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  • Htn05

    1. 1. Pharmacology of ACE inhibitors ARBs and CCBs Ed Sheridan, Pharm.D.
    2. 2. Pharmacology ACEi, ARBs, CCB <ul><li>Review the Mechanism of Action </li></ul><ul><li>Review Safety </li></ul><ul><li>Review Efficacy </li></ul><ul><li>Hypertension </li></ul>
    3. 3. The Renin-Angiotensin System <ul><li>Renin release from the juxtaglomerular cell </li></ul><ul><ul><li>Sympathetic nerve stimulation – beta-1 receptor </li></ul></ul><ul><ul><li>Low blood sodium </li></ul></ul><ul><ul><li>Low renal artery pressure </li></ul></ul><ul><li>Renin acts upon angiotensinogen to form angiotensin I </li></ul><ul><li>Angiotensin I is converted to Angiotensin II by a converting enzyme called ACE </li></ul>
    4. 4. The Renin-Angiotensin System <ul><li>Angiotensin II is one of the most potent vasoconstrictors known to man </li></ul><ul><li>Angiotensin II releases aldosterone from the adrenal cortex </li></ul><ul><li>Aldosterone enhances sodium and water retention and potassium loss from the kidney </li></ul><ul><li>Blood volume and BP increase as a result </li></ul>
    5. 5. Angiotensin II Effects on the Kidney <ul><li>Angiotensin II constricts the renal efferent arteriole more than the afferent arteriole </li></ul><ul><li>It therefore increases or maintains high glomerular filtration pressure </li></ul><ul><li>As mentioned previously, AT-II causes high levels of aldosterone, and therefore leads to water and salt conservation </li></ul>
    6. 6. Liver Angiotensinogen Angiotensin I Angiotensin II Aldosterone Increased Blood Volume Increase BP Kidney Renin ACE Renin-Angiotensin System Increased TPR Increased CO Salt & Water Retension
    7. 7. ACE Inhibitors Brand Generic Mavik Trandolapril Altace Ramipril Accupril Quinapril Aceon Perindopril Univasc Moexipril Prinivil Lisinopril Monopril Fosinopril Vasotec Enalapril Capoten Captopril Lotensin Benazepril
    8. 8. Not to be confused with those of you who voted Ace Young off American Idol
    9. 9. ACEi Uses <ul><li>Hypertension </li></ul><ul><li>CHF </li></ul><ul><li>Renal Insufficiency </li></ul><ul><li>Diabetes </li></ul><ul><li>CVD </li></ul><ul><li>Stroke </li></ul>
    10. 10. MOA of ACE Inhibitors <ul><li>Block formation of angiotensin II </li></ul><ul><ul><li>Lowers TPVR </li></ul></ul><ul><ul><li>Reduces the release of aldosterone </li></ul></ul><ul><ul><ul><li>Increases Na + excretion </li></ul></ul></ul><ul><ul><ul><li>Increases K + retention </li></ul></ul></ul>
    11. 11. Angiotensinogen Angiotensin I Angiotensin II Vasoconstriction Increased peripheral vascular resistance Increased blood pressure Aldosterone secretion Increased sodium and water retention Kininogen Bradykinin Inactive Increased prostaglandin synthesis Vasodilation Decreased peripheral vascular resistance Decreased blood pressure Kalikrein Converting Enzyme 2 2 1 1 X Renin
    12. 12. Blocking the Renin-Angiotensin System <ul><li>BP decreases MAINLY by lowered TPVR </li></ul><ul><li>Cardiac output is usually NOT significantly affected </li></ul><ul><li>For some reason, reflex sympathetic stimulation DOES NOT OCCUR </li></ul><ul><li>Absence of cardiostimulation makes these drugs safe in patients with ischemia </li></ul>
    13. 13. ACEi Efficacy <ul><li>African American patients less responsive </li></ul><ul><li>Achieve blood pressure goals in 30-40% of patients monotherapy, 75-85% if with diuretic </li></ul><ul><li>? possible prophylaxis of microalbuminuria (MA) </li></ul><ul><ul><li>Definite decrease in progression to ERSD if already have MA </li></ul></ul><ul><li>? possible decrease in incidence of diabetes </li></ul><ul><li>Studies have proven: decrease in nephropathy in type 1 diabetics, decrease in mortality in CHF, post-MI, in high risk cad patients (CAPPP—captopril maybe decrease CV events to same extent as Beta blockers but not stroke, HOPE, UKPDS) </li></ul>
    14. 14. ACE Inhibitors- Side Effects <ul><li>Angioedema possible (0.1%) </li></ul><ul><li>Hypotension (especially with diuretics) </li></ul><ul><li>Acute renal failure in patients with renal artery stenosis (what with NSAIDs) </li></ul><ul><li>Hyperkalemia in patients taking potassium supplements or potassium sparing diuretics </li></ul>
    15. 15. ACE Inhibitors- Side Effects <ul><li>Dry, non-productive cough – 25% incidence </li></ul><ul><li>Alteration of taste </li></ul><ul><li>Allergic skin rashes, drug fevers </li></ul><ul><li>Absolutely contraindicated during 2 nd and 3 rd trimesters of pregnancy </li></ul><ul><ul><li>Fetal hypotension </li></ul></ul><ul><ul><li>Fetal renal failure </li></ul></ul><ul><ul><li>Fetal malformation or death </li></ul></ul>
    16. 16. <ul><li>Captopril : sulfhydryl may be responsible for rash, blood dyscrasias. Oral bid, tid;1- 2hr before meal, t1/2= 2-3hr </li></ul><ul><li>Enalapril et al : PRODRUGS activated in liver or small intestines. Oral once or bid; t1/2= 11hr </li></ul><ul><li>Lisinopril : lysine derivative of enalaprilat the active form of Enalapril Once daily; t1/2 = 12hr </li></ul>ACE Inhibitors- Comments
    17. 17. Angiotensin Receptor Blockers Brand Generic Diovan Valsartan Micardis Telmisartin Cozaar Losartan Avapro Irbesartan Atacand Candesartan
    18. 18. ARBs Uses <ul><li>Usually Secondary to ACEi </li></ul><ul><ul><li>Hypertension </li></ul></ul><ul><ul><li>CHF </li></ul></ul><ul><ul><li>Renal Insufficiency </li></ul></ul><ul><ul><li>Diabetes </li></ul></ul><ul><li>Migraine prophylaxis </li></ul>
    19. 19. Angiotensin Receptor Blockers: Mechanisms <ul><li>Agents block Angiotensin type 1 receptors (NOT angiotensin I receptors!!!) </li></ul><ul><li>Have no effect on bradykinin metabolism </li></ul><ul><li>Probably reduced cough and angioedema possibilities </li></ul><ul><li>Contraindicated during pregnancy </li></ul><ul><li>Losartan (Cozaar) and Valsartan (Diovan) </li></ul>
    20. 20. Angiotensinogen Angiotensin I Angiotensin II Vasoconstriction Increased peripheral vascular resistance Increased blood pressure Aldosterone secretion Increased sodium and water retention Kininogen Bradykinin Inactive Increased prostaglandin synthesis Vasodilation Decreased peripheral vascular resistance Decreased blood pressure Kalikrein Converting Enzyme 2 2 1 1 X X Renin
    21. 21. ARB Side effects <ul><li>Hyperkalemia </li></ul><ul><li>Precipitate renal failure in bilateral renal artery stenosis </li></ul><ul><li>Contraindicated in patients experiencing angioedema from ACEi </li></ul><ul><li>Contraindicated during pregnancy </li></ul>
    22. 22. ARB Efficacy <ul><li>ADA recommends ARBs for type 2 diabetics with microalbuminuria </li></ul><ul><li>As effective in blood pressure lowering as ACEi </li></ul><ul><li>May reduce overall cardiovascular death in diabetics with LVH, and in non-deabetic hypertensives (LIFE) </li></ul><ul><li>Decreases progression of microalbuminuria in type 2 diabetics </li></ul><ul><li>Decreases mortality in CHF (ELITE) </li></ul>
    23. 23. Calcium Channel Blockers <ul><li>Divided into 2 groups chemically and pharmacologically </li></ul><ul><li>Common property: they all antagonize Ca ++ movement across cell membranes by blocking L type channels </li></ul><ul><ul><li>decrease frequency of opening in response to depolarization </li></ul></ul><ul><li>Also called: </li></ul><ul><ul><li>Slow Ca ++ channel blockers </li></ul></ul><ul><ul><li>Ca ++ channel antagonists </li></ul></ul><ul><ul><li>Ca ++ entry blockers </li></ul></ul>
    24. 24. Two groups <ul><li>Diliazem (Cardizem), verapamil (Calan) -primary action on heart </li></ul><ul><li>Dihydropyridines - primary action on arterioles </li></ul><ul><ul><li>nifedipine (Procardia) </li></ul></ul><ul><ul><li>nimodipine (Nimotop) </li></ul></ul><ul><ul><li>amlodipine (Norvac) </li></ul></ul><ul><ul><li>felodipine (Plendil) </li></ul></ul><ul><ul><li>isradipine (DynaCirc) </li></ul></ul>
    25. 25. Cardiac effects <ul><li>Verapamil and diltiazem type reduce Ca ++ entry in the heart </li></ul><ul><ul><li>Slow pacemaker activity - HR decreases </li></ul></ul><ul><ul><li>Slows conduction between atria and ventricles </li></ul></ul><ul><ul><li>Lessens strength of contraction - decreased stroke volume </li></ul></ul><ul><li>Dihydropyridines have minimal effects on Ca ++ entry in heart muscle </li></ul>
    26. 26. Vascular effects <ul><li>dihydropyridines </li></ul><ul><ul><li>Arteries and arterioles dilate more than veins </li></ul></ul><ul><ul><li>Fall in BP due to reduced TPVR </li></ul></ul><ul><ul><li>Reflex tachycardia </li></ul></ul><ul><li>verapamil and diltiazem - lesser effect on arterioles and more depression of heart (no tachycardia) </li></ul>
    27. 27. CCB Efficacy <ul><li>As effective as other agents in reducing blood pressure 40-50% respond as monotherapy </li></ul><ul><li>Especially effective in African Americans </li></ul><ul><li>Morbidity and mortality????? HOT trial at least may offer that CCB are not deleterious…Sys Eur trial/SHEP trial suggested CCB’s decrease cardiac and cerebrovascular outcomes in the elderly </li></ul>
    28. 28. CCB Safety <ul><li>DO NOT USE SHORT ACTING DHP’S!!!!!! </li></ul><ul><li>DHP except plendil and norvasc may be detrimental in CHF </li></ul><ul><li>Discontinue slowly tapering dose if used for angina </li></ul><ul><li>Diltiaziem/verapamil contraindicated in sick sinus syndrome, 2 nd or 3 rd degree heart block, severe CHF, cardiogenic shock, interact with statins…dramatically increasing levels (except pravachol and lescol) </li></ul>
    29. 29. Calcium Blockers Side effects <ul><li>Headache </li></ul><ul><li>Edema (nifedipine) </li></ul><ul><li>Constipation (verapamil) </li></ul><ul><li>Gingival hyperplasia </li></ul><ul><li>AV block & heart failure (verapamil and diltiazem) </li></ul><ul><li>Drug interactions: beta blockers (verapamil and diltiazem), cimetidine </li></ul>
    30. 30. Pharmacology ACEi, ARBs, CCB <ul><li>Review the Mechanism of Action </li></ul><ul><li>Review Safety </li></ul><ul><li>Review Efficacy </li></ul><ul><li>Hypertension </li></ul>
    31. 31. Treatment of Hypertension <ul><li>Ed Sheridan, PharmD </li></ul>*BP=CO x PVR
    32. 32. Treatment of Hypertension <ul><li>Brief introduction </li></ul><ul><li>Review current hypertension guidelines </li></ul><ul><li>Review choice of antihypertensive agents </li></ul>
    33. 33. Treatment of Hypertension Introduction <ul><li>Current guidelines, JNC VII, available at </li></ul><ul><li>Now have evidence from clinical trials supporting the use of many pharmacologic classes </li></ul><ul><li>Always remember: Not all things that lower blood pressure prevent mortality to the same extent </li></ul>
    34. 34. <ul><li>HTN prevalence ~ 50 million people in the United States. </li></ul><ul><li>For persons over age 50, SBP is a more important than DBP as CVD risk factor. </li></ul><ul><li>Persons who are normotensive at age 55 have a 90% lifetime risk for developing HTN. </li></ul><ul><li>Those with SBP 120–139 mmHg or DBP 80–89 mmHg should be considered prehypertensive who require health-promoting lifestyle modifications to prevent CVD. </li></ul>Hypertension Introduction
    35. 35. CVD Risk <ul><li>The BP relationship to risk of CVD is continuous, consistent, and independent of other risk factors. </li></ul><ul><li>Each increment of 20/10 mmHg doubles the risk of CVD across the entire BP range starting from 115/75 mmHg. </li></ul><ul><li>Prehypertension signals the need for increased education to reduce BP in order to prevent hypertension. </li></ul>
    36. 36. Blood Pressure Classification <80 and <120 Normal 80–89 or 120–139 Prehypertension 90–99 or 140–159 Stage 1 Hypertension > 100 or > 160 Stage 2 Hypertension DBP mmHg SBP mmHg BP Classification
    37. 37. Patient Evaluation <ul><li>Evaluation of patients with documented HTN has three objectives: </li></ul><ul><li>Assess lifestyle and identify other CV risk factors or concomitant disorders that affects prognosis and guides treatment. </li></ul><ul><li>Reveal identifiable causes of high BP. </li></ul><ul><li>Assess the presence or absence of target organ damage and CVD . </li></ul>
    38. 38. CVD Risk Factors <ul><li>Hypertension* </li></ul><ul><li>Cigarette smoking </li></ul><ul><li>Obesity* (BMI > 30 kg/m 2 ) </li></ul><ul><li>Physical inactivity </li></ul><ul><li>Dyslipidemia* </li></ul><ul><li>Diabetes mellitus* </li></ul><ul><li>Microalbuminuria or estimated GFR <60 ml/min </li></ul><ul><li>Age (older than 55 for men, 65 for women) </li></ul><ul><li>Family history of premature CVD </li></ul><ul><li>(men under age 55 or women under age 65) </li></ul>* Components of the metabolic syndrome .
    39. 39. Identifiable Causes of Hypertension <ul><li>Sleep apnea </li></ul><ul><li>Drug-induced or related causes </li></ul><ul><li>Chronic kidney disease </li></ul><ul><li>Primary aldosteronism </li></ul><ul><li>Renovascular disease </li></ul><ul><li>Chronic steroid therapy and Cushing’s syndrome </li></ul><ul><li>Pheochromocytoma </li></ul><ul><li>Coarctation of the aorta </li></ul><ul><li>Thyroid or parathyroid disease </li></ul>
    40. 40. Target Organ Damage <ul><li>Heart </li></ul><ul><ul><li>Left ventricular hypertrophy </li></ul></ul><ul><ul><li>Angina or prior myocardial infarction </li></ul></ul><ul><ul><li>Prior coronary revascularization </li></ul></ul><ul><ul><li>Heart failure </li></ul></ul><ul><li>Brain </li></ul><ul><ul><li>Stroke or transient ischemic attack </li></ul></ul><ul><li>Chronic kidney disease </li></ul><ul><li>Peripheral arterial disease </li></ul><ul><li>Retinopathy </li></ul>
    41. 41. Laboratory Tests <ul><li>Routine Tests </li></ul><ul><ul><li>Electrocardiogram </li></ul></ul><ul><ul><li>Urinalysis </li></ul></ul><ul><ul><li>Blood glucose, and hematocrit </li></ul></ul><ul><ul><li>Serum potassium, creatinine, or the corresponding estimated GFR, and calcium </li></ul></ul><ul><ul><li>Lipid profile, after 9- to 12-hour fast, that includes high-density and low-density lipoprotein cholesterol, and triglycerides </li></ul></ul><ul><li>Optional tests </li></ul><ul><ul><li>Measurement of urinary albumin excretion or albumin/creatinine ratio </li></ul></ul><ul><li>More extensive testing for identifiable causes is not generally indicated unless BP control is not achieved </li></ul>
    42. 42. Goals of Therapy <ul><li>Reduce CVD and renal morbidity and mortality. </li></ul><ul><li>Treat to BP <140/90 mmHg or BP <130/80 mmHg in patients with diabetes or chronic kidney disease. </li></ul><ul><li>Achieve SBP goal especially in persons > 50 years of age . </li></ul>
    43. 43. Benefits of Lowering BP Average Percent Reduction Stroke incidence 35–40% Myocardial infarction 20–25% Heart failure 50%
    44. 44. Benefits of Lowering BP In stage 1 HTN and additional CVD risk factors, achieving a sustained 12 mmHg reduction in SBP over 10 years will prevent 1 death for every 11 patients treated.
    45. 45. BP Control Rates Trends in awareness, treatment, and control of high blood pressure in adults ages 18–74 Sources: Unpublished data for 1999–2000 computed by M. Wolz, National Heart, Lung, and Blood Institute; JNC 6 . 34 27 29 10 Control 59 54 55 31 Treatment 70 68 73 51 Awareness 1999–2000 II (Phase 2) 1991–94 II (Phase 1) 1988–91 II 1976–80 National Health and Nutrition Examination Survey, Percent
    46. 46. Treatment Overview <ul><li>Lifestyle modification/DASH diet </li></ul><ul><li>Pharmacologic treatment </li></ul><ul><ul><li>Algorithm for treatment of hypertension </li></ul></ul><ul><li>Classification and management of BP for adults </li></ul><ul><li>Followup and monitoring </li></ul>
    47. 47. Lifestyle Modification Approximate SBP reduction (range) Modification 5–20 mmHg/10 kg weight loss Weight reduction 8–14 mmHg Adopt DASH eating plan 2–8 mmHg Dietary sodium reduction 4–9 mmHg Physical activity 2–4 mmHg Moderation of alcohol consumption
    48. 48. DASH Fact Sheet
    49. 49. Review of Agents Pharmacology for Hypertension <ul><li>Thiazides (loops not good antihypertensives) </li></ul><ul><li>Beta-Blockers </li></ul><ul><li>ACE inhibitors </li></ul><ul><li>ARBs </li></ul><ul><li>Calcium Channel Blockers </li></ul><ul><li>Alpha blockers </li></ul><ul><li>Central alpha adrenergics </li></ul>
    50. 51. Review of Important Aspects of Diuretics in the Treatment of Hypertension <ul><li>Thiazides </li></ul><ul><ul><li>Decreased Sodium may lead to decrease vessel stiffness, and possibly decreased neuronal reactivity </li></ul></ul><ul><li>Loops </li></ul><ul><ul><li>If used for hypertension should be use twice daily because of duration of action </li></ul></ul><ul><ul><li>Retain activity in decreased renal function </li></ul></ul><ul><li>Potassium Sparing Diuretics </li></ul><ul><ul><li>Usually weak antihypertensives </li></ul></ul>
    51. 52. Centrally Acting Drugs <ul><li>Mechanism </li></ul><ul><ul><li>Stimulates central alpha receptors </li></ul></ul><ul><li>Side Effects </li></ul><ul><ul><li>Tend to cause sedation </li></ul></ul><ul><li>Examples </li></ul><ul><ul><li>Methyldopa </li></ul></ul><ul><ul><li>Clonidine (hypertensive crisis) </li></ul></ul>
    52. 53. Adrenergic Neuron Blocking Agents <ul><li>Mechanism </li></ul><ul><ul><li>Prevent release of norepinephrine from postganglionic neurons </li></ul></ul><ul><li>Guanethidine </li></ul><ul><ul><li>replaces norepinephrine in neuron, decreases release </li></ul></ul><ul><ul><li>Increases toxicity of sympathetic amines </li></ul></ul><ul><ul><li>Postural hypertension </li></ul></ul><ul><li>Reserpine </li></ul><ul><ul><li>Irreversibly inhibit norepinephrine reuptake, creating general norepinephrine deficit </li></ul></ul><ul><ul><li>sedation, depression parkinson’s like symptoms </li></ul></ul>
    53. 54. Beta Receptor Blocking Agents <ul><li>Mechanism </li></ul><ul><ul><li>Decreased cardiac output or PVR </li></ul></ul><ul><ul><li>Decreased stimulation of renin </li></ul></ul><ul><li>Side Effects </li></ul><ul><ul><li>Decreased heart rate </li></ul></ul><ul><ul><li>Asthma exacerbation </li></ul></ul>
    54. 55. Alpha Receptor Blockers <ul><li>Mechanism </li></ul><ul><ul><li>Block Alpha 1 Receptors in arterioles and venules </li></ul></ul><ul><li>First dose syncope </li></ul>
    55. 56. Vasodilators <ul><li>Hydralazine </li></ul><ul><ul><li>Dilates arteries, not veins </li></ul></ul><ul><ul><li>Kinetics </li></ul></ul><ul><ul><ul><li>Absorption: 25% bioavailability </li></ul></ul></ul><ul><ul><ul><li>Metabolism: bimodal acetylation, Half-life 4hrs </li></ul></ul></ul><ul><ul><li>Side Effects </li></ul></ul><ul><ul><ul><li>Headache, nausea, sweating, anorexia </li></ul></ul></ul><ul><ul><ul><li>Reflex tachycardia </li></ul></ul></ul><ul><ul><ul><li>lupus like reaction ESPECIALLY IN SLOW ACETYLATORS </li></ul></ul></ul>
    56. 57. Vasodilators <ul><li>Minoxidil </li></ul><ul><ul><li>Mechanism </li></ul></ul><ul><ul><ul><li>opens potassium channels, stablizes membranes, decreases contraction </li></ul></ul></ul><ul><ul><ul><li>dilates arterioles not veins </li></ul></ul></ul><ul><ul><li>Side effects </li></ul></ul><ul><ul><ul><li>reflex salt and volume retention </li></ul></ul></ul><ul><ul><ul><li>increased heart rate, palpitations, angina, edema, hirsutism </li></ul></ul></ul>
    57. 58. Vasodilators <ul><li>Sodium nitroprusside </li></ul><ul><ul><li>Mechanism </li></ul></ul><ul><ul><ul><li>activates guanylyl cyclase increases cGMP, relaxes smooth muscle </li></ul></ul></ul><ul><ul><ul><li>dilates arterioles and veins </li></ul></ul></ul><ul><ul><li>Kinetics </li></ul></ul><ul><ul><ul><li>Absorption:IV </li></ul></ul></ul><ul><ul><ul><li>Metabolism: RBC to cyanide, then to thiocyanate </li></ul></ul></ul><ul><ul><ul><li>Elimination: Renal </li></ul></ul></ul><ul><ul><li>Toxicity: cyanide poisoning (tx with hydroxycobolamine) </li></ul></ul>
    58. 59. Vasodilator <ul><li>Diazoxide </li></ul><ul><ul><li>Mechanism </li></ul></ul><ul><ul><ul><li>opens potassium channels </li></ul></ul></ul><ul><ul><li>kinetics </li></ul></ul><ul><ul><ul><li>Distribution: highly bound to protein </li></ul></ul></ul><ul><ul><ul><li>Metabolism: Half life 24 hrs (duration of b/p effect only 4-12 hours) </li></ul></ul></ul>
    59. 60. Vasodilators <ul><li>Fenoldapam </li></ul><ul><ul><li>Mechanim of action </li></ul></ul><ul><ul><ul><li>dopamine agonist </li></ul></ul></ul><ul><ul><ul><li>peripheral arteriole dilator </li></ul></ul></ul><ul><ul><li>Kinetic </li></ul></ul><ul><ul><ul><li>Absorption: IV </li></ul></ul></ul><ul><ul><ul><li>Metabolism: Half life 10min </li></ul></ul></ul><ul><ul><li>Side effect </li></ul></ul><ul><ul><ul><li>Reflex tachycardia </li></ul></ul></ul><ul><ul><ul><li>Headache </li></ul></ul></ul>
    60. 62. Algorithm for Treatment of Hypertension Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease ) Initial Drug Choices Lifestyle Modifications Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. With Compelling Indications Stage 2 Hypertension (SBP > 160 or DBP > 100 m mHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB) Stage 1 Hypertension (SBP 140 –159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Without Compelling Indications Not at Goal Blood Pressure Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with hypertension specialist.
    61. 63. Classification and Management of BP for adults * Treatment determined by highest BP category. † Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension. ‡ Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mmHg. Two-drug combination for most † (usually thiazide-type diuretic and ACEI or ARB or BB or CCB). Yes > 100 > 160 Stage 2 Hypertension Drug(s) for the compelling indications. ‡ Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Yes 90–99 140–159 Stage 1 Hypertension Drug(s) for compelling indications. ‡ No antihypertensive drug indicated. Yes 80–89 120–139 Prehypertension Encourage <80 <120 Normal With compelling indications Without compelling indication Initial drug therapy Lifestyle modification DBP* mmHg SBP* mmHg BP classification
    62. 64. Compelling Indications for Individual Drug Classes Clinical Trial Basis Initial Therapy Options Compelling Indication ALLHAT, HOPE, ANBP2, LIFE, CONVINCE ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS ACC/AHA Heart Failure Guideline, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES THIAZ, BB, ACE, CCB BB, ACEI, ALDO ANT THIAZ, BB, ACEI, ARB, ALDO ANT High CAD risk Postmyocardial infarction Heart failure
    63. 65. Compelling Indications for Individual Drug Classes Recurrent stroke prevention Chronic kidney disease Diabetes Clinical Trial Basis Initial Therapy Options Compelling Indication PROGRESS NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK NKF-ADA Guideline, UKPDS, ALLHAT THIAZ, ACEI ACEI, ARB THIAZ, BB, ACE, ARB, CCB
    64. 66. Special Considerations <ul><li>Compelling Indications </li></ul><ul><li>Other Special Situations </li></ul><ul><ul><li>Minority populations </li></ul></ul><ul><ul><li>Obesity and the metabolic syndrome </li></ul></ul><ul><ul><li>Left ventricular hypertrophy </li></ul></ul><ul><ul><li>Peripheral arterial disease </li></ul></ul><ul><ul><li>Hypertension in older persons </li></ul></ul><ul><ul><li>Postural hypotension </li></ul></ul><ul><ul><li>Dementia </li></ul></ul><ul><ul><li>Hypertension in women </li></ul></ul><ul><ul><li>Hypertension in children and adolescents </li></ul></ul><ul><ul><li>Hypertension urgencies and emergencies </li></ul></ul>
    65. 67. Minority Populations <ul><li>In general, treatment similar for all demographic groups. </li></ul><ul><li>Socioeconomic factors and lifestyle important barriers to BP control. </li></ul><ul><li>Prevalence, severity of HTN increased in African Americans. </li></ul><ul><li>African Americans demonstrate somewhat reduced BP responses to monotherapy with BBs, ACEIs, or ARBs compared to diuretics or CCBs. </li></ul><ul><li>These differences usually eliminated by adding adequate doses of a diuretic. </li></ul>
    66. 68. Left Ventricular Hypertrophy <ul><li>LVH is an independent risk factor that increases the risk of CVD. </li></ul><ul><li>Regression of LVH occurs with aggressive BP management: weight loss, sodium restriction, and treatment with all classes of drugs except the direct vasodilators hydralazine and minoxidil. </li></ul>
    67. 69. Peripheral Arterial Disease (PAD) <ul><li>PAD is equivalent in risk to ischemic heart disease. </li></ul><ul><li>Any class of drugs can be used in most PAD patients. </li></ul><ul><li>Other risk factors should be managed aggressively. </li></ul><ul><li>Aspirin should be used. </li></ul>
    68. 70. Hypertension in Older Persons <ul><li>More than two-thirds of people over 65 have HTN. </li></ul><ul><li>This population has the lowest rates of BP control. </li></ul><ul><li>Treatment, including those who with isolated systolic HTN, should follow same principles outlined for general care of HTN. </li></ul><ul><li>Lower initial drug doses may be indicated to avoid symptoms; standard doses and multiple drugs will be needed to reach BP targets . </li></ul>
    69. 71. Postural Hypotension <ul><li>Decrease in standing SBP >10 mmHg, when associated with dizziness/fainting, more frequent in older SBP patients with diabetes, taking diuretics, venodilators, and some psychotropic drugs. </li></ul><ul><li>BP in these individuals should be monitored in the upright position. </li></ul><ul><li>Avoid volume depletion and excessively rapid dose titration of drugs. </li></ul>
    70. 72. Dementia <ul><li>Dementia and cognitive impairment occur more commonly in people with HTN. </li></ul><ul><li>Reduced progression of cognitive impairment occurs with effective antihypertensive therapy. </li></ul>
    71. 73. Hypertension in Women <ul><li>Oral contraceptives may increase BP, and BP should be checked regularly. In contrast, HRT does not raise BP. </li></ul><ul><li>Development of HTN—consider other forms of contraception. </li></ul><ul><li>Pregnant women with HTN should be followed carefully. Methyldopa, BBs, and vasodilators, preferred for the safety of the fetus. ACEI and ARBs contraindicated in pregnancy. </li></ul>
    72. 74. Children and Adolescents <ul><li>HTN defined as BP—95th percentile or greater, adjusted for age, height, and gender. </li></ul><ul><li>Use lifestyle interventions first, then drug therapy for higher levels of BP or if insufficient response to lifestyle modifications. </li></ul><ul><li>Drug choices similar in children and adults, but effective doses are often smaller. </li></ul><ul><li>Uncomplicated HTN not a reason to restrict physical activity. </li></ul>
    73. 75. Hypertensive Urgencies and Emergencies <ul><li>Patients with marked BP elevations and acute TOD (e.g., encephalopathy, myocardial infarction, unstable angina, pulmonary edema, eclampsia, stroke, head trauma, life-threatening arterial bleeding, or aortic dissection) require hospitalization and parenteral drug therapy. </li></ul><ul><li>Patients with markedly elevated BP but without acute TOD usually do not require hospitalization, but should receive immediate combination oral antihypertensive therapy. </li></ul>
    74. 76. Additional Considerations in Antihypertensive Drug Choices <ul><li>Potential favorable effects </li></ul><ul><li>Thiazide-type diuretics useful in slowing demineralization in osteoporosis. </li></ul><ul><li>BBs useful in the treatment of atrial tachyarrhythmias/fibrillation, migraine, thyrotoxicosis (short-term), essential tremor, or perioperative HTN. </li></ul><ul><li>CCBs useful in Raynaud’s syndrome and certain arrhythmias. </li></ul><ul><li>Alpha-blockers useful in prostatism . </li></ul>
    75. 77. Additional Considerations in Antihypertensive Drug Choices <ul><li>Potential unfavorable effects </li></ul><ul><li>Thiazide diuretics should be used cautiously in gout or a history of significant hyponatremia. </li></ul><ul><li>BBs should be generally avoided in patients with asthma, reactive airways disease, or second- or third-degree heart block. </li></ul><ul><li>ACEIs and ARBs are contraindicated in pregnant women or those likely to become pregnant. </li></ul><ul><li>ACEIs should not be used in individuals with a history of angioedema. </li></ul><ul><li>Aldosterone antagonists and potassium-sparing diuretics can cause hyperkalemia. </li></ul>
    76. 78. Followup and Monitoring <ul><li>Patients should return for followup and adjustment of medications until the BP goal is reached. </li></ul><ul><ul><li>-(pharmacokinetics v. pharmacodynamics) </li></ul></ul><ul><li>More frequent visits for stage 2 HTN or with complicating comorbid conditions. </li></ul><ul><li>Serum potassium and creatinine monitored 1–2 times per year . </li></ul>
    77. 79. Followup and Monitoring (continued) <ul><li>After BP at goal and stable, followup visits at 3- to 6-month intervals. </li></ul><ul><li>Comorbidities, such as heart failure, associated diseases, such as diabetes, and the need for laboratory tests influence the frequency of visits. </li></ul>
    78. 81. Improving Hypertension Control <ul><li>Adherence to regimens </li></ul><ul><li>Resistant hypertension </li></ul>
    79. 82. Strategies for Improving Adherence to Regimens <ul><li>Clinician empathy increases patient trust, motivation, and adherence to therapy. </li></ul><ul><li>Physicians should consider their patients’ cultural beliefs and individual attitudes in formulating therapy. </li></ul>
    80. 83. Causes of Resistant Hypertension <ul><li>Improper BP measurement </li></ul><ul><li>Excess sodium intake </li></ul><ul><li>Inadequate diuretic therapy </li></ul><ul><li>Medication </li></ul><ul><ul><li>Inadequate doses </li></ul></ul><ul><ul><li>Drug actions and interactions (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs), illicit drugs, sympathomimetics, oral contraceptives) </li></ul></ul><ul><ul><li>Over-the-counter ( OTC) drugs and herbal supplements </li></ul></ul><ul><li>Excess alcohol intake </li></ul><ul><li>Identifiable causes of HTN </li></ul>
    81. 84. Treatment of Hypertension <ul><li>Brief introduction </li></ul><ul><li>Review current hypertension guidelines </li></ul><ul><li>Review choice of antihypertensive agents </li></ul>
    82. 85. Abbreviated References <ul><li>Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 2005, 1 st edition. </li></ul><ul><li>Basic and Clinical Pharmacology, 2004, 9 th edition. </li></ul><ul><li>The Pharmacological Basis of Therapeutics, 1996, 9 th edition. </li></ul><ul><li>AHFS Drug Information, 2004. </li></ul><ul><li>Drug Facts and Comparisons, 2005. </li></ul><ul><li>Pharmacology Examination and Board Review, 2005. </li></ul><ul><li>High-Yield Pharmacology, 2004, 2 nd edition </li></ul>