HYPERTENSION ABC & Update Mahmoud Khattab, Ph.D. Professor of Pharmacology & Toxicology 1 Development of Structural and Functional Alterations in the Hypertensive Vessel Wall 2 Smooth Muscles & Endothelial Morphologic Changes In Hypertension The smooth muscle content of arteries can be augmented by an increase in cell number (hyperplasia) or an increase in cell mass (hypertrophy) The volume of the endothelial cells increases and the surface configuration becomes more globular, so that the cells protrude into the lumen of the vessel 3 Linkage Between Structural & Functional Changes Poiseuille’s Law: Resistance α 1/r4 4 Possible mechanisms of Apparent Increased Sensitivity to Vasoconstrictors Patients with essential hypertension have apparent increased sensitivity to forearm infusion of norepinephrine (0.40 μg/min) (increase in resistance) o True increased sensitivity to vasoconstrictors o Increased receptor sensitivity o Increased activation of second messengers or ion channels o Apparent increased sensitivity due to effects of structure or function to increase resistance o Hypertrophy or hyperplasia o Decreased endothelial-dependent vasodilator 5 mechanisms Characteristics of Hypertension Elevated BP at maintained cardiac output Interaction of environmental and genetic factors Both structural and functional changes in arterioles leading to increased resistance Structural changes resulting from growth or remodeling of the vessel due to the positive influence of growth factors or the removal of growth inhibitors Functional abnormalities involving endothelial and vascular smooth muscle dysfunction Abnormalities in membrane ionic control mechanisms likely underlying abnormalities in both contraction and growth Enhanced vascular responsiveness to vasoconstrictors 6 AHA Classification Classification Normal SBP DBP (mm Hg) (mm Hg) <120 AND <80 Prehypertension 120-139 OR 80-89 Stage 1 Hypertension 140-159 OR 90-99 Stage 2 Hypertension ≥160 OR ≥100 7 Classification and Goal JAMA 2003;289:2560–2572 The seventh Report of the Joint National Committee on Detection, Evaluation, and Treatment of High BP (JNC 7) classified hypertension as in the given table A clinical HTN is based upon two or more seated BP measurements on two more occasions Ultimate GOALs: Decrease BP Reduce associated morbidity manifested as TARGET-ORGAN DAMAGE CVS risk factors increase frequency of target organ damage (HP+LVH: CHF) 8 Hypertension -related Target Organ Damage Brain: stroke/transient ischemic attack Eyes: retinopathy Heart: LV hypertrophy, HF, angina Kidney: chronic kidney disease Peripheral vasculature: peripheral arterial disease 9 Hypertension -related Target Organ Damage Heart Promoting atherosclerotic changes (indirectly) Pressure-related: o Enhancement of CVD o Increase risk for IHD (angina & MI) Antihypertensive therapy reduce such risks Enhance the progress of LVH (LVH+HP; Framingham Study: Increased CHF) BRAIN HTN frequently leads to cerebro-vascular disease as: Transient ischemic attacks Ischemic strokes Cerebral infarcts Antihypertensive therapy reduce the risk of initial and recurrent stroke 10 Hypertension -related Target Organ Damage Kidney HP leads to increased intraglomerular pressure causing nephrosclerosis HTN-Kidney lesion, What comes first? Chronic kidney disease can proceed to kidney failure (dialysis) Moderate (Stage 3) Kidney disease (GFR 30-59 mL/min) indicates target organ damage (Creatinine 1.3-1.5 mg/dL) Albuminurea (>300 mg/day or 200 mg albumin/g creatinine) indicates target organ damage 11 Hypertension -related Target Organ Damage Peripheral Arterial Disease An atherosclerotic vascular disease equivalent in risk to CAD BP reduction, risk factor modification & antiplatelets are needed to stop progress Complications can attain infection & necrosis o o o o EYE Hypertension can induce retinopathy that may proceed to blindness G 1: arterial vasoconstriction G2: Arteriovenous nicking (atherosclerosis) G3: Cotton wool exudates & hemorrhage (untreated HP or accelerated 12 Major CVS Risk Factors Age: more than 55 years men, 65 years women Cigarette smoking Diabetes mellitus Hypertension Dyslipedimia Obesity Physical inactivity Kidney disease: GFR ≤60mL/min 13 CVS Risk versus BP Direct correlation between risk of CVD & BP values (epidemiological studies) Above 115/75 mm Hg, with each increment of 20/10 mm Hg, the risk of CVD doubles Pre-hypertensive patients are at higher CVD risk than normal Clinically, elevated SBP is a more predictor of CVD than elevated DBP in patients over 50 years 14 BP Numerical Values Goal In most patients, the target BP value is reduce BP lower than 140/90 mm Hg In diabetic patients and chronic kidney disease patients (estimated GFR ≤60 mL/min or albumin-urea), Coronary Artery Disease (CAD): BP goal is less than 130/80 mm Hg In LV dysfunction, goal BP is <120/80 These patients are at high risk for target organ damage 15 Hypertension Misconceptios Stress-related: Apart from white coat HP, most HP patients have elevated BP independent of their stress status Headache (and other symptoms) have no correlation with hypertension Hypertension though asymptomatic, it has serious long-term complications; long-term therapy Stress management is not that beneficial in controlling HP Clinically evidenced, a better quality of life with proper medication; drugs are NOT worsening quality of life 16 Patient Evaluation/Risk Assessment I. II. III. Absence or presence of various forms of hypertension-related target organ damage Identifiable (secondary) causes of hypertension Concomitant major CV risk factors, other disorders, and assessment of lifestyle habits 17 HYPERTENSION THERAPY Lifestyle Modification For BP lowering & reduction of CV risk In prehypertensives: lifestyle modification leads to BP lowering + inhibition or minimizing HTN progress Possible reduction of dose and/or No of antihypertensive drugs used PATIENT EDUCATION IS NEEDED 18 Lifestyle Modification Weight Reduction 5-10% wt reduction in overweight persons may lower CV risk For every 1 kg wt loss, there is lowering of SBP & DBP by 2.5 & 1.5 mm Hg respectively DASH Diet Dietary Approaches to Stop Hypertension (DASH) diet is rich in fruits, vegetables & low-at dairy foods, combined to less saturated & total fat A 8-14 mm Hg reduction in SBP can be produced 19 DASH Diet 20 Lifestyle Modification Dietary Sodium Restriction Epidemiology: positive correlation between BP and sodium intake Trials: 2-8 mm Hg reduction in SBP on restricted sodium diet ≤ 2.4 g/day Physical Activity There is 4-9 mm Hg reduction in SBP in most patients upon regular PA HTN patients with compromised CVD need medical evaluation before PA Physical activity: at least 30 min for 3-5 days/week Walking, running, cycling, swimming 21 Lifestyle Modification Smoking Cessation The most important Unproven Modifications High levels of K+, Ca2+, & modifiable CV risk factor Cigarette smoking increases CV & total mortality, cessation lowers CVD incidence It interferes with response to some drugs (β blockers) Patient education Mg2+ relate to lower BP, no reduction of CV risk K+& Mg2+ intake in HP/chronic renal disease may be harmful (cardiac toxicity) Caffeine drinks limitation is not essential unless for other medical reason 22 Algorithm for Treatment of Hypertension Beta-blockers not first-line in AHA guidelines 2007 23 Patient Education About Treatment Assess patient’s understanding and acceptance of the diagnosis of o o o hypertension Discuss patient’s concerns and clarify misunderstandings Tell patient BP reading and provide a written copy Come to agreement with the patient on goal BP Ask patient to rate (1 to 10) his or her chance of staying on treatment Inform patient about recommended treatment and provide specific written information about the role of lifestyle, including diet, physical activity, dietary supplements, and alcohol intake; use standard brochures when available Emphasize: Need to continue treatment Control does not mean cure One cannot tell if BP is elevated by feeling or symptoms; BP must be measured 24 Evidence-Based Hypertension Therapy SELECTION JNC7 drug therapy algorithm follows evidence- based approach linked to clinical trials interpretation Thiazide-type diuretic-based therapy leads to significant reductions in: o Stroke (25-47%), Heart attacks (13-27%), Allcause CVD (17-40%), & Survival improvement Systolic Hypertension in Elderly Program (SHEP), Swedish Trial of Old Patients with Hypertension (STOP-hypertension) Medical Research Council (MRC) 25 Thiazide-Based Therapy versus Newer Agents (The ALLHAT study) Several clinical trials using newer agents (ACE inhibitors, ARBs, and CCBs) found reduction of BP and CV risk in a similar to thiazides Possibly ACEIs having better effects The 2007 AHA HTN guidelines are now the most recent for treatment (Circulation 2007, 115: 2761) 26 Algorithm for Treatment of Hypertension Betablockers NOT 1st line in 2007 AHA guidelines 27 The ALLHAT Study The Antihypertensive & Lipid Lowering Treatment to prevent Heart Attack Trial provides recent evidence for thiazide efficacy as used by JNC7 Designed to testify hypothesis of superiority of newer drugs: amlodipine, doxazosin & lisinopril over the thiazide diuretic chlorthalidone End-point: combined fatal CHD & non-fatal MI 42,418 patients for a mean of 4.9 years Doxazosin arm prematurely terminated because of increased HF risk 28 The ALLHAT Study Outcome: No significant difference between chlorthalidone and either amlodipine or lisinopril as regards combined end point Secondary endpoints pointed to better efficacy of thiazide over amlodipine (less HF) and lisinopril (less combined CVD, HF, & stroke) Investigators concluded superiority of thiazide diuretics or at least unsurpassed activity A 2003 network meta-analysis of 42 clinical trials found that low-dose diuretic were most effective first-line treatment for prevention CVD & mortality JAMA;289: 2534 (2003) 29 Hypertension with Compelling Indications Compelling Indication 1ST Line Diabetes Mellitus ACEI/ARB Chronic Kidney Disease ACEI/ARB Acute/Chronic CAD Prior Ischemic Stroke Left Ventricular Dysfunction β-blockers & ACEI (or ARB) Sequential Therapy thiazide diuretic, CCB or βblockers thiazide diuretic for BP control, CCB for ischemia control ACEI & thiazide diuretic, or ARB ACEI (or ARB) & thiazide (loop) diuretic & β-blockers Aldosterone antagonist in severe HF, 30 Hydralazine/dinitrate in black Starting Drug Therapy MONOTHERAPY when INITIAL BP IS CLOSE TO GOAL VALUE, 15-20 mm Hg SBP & 10 mm Hg DBP (JNC 7 & others) STEPPED CARE, o A single drug is chosen & dose increased till BP control occurred, max dose reached, or dose-limiting toxicity o A second drug from a different class is added 31 Starting Drug Therapy SEQUENTIAL THERAPY o If goal BP is not achieved an alternative drug is chosen, to replace an initial one o It is more advised when the initial drug is not well tolerated or achieved poor BP efficacy Combination Therapy Encouraged for patients stage 2 hypertension or far from BP goal Initial combination therapy can be useful for chronic renal disease/diabetes/other resistant patients 32 THERAPY MONITORING Four aspects are considered upon monitoring: BP control evaluated 1-4 weeks after therapy o o o initiation/modification Initial BP lowering needs 1-2 weeks, but steady BP up to 4 weeks Average of 2 measurements is used Standing BP measurement for orthostatic hypotension evaluation (whenever dizziness occurs) Compliance (adherence) Progression of the disease; target-organ damage points to therapy modification 33 Toxicity Diuretics Thiazides Are diuretic of choice achieving goal BP values in 50-80% of patients Hydrochlorthiazide (HCTZ) & chlorthalidone are the most frequently used Dose of 12.5-25 mg once daily can lower SBP by 15-20 mm Hg & DBP 8-15 mm Hg Low-dose therapy is equi-effective for both agents according to huge clinical evidence 34 Diuretics Loop Diuretics HCTZ is more effective than loop diuretics though less potent Furosemide is the most frequently used agent, but given more than once daily They are diuretics of choice in hypertensive patients with severe kidney disease or failure (creatinine 2.5-3 mg/dL) They are preferred in patients with CHF or severe edema 35 Diuretics K+-sparing Diuretics Amiloride/triametrene are reserved for patients developing diuretic-induced hypokalemia Fixed-dose products including HCTZ & K+-sparing diuretic are available, but initial usage to avoid hypokalemia is not rationalized They have modest antihypertensive effect when used as monotherapy 36 Diuretics Aldosterone Receptor Antagonists • Spironolactone & eplerenone cause hyperkalemia, • • • • especially in chronic renal disease Eplerenone is more specific, less gynecomastia but causes greater hyperkalemia Eplerenone is contraindicated in patients at high risk of hyperkalemia including diabetic 2 patients/albuminurea Spironolactone is beneficial in hypertensive patients with CHF where it reduces morbidity & mortality Eplerenone reduces mortality in HF & LV failure in early post MI patients 37 Diuretics Side-Effects Contraindication Annoying Harmful ThiazideDiuretics Urination (initial), weakness, muscle cramps, GIT upset, hyperuricemia Hypokalemia, hyponatremia, hyperglycemia, hypercalcemia, azotemia, skin rash, photosensitivity, lithium toxicity, hyper-TG & cholesterolemia Persistant anuria/oliguria, kidney failure Loop Diuretics Urination (initial), weakness, muscle cramps, GIT upset, hyperuricemia Hypokalemia, hyponatremia, hyperglycemia, hypocalcemia, azotemia, skin rash, photosensitivity, lithium toxicity, hyper-TG & cholesterolemia Hearing loss (large IV doses) Not contraindicated in renal failure Hyperkalemia, hyponatremia Kidney failure, hyperkalemia, hyponatremia Aldosterone Hirsutism, Antagonists menstrual irregularities, gynecomastia, GIT upset 38 β-Adrenoceptor Blockers β-Blockers reduce morbidity & mortality in hypertensive patients with compelling indications; CHF, post-MI, high-risk CHD, & diabetes All β-Blockers have similar activity on BP lowering Incidence of side-effects is low in practice and is dose-dependent, i.e., can be minimized with lowto moderate-doses 39 Pharmacologic Characteristics of β-Blockers β1-SELECTIVITY ISA α-BLOCKADE NODonotaing Acebutolol + + − Alprenolol − + − Atenolol + − − Betaxolol + − − Bisoprolol + − − Bopindolol − + − Carvedilol + − + Celiprolol + +β2 − Dilevolol + +β2 − Labetalol − − + Metoprolol + − − Nadolol − − − Nebivolol + − − Oxprenolol − + − Pindolol − + − Propranolol − − − Sotalol − − − Timolol − − 40 Hemodynamic Response to β-Adrenoceptor Blockade BP decrease after acute response) is modest, with continued treatment the BP decrease becomes much larger in most patients The magnitude of the decrease in heart rate and cardiac output and the reactive increase in PVR vary with the degree of ISA These responses do not account for the long-term decrease in BP 41 Adverse Effects of β-Adrenoceptor Blockers Annoying Beta Bradycardia, Blockers Weakness, Lethargy, GIT disturbance Harmful Contraindication •Systolic heart failure (carvedilol & •Asthma metoprolol approved for systolic HF) •Bronchospasm (asthma patients) •Hypoglycemia (non-selectives can mask symptoms of /potentiate hypoglycemia •Hyperglycemia (non-selectives can lower insulin secretion in Type 2 diabetes patients) •Peripheral arterial disease aggravation •Nightmares, insomnia, •Impotence •Hypertriglceridemia, decreased HDL (Severe) •2nd/3rd degree heart block •Systolic HF exacerbation •“Brittle” diabetes mellitus 42 β-Blockers Nonselective β-Blockers are preferred in patients with non-CV indications like migraine prophylaxis/tremor ISA β-Blockers are indicated for patients responding with severe bradycardia to nonISA β-blockers ISA β-Blockers should be avoided in patients with MI history where agonistic properties may worsen the cardiac function 43 β-Blockers Lipid Solubility Lipid solubility is of max clinical relevance in patients with renal/hepatic impairment o High lipid sol drugs like propranolol are hepatically cleared o Hydrophilic ones (atenolol) have main renal excretion (require dose adjustment) o Lipophilic agents are probably associated with increases CNS side effects like nightmares, depression High lipid soluble drugs are desirable for migraine prophylaxis due to better CNS access 44 β-Blockers Compelling Indications Heart failure (systolic); metoprolol & carvedilol are approved with reduced CV morbidity & mortality • Start with LOW DOSE & gradually increase it Post-MI & acute MI patients (including relatively contraindicated ones) have prolonged survival & reduced re-infarction High-Risk CHD: HTN patients with chronic angina or acute CHD (non-ST segment elevation MI & unstable angina) may proceed to fatal MI or others o Decreased HR, contractility & myocardial O2 demand produced by β-blockers reduce the risk 45 β-Blockers Compelling Indications Diabetes; a cardio-selective agent is preferred β-Blockers decrease coronary events, the renal disease progression, and stroke in diabetics All agents can mask symptoms of epinephrine-associated hypoglycemia (tremors, hunger & palpitations) but not sweating They cause insulin release inhibition Non-selective agents can worsen hypoglycemia & prolong recovery from hypoglycemia β-Blockers are best avoided in Type 1 diabetes but hypoglycemic effects are less common in Type 2 Non-selective agents should be avoided in “brittle” diabetics especially insulin-dependent patients 46 ACE Inhibitors Effects of Chronic ACE Inhibition on the RAA System Angiotensin II disappears from the circulation at peak ACE block Plasma renin activity, active & inactive renin concentrations increase The hyperreninemia leads to a rise in plasma angiotensin I levels The plasma levels of aldosterone are reduced during ACE inhibition There is an induction of ACE synthesis during long-term treatment Generic Names Brand Names Captopril Capoten, Benazepril Lotensin Enalapril Innovace Fosinopril Staril Imidapril Tanatril Lisinopril Carace, Zestril Moexipril Perdix Perindopril Coversyl Quinapril Accupro Ramipril Tritace 47 ACE Inhibitors Clinical Pharmacological Profile ACEIs lower BP via peripheral vasodilation with no alteration of CO/HR/or GFR through RAA system & increased vasodilating bradykinin & PGs Beneficial effects include correction of endothelial dysfunction, LVH regression, insulin sensitivity improvement & collateral vessel development They can raise serum K+ especially in renal impairment patients Acute renal compromise in patients with bilateral renal stenosis can occur Modest creatinine rise, NOT discontinue ACEIs 48 ACE Inhibitors Risk of Hypotension First dose ACEIs can induce dizziness, orthostatic hypotension, or even syncope in volume depleted, hyponatremic or exacerbated HF patients First-dose response is related to increased pretreatment activity of RAA system Concurrent diuretic therapy may increase the incidence of first-dose response in sensitive patients Elderly & African American patients mostly have low renin hypertension & less responsive to ACEIs Diuretic-ACEI combination overcome age- & racerelated poor response 49 ACE Inhibitors Compelling Indications Heart Failure: ACEI (+diuretic) is considered fist-line & standard regimen in HTN+ systolic HF Post-MI: ACEI+β-blocker showed reduction of CV risk independent of LV function & BP High-Risk CHD: ACEIs must be early given in nonST elevation MI & Unstable angina (as β-blocker) o In chronic angina: ACEI can be added after βblocker or non-DHP CCB Diabetes ACEIs reduced hypertension-related CV events & nephropathy in diabetic (mostly type 2) patients (HOPE & UKPDS studies) 50 ACE Inhibitors: Compelling Indications Diabetes ACEIs are comparable or better than diuretics & better than CCBS in reduction of CV risk NO adverse effect on glucose metabolism Chronic Kidney Disease (CKD) CKD: increased intra-glomerular pressure+mesangial cell proliferation resulting in proteinuria & progressive renal damage (reduced RBF-increased RAA-efferent arteriolar vasoconstriction- renal impairment) • ACEIs dilate efferent arteriole-relieves intraglomerular P • ACEIs may be of unique renal preserving apart from its BP lowering properties • ACEIs are highly efficacious in preserving renal 51 function in diabetes type-1 & -2 ACE Inhibitors: Compelling Indications Recurrent Stroke Prevention ACEI + Thiazide diuretic reduced the incidence of stroke & total vascular events in hypertensive/nonhypertensive patients with history of stroke/TIA The reductions were independent of baseline BP & BP lowering ( the PROGRESS trial) Elderly Patients: ACEIs are less effective in lowering BP in elderly ACEIs (& CCBs) are equivalent to old agents (diuretic- β-blockers) in reduction of fatal CV events (MI, Stroke, ..etc., STOP-2 trial) 52 Angiotensin II Type-1 Receptor Blockers (ARBs) Pharmacological Profile ARBs are the newest class of Generic Trade antihypertensive agents Name Name ARBs selectively block the effects Losartan Cozaar of Angiotensin II (ANG II) on type1 receptors Valsartan Diovan Type-1 receptors mediate Candesartan Atacand vasoconstriction, aldosterone Eprosartan Teveten secretion (salt & water retention), myocyte and SM hypertrophy & Irbesartan Aprovel sympathetic NS stimulation Olmesartan Benicar Type-2 receptors mediate antiprofilerative actions, tissue repair, Temisartan Micardis & cell differentiation 53 ARBs Pharmacological Profile vs ACI Unlike ARBs, ACE inhibition suppresses stimulation of both ANG II type-1 & -2 receptors o Hence, it is possible that ARBs are superior to ACEIs in amelioration of HTN-related damage o However, this is just speculation, & there NO supportive clinical data Vasodilating bradykinin increase with ACEI but NOT with ARB, but without changing BP lowering efficacy Similar to ACEIs, combinations with a thiazide diuretic are of high efficacy 54 ARBs Pharmacological Profile Losartan & valsartan have lower blockade potency of type-1 receptors than others, but NO significant clinical difference exist agents They can be dosed ONCE daily, but twice daily may be used whenever high doses of losartan, eprosartan or candesartan are needed Initial dose may be lowered in elderly & diuretictreated or volume-depleted patients? 55 ARBs Compelling Indications Heart Failure ARBs are probable Diabetes ARB reduce diabetic nephropathy progression alternatives in hypertension especially in type2 diabetes + HF ACEI-intolerant more than CCBs patients (ACEI-induced o ARBs are the only angioedema; AHA & ACC) antihypertensive agent showing o ACEIs & ARBs are evidence of reduction of renal equivalent in symptomatic failure in type 2 diabetes & HF relief, but ARBs are of nephropathy similar or weaker mortality o Benefits are BP loweringrate reduction independent o Val-HeFT study: Patients are recommended to with systolic HF treated with o ARBs lower nephropathy in HTN, valsartan have less diabetes & proteinuria combined morbidity/ (American Diabetes Association mortality vs placebo 56 ARBs Compelling Indications Chronic Kidney Disease ARBs, similar to ACEIs, protect against renal damage in CKD o Both ACEIs & ARBs dilate the efferent arteriole o For non-diabetic renal disease, evidence is weaker, & ARBs are reserved as ACEIs alternatives Hypertension with LVH: FDA approved losartan for stroke reduction in hypertensive patients with LVH The LIFE trial found reduced CV events (mainly stroke) with losartan more than atenolol 57 Side Effects of ACEIs & ARBs Annoying Harmful ACE Inhibitor Dizziness, faintness, lightheadedness, cough, taste changes ARBs As ACEIs Except cough Hypotension (elderly), skin rash (disappear or discontinue), proteinuria, leukopenia Same as ACEIs Contraindication Bilateral renal stenosis, volume depletion, hyponatremia, pregnancy Same as ACEIs 58 Calcium Channel Blockers (DHPs) Amlodipine, felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nitrendipine, nifedipine They are effective antihypertensive agents Elderly & African American get better BP lowering than other agents They have no metabolic effects Addition to a diuretic is additive Verapamil Diltiazem Dihydropyrines Peripheral Vasodilation Increase Increase marked increase Heart Rate Marked decrease decrease increase Contractility Marked decrease decrease No change /decrease SA/AV conductivity Decrease Decrease NO change Coronary B Flow Increase Increase Marked increase 59 Immediate-Release (IR) Nifedipine IR CCBs-MI link was first reported in 1995 Observational analysis showed that IR CCBs are associated with higher risk of MI compared with thiazide diuretics & β-lockers This risk is present with the three CCBs classes, being strongest with NIFEDIPINE FDA concluded that IR CCBs, especially nifedipine, are neither SAFE nor EFFICACEOUS and should be avoided 60 Sustained-Release (SR) Formulations Except for AMLODIPINE, all CCBs are of short half-lives, requiring frequent doses/day SR preparations are preferred when CCBs are used for hypertension treatment Chronotherapeutic Verapamil: Circadian rhythm of BP & MI incidence can be targeted by designed formulations 61 Calcium Channel Blockers Compelling Indications High Coronary Disease Risk CCBs can be used as alternatives, after β-blockers in chronic angina, unstable angina, and non-ST elevation MI when intolerance occurs Diabetes: CCBs are option in hypertensive diabetics; no effect on glucose/insulin Stroke risk is reduced by DHPs (clinical evidence) ACEIs have more CV protection than CCBS (FACET & ABCD trials) 62 Fixed-Dose Combinations for Hypertension COMBINATION TYPE FIXED‐DOSE COMBINATION (mg/mg)* ACEI and CCB Amlodipine/benazepril hydrochloride (2.5/10, 5/10, 5/20, 10/20) Enalapril/felodipine (5/5) Trandolapril/verapamil (2/180, 1/240, 2/240, 4/240) ACEI and Diuretic Benazepril/hydrochlorothiazide (5/6.25, 10/12.5, 20/12.5, 20/25) Captopril/hydrochlorothiazide (25/25, 25/25, 50/15, 50/25) Enalapril/hydrochlorothiazide (5/12.5, 10/25) Fosinopril/hydrochlorothiazide (10/12.5, 20/12.5) Lisinopril/hydrochlorothiazide (10/12.5, 20/12.5, 20/25) Moexipril/hydrochlorothiazide (7.5/12.5, 15/25) Quinapril/hydrochlorothiazide (10/12.5, 20/12.5, 20/25) ARB and Diuretic Candesartan/hydrochlorothiazide (16/12.5, 32/12.5) Eprosartan/hydrochlorothiazide (600/12.5, 600/25) Irbesartan/hydrochlorothiazide (150/12.5, 300/12.5) Losartan/hydrochlorothiazide (50/12.5, 100/25 Olmesartan medoxomil/hydrochlorothiazide (20/12.5, 40/12.5, 40/25) Valsartan/hydrochlorothiazide (80/12.5, 160/12.5, 160/25) Telmisartan/hydrochlorothiazide (40/12.5, 80/12.5) 63 Fixed-Dose Combinations for Hypertension Beta-blocker & Diuretic Atenolol/chlorthalidone (50/25, 100/25) Bisoprolol/hydrochlorothiazide (2.5/6.25, 5/6.25, 10/6.25) Metoprolol/hydrochlorothiazide (50/25, 100/25) Nadolol/bendroflumethiazide (40/5, 80/5) Propranolol LA/hydrochlorothiazide (40/25, 80/25) Timolol/hydrochlorothiazide (10/25) Centrally Acting Drug Methyldopa/hydrochlorothiazide (250/15, 250/25, 500/30, 500/50) & Diuretic Reserpine/chlorthalidone (0.125/25, 0.25/50) Reserpine/chlorothiazide (0.125/250, 0.25/500) Reserpine/hydrochlorothiazide (0.125/25, 0.125/50) Diuretic & K+-sparing Amiloride/hydrochlorothiazide (5/50) Diuretic Spironolactone/hydrochlorothiazide (25/25, 50/50) Triamterene/hydrochlorothiazide (37.5/25, 75/50) 64 Special Populations Black patients (JNC& & AHA 2007): Black patients have higher HTN incidence, more need for combination therapy As monotherapy, thiazide diuretic and CCB are highly effective ACEI, ARB, or β-blockers are less effective in black patients but addition of a thiazide diuretic greatly improve efficacy Elderly Patients: Patients of ≥65 years old have lower BP control Patients of ≥75 years old respond best to thiazes & CCB and less to ACEI, ARB, and β-blockers 65 Recall (Self-Assessment) Questions Define different stages of HTN according to JNC-7 2003 Enumerate the first-line HTN therapeutics according to AHA 2007 guideline. Mention five HTN-related target organ damage. Outline pharmacological HTN treatment algorithm For Each of the 1st & 2nd line HTN therapeutics: Mention the name of two drugs Three harmful adverse effects and a contraindication Compelling indication (s) for each group Drugs most- & least-effective in black & elderly patients JAMA; 289: 2534 (2003) JNC-7 66 Circulation; 115: 2761 (2007) AHA guidelines