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IVMS-CV-Pharmacology- Anti-hypertensive Agents

Individualized Webcam facilitated and e-Classroom USMLE Step 1 Tutorials with Dr. Cray. 1 BMS Unit is 4 hr. General Principles and some Organ System require multiple units to complete in preparation for the USMLE Step 1 A HIGH YIELD FOCUS IN Biochemistry / Cell Biology, Microbiology / Immunology and the 4 P’s-Phiso, Pathophys, Path and Pharm. Webcam Facilitated USMLE Step 2 Clinical Knowledge and Clinical Skills diadactic tutorials /1 Unit is 4 hours, individualized one-on-one and group sessions, Including all Internal Medicine sub-sub-specitialities. For questions or more information.. drcray@imhotepvirtualmedsch.com

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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
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
3
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
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/guideline
s/hypertension/phycard.pdf
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
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

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IVMS-CV-Pharmacology- Anti-hypertensive Agents

  • 1. 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
  • 2. 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
  • 3. 3 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
  • 4. 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/guideline s/hypertension/phycard.pdf
  • 5. 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
  • 6. 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
  • 7. 7 Physiological Factors Influencing Arterial Pressure Arterial pressure is determined by a number of interacting factors  Preload & Contractility  Heart rate  Peripheral resistance
  • 8. 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
  • 9. 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
  • 10. 10 Physiological Factors Influencing Arterial Pressure Preload & Contractility(3) The Nitrates are an example of preload reducing agents See: CV Pharmacology Anti-Anginal Agents Ppt
  • 11. 11 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 (ß- adrenergic receptor antagonists, e.g.)  Heart Rate X Stroke Volume = Cardiac Output (CO)  Cardiac Output X Total Peripheral Resistance (TPR) = Mean Arterial Pressure (MAP)
  • 12. 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)
  • 13. 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
  • 14. 14 Anti-Hypertensive Drug Classes 1. Diuretics 2. Sympatholytics 3. Vasodilators 4. Calcium Channel Blockers 5. Angiotensin Converting Enzyme (ACE) Inhibitor
  • 15. 15 Anti-Hypertensive Drug Classes-1) Diuretics Thiazides •Hydrochlorothiazide (HydroDIURIL) •Chlorthalidone (Hygroton) •Chlorothiazide (Diuril) •Indapamide (Lozol) •Metolazone (Zaroxolyn) Potassium Sparing •Amiloride (Midamor) •Spironolactone (Aldactone) •Triamterene (Dyrenium) Loop Diuretics •Furosemide (Lasix), Bumetanide (Bumex), Ethacrynic acid (Edecrin) •Torsemide (Demadex)
  • 16. 16 Anti-Hypertensive Drug Classes- 2) Sympatholytics Centrally Active •Clonidine (Catapres) •Methyldopa (Aldomet) •Guanabenz (Wytensin) •Guanfacine (Tenex) Adrenergic Neuron Blocker •Guanadrel (Hylorel) •Guanethidine (Ismelin) •Reserpine Adrenoceptor Antagonists • Labetalol (Trandate, Normodyne) (alpha & beta) •Prazosin (Minipress) (alpha), Terazosin (Hytrin) (alpha)
  • 17. 17 Anti-Hypertensive Drug Classes- 3) Vasodilators Diazoxide (Hyperstat) Hydralazine (Apresoline) Minoxidil (Loniten) Nitroprusside sodium (Nipride)
  • 18. 18 Anti-Hypertensive Drug Classes- 4) Calcium Channel Blockers •Dihydropyridines •Amlodipine (Norvasc), Felodipine (Plendil) •Nimodipine •Isradipine •Nicardipine •Nifedipine •Non-Dihydropyridines •Bepridil (Vascor) •Diltiazem (Cardiazem) •Verapamil (Isoptin, Calan)
  • 19. 19 Anti-Hypertensive Drug Classes- 5) 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
  • 20. 20 Antihypertensive Agents: Categories Discussion  Adrenergic agents  Angiotensin-converting enzyme inhibitors  Angiotensin II receptor blockers  Calcium channel blockers  Diuretics  Vasodilators
  • 21. 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
  • 22. 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
  • 23. 23 Antihypertensive Agents: Adrenergic Agents Alpha1 Blockers  doxazosin (Cardura)  prazosin (Minipress)  terazosin (Hytrin)
  • 24. 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
  • 25. 25 Antihypertensive Agents: Adrenergic Agents Central-Acting Adrenergics  clonidine (Catapres)  methyldopa (Aldomet) (drug of choice for hypertension in pregnancy)
  • 26. 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
  • 27. 27 Antihypertensive Agents: Adrenergic Agents Adrenergic Neuronal Blockers (peripherally acting)  reserpine  guanadrel (Hylorel)  guanethidine (Ismelin)
  • 28. 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
  • 29. 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
  • 30. 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
  • 31. 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
  • 32. 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
  • 33. 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
  • 34. 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
  • 35. 35 Antihypertensive Agents: Mechanism of Action(2) ACE Inhibitors  Result of vasoconstriction: increased systemic vascular resistance and increased afterload  Therefore, increased BP
  • 36. 36 Antihypertensive Agents: Mechanism of Action(3) ACE Inhibitors  Aldosterone stimulates water and sodium resorption.  Result: increased blood volume, increased preload, and increased B
  • 37. 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
  • 38. 38 Diagram illustrates the renin- angiotensin-aldosterone axis
  • 39. 39
  • 40. 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
  • 41. 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
  • 42. 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
  • 43. 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!!
  • 44. 44 Antihypertensive Agents: Categories Angiotensin II Receptor Blockers (A II Blockers or ARBs)  Newer class  Well-tolerated  Do not cause coughing
  • 45. 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
  • 46. 46 Antihypertensive Agents: Angiotensin II Receptor Blockers  losartan (Cozaar)  eposartan (Teveten)  valsartan (Diovan)  irbesartan (Avapro)  candesartan (Atacand)  telmisartan (Micardis)
  • 47. 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
  • 48. 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
  • 49. 49 Antihypertensive Agents: Categories Calcium Channel Blockers  Benzothiazepines  Dihydropyridines  Phenylalkylamines
  • 50. 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
  • 51. 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)
  • 52. 52 Antihypertensive Agents: Therapeutic Uses Calcium Channel Blockers  Angina  Hypertension  Dysrhythmias  Migraine headaches
  • 53. 53 Antihypertensive Agents: Side Effects Calcium Channel Blockers  Cardiovascular  hypotension, palpitations, tachycardia  Gastrointestinal  constipation, nausea  Other  rash, flushing, peripheral edema, dermatitis
  • 54. 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
  • 55. 55 Antihypertensive Agents: Mechanism of Action Vasodilators  Directly relaxes arteriolar smooth muscle  Result: decreased systemic vascular response, decreased afterload, and PERIPHERAL VASODILATION
  • 56. 56 Nitric 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?re f=7003sc
  • 57. 57 Antihypertensive Agents Vasodilators  diazoxide (Hyperstat)  hydralazine HCl (Apresoline)  minoxidil (Loniten, Rogaine)  sodium nitroprusside (Nipride, Nitropress)
  • 58. 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
  • 59. 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
  • 60. 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
  • 61. 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,