1. Renin Angiotensin System Trachte Cardiovascular Medicine 9/23/08 11:00-11:59 AM

3. Renin Physiology Secreted by juxtaglomerular cells of kidney Released by: – decreased renal artery pressure –decreased Na + load to macula densa –sympathetic nerve activation –Prostaglandins

4. Renin Physiology Release inhibited by: – ß receptor antagonists –atrial natriuretic peptide (ANP) –increased renal artery pressure –increased sodium load to macula densa –cyclooxygenase antagonists Is an enzyme which cleaves angiotensin I from angiotensinogen Half-life of 15 to 30 min

5. Angiotensinogen  2 plasma macroglobulin Produced by liver Function is as precursor to angiotensin I Formation is stimulated by estrogens, angiotensin II and glucocorticoids

6. Angiotensin I Decapeptide with low potency Precursor to angiotensin II

7. Angiotensin II Octapeptide Activity –vasoconstrictor - increases blood pressure –steroidogenic agent - retains sodium; promotes aldosterone secretion –cardiac- promotes growth; also inotropic –increases outflow of norepinephrine from nerves and adrenal –central effects - thirst, ADH and ACTH release, sympathetic stimulation Degradation

8. Converting Enzyme (dipeptidyl peptidase) (ACE) Converts angiotensin I to II Also degrades bradykinin Zn ++ containing enzyme

9. Mechanism of Angiotensin II Action Inositol trisphosphate - generated from phosphatidyl inositol bis phosphate via phospholipase C activation (mediated by type 1 receptor ) Another receptor (type 2) appears to reduce blood pressure

10. Clinical applications angiotensin amide (Hypertensin) raises blood pressure (never used)

11. Angiotensin II type I Antagonists Losartan (Cozaar)- Antihypertensive (25-100 mg once daily) –Diminishes effects of the renin-angiotensin system by inhibiting type I receptors –advantage: does not cause cough like converting enzyme inhibitors –Side effects: dizziness and hepatic dysfunction are potential side effects –metabolized in liver to a more active substance, excreted in bile or urine –avoid in pregnancy- ACE inhibitors increase fetal morbidity and mortality; therefore, losartan should also –less effective in blacks than Caucasians, as are converting enzyme inhibitors –thiazide diuretics dramatically increase antihypertensive actions, as they do with converting enzyme inhibitors (reduce dose if they are combined)

12. Angiotensin II type I Antagonists Candesartan (Atacand) 8 to 32 mg once daily Eprosartan (Teveten) 400 to 800 mg once or twice daily Irbesartan (Avapro) administered once daily (150-300 mg) Losartan (Cozaar)- 25-100 mg once or twice daily Olmesartan (Benicar)- 20-40 mg once daily Telmisartan (Micardis) 40 to 80 mg once daily Valsartan (Diovan)- administered once daily (80 to 320 mg) Cost is $49 to $62 per month (Medical Letter 49: 30, 2007)

13. Converting Enzyme Inhibitors Benazopril (Lotensin) CAPTOPRIL (Capoten) ENALAPRIL (Vasotec) Fosinopril (Monopril) LISINOPRIL (Prinivil; Zestril) Moexipril (Univasc) Perindopril (Aceon) quinapril (Accupril) Ramipril (Altace) Trandolapril (Mavik) Cost $20 to $45 per month (Medical Letter 49: 30, 2007)

14. Converting Enzyme Inhibitors orally active (25-150 mg captopril); 10-40 mg once daily for enalapril; 20-40 mg once daily for lisinopril; 5-20 mg in one or two doses for quinapril [from Med. Let. 41: 23, 1999] extremely potent block of conversion to biologically active compounds (angiotensin II) antihypertensive also utilized in heart failure (improve survival) improve survival in post-MI (myocardial infarction) patients reduces or prevents renal damage in diabetic nephropathy

15. Converting Enzyme Inhibitors side effects include cough, proteinuria, rash, dysgeusia (inability to taste), hypotension, hyperkalemia, angioedema, teratogenic (increases frequency of fetal death oligohydramnios, growth restriction, hypotension, anuria, renal tubular dysgenesis, patent ductus arteriosus reference is Barr, Teratology 50: 399-409, 1994 ENALAPRIL is a prodrug These agents are most effective when combined with a diuretic (synergism)- diuretic decreases sodium, resulting in increased renin release, so blood pressure is more dependent on the renin-angiotensin system

16. Renin Inhibitors Aliskirin (Tekturna) –Blocks renin activity –Reduces both Angiotensin I and II levels –Reduces Aldosterone levels –Reduces blood pressure –Approved for treatment of hypertension

17. Renin Inhibitors Aliskirin (Tekturna) –Oral dose of 150-300 mg once daily –Less effective in African Americans than in Caucasions –Effects potentiated by thiazide diuretics Thiazides deplete Na, making blood pressure more dependent on the renin-angiotensin system Combination reduces blood pressure more impressively than either alone

18. Renin Inhibitors Aliskirin (Tekturna) –Does not increase bradykinin levels, like converting enzyme inhibitors do –Bradykinin is thought to mediate the cough and angioedema side effects of ACE inhibitors –Caused some mucosal hyperplasia and colon tumors in animal trials- a major concern –Cost is about $80/month (Medical Letter 49: 30, 2007)

19. Which of the following is most likely drug x: a) Angiotensin I b) Angiotensin II c) Bradykinin d) Dobutamine e) Phenylephrine

20. Miscellaneous Other Vasoactive Agents Arachidonic Acid Metabolites –prostacyclin (iloprost) vasodilates and prevents platelet aggregation –thromoxane A 2 vasoconstricts and aggregates platelets –prostaglandin E 2 (Dinoprostone) or prostagandin F 2  (carbaprost) produce hyperemia (vasodilation) and sensitization to pain – prostaglandins also maintain patency of ductus arteriosus in the fetus –Leukotriene C 4 and D 4 cause hypotension believed to be the primary cause of hypotension in anaphylaxis

21. Miscellaneous Other Vasoactive Agents Histamine vasodilates (involves both H 1 and H 2 receptors) Endothelin, Atrial natriuretic peptide, serotonin –Endothelin is a potent vasoconstrictor – Atrial natriuretic peptide is a vasodilator that facilitates sodium excretion Serotonin is a Tryptophan metabolite ( 5- hyroxytryptamine) that can vasoconstrict or vasodilate (stored in platelets, gut and brain) Bradykinin –Vasodilator degraded by angiotensin converting enzyme

22. Congestive Heart Failure 9/23/08 good review in Medical Letter 41: 12-14, 1999 and Treatment Guidelines from Med. Lett 4: 91-94, 2006 http://www.icsi.org/knowledge/detail.asp?c atID=29&itemID=161

23. Congestive Heart Failure Objectives: –To be familiar with the therapeutic strategies in treating CHF. –To know the generic names and mechanisms of action of the six groups of drugs used to treat CHF. cardiac inotropes diuretics balanced vasodilators (converting enzyme inhibitors) aldosterone receptor antagonist (Spironolactone) ß receptor antagonists (blockers) Venodilators

24. Congestive Heart Failure Characteristics of the disease state –Cause can be left ventricular dysfunction (general discussion of treatment of this is the generic form) –Can be diastolic abnormality related to altered compliance –Can be right ventricular problem –Can be a problem with arrhythmias (lots of potential causes) Cardiogenic –Contractility decreased (stenosis, anemia, Infarction) –Arrhythmias –Hypertension

25. Congestive Heart Failure Cardiogenic –Contractility decreased (stenosis, anemia, Infarction) –Arrhythmias –Hypertension

26. Compensatory Mechanisms Sympathetic & renin-angiotensin system activation) –Tachycardia- sympathetic nervous system activation –Arteriole Constriction –Renal sodium and water retention, edema –Afterload elevated relative to cardiac output and venous return (preload increased) –involves activation of both the renin-angiotensin and sympathetic nervous systems

27. Therapeutic Strategies Objective is to improve myocardial performance (i.e., repress compensatory mechanisms and thereby restore cardiac output and tissue perfusion) Pharmacology –Compensatory Mechanism - »Inhibit sympathetic nervous system »renin-angiotensin inhibition –Inhibition of aldosterone (sodium retention) –Vasodilation - decrease afterload or preload –Cardioselective - increase contractility –Volume Depletion - diuresis, decrease preload –Other Therapies- Restrict salt intake

28. Inhibitors of the Renin- angiotensin system balanced vasodilators reducing both preload and afterload (increase cardiac output)

29. Inhibitors of the Renin- angiotensin system CAPTOPRIL (Capoten), ENALAPRIL (Vasotec) & LISINOPRIL (p.o.,i.v.) »vasodilation - inhibits Angiotensin II (constrictor) formation and inhibits the degradation of Bradykinin (dilator) » diuresis »reduces preload and afterload »decreases filling pressure »increases cardiac output »reduces heart size (hypertrophic effect of angiotensin II) »improves survival

30. Inhibitors of the Renin- angiotensin system Losartan (Cozaar)- angiotensin receptor antagonist –Was superior to converting enzyme inhibitors in one large trial but generally is regarded as inferior or equal Aliskiren (Tekturna)- not known if it is a good treatment for heart failure but should be

31. ß Receptor Antagonists- Carvedilol (Coreg) slows progression of disease in milder forms of heart failure, improves survival 33% believed to prevent deleterious effects of catecholamines on the heart Metoprolol also known to have beneficial effects in heart failure similar to carvedilol

32. Aldosterone Receptor Antagonists Spironolactone (Aldactone) Eplerenone (Inspra) Activation of Aldosterone receptors on heart contribute to deleterious remodeling in congestive heart failure Beneficial to block aldosterone action

34. Vasodilators Strategy is if myocardium can still contract then decreasing preload will reduce the stress on the heart and reducing afterload will increase cardiac output, stroke volume and ejection fraction

35. Vasodilators Arterial vasodilators - decrease afterload, increase cardiac output, little or no change in preload –Hydralazine (Apresoline) (p.o.) effectively improves survival when combined with isosorbide dinitrate; no beneficial effect on survival when given alone; most effectively in African Americans –Minoxidil (Loniten) (p.o.) debated use, one study minoxidil worsened CHF

36. Vasodilators Nitrovasodilators (ISOSORBIDE DINITRATE, NITROGLYCERIN) (p.o. sublingual) –in general, more potent venodilators than arteriolar dilators- activate soluble guanylyl cyclase to increase cGMP –ISOSORBIDE DINITRATE ( Isordil, Sorate) (p.o.) is demonstrated to be effective for up to 3 months –most useful in heart failure resulting from ischemic disease –combination therapy with Isosorbide Dinitrate & Dobutamine, large increase in CO, reduced pulmonary wedge pressure and reduction in systemic and pulmonary resistance –combination of Isosorbide dinitrate & hydralazine effectively improves survival, most dramatically in African American patients (N Engl J Med. 2004 Nov 11;351(20):2049-57.) –can cause headache

37. Vasodilators Mixed vasodilators- dilate both arteries and veins –Converting enzyme inhibitors or angiotensin receptor blockers are classics Brain natriuretic peptide (Nesiritide) –naturally-occurring diuretic substance produced by the ventricle in heart failure –peptide, so needs to be infused i.v. –for stage IV heart failure –B-type natriuretic peptide levels are great indicator of heart failure severity

38. Diuretics - decrease blood volume natriuretic - salt loss, decrease edema used if volume overload cannot be controlled by other drugs FUROSEMIDE (Lasix), ethacrynic acid (loop diuretics) most common cautions - hypokalemia, alkalosis, electrolyte imbalances no proof that FUROSEMIDE improves survival

39. Inotropic Agents Cardiac Glycosides (Digitalis, Digitoxin, DIGOXIN) (p.o., i.v.) –Cardiac output is increased via increased stroke volume –Heart rate decrease by vagal stimulation –Total Peripheral Resistance decreased because of improved perfusion (reduced sympathetic activation) –Reduced heart size and wall tension (T = P x r/2) reduces O 2 demand –Blood volume decreased due to increased renal perfusion –Best for failure caused by chronic overload (hypertension, valvular lesions) –Toxicity - GI most common, A-V block, arrhythmias –Mechanism of action is to suppress Na/K pump

40. Dobutamine (Dobutrex) (i.v.) Mechanism of Action - ß 1 agonist (positive inotrope) Untoward effects- Arrhythmias, headache, palpitations, dyspnea, nausea Pharmacokinetics –Poor oral absorption (i.v. administration) –Half-life = 2 min Therapeutic utility- Acute management of CHF

41. Dopamine (Inotropin, Dopastat) (i.v.) preferential dilation of the renal vasculature - diuresis not used commonly in CHF any more increases contractility by acting on ß 1 receptors undesirable effects can include: tachycardia, tachyarrhythmias, angina, vasoconstriction, dyspnea, headache, nausea, vomiting undesirable method of administration - i.v.

42. Milrinone (Corotrope) inotrope vasodilator, decreases TPR increases cAMP by inhibiting phosphodiesterase approved for CHF refractory to other inotropic agents

44. Actual Treatment Acute- must relieve symptoms Treat with: –loop diuretics (Furosemide) to remove fluid –Morphine sulfate (venodilation plus analgesic) –Nitroprusside or Nitroglycerine (i.v.) –Oxygen

46. Actual Treatment Chronic- must relieve symptoms, reduce hospitalization & improve survival –Angiotensin converting enzyme inhibitor or receptor blocker- good for improving survival –Digoxin- improves quality of life (no evidence for survival effect, but can prevent hospitalization); suspected to be less effective in women –Furosemide- reduces fluid accumulation (no evidence for survival effect but can prevent hospitalization) –ß Blockers- good addition to 3 agents mentioned above but must slowly wean patient onto drug (Carvedilol [Coreg] -  & ß blocker best agent so far); improves survival equally in either gender; Metoprolol (Lopressor) also –Spironolactone (Aldactone)- aldosterone receptor antagonist definitively shown to improve survival

47. Which drug shifts curve to the left? a)Digoxin b)Enalapril c)Furosemide d)Phenylephrine e)Propranolol

48. Which drug shifts curve up? a)Digoxin b)Enalapril c)Furosemide d)Phenylephrine e)Propranolol