Presentation on theme: "Objectives for Lecture on Pharmacotherapy of Hypertension"— Presentation transcript:
1 Objectives for Lecture on Pharmacotherapy of Hypertension By the end of this class students will be able to:Describe the epidemiology of essential hypertension and explain the goals and importance of blood pressure controlClassify the severity of hypertensionMatch the recommended diet/lifestyle changes and pharmacotherapy to the severity of hypertensionName the major drugs and drug classes used to reduce blood pressureDescribe the actions in the body of each drug, explain the mechanism by which it produces those actions and explain why the drug is useful in treating hypertension
3 Blood Pressure Variables P1 – Mean arterial pressureP2 – Central venous pressure (relatively low and essentially constant)Q – Cardiac outputη – ViscosityL – Length of the vasculatureR – Radius of the arteriolesLarge effect on blood pressure with little change in r
4 Key References for Antihypertensive Therapy 7th report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7). JAMA, 289, (2003). 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults (JNC8). JAMA, 311, (2014).An Effective Approach to High Blood Pressure Control: A Science Advisory From the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention. Hypertension, 63, (2014).Clinical practice guidelines for the management of hypertension in the community. J. Clin. Hypertens., 32, 3-15 (2014).
5 Essential Hypertension Arbitrarily defined as a blood pressure >140/90 mm Hg.Hypertension is a symptom, not a disease. The underlying disease is a cardiovascular abnormality that leads to morbid events.Many causes, all thought to be genetic in origin.Environmental and psychosocial factors interact with the genetic background to produce the hypertensive phenotype.
6 Major Risk Factors Cigarette smoking Obesity (BMI 30) Physical inactivityDyslipidemiaDiabetes mellitusMicroalbuminemia or GFR <60 mL/minAge (>55 yr for men, >65 yr for women)Family history of premature cardiovascular disease (<55 yr for men, <65 yr for women)
7 Secondary Hypertension Examination should seek to exclude this possibilityPhysical findings suggestive of secondary hypertension:Abdominal or flank masses (polycystic kidneys)Abdominal bruits (renovascular disease)Delayed or absent femoral arterial pulses or BP in lower extremities (aortic coarctation)Truncal obesity with pigmented striae (Cushing’s syndrome)Tachycardia, orthostatic hypotension, sweating, pallor (pheochromocytoma)
8 DiagnosisBased on two or more blood pressure measurements with the patient seated. Average of the readings should be used.Confirmed with measurements taken during two or more office visits.Verification in the contralateral arm.At home monitoring recommended in Europe to avoid the phenomenon of “white coat hypertension”
9 Hypertension Contributes to or Exacerbates: AtherosclerosisCoronary artery diseaseCongestive heart failure*DiabetesStroke*Renal failure*Retinal disease
11 Impact of Blood Pressure on Renal Disease SystolicDiastolicRange(mm Hg)Adjusted RR<1171.0<7575-791.31.5*80-851.4*2.2*86-912.0*>1405.0*>914.0*
12 Rates for African-Americans vs. Other Races Hypertension-Related Morbidity and Mortality in African-American Individuals Compared to WhitesRates for African-Americans vs. Other RacesOverall mortality6-13XNon-fatal stroke1.3XFatal stroke3-6XHeart disease death1.5XEnd-stage renal disease5X
13 Epidemiology of Essential Hypertension National Health and Nutrition Examination SurveyWhiteBlackPrevalence(40-59 yr)30%36%50%Diagnosed69%74%Treatment (any)58%62%Control with drugs54%40%
14 Effect of Antihypertensive Pharmacotherapy on Outcomes (Combined Results from Major Clinical Trials) CHFStrokeLVHCV DeathsCoronary Events->50%-35-40%-34%-21%-20-25%
15 Major Conclusions of JNC 7 (other than specific pharmacotherapy) In persons >50, systolic blood pressure is a more important CVD risk factor than diastolic blood pressure.The risk of CVD doubles with each increment of 20/10 mm Hg beginning at 115/75 mm Hg.Individuals with systolic BP of or diastolic BP of should be considered prehypertensive.Individuals normotensive at age 55 have a 90% lifetime risk for developing hypertension.Most patients with hypertension will require 2 or more antihypertensive medications to achieve goal blood pressure.Success depends on a motivated patient. Motivation improves when patients have positive experiences with and trust in the clinician. Non-adherence to therapy is a major factor in poor control of blood pressure.
16 Clinical Classification of Blood Pressure CategorySystolic(mm Hg)DiastolicNormal<120and<80Prehypertensionor80-89HypertensionStage 190-99Stage 2≥160≥100
17 Classification and Management of Blood Pressure BP ClassificationLifestyle ModificationWithout Compelling Indications*With Compelling Indications*PrehypertensionYesNo drug indicatedDrug(s) for the compelling indicationsStage 1 hypertensionDrug monotherapyOther antihyper-tensive drug(s) as neededStage 2 hypertensionTwo-drug combination (usually thiazide diuretic +)
18 Compelling Indications Congestive heart failure (diuretic, beta blocker, ACE inhibitor [or ARB], aldosterone antagonist)Post-myocardial infarction (beta blocker, ACE inhibitor [or ARB], aldosterone antagonist)High coronary disease risk (diuretic, beta blocker, ACE inhibitor [or ARB], calcium channel blocker)Recurrent stroke prevention (diuretic, ACE inhibitor [or ARB])Note that ACE inhibitor/ARB should be the first or second drug used to treat hypertension in the presence of diabetes, post-MI, or chronic kidney disease.
19 Treatment Protocol 4. Not at goal blood pressure 1. Lifestyle modifications 2. Not at goal blood pressure (<140/90; this may change in 2016) 3. Initial drug choices:Hypertension without compelling indications Stage 1 – See tableStage 2 - Two-drug combination for most (usually thiazide diuretic +)Hypertension with compelling indications Drug(s) for compelling indicationsOther antihypertensive drugs as needed4. Not at goal blood pressure 5. Optimize dosages or add additional drugs; consider consultation with hypertension specialist
20 Blood Pressure Goals and Antihypertensive Drug Recommmendations - 2014 JNC8ACC/AHA/CDCASH/ISHADAGoal BP <60 YO140/90Goal BP >60<80 YO150/90Goal BP >80 YOGoal BP diabetes or CKDStage 1 Non-BlackACEI, ARB, Thiazide diuretic, or CCBThiazide diureticACEI or ARB if <60 YO, Thiazide diuretic or CCB if >60 YOStage 1 BlackThiazide diuretic or CCBStage 1 DiabeticNo modificationACEI or ARB as first or second drugACC – American College of Cardiology; ACEI – angiotensin converting enzyme inhibitor; ADA – American Diabetes Association; AHA – American Heart Association; ARB – angiotensin receptor blocker; ASH – American Society of Hypertension; BP – blood pressure; CCB – calcium channel blocker; CDC – Centers for Disease Control and Prevention; CKD – chronic kidney disease; ISH – International Society of Hypertension.
21 Lifestyle Modifications RecommendationExpected Reduction in Systolic BPWeight reductionMaintain normal body weight (BMI of )5-20 mm Hg for each 10 kg lostAdopt the DASH dietConsume diet rich in fruits, vegetables, and low-fat dairy products with reduced saturated and total fat8-14 mm HgDietary sodium reductionReduce intake to no more than 100 mEq/L (6 g NaCl) per day2-8 mm HgPhysical activityEngage in aerobic physical activity (e.g., brisk walking) for at least 30 min/day most days of the week4-9 mm HgModeration of alcohol consumptionNo more than 1 oz/day for most men and no more than 0.5 oz/day for women and lighter-weight men2-4 mm HgStop smoking!
24 Diets Tested in the DASH Study ControlFruits & VegCombination DietFat (% of kcal)Cholesterol (mg/day)Fiber (g/day)K+/dayMg2+/dayCa2+/day36233917521764431843141014235342615144154801265Food Groups (servings/day)Low-fat dairyBeef, pork, hamFishFats and oilsSnacks and sweets0.11.50.25.84.10.01.80.35.31.42.00.52.50.7
25 Diet/Lifestyle Therapy vs Drugs Adherence to the recommended diet/lifestyle changes can reduce blood pressure as much as a single first-line antihypertensive drugDiet/lifestyle changes may therefore substitute for one drug in the antihypertensive regimenHowever, adherence to diet/lifestyle therapy is probably worse than adherence to pharmacotherapy; e.g., only 20% adhere to the DASH diet
27 First-Line Antihypertensive Drugs Combat Cardiovascular Remodeling Remodeling (resulting in arteriosclerosis and/or congestive heart failure) may include oxidative damage, overgrowth of smooth muscle or cardiac muscle, fibrosis, apoptosis of cardiac muscle, overgrowth of connective tissue, endothelial damage, etc.Factors that promote remodeling include (among others) excess sodium, glucose, angiotensin II, catecholamines, aldosterone. NO inhibits remodeling.First-line antihypertensive drugs reduce cardiovascular morbidity and mortality even if they little reduce blood pressure. This additional benefit, beyond that provided by blood pressure reduction, may be explained by inhibition or reversal of remodeling.
29 ACE Inhibitors Molecular Mechanism Physiological Mechanisms Competitive inhibition of angiotensin converting enzyme (kininase II)*Physiological MechanismsBlock of angiotensin II-mediated vasoconstriction*norepinephrine release by block of angiotensin II-mediated enhancementsympathetic outflow from the brain stembradykinin-mediated vasodilationaldosterone secretion (reverses in many cases)*Block of angiotensin II-mediated arterial and left ventricular remodeling*
30 ACE Inhibitors Other Actions Dry cough (partly caused by bradykinin)* Rapid swelling of nose, throat, mouth, tongue (angioedema; partly caused by bradykinin)*Teratogenesis in the second and third trimesters*Hyperkalemia (in the absence of diuretic)*
32 AT1 Receptor Blockers (ARBs) Molecular MechanismCompetitive antagonism of angiotensin II at the AT1 receptor*Physiological MechanismsBlock of angiotensin II-mediated vasoconstriction*norepinephrine release by block of angiotensin II-mediated enhancementsympathetic outflow from the brain stemaldosterone secretion (reverses in many cases)*Block of angiotensin II-mediated left ventricular remodeling*
33 AT1 Receptor Blockers No change in bradykinin levels Much lower risk of dry cough than with ACE inhibitors*Much lower risk of angioedema than with ACE inhibitors*As teratogenic as ACE inhibitors*Hyperkalemia (in the absence of diuretic)*No benefit to combining ACE inhibitor and ARB
34 Ca2+ Channel Blockers Molecular Mechanisms Physiological Mechanisms Reversible block of L-type Ca2+ channels in vascular smooth muscle cells*Reversible block of L-type Ca2+ channels in cardiac muscle cells* (verapamil, diltiazem only)Physiological Mechanismssympathetically-mediated vasoconstriction due to block of Ca2+ action potentials and Ca2+-mediated Ca2+ release from sarcoplasmic reticulum*inotropy, cardiac output (verapamil, diltiazem only)*
35 Ca2+ Channel Blockers Other Actions Reflex tachycardia (risk in ischemic heart disease; nifedipine, diltiazem, but not amlodipine)*inotropy (verapamil, diltiazem only)*Edema from precapillary dilatation with reflex postcapillary constriction (all)Reflux due to relaxation of the lower esophageal sphincter (all)Useful in isolated systolic hypertension (with thiazide diuretic) and other combination therapies. The best third drug for patients already receiving thiazide/ACEI or ARB. Works equally well in all racial/ethnic groups.
37 Beta Blockers Molecular Mechanisms Major importance Lesser importance Competitive antagonism of β1 adrenergic receptors (atenolol, metoprolol)*Competitive antagonism of 1, 2, 1, anti-oxidant and anti-apoptotic effects (carvedilol)*Competitive antagonism of β1 + increased NO availability (nebivolol)*Lesser importance+ intrinsic sympathomimetic activity (acebutolol)+ β2 agonist activity (celiprolol)+ β2 antagonist activity (propranolol)+ CNS depression (propranolol)
38 Beta Blockers Possible Physiological Mechanisms Majormyocardial contractility (reduced cardiac output)*Othersrenin secretionnorepinephrine release by block of positive β2 feedbacksympathetic outflow from the brain stemBlock of catecholamine-induced cardiac remodeling*Vasodilation (carvedilol, nebivolol)*
39 Beta Blockers Other Actions inotropy and chronotropy* (mainly β1 antagonism). Blunt recognition of hypoglycemia.Bronchoconstriction* (β2 antagonism)Block of epinephrine-mediated vasodilation of skeletal muscle beds (β2 antagonism)Glycogenolysis and blood glucose (β2 antagonism)Plasma triglycerides and HDL (β2/β3 antagonism)Carvedilol (combined 1,2,1 antagonism avoids metabolic effects of other beta blockers)*Exercise intolerance* (β1- and β2-mediated)Nebivolol causes little or no exercise intolerance or sexual dysfunction
40 Alpha Blockers Molecular Mechanism Physiological mechanism Competitive antagonism of 1 adrenergic receptors*Physiological mechanismDirect postsynaptic blockade of sympathetically-mediated vasoconstriction*
41 Alpha Blockers Other Actions Transient reflex in heart rate, cardiac output, plasma renin* (risk in ischemic heart disease)Depression of the baroreceptor reflex, leading to orthostatic hypotension*Edema (similar to Ca2+ channel blockers)total and LDL cholesterol, HDL cholesterol
42 Renin Antagonist Aliskerin Inhibits the renin-mediated conversion of angiotensinogen to angiotensin IAppears to be as efficacious as ACE inhibitors with lower incidence of side effectsCounteracts the up regulation of renin by diureticsBeing used in combination therapies