Renin Angiotensin System

Trachte

Cardiovascular Medicine

9/23/08 11:00-11:59 AM

---->renin Converting Enzyme

Angiotensinogen---> Angiotensin I --> Angiotensin II --> Receptor --> Vasoconstriction

> Aldosterone

(from adrenal)

Renin Physiology

• Secreted by juxtaglomerular cells of kidney

• Released by:– decreased renal artery pressure – decreased Na+ load to macula densa – sympathetic nerve activation – Prostaglandins

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

Angiotensinogen

2 plasma macroglobulin

• Produced by liver

• Function is as precursor to angiotensin I

• Formation is stimulated by estrogens, angiotensin II and glucocorticoids

Angiotensin I

• Decapeptide with low potency

• Precursor to angiotensin II

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

Converting Enzyme (dipeptidyl peptidase) (ACE)

• Converts angiotensin I to II

• Also degrades bradykinin

• Zn++ containing enzyme

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

Clinical applications

• angiotensin amide (Hypertensin) raises blood pressure (never used)

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)

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)

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)

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

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

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

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

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)

Which of the following is most likely drug x:

1 2 3 4 5

20% 20% 20%20%20%a) Angiotensin I

b) Angiotensin II

c) Bradykinin

d) Dobutamine

e) Phenylephrine

302010070

100

130

TIME (min)

Blood Pressure (mmHg)

Drug X Drug XEnalapril

Miscellaneous Other Vasoactive Agents

• Arachidonic Acid Metabolites– prostacyclin (iloprost) vasodilates and prevents platelet

aggregation– thromoxane A2 vasoconstricts and aggregates platelets– prostaglandin E2 (Dinoprostone) or prostagandin F2

(carbaprost) produce hyperemia (vasodilation) and sensitization to pain

– prostaglandins also maintain patency of ductus arteriosus in the fetus

– Leukotriene C4 and D4 cause hypotension• believed to be the primary cause of hypotension in anaphylaxis

Miscellaneous Other Vasoactive Agents

• Histamine vasodilates (involves both H1 and H2 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

Congestive Heart Failure9/23/08

• 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?catID=29&itemID=161

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

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

Congestive Heart Failure

• Cardiogenic– Contractility decreased (stenosis, anemia, Infarction)– Arrhythmias– Hypertension

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

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

Inhibitors of the Renin-angiotensin system

• balanced vasodilators reducing both preload and afterload (increase cardiac output)

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

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

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

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

Angiontensinogen ‡ angiotensin I ‡ angiotensin II Aldosterone

Adrenal glomerulosa

Aldo Receptor

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

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

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

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

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

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 O2

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

Dobutamine (Dobutrex) (i.v.)

• Mechanism of Action - ß1 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

Dopamine (Inotropin, Dopastat) (i.v.)

• preferential dilation of the renal vasculature - diuresis

• not used commonly in CHF any more

• increases contractility by acting on ß1 receptors

• undesirable effects can include: tachycardia, tachyarrhythmias, angina, vasoconstriction, dyspnea, headache, nausea, vomiting

• undesirable method of administration - i.v.

Milrinone (Corotrope)

• inotrope

• vasodilator, decreases TPR

• increases cAMP by inhibiting phosphodiesterase

• approved for CHF refractory to other inotropic agents

Norepinephrine Dobutamine G Protein AMP (+) Adenylyl Cyclase cAMP (-) Milrinone

Beta1 Receptor

Phosphodiesterase

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

Pulmonary Artery

P = 25/9

Albumin

Oncotic P = 25

No fluid exudation from the artery until hydrostatic Pressure exceeds 25 mmHg.

If fluid backs up from a failing left ventricle, pressure rises, fluid leaks out and

patients experience shortness of breath.

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

Which drug shifts curve to the left?

1 2 3 4 5

20% 20% 20%20%20%

a) Digoxinb) Enalaprilc) Furosemided) Phenylephrinee) Propranolol

1050-50

2

4

6

8

Cardiac OutputVenous Return

RIGHT ATRIAL PRESSURE (mmHg)

Cardiac Output (L/min)

Which drug shifts curve up?

1 2 3 4 5

20% 20% 20%20%20%a) Digoxinb) Enalaprilc) Furosemided) Phenylephrinee) Propranolol

1050-50

2

4

6

8

Cardiac OutputVenous Return

RIGHT ATRIAL PRESSURE (mmHg)

Cardiac Output (L/min)