CV Pharmacology-Antihypertensive Agents :CV Pharmacology-Antihypertensive Agents Prepared and Presented by: Marc Imhotep Cray, M.D. Professor Pharmacology Recommended Reading: Antihypertensive Drugs Formative Assessment Practice question Clinical: E-Medicine Articles Hypertension


Normal Control of BP :10/17/2009 2 Normal Control of BP Normal control of BP: sympathoadrenal axis-- response to a decrease in BP Sensed by Central baroreceptors {heart & great arteries} Stimulation of ß-adrenergic systems increased heart rate (positive chronotropic response) increased force of contraction (contractility, positive inotropic response) increased renin secretion {juxtaglomerular renal cells} Stimulation of a-adrenoceptor systems: causes vasoconstriction


Essential Hypertension :10/17/2009 3 Essential Hypertension With essential hypertension, previous slide mechanisms function inappropriately Excessive sympathetic activation Elevated norepinephrine may promote through vascular endothelium injury: vascular hypertrophy atherogenesis ß-adrenergic receptor down-regulation Reduced endothelium-mediated vascular relaxation Consequence: increased vasoconstrictive tone (chronic vasoconstriction) Excessive sympathetic activation promotes enhanced peripheral vascular resistance in hypertensive patients


Hypertension Defined :10/17/2009 4 Hypertension Defined Re: Table in the next slide Based on recommendations of the Seventh Report of the Joint National Committee of Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) Also see: E-Medicine Article Hypertension New Hypertension Guidelines Quick Reference Card http://www.nhlbi.nih.gov/guidelines/hypertension/phycard.pdf


Classification of Blood Pressure (JNC VII) :10/17/2009 5 Classification of Blood Pressure (JNC VII) Category Systemic BP (mm Hg) Diastolic BP (mm Hg) Normal <130 <85 High normal 130-139 85-89 Hypertension Stage 1 140-159 90-99 Stage 2 160-169 100-109 Stage 3 180-209 110-119 Stage 4  210  120


Classification of HTN :10/17/2009 6 Classification of HTN Primary Hypertension Specific cause unknown 90% of the cases Also known as essential or idiopathic hypertension Secondary Hypertension Cause is known (such as eclampsia of pregnancy, renal artery disease, pheochromocytoma) 10% of the cases


Physiological Factors Influencing Arterial Pressure :10/17/2009 7 Physiological Factors Influencing Arterial Pressure Arterial pressure is determined by a number of interacting factors Preload & Contractility Heart rate Peripheral resistance


Physiological Factors Influencing Arterial Pressure Preload & Contractility :10/17/2009 8 Physiological Factors Influencing Arterial Pressure Preload & Contractility As blood volume returning to heart increases, preload increases and there is enhanced filling with ventricular dilation According to Starling's Law, increased ventricular stretch usually leads to increased contractility


Physiological Factors Influencing Arterial Pressure Preload & Contractility(2) :10/17/2009 9 Physiological Factors Influencing Arterial Pressure Preload & Contractility(2) Increased preload and increased contractility lead to increased stroke volume and ultimately an increase in arterial pressure, all other factors remaining equal Some antihypertensive drugs decrease preload


Physiological Factors Influencing Arterial Pressure Preload & Contractility(3) :10/17/2009 10 Physiological Factors Influencing Arterial Pressure Preload & Contractility(3) The Nitrates are an example of preload reducing agents See: IAU CV PharmacologyAnti-Anginal Agents


Physiological Factors Influencing Arterial Pressure Heart Rate :10/17/2009 11 Physiological Factors Influencing Arterial Pressure Heart Rate Heart rate: Since the product of heart rate and stroke volume equals cardiac output, an increase in heart rate will increase arterial blood pressure, all other factors remaining equal Some antihypertensive agents decrease heart rate (ß-adrenergic receptor antagonists, e.g.) Heart Rate X Stroke Volume = Cardiac Output Cardiac Output X Peripheral Resistance = Arterial Pressure


Physiological Factors Influencing Arterial Pressure Peripheral resistance :10/17/2009 12 Physiological Factors Influencing Arterial Pressure Peripheral resistance Peripheral resistance: For a given cardiac output, blood pressure depends only on peripheral resistance Some antihypertensive drugs act to reduce peripheral resistance (Also known as afterload reducing agents)


Physiological Factors Influencing Arterial Pressure :10/17/2009 13 Physiological Factors Influencing Arterial Pressure Depending on mechanism of action, a given antihypertensive may: Reduce preload Reduce afterload Decrease heart rate Reduce peripheral resistance Reduce contractility.  Many antihypertensive drugs have multiple effects


Anti-Hypertensive Drug Classes :10/17/2009 14 Anti-Hypertensive Drug Classes Diuretics Sympatholytics Vasodilators Calcium Channel Blockers Angiotensin Converting Enzyme (ACE) Inhibitor


Anti-Hypertensive Drug Classes-1) Diuretics :10/17/2009 15 Anti-Hypertensive Drug Classes-1) Diuretics


Anti-Hypertensive Drug Classes- 2) Sympatholytics :10/17/2009 16 Anti-Hypertensive Drug Classes- 2) Sympatholytics


Anti-Hypertensive Drug Classes- 3) Vasodilators :10/17/2009 17 Anti-Hypertensive Drug Classes- 3) Vasodilators


Anti-Hypertensive Drug Classes- 4) Calcium Channel Blockers :10/17/2009 18 Anti-Hypertensive Drug Classes- 4) Calcium Channel Blockers


Anti-Hypertensive Drug Classes- 5) Angiotensin Converting Enzyme Inibitors :10/17/2009 19 Anti-Hypertensive Drug Classes- 5) Angiotensin Converting Enzyme Inibitors


Antihypertensive Agents: Categories Discussion :10/17/2009 20 Antihypertensive Agents: Categories Discussion Adrenergic agents Angiotensin-converting enzyme inhibitors Angiotensin II receptor blockers Calcium channel blockers Diuretics Vasodilators


Antihypertensive Agents: Categories :10/17/2009 21 Antihypertensive Agents: Categories Adrenergic Agents Alpha1 blockers Beta blockers (cardioselective and nonselective) Centrally acting alpha blockers Combined alpha-beta blockers Peripheral-acting adrenergic agents


Antihypertensive Agents: Mechanism of Action :10/17/2009 22 Antihypertensive Agents: Mechanism of Action Adrenergic Agents Alpha1 Blockers (peripherally acting) Block the alpha1-adrenergic receptors The SNS is not stimulated Result: DECREASED blood pressure Stimulation of alpha1-adrenergic receptors causes HYPERtension Blocking alpha1-adrenergic receptors causes decreased blood pressure


Antihypertensive Agents: :10/17/2009 23 Antihypertensive Agents: Adrenergic Agents Alpha1 Blockers doxazosin (Cardura) prazosin (Minipress) terazosin (Hytrin)


Antihypertensive Agents: Mechanism of Action :10/17/2009 24 Antihypertensive Agents: Mechanism of Action Adrenergic Agents Central-Acting Adrenergics Stimulate alpha2-adrenergic receptors Sympathetic outflow from the CNS is decreased Result: decreased blood pressure


Antihypertensive Agents: :10/17/2009 25 Antihypertensive Agents: Adrenergic Agents Central-Acting Adrenergics clonidine (Catapres) methyldopa (Aldomet) (drug of choice for hypertension in pregnancy)


Antihypertensive Agents: Mechanism of Action :10/17/2009 26 Antihypertensive Agents: Mechanism of Action Adrenergic Agents Adrenergic Neuronal Blockers (peripherally acting) Inhibit release of norepinephrine Also deplete norepinephrine stores SNS (peripheral adrenergic nerves) is not stimulated Result: decreased blood pressure


Antihypertensive Agents: :10/17/2009 27 Antihypertensive Agents: Adrenergic Agents Adrenergic Neuronal Blockers(peripherally acting) reserpine guanadrel (Hylorel) guanethidine (Ismelin)


Antihypertensive Agents: Adrenergic Agents :10/17/2009 28 Antihypertensive Agents: Adrenergic Agents Therapeutic Uses Alpha1 blockers (peripherally acting) Treatment of hypertension Relief of symptoms of BPH Management of of severe CHF when used with cardiac glycosides and diuretics


Antihypertensive Agents: Adrenergic Agents :10/17/2009 29 Antihypertensive Agents: Adrenergic Agents Therapeutic Uses Central-Acting Adrenergics Treatment of hypertension, either alone or with other agents Usually used after other agents have failed due to side effects


Antihypertensive Agents: Adrenergic Agents :10/17/2009 30 Antihypertensive Agents: Adrenergic Agents Therapeutic Uses Central-Acting Adrenergics(2) Also may be used for treatment of severe dysmenorrhea, menopausal flushing, glaucoma Clonidine is useful in the management of withdrawal symptoms in opioid- or nicotine-dependent persons


Antihypertensive Agents: Adrenergic Agents :10/17/2009 31 Antihypertensive Agents: Adrenergic Agents Therapeutic Uses Adrenergic neuronal blockers (peripherally acting) Treatment of hypertension, either alone or with other agents Seldom used because of frequent side effects


Antihypertensive Agents: Adrenergic Agents :10/17/2009 32 Antihypertensive Agents: Adrenergic Agents Side Effects Most common: dry mouth drowsiness sedation constipation Other: headaches sleep disturbances nausea rash cardiac disturbances (palpitations) HIGH INCIDENCE OF ORTHOSTATIC HYPOTENSION


Antihypertensive Agents: Categories- (ACE Inhibitors) :10/17/2009 33 Antihypertensive Agents: Categories- (ACE Inhibitors) Angiotensin-Converting Enzyme Inhibitors (ACE Inhibitors) Large group of safe and effective drugs Often used as first-line agents for CHF and hypertension May be combined with a thiazide diuretic or calcium channel blocker


Antihypertensive Agents: Mechanism of Action :10/17/2009 34 Antihypertensive Agents: Mechanism of Action ACE Inhibitors RAAS: Renin Angiotensin-Aldosterone System When the enzyme angiotensin I is converted to angiotensin II, the result is potent vasoconstriction and stimulation of aldosterone


Antihypertensive Agents: Mechanism of Action(2) :10/17/2009 35 Antihypertensive Agents: Mechanism of Action(2) ACE Inhibitors Result of vasoconstriction: increased systemic vascular resistance and increased afterload Therefore, increased BP


Antihypertensive Agents: Mechanism of Action(3) :10/17/2009 36 Antihypertensive Agents: Mechanism of Action(3) ACE Inhibitors Aldosterone stimulates water and sodium resorption. Result: increased blood volume, increased preload, and increased B


Antihypertensive Agents: Mechanism of Action(4) :10/17/2009 37 Antihypertensive Agents: Mechanism of Action(4) ACE Inhibitors ACE Inhibitors block the angiotensin-converting enzyme, thus preventing the formation of angiotensin II. Also prevent the breakdown of the vasodilating substance, bradykinin Result: decreased systemic vascular resistance (afterload), vasodilation, and therefore, decreased blood pressure


Diagram illustrates the renin-angiotensin-aldosterone axis :10/17/2009 38 Diagram illustrates the renin-angiotensin-aldosterone axis


Slide 39:10/17/2009 39


Antihypertensive Agents :10/17/2009 40 Antihypertensive Agents ACE Inhibitors captopril (Capoten) Short half-life, must be dosed more frequently than others enalapril (Vasotec) The only ACE inhibitor available in oral and parenteral forms


Antihypertensive Agents- ACE Inhibitors(2) :10/17/2009 41 Antihypertensive Agents- ACE Inhibitors(2) lisinopril (Prinivil and Zestril) quinapril (Accupril) Newer agents, long half-lives, once-a-day dosing Several other agents available


Antihypertensive Agents: Therapeutic Uses :10/17/2009 42 Antihypertensive Agents: Therapeutic Uses ACE Inhibitors Hypertension CHF (either alone or in combination with diuretics or other agents) Slows progression of left ventricular hypertrophy after an MI Renal protective effects in patients with diabetes Drugs of choice in hypertensive patients with CHF


Antihypertensive Agents: Side Effects :10/17/2009 43 Antihypertensive Agents: Side Effects ACE Inhibitors Fatigue Dizziness Headache Mood changes Impaired taste Dry, nonproductive cough, reverses when therapy is stopped NOTE: first-dose hypotensive effect may occur!!


Antihypertensive Agents: Categories :10/17/2009 44 Antihypertensive Agents: Categories Angiotensin II Receptor Blockers (A II Blockers or ARBs) Newer class Well-tolerated Do not cause coughing


Antihypertensive Agents: Mechanism of Action :10/17/2009 45 Antihypertensive Agents: Mechanism of Action Angiotensin II Receptor Blockers Allow angiotensin I to be converted to angiotensin II, but block the receptors that receive angiotensin II Block vasoconstriction and release of aldosterone


Antihypertensive Agents: :10/17/2009 46 Antihypertensive Agents: Angiotensin II Receptor Blockers losartan (Cozaar) eposartan (Teveten) valsartan (Diovan) irbesartan (Avapro) candesartan (Atacand) telmisartan (Micardis)


Antihypertensive Agents: Therapeutic Uses :10/17/2009 47 Antihypertensive Agents: Therapeutic Uses Angiotensin II Receptor Blockers Hypertension Adjunctive agents for the treatment of CHF May be used alone or with other agents such as diuretics


Antihypertensive Agents: Side Effects :10/17/2009 48 Antihypertensive Agents: Side Effects Angiotensin II Receptor Blockers Upper respiratory infections Headache May cause occasional dizziness, inability to sleep, diarrhea, dyspnea, heartburn, nasal congestion, back pain, fatigue


Antihypertensive Agents: Categories :10/17/2009 49 Antihypertensive Agents: Categories Calcium Channel Blockers Benzothiazepines Dihydropyridines Phenylalkylamines


Antihypertensive Agents: Mechanism of Action :10/17/2009 50 Antihypertensive Agents: Mechanism of Action Calcium Channel Blockers Cause smooth muscle relaxation by blocking the binding of calcium to its receptors, preventing muscle contraction This causes decreased peripheral smooth muscle tone, decreased systemic vascular resistance Result: decreased blood pressure


Antihypertensive Agents-Calcium Channel Blockers :10/17/2009 51 Antihypertensive Agents-Calcium Channel Blockers Benzothiazepines: diltiazem (Cardizem, Dilacor) Phenylalkamines: verapamil (Calan, Isoptin) Dihydropyridines: amlodipine (Norvasc), bepridil (Vascor), nicardipine (Cardene) nifedipine (Procardia), nimodipine (Nimotop)


Antihypertensive Agents: Therapeutic Uses :10/17/2009 52 Antihypertensive Agents: Therapeutic Uses Calcium Channel Blockers Angina Hypertension Dysrhythmias Migraine headaches


Antihypertensive Agents: Side Effects :10/17/2009 53 Antihypertensive Agents: Side Effects Calcium Channel Blockers Cardiovascular hypotension, palpitations, tachycardia Gastrointestinal constipation, nausea Other rash, flushing, peripheral edema, dermatitis


Antihypertensive Agents: Diuretics :10/17/2009 54 Antihypertensive Agents: Diuretics Decrease the plasma and extracellular fluid volumes Results: decreased preload decreased cardiac output decreased total peripheral resistance Overall effect: decreased workload of the heart, and decreased blood pressure


Antihypertensive Agents: Mechanism of Action :10/17/2009 55 Antihypertensive Agents: Mechanism of Action Vasodilators Directly relaxes arteriolar smooth muscle Result: decreased systemic vascular response, decreased afterload, and PERIPHERAL VASODILATION


Nitrous Oxide and Vasodilation :10/17/2009 56 Nitrous Oxide and Vasodilation After receptor stimulation, L-arginine-dependent metabolic pathway produces nitric oxide (NO) or thiol derivative (R-NO). NO causes increase in cyclic guanosine monophosphate (cGMP), which causes relaxation of vascular smooth muscle. EDRF=endothelium-derived relaxing factor. From: Inhaled Nitric Oxide Therapy ROBERT J. LUNN, M.D. From the Department of Anesthesiology, Mayo Clinic Rochester, Rochester, Minnesota. http://www.mayoclinicproceedings.com/inside.asp?ref=7003sc


Antihypertensive Agents :10/17/2009 57 Antihypertensive Agents Vasodilators diazoxide (Hyperstat) hydralazine HCl (Apresoline) minoxidil (Loniten, Rogaine) sodium nitroprusside (Nipride, Nitropress)


Antihypertensive Agents: Therapeutic Uses :10/17/2009 58 Antihypertensive Agents: Therapeutic Uses Vasodilators Treatment of hypertension May be used in combination with other agents Sodium nitroprusside and diazoxide IV are reserved for the management of hypertensive emergencies


Antihypertensive Agents: Side Effects :10/17/2009 59 Antihypertensive Agents: Side Effects Vasodilators Hydralazine: dizziness, headache, anxiety, tachycardia, nausea and vomiting, diarrhea, anemia, dyspnea, edema, nasal congestion Sodium nitroprusside: bradycardia, hypotension, possible cyanide toxicity


Stepwise Approach to Tx of Essential HTN :10/17/2009 60 Stepwise Approach to Tx of Essential HTN beginning with a low dosage of either an ACE inhibitor, calcium channel blocker or beta blocker and proceeding, if needed to add a diuretic and ultimately additional more powerful drugs, such as centrally acting sympatholytics, peripheral vasodilators or combination. At each step dosages are reviewed and if the patient's hypertension is controlled then therapy may be continued with review for possible removal of medication. Figure adapted from Harrison's "Principles of Internal Medicine, Thirteenth Edition, p. 1128 Antihypertensive Medication Sequence


Resources :10/17/2009 61 Resources JNC GUIDELINES  The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)  On the JNC home page, there are a number of important resources for clinicians as well as patient resources, including: JNC 7 Complete Report: The Science Behind the New Guidelines  (86 pages) JNC 7 Express Highlights "Must Know" Clinical Practice Updates (34 pages) JNC 7 Reference Card (2 pages)- A great summary of Evaluation, Treatment,