CV Pharmacology-
Antihypertensive Agents Reading: Antihypertensive Drugs Formative Assessment Practice question Clinical: e-Medicine article Hypertension
Prepared and presented by: Marc Imhotep Cray, M.D. BMS and CK/CS Teacher
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 2
Essential Hypertension With essential hypertension, mechanisms in the previous slide 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
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Hypertension Defined Re: Table in the next slide ď Ž
New Hypertension Guidelines Quick Reference Card
Based on recommendations of the Seventh Report of the Joint National Committee of Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII)
http://www.nhlbi.nih.gov/guideline s/hypertension/phycard.pdf
Also see: e-Medicine article Hypertension
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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 Stage 2 Stage 3 Stage 4
140-159 160-169 180-209 210
90-99 100-109 110-119 120
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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
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Physiological Factors Influencing Arterial Pressure Arterial pressure is determined by a number of interacting factors Preload & Contractility Heart rate Peripheral resistance
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Physiological Factors Influencing Arterial Pressure Preload & Contractility ď Ž
ď Ž
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 8
Physiological Factors Influencing Arterial Pressure Preload & Contractility(2) ď Ž
ď Ž
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 9
Physiological Factors Influencing Arterial Pressure Preload & Contractility(3)
The Nitrates are an example of preload reducing agents See: CV Pharmacology Anti-Anginal Agents Ppt 10
Physiological Factors Influencing Arterial Pressure Heart Rate Heart rate: Since 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 (ßadrenergic receptor antagonists, e.g.) Heart Rate X Stroke Volume = Cardiac Output (CO)
Cardiac Output X Total Peripheral Resistance (TPR) = Mean Arterial Pressure (MAP) 11
Physiological Factors Influencing Arterial Pressure Peripheral resistance Peripheral resistance: ď Ž For a given cardiac output, blood pressure depends only on peripheral resistance ď Ž Some antihypertensive drugs act to reduce peripheral resistance (Also known as afterload reducing agents) 12
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 13
Anti-Hypertensive Drug Classes 1. 2. 3. 4. 5.
Diuretics Sympatholytics Vasodilators Calcium Channel Blockers Angiotensin Converting Enzyme (ACE) Inhibitor
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Anti-Hypertensive Drug Classes-1) Diuretics Thiazides
Potassium Sparing
Loop Diuretics
•Hydrochlorothiazide (HydroDIURIL) •Chlorthalidone (Hygroton) •Chlorothiazide (Diuril) •Indapamide (Lozol) •Metolazone (Zaroxolyn)
•Amiloride (Midamor) •Spironolactone (Aldactone) •Triamterene (Dyrenium)
•Furosemide (Lasix), Bumetanide (Bumex), Ethacrynic acid (Edecrin) •Torsemide (Demadex)
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Anti-Hypertensive Drug Classes2) Sympatholytics Centrally Active •Clonidine (Catapres) •Methyldopa (Aldomet) •Guanabenz (Wytensin) •Guanfacine (Tenex)
Adrenergic Neuron Blocker
Adrenoceptor Antagonists
•Guanadrel (Hylorel) •Guanethidine (Ismelin) •Reserpine
• Labetalol (Trandate, Normodyne) (alpha & beta) •Prazosin (Minipress) (alpha), Terazosin (Hytrin) (alpha)
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Anti-Hypertensive Drug Classes3) Vasodilators
Diazoxide (Hyperstat)
Hydralazine (Apresoline)
Minoxidil (Loniten)
Nitroprusside sodium (Nipride)
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Anti-Hypertensive Drug Classes4) Calcium Channel Blockers •Dihydropyridines •Amlodipine (Norvasc), Felodipine (Plendil) •Nimodipine •Isradipine •Nicardipine •Nifedipine
•Non-Dihydropyridines •Bepridil (Vascor) •Diltiazem (Cardiazem) •Verapamil (Isoptin, Calan)
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Anti-Hypertensive Drug Classes5) Angiotensin Converting Enzyme Inhibitors
•Benazepril (Lotensin) •Captopril (Capoten) •Enalapril (Vasotec) •Fosinopril (Monopril) •Lisinopril (Prinvivil, Zestril)
•Moexipril (Univasc) •Quinapril (Accupril) •Ramipril (Altace) •Losartin (Cozaar), Irbesartin*** *** ***angiotensin receptor blocker
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Antihypertensive Agents: Categories Discussion
Adrenergic agents Angiotensin-converting enzyme inhibitors Angiotensin II receptor blockers Calcium channel blockers Diuretics Vasodilators 20
Antihypertensive Agents: Categories
Adrenergic Agents
Alpha1 blockers Beta blockers (cardioselective and nonselective) Centrally acting alpha blockers Combined alpha-beta blockers Peripheral-acting adrenergic agents
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Antihypertensive Agents: Mechanism of Action Adrenergic Agents
Alpha1 Blockers (peripherally acting) ď Ž ď Ž
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 22
Antihypertensive Agents: Adrenergic Agents Alpha1 Blockers
doxazosin (Cardura) prazosin (Minipress) terazosin (Hytrin)
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Antihypertensive Agents: Mechanism of Action Adrenergic Agents Central-Acting Adrenergics ď Ž ď Ž
Stimulate alpha2-adrenergic receptors Sympathetic outflow from the CNS is decreased Result: decreased blood pressure
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Antihypertensive Agents: Adrenergic Agents Central-Acting Adrenergics ď Ž ď Ž
clonidine (Catapres) methyldopa (Aldomet) (drug of choice for hypertension in pregnancy)
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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
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Antihypertensive Agents: Adrenergic Agents Adrenergic Neuronal Blockers (peripherally acting)
reserpine guanadrel (Hylorel) guanethidine (Ismelin)
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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
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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
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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
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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
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Antihypertensive Agents: Adrenergic Agents Side Effects Most common: Other:
dry mouth drowsiness sedation constipation headaches sleep disturbances nausea rash cardiac disturbances (palpitations)
HIGH INCIDENCE OF ORTHOSTATIC HYPOTENSION
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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 33
Antihypertensive Agents: Mechanism of Action ACE Inhibitors RAAS: Renin Angiotensin-Aldosterone System ď Ž
When the enzyme angiotensin I is converted to angiotensin II, the result is potent vasoconstriction and stimulation of aldosterone 34
Antihypertensive Agents: Mechanism of Action(2) ACE Inhibitors ď Ž
ď Ž
Result of vasoconstriction: increased systemic vascular resistance and increased afterload
Therefore, increased BP
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Antihypertensive Agents: Mechanism of Action(3) ACE Inhibitors ď Ž
ď Ž
Aldosterone stimulates water and sodium resorption. Result: increased blood volume, increased preload, and increased B
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Antihypertensive Agents: Mechanism of Action(4) ACE Inhibitors ď Ž
ď Ž
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 37
Diagram illustrates the reninangiotensin-aldosterone axis
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Antihypertensive Agents ACE Inhibitors captopril (Capoten) ď Ž
Short half-life, must be dosed more frequently than others
enalapril (Vasotec) ď Ž
The only ACE inhibitor available in oral and parenteral forms 40
Antihypertensive AgentsACE Inhibitors(2) lisinopril (Prinivil and Zestril) quinapril (Accupril) ď Ž
ď Ž
Newer agents, long half-lives, once-aday dosing Several other agents available
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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 42
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!! 43
Antihypertensive Agents: Categories Angiotensin II Receptor Blockers (A II Blockers or ARBs)
Newer class Well-tolerated Do not cause coughing
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Antihypertensive Agents: Mechanism of Action Angiotensin II Receptor Blockers ď Ž
ď Ž
Allow angiotensin I to be converted to angiotensin II, but block the receptors that receive angiotensin II Block vasoconstriction and release of aldosterone
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Antihypertensive Agents: Angiotensin II Receptor Blockers
losartan (Cozaar) eposartan (Teveten) valsartan (Diovan) irbesartan (Avapro) candesartan (Atacand) telmisartan (Micardis) 46
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
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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
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Antihypertensive Agents: Categories Calcium Channel Blockers
Benzothiazepines Dihydropyridines Phenylalkylamines
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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 50
Antihypertensive AgentsCalcium Channel Blockers
Benzothiazepines:
Phenylalkamines:
diltiazem (Cardizem, Dilacor)
verapamil (Calan, Isoptin)
Dihydropyridines:
amlodipine (Norvasc), bepridil (Vascor), nicardipine (Cardene) nifedipine (Procardia), nimodipine (Nimotop)
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Antihypertensive Agents: Therapeutic Uses Calcium Channel Blockers
Angina Hypertension Dysrhythmias Migraine headaches
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Antihypertensive Agents: Side Effects Calcium Channel Blockers
Cardiovascular
Gastrointestinal
hypotension, palpitations, tachycardia constipation, nausea
Other
rash, flushing, peripheral edema, dermatitis 53
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
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Antihypertensive Agents: Mechanism of Action Vasodilators
Directly relaxes arteriolar smooth muscle
Result:
decreased systemic vascular response,
decreased afterload, and PERIPHERAL VASODILATION
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Nitric Oxide and Vasodilation After receptor stimulation, L-argininedependent 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?re f=7003sc
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Antihypertensive Agents Vasodilators
diazoxide (Hyperstat) hydralazine HCl (Apresoline) minoxidil (Loniten, Rogaine) sodium nitroprusside (Nipride, Nitropress)
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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
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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 59
Stepwise Approach to Tx of Antihypertensive Essential HTN Medication Sequence
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 60
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, 61