Congestive Heart Failure

 

 

Chapter 10:  Pharmacological Management of Congestive Heart Failure

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Congestive Heart Failure

  • The fundamental abnormality in heart failure is embodied in:

    • depression of the myocardial force-velocity relationship and length-active tension curves that result in impairment of myocardial contractility.(see Figure, right)

  •  When a normal heart transitions from the resting state (1) to exercise (2) a significant increase in ventricular performance occurs. By contrast in the failing heart, the exercise-induced increases in ventricular performance are minimal (3' to 3).

 

  • Source:  Braunwald, E   Normal and Abnormal Myocardial Function Section 3:  Disorders of the Heart:  In: Harrison's Principle of Internal Medicine, 16th Edition, p 1361 (Kasper, DL, Braunwalkd, E, Fauci, A, Hauser, S, Longo, D, Jameson, J, eds) McGraw-Hill Medical Publishing Divison, New York, 2005.--For more detailed discussion, consult this text.

See description below, also.

 

  1.  With disease progression increases in left ventricular preload causes pulmonary capillary pressure to increase

  2. which produces pulmonary congestion and dyspnea.

  3. Systemic compensatory responses to heart failure include fluid retention and increased in left ventricular afterload.(see Figure, right)

Figures from "Harrison's Principles of Internal Medicine", Thirteenth Edition, pages 995 and 996.

 

 

 

Pharmacological Management of Heart Failure

Factors Influencing Cardiac performance and Output

  1. Ventricular end-diastolic volume (preload)

  2. Atrial contraction

  3. Inotropic state (myocardial contractility)

  4. Ventricular afterload 

  5. Exercise

  • "Diagram showing the interrelations among influences on ventricular end-diastolic volume (EDV) through stretching of the myocardium and the contractile state of the myocardium.

  • Levels of ventricular EDV associated with filling pressures that result in dyspnea and pulmonary edema are shown on the abscissa.

  • Levels of ventricular performance required when the subject is at rest, while walking, and during maximal activity are designated on the ordinate.

  • The broken lines are the descending limbs of the ventricular-performance curves, which are rarely seen during life but which show the level of ventricular performance if end-diastolic volume could be elevated to very high levels." For further explanation see text.
    (Modified from E Braunwald et al: Mechanisms of Contraction of the Normal and Failing Heart. Boston, Little, Brown, 1976. http://www.lww.com)

  • Source:  Braunwald, E   Normal and Abnormal Myocardial Function Section 3:  Disorders of the Heart:  In: Harrison's Principle of Internal Medicine, 16th Edition, p 1361 (Kasper, DL, Braunwalkd, E, Fauci, A, Hauser, S, Longo, D, Jameson, J, eds) McGraw-Hill Medical Publishing Divison, New York, 2005.--For more detailed discussion, consult this text.
     

 

Reference:  Isselbacher et al. (eds): "Harrison's Principles of Internal Medicine"New York, McGraw-Hill Inc, 1994, p. 999.

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Clinical Use: Sympathomimetic Agents

Overview--Clinical Uses

Drugs Used in Treating Shock

Dopamine and Dobutamine

Dopamine

 

Dobutamine

 

Drugs in Cardiogenic Shock: Nitrates, Adrenergic Agonists, Amrinone (Inocor) and Milrinone (Primacor)

  • In cardiogenic shock precipitated by acute myocardial infarction, salvage of reversibly damaged myocardial may be accomplished by:

    • supplemental oxygen

    • i.v. nitroglycerin (decreasing preload)

    • intra-aortic balloon pump (reducing afterload)

    • surgery to repair valve pathologies or to revascularize

  • Nitroglycerin

    •  Sublingual nitroglycerin is used to relieve symptoms of angina or as a prophylactic before demanding  activities that would otherwise cause angina.

    • Angina pectoris caused by temporary myocardial ischemia is responsive to treatment by organic nitrates.

    • These agents act primarily by vasodilation (especially demodulations) which reduces myocardial preload and therefore myocardial oxygen demand.

    • Nitrates also promote redistribution of blood flow to relatively ischemic areas.

    • The organic nitrates and nitrites are denitrated to produce nitric oxide (NO) which:

      •  activates guanylyl cyclase.

      •  Activation of cyclase results in increased concentrations of cyclic guanosine 3',5'-monophosphate (cyclic GMP) which results in vasodilation by increasing the rate of  light-chain myosin dephosphorylation.

      •  Nitric oxide synthetase produces endogenous nitrates by action on L-arginine.

    • Some arteriolar dilation, evidenced by flushing and dilation of meningeal arterial vessels, is responsible for headache associated with nitroglycerin use.

  • Cardiogenic Shock may be caused myocardial stunning due to prolonged cardiopulmonary bypass.

    • Dopamine (Intropin) and Dobutamine (Dobutrex) may be useful as positive inotropic agents

      • Dobutamine (Dobutrex) may be preferable because of a decreased likelihood of increasing heart rate and peripheral resistance (increasing afterload increases myocardial work).

    • Amrinone (Inocor) and milrinone (Primacor) (phosphodiesterase inhibitors) have positive inotropic effects that may be useful if other agents are ineffective.

      • Amrinone (Inocor) and milrinone (Primacor) are bipyridine derivatives that are relatively selective inhibitors of cGMP-inhbited, cyclic AMP phosphodiesterase (type III).

      • These agents cause vasodilation (decreased afterload) and increase myocardial contractility.

      •  Milrinone (Primacor) is the agent of choice among the phosphodiesterase inhibitors for short-term parenteral support in severe heart failure patients.

        • Oral formulations are not used due to intolerable side-effects including increases in mortality.

      •  Adverse Effects:  Amrinone (Inocor) has been associated with a reversible thrombocytopenia.

  • Congestive Heart Failure

    • adrenergic receptor agonists have had limited use in chronic management of congestive heart failure.

    • In congestive failure, a significant loss of 1 receptors (50%) occurs. Loss of receptor number and desensitization limit adrenergic receptor agonist efficacy.

     

Hollenberg, S.M. and Parrillo, J.E., Shock, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 215-222

Hoffman, B.B and Lefkowitz, R.J, Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.222-224.

Stoelting, R.K., "Sympathomimetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, p.259.

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Clinical Manifestations and Physical Findings in Congestive Heart Failure

  • Dyspnea: The most common symptom of heart failure, dyspnea or respiratory distress occurs because of increased effort of breathing.

    • Dyspnea occurs initially upon exertion, but in advanced CHF may occur at rest.

    • Cardiac dypsnea is usually seen in patients with increased pulmonary venous and capillary pressure.

      • The combination of interstitial pulmonary edema and vessel enlargement result in reduced lung compliance and increased respiratory muscle work of breathing.

  • Enhanced activity of respiratory muscles further compromise available oxygen and contributes to the sensation of breathlessness.

  • Orthopnea, dyspnea while recumbent, is due fluid redistribution from the lower extremities into the chest with a resultant increase in pulmonary capillary hydrostatic pressure.

  • Paroxysmal (nocturnal) dyspnea is a sudden-onset of severe shortness of breath and coughing, awakening the patient.

    • Factors that produce paroxysmal dyspnea include:

      •  depression of respiratory center during sleep (decreases arterial oxygen)

      •  decreased ventricular function due to decreased sympathetic tone (decrease myocardial contractility and hence cardiac output) and

      •  redistribution of fluid to the chest.

Acute pulmonary edema: severe form of cardiac asthma

 

  • Initially, the edema is found in the lower lobes; however, in advanced disease all lobes may be involved.

  • Sectioning of the lobes reveals a sanguineous fluid consisting of a mixture of air and edema fluid.

    • Loop diuretics such as furosemide, bumetanide, torsemide, and ethacrynic acid are effective in reducing pulmonary edema in CHF.

  •  By intravenous administration a pronounced naturesis may begin within minutes

    • Furosemide (Lasix), bumetanide (Bumex), torsemide (Demadex), and ethacrynic acid (Edecrin) are "high-ceiling" loop diuretics acting primarily at the ascending limb of the loop of Henle.

      • The effectiveness of these agents is related to their site of action because reabsorption of about 30 - 40% of the filtered sodium and chloride load occurs at the ascending loop.

      • Distal sites are not able to compensate completely for this magnitude of reduction of NaCl reabsorption.

    • Loop diuretics increase urinary Ca2+ in contrast to the action of thiazides.

    • Loop diuretics also increase renal blood flow by decreasing renal vascular resistance.

    • These drugs are beneficial in managing systemic and pulmonary fluid overload produced by congestive heart failure (CHF).

      • By i.v. administration they are particularly effective in resolving acute pulmonary edema.

    • Adverse Effects:

      • Ototoxicity

      • Furosemide and ethacrynic acid block renal excretion of uric acid by competition with renal secretory and biliary secretory systems.Therefore these agents can precipitate gout.

      • Potassium depletion.

  • Figure and description above adapted from "Robbins: The Pathological Basis of Disease" Fifth Edition, p. 96

Pulmonary Edema

  • Pulmonary edema is common in congestive heart failure.

  • As pulmonary capillary pressures increase, the initial fluid excess is removed by increased lymphatic drainage.

  • When lymphatic system capacity is exceeded, pulmonary edema occurs.

  • Radiographic signs include septal lines, bronchial wall thickening and subpleural pulmonary edema.

  • This radiograph illustrates generalized fissural thickening and lack of clarity of intrapulmonary vessels and septal lines.

  • Figure above and description from "Imaging Diseases of the Chest" , p. 388, by Peter Armstrong, Alan G. Wilson, and Paul Dee, Yearbook Medical Publishers, Inc. 1990.

 

 

  •  Cardiac asthma, related to paroxysmal dyspnea, is characterized by wheezing due to bronchospasm.

  • Acute pulmonary edema, however, involves a significant elevation of pulmonary capillary pressure leading to alveolar edema, extreme shortness of breath and rales.

    • Expectoration of blood-tinged fluid may occur.

  • Acute pulmonary edema may be fatal.

  • Fatigue, weakness and reduced exercise capacity are common in congestive heart failure patients.

    •  Exercise capacity is reduced because increased cardiac output required to support increased levels of physical activity is unavailable or inadequate.

  • Pulmonary Rales

  • Peripheral (cardiac) edema is commonly seen symmetrically in the legs, particular in the pretibial region and ankles.

    • Peripheral Edema

      • Subcutaneous edema of the legs is an important and common manifestation of congestive heart failure.

        • This type of edema is termed "dependent" since it is influenced by gravity.

        • If finger pressure over edematous subcutaneous tissue squeezes out fluid and produces depression, the edema is referred to as "pitting".

      • Loop diuretics such as furosemide, bumetanide, torsemide, and ethacrynic acid are effective in reducing peripheral edema in CHF.

      • Figure above and description adapted from "Robbins: The Pathological Basis of Disease" Fifth Edition, p. 96

  • Ascites and pleural effusion. Pleural effusion results from increased pulmonary capillary hydrostatic pressure and the attendant movement of fluid into the pleural cavity.

    • Congestive Hepatomegaly

    • Jaundice

  • Cardiac Cachexia. Serious weight loss and cachexia may occur in chronic, severe congestive heart failure due to:

    1. increased circulating tumor necrosis factor

    2. hepatomegaly, and abdominal fullness

    3. increased metabolic rate need to support the increased effort of breathing

    4. impairment of intestinal absorption due to intestinal venous congestion

    5. anorexia, nausea, vomiting due to digitalis intoxication, congestive

    6. protein-losing enteropathy (rare)

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Aspects of Digitalis (cardiac glycosides)

 

Cardiac Glycoside: Structure 

 

Digoxin

  • Cardiac glycosides are inhibitors of sodium and potassium transmembrane transport by binding to the alpha subunit of Na+ -K+ -ATPase.

  • The structure of digoxin is shown at the right and the lactone, steroid nucleus, and sugar residue component moieties illustrated.

  • Removal of the glycoside moiety only minimally affects Na+ -K+ -ATPase binding but changes pharmacokinetic behavior. With the glycoside component removed, the resultant molecule is the "genin" or "aglycone".

  • Digitoxin differs from digoxin only by the lack of a hydroxyl group at C12. This difference changes the hydrophilicity of the compound and affects its pharmacokinetics.

  • top figure: from: "Goodman and Gilman's The Pharmacological Basis of Therapeutics, Ninth Edition, p. 810.

 

  • Positive inotropic responses to cardiac glycosides results from increasing calcium concentrations in the vicinity of myofilaments during excitation.

  • Increased calcium is secondary to an increase in intracellular sodium which occurs because of Na+ -K+ -ATPase inhibition. Na+ -K+ -ATPase inhibition is caused by digitalis.

"Applied Therapeutics: The Clinical Use of Drugs", Sixth edition, edited by Lloyd Lee-Young and Mary Ann Koda-Kimble, p 15-5, Applied Therapeutics, Inc., 1995, Seattle, WA.

  • Prolongation of the effective refractory period by enhancement of vagal tone.

  •  High concentration: increased diastolic depolarization and decreased resting membrane potential lead to enhanced automaticity and ectopy.

  • Quinidine and Digitalis Combination Treatment: Context

    • Quinidine administration results in vagal inhibition (anti-muscarinic).

    • The antimuscarinic effect of quinidine facilitates transmission of atrial impulses to the ventricles

    •  In atrial fibrillation such action can increase ventricular rate.

    • To protect against this effect digitalis (digoxin/digitoxin) may be administered because digitalis inhibits transmission through the AV node.

  • Digitalis glycosides &  Atrial fibrillation

    • Atrial fibrillation may result in a high ventricular rate.

    • Drugs which reduce ventricular rate by reducing AV nodal conduction include:

      •  Digitalis glycosides

      •  calcium channel blockers

    • ECG rhythm strip illustrating atrial fibrillation. Note the absence of "P" waves and the irregularly irregular spaced QRS complexes.

.

 

Other Useful Drugs

  • Calcium channel blockers

    •  Blocks cardiac calcium channels in slow response tissues, such as the sinus and AV nodes.

    • Useful in treating AV reentrant tachyarrhythmias and in management of high ventricular rates secondary to atrial flutter or fibrillation.

    •  Major adverse effect (i.v. administration) is hypotension. Heart block or sinus bradycardia can also occur.

  • -adrenergic receptor blockers

    • Antiarrhythmic effects are due mainly to beta-adrenergic receptor blockade. Normally, sympathetic drive results in increased in Ca2+ ,K+ ,and Cl- currents.

    • Increased sympathetic tone also increases phase 4 depolarization (heart rate goes up), and increases DAD (delayed afterdepolarizations) and EAD (early afterdepolarization) mediated arrhythmias. These effects are blocked by beta-adrenergic receptor blockers.

    • -adrenergic receptor blockers increase AV conduction time and increase AV nodal refractoriness, thereby helping to terminate nodal reentrant arrhythmias.

    • -adrenergic receptor blockade can also help reduce ventricular following rates in atrial flutter and fibrillation, again by acting at the AV node.

    • Adverse effects of beta blocker therapy can lead to fatigue, bronchospasm, depression, impotence, and attenuation of hypoglycemic symptoms in diabetic patients and worsening of severe congestive heart failure.

  •  Quinidine assists in restoring and maintaining normal sinus rhythm

    • Although classified as a sodium channel blocker, quinidine also blocks K+ channels. Most antiarrhythmic agents have such multiple actions.

    •  Sodium channel blockade results in an increased threshold and decreased automaticity.

    • Potassium channel blockade results in AP prolongation.

    • Quindine is used to maintain normal sinus rhythm in patients who have experienced atrial flutter or fibrillation. Also, it is used to prevent ventricular tachycardia or fibrillation.

    • Quinidine administration results in vagal inhibition (anti-muscarinic) and alpha-adrenergic receptor blockade.

    • Adverse effects include cinchonism (headaches and tinnitus), diarrhea.

    • Quinidine is also associated with torsades de pointes, a ventricular arrhythmias associated with marked QT prolongation. This potentially serious arrhythmia occurs in 2% - 8% if patients, even if they have a therapeutic or subtherapeutic quinidine blood level.

  • Digitalis Toxicity

    • Central Nervous System effects:

      • Psychiatric: delirium, fatigue, abnormal dreams

      • Visual: disturbed color vision

      • Gastrointestinal: anorexia, nausea, vomiting, abdominal pain

      • Cardiac: proarrhythmic effects

    • Electrophysiological effects:

      • Ectopic beats of AV junctional or ventricular origin.

      • First-degree AV block

 

  • Sinus bradycardia

  • Ventricular arrhythmias

  • Antidigoxin immunotherapy is an effective antidote for digitalis intoxication and is based on digoxin-specific Fab fragments.

  • Potassium administration and used of phenytoin or lidocaine be useful in managing serious ventricular arrhythmias.

 

  • Amrinone (Inocor)  /Milrinone (Primacor) 

    • Amrinone (Inocor) and milrinone (Primacor) are bipyridine derivatives that are relatively selective inhibitors of cGMP-inhbited, cyclic AMP phosphodiesterase (type III).

    • These agents cause vasodilation (decreased afterload) and increase myocardial contractility.

    •  Milrinone (Primacor) is the agent of choice among the phosphodiesterase inhibitors for short-term parenteral support in severe heart failure patients.

      •  Oral formulations are not used due to intolerable side-effects including increases in mortality.

    • Adverse Effects:  Amrinone has been associated with a reversible thrombocytopenia.

 

Angiotensin Converting Enzyme Inhibitors

  • Angiotensin II, a potent vasoconstrictor, is produced by the action of angiotensin converting enzyme (ACE) on the substrate angiotensin I.

  • Angiotensin II activity produces:

    • (a) a rapid pressor response

    • (b) a slow pressor response

    • (c) vascular and cardiac hypertrophy and remodeling.

  •  Benefits of ACE inhibitors in treating congestive heart failure and antihypertension are due to the reduction in the amount of angiotensin II produced.

    •  Reduction in angiotensin II levels results in venous and arterial vasodilation which decreases both preload and afterload.

    •  Cardiac output improvement reduces sympathetic tone which may further decrease peripheral resistance.

  •  Use of ACE inhibitors improves survival (40%) in patients with overt heart failure (CONSENSUS,1987 study).

  • ACE inhibitors are efficacious in management of congestive heart failure and hypertension and have a favorable side effect profile.

  • ACE inhibitor are advantageous in management of diabetic patients by reducing the development of diabetic neuropathy and glomerulosclerosis.

  • ACE inhibitor are probably the antihypertensive drug of choice in treatment of hypertensive patient who have hypertrophic left ventricles.

  • Hypertensive patients who have ischemic heart disease with impaired left ventricular function also benefit from ACE inhibitor treatment.

  •  ACE inhibitors reduce the normal aldosterone response to sodium loss (normally aldosterone opposes diuretic-induced sodium loss).

    • Therefore, the use of ACE inhibitors enhance the efficacy of diuretic treatment, allowing the use of lower diuretic dosages and improving control of hypertension.

    • If diuretics are administered at higher dosages in combination with ACE inhibitors significant and undesirable hypotensive reactions can occur with attendant excessive sodium loss.

  •  Reduction in aldosterone production by ACE inhibitors also affects potassium levels. The tendency is for potassium retention, which may be serious in patients with renal disease or if the patient is also taking potassium sparing diuretics, nonsteroidal anti-inflammatory agents or potassium supplements.

  • Adverse Effects:

    • Angioedema, although rare, may be potentially fat

    • ACE inhibitors should not be used during pregnancy.

    • Dry cough.

    • In renovascular hypertension, glomerular filtration pressures are maintained by vasoconstriction of the post-glomerular arterioles, an effect mediated by angiotensin II. Used of ACE inhibitors in patients with renovascular hypertension due to bilateral renal artery stenosis can therefore precipitate a significant reduction in GFR and acute renal failure.

    • Initial dose of an ACE inhibitor may precipitate an excessive hypotensive response.

High-ceiling loop diuretics and fluid load reduction in congestive heart failure.

Fluid Load Reduction in Congestive Heart Failure

Loop Diuretcs: Inhibitors of Na+-K+-2Cl- Synport

Furosemide (Lasix), Bumetanide (Bumex), Torsemide (Demadex), Ethacrynic acid (Edecrin)
  • Basic Tubular Section of the Nephron.
  • Note that the site of action for "High-Ceiling" Diuretics is in the Thick Ascending Limb of the Loop of Henle.
  • Furosemide, bumetanide, ethacrynic acid, and torsemide are high-ceiling or loop diuretics that increase significantly Na+ and Cl- excretion by blocking the Na+ ,K+ -2Cl- synporter.
  • Blockade of the Na+ ,K+ -2Cl- synporter stops ion transport in the thick ascending limb.
  • About 25% of the filtered solute load is normally reabsorbed at this site and the remaining nephron segment past this point do not have the reabsorptive capability to make up the difference: hence a significant diuresis ensues.
Top Figure: Guyton's Textbook of Physiology, Ninth Edition, p. 318. Bottom Figure: Goodman and Gillman's "The Pharmacological Basis of Therapeutics", Ninth Edition, p. 699

 

 

Drugs Used in Management of Congestive Heart Failure

  • Digitalis

    • Digoxin (Lanoxin, Lanoxicaps,) Digitoxin

      • Digitalis glycosides are composed of a steroid nucleus to which an unsaturated lactone ring is attached at C-17. These two components, the aglycone or genin moieties, are responsible for the inotropic activity of glycosides.

      • Digoxin has a half-life of about 1.6 days. By contrast digitoxin's half-life is about 5 days. Digitoxin is rarely used and may no longer be readily available in the United States.

      • Digoxin is mainly excreted in the urine (85%). By contrast digitoxin is mainly metabolized in the liver.

      • Ouabain is very rapidly acting (5 to 10 min onset) after i.v. injection.

      • The clinical efficacy of digitalis glycosides is based on improving cardiac contractility (positive inotropism) and on decreasing transmission through the A-V node.

      • The most important cardiac effect is the shift of the force-velocity relationship upward.

  • Bipyridines

    • Amrinone (Inocor) and milrinone (Primacor) are bipyridine derivatives that are relatively selective inhibitors of cGMP-inhbited, cyclic AMP phosphodiesterase (type III).

    • These agents cause vasodilation (decreased afterload) and increase myocardial contractility.

    •  Milrinone (Primacor) is the agent of choice among the phosphodiesterase inhibitors for short-term parenteral support in severe heart failure patients.

      •  Oral formulations are not used due to intolerable side-effects including increases in mortality.

    • Amrinone has been associated with a reversible thrombocytopenia.

  • Adrenergic agonists: Dopamine (Intropin),  Dobutamine (Dobutrex); Dopamine (Intropin) and dobutamine (Dobutrex) are used for short-term inotropic support of the failing heart. 

  • Dobutamine (Dobutrex) is less arrhythmogenic and produces less tachycardia compared to endogenous catecholamines or isoproterenol (Isuprel).

  • Dobutamine (Dobutrex)

    • Dobutamine (Dobutrex) is a racemate that binds to and activates -1 and -2 adrenoceptor subtypes.

      • The (-) enantiomer stimulates 1 and 2 receptors, but this effect in humans appear negated by binding of the inactive (+) enantiomer.

      • Therefore the positive inotropic action mediated by beta receptor activation predominates.

    •  Dobutamine (Dobutrex) does not activate dopamine receptors and therefore does not increase renal blood flow.

    • Because of its vasodilator properties, dobutamine's positive inotropism is accompanied by a decrease in afterload. For this reason dobutamine may be favored over dopamine for most advanced heart failure patients who have not improved with digoxin, diuretics, and vasodilator therapy.

  • Dopamine (Intropin)

    • Dopamine (Intropin)may produce tachycardia which may increase left ventricular work.

    • Dopamine (Intropin)-induced vasodilation is mediated by direct stimulation of D1 and D2 post-synaptic dopamine receptors.

    • Vasodilation of renal vasculature is noteworthy and may benefit patients with marginal GFR due to poor renal perfusion.

  • Vasodilators (Hydralazine (Apresoline), Minoxidil (Loniten))

    • Vasodilators may be used in the management of congestive heart failure as a means of reducing afterload.

    • Hydralazine (Apresoline) and minoxidil (Loniten) are the prominent members of the class, although minoxidil is preferred.

    • Both drugs can induce reflex-mediated cardiac stimulation and water retention although in patients with advanced failure significant sympathetic tone may already be present. In that situation intervention that improve cardiac output and tissue perfusion may actually reduce overall sympathetic activity.

    • Vasodilator therapy is typically not used initially. ACE inhibitors, diuretics and digoxin would be likely tried first. More aggressive diuretic treatment and/or addition of vasodilators could follow.

    •  Adverse effects include those induced by vasodilation such as hypotension, palpitation, tachycardia, angina, fluid retention and headache.

      •  A drug-induced lupus syndrome is associated with hydralazine.

      •  A drug-induced hypertrichosis is associate with minoxidil

  • Loop Diuretics: Furosemide (Lasix),  Bumetanide (Bumex,  Ethacrynic acid (Edecrin)

    •  Furosemide (Lasix), bumetanide (Bumex), torsemide (Demadex), and ethacrynic acid (Edecrin) are "high-ceiling" loop diuretics acting primarily at the ascending limb of the loop of Henle.

      • The effectiveness of these agents is related to their site of action because reabsorption of about 30 - 40% of the filtered sodium and chloride load occurs at the ascending loop.

      • Distal sites are not able to compensate completely for this magnitude of reduction of NaCl reabsorption.

    • Loop diuretics increase urinary Ca2+ in contrast to the action of thiazides.

    • Loop diuretics also increase renal blood flow by decreasing renal vascular resistance.

    • These drugs are beneficial in managing systemic and pulmonary fluid overload produced by congestive heart failure (CHF).

      • By i.v. administration they are particularly effective in resolving acute pulmonary edema.

    • Adverse Effects:

      • Ototoxicity

      • Furosemide (Lasix) and ethacrynic acid (Edecrin) block renal excretion of uric acid by competition with renal secretory and biliary secretory systems.Therefore these agents can precipitate gout.

      • Potassium depletion.

  • ACE Inibitors: Three Major Effects of Angiotensin II and Underlying Mechanisms

    •  

      Three Major Effects of Angiotensin II and Underlying Mechanisms

 

  • Benazepril (Lotensin)

  • Captopril (Capoten):  Prototype drug

    • Angiotensin II, a potent vasoconstrictor, is produced by the action of angiotensin converting enzyme (ACE) on the substrate angiotensin I.

    • Angiotensin II activity produces:

      • (a) a rapid pressor response

      • (b) a slow pressor response

      • (c) vascular and cardiac hypertrophy and remodeling.

    • ACE inhibitors are efficacious in management of congestive heart failure and hypertension and have a favorable side effect profile.

      • Benefits of ACE inhibitors in treating congestive heart failure and antihypertension are due to the reduction in the amount of angiotensin II produced. Reduction in angiotensin II levels results in venous and arterial vasodilation which decreases both preload and afterload. Cardiac output improvement reduces sympathetic tone which may further decrease peripheral resistance.

      • Use of ACE inhibitors improves survival (40%) in patients with overt heart failure (CONSENSUS,1987 study).

    • ACE inhibitor are advantageous in management of diabetic patients by reducing the development of diabetic neuropathy and glomerulosclerosis.

    • ACE inhibitor are probably the antihypertensive drug of choice in treatment of hypertensive patient who have hypertrophic left ventricles. Hypertensive patients who have ischemic heart disease with impaired left ventricular function also benefit from ACE inhibitor treatment.

    •  ACE inhibitors reduce the normal aldosterone response to sodium loss (normally aldosterone opposes diuretic-induced sodium loss).

      • Therefore, the use of ACE inhibitors enhance the efficacy of diuretic treatment, allowing the use of lower diuretic dosages and improving control of hypertension.

      • If diuretics are administered at higher dosages in combination with ACE inhibitors significant and undesirable hypotensive reactions can occur with attendant excessive sodium loss.

    • Reduction in aldosterone production by ACE inhibitors also affects potassium levels. 

    • The tendency is for potassium retention, which may be serious in patients with renal disease or if the patient is also taking potassium sparing diuretics, nonsteroidal anti-inflammatory agents or potassium supplements.

    •  Adverse Effects

      • Angioedema, although rare, may be potentially fatal.

      • ACE inhibitors should not be used during pregnancy.

      • Dry cough.

      • In renovascular hypertension, glomerular filtration pressures are maintained by vasoconstriction of the post-glomerular arterioles, an effect mediated by angiotensin II.

        • Use of ACE inhibitors in patients with renovascular hypertension due to bilateral renal artery stenosis can therefore precipitate a significant reduction in GFR and acute renal failure.

      •  Initial dose of an ACE inhibitor may precipitate an excessive hypotensive response.

  • Enalapril (Vasotec)

  • Fosinopril (Monopril)

  • Lisinopril (Prinvivil)

  • Moexipril (Univasc)

  • Quinapril (Accupril)

  • Ramipril (Altace)