antagonists ACE inhibitors Angiotensin II receptor blockers Direct Renin inhibitors blood pressure BUN/serum creatinine serum potassium Calcium channel blockers blood pressure heart rate DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/ 97 Combination Therapy Most patients require > 2 agents to control BP A thiazide-type diuretic should be one of these agents unless contraindicated Combination regimens should include a diuretic (preferably a thiazide) Resistant hypertension: failure to achieve BP goal on full doses of 3 drug regimen including a diuretic 98 Acknowledgements Prepared By/Series Editor: April Casselman, Pharm.D. Editor-in-Chief: Robert L. Talbert, Pharm.D., FCCP, BCPS, FAHA Chapter Authors: Joseph J. Saseen, Pharm.D., FCCP, BCPS Eric J. Maclaughlin, Pharm.D., BS Pharm Section Editor: Robert L. Talbert, Pharm.D., FCCP, BCPS, FAHA 99 100