Pharmacology of Ionotropic Drug �(Drug Used in CCF)�

Dr Bassi PU

College of Health Sciences

University of Abuja

Cardiovascular Pharmacology

Review of Cardiovascular Form and Function

What is heart failure?

• The term "heart failure" can be frightening. It doesn't mean the heart has "failed" or stopped working.

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• It means the heart doesn't pump as well as it should.

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• Heart failure occurs when cardiac output is inadequate to provide the oxygen demand of the body

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• As a state in which the heart cannot provide sufficient cardiac output to satisfy the metabolic needs of the body

What is heart failure?

• HF is the final common pathway for many CVD whose natural history results in symptomatic or asymptomatic left ventricular dysfunction

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• It is commonly termed congestive heart failure (CHF) since symptoms of increase venous pressure are often prominent.
• Cardinal manifestations of heart failure include dyspnea, fatigue and fluid retention

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Types of heart failure

• Heart failure with reduced left ventricular function (HF-rEF)

The lower left chamber of the heart (left ventricle) gets bigger (enlarges) and cannot squeeze (contract) hard enough to pump the right amount of oxygen-rich blood to the rest of the body.

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• Heart failure with preserved left ventricular function (HF-pEF)

The heart contracts and pumps normally, but the bottom chambers of the heart (ventricles) are thicker and stiffer than normal. Because of this, the ventricles can't relax properly and fill up all the way. Because there's less blood in the ventricles, less blood is pumped out to the rest of the body when the heart contracts.

Ejection fraction (EF)

• EF refers to the amount of blood being pumped out of the left ventricle each time it contracts.
• An EF that is below normal (reduced) EF (HF-rEF), can be a sign of heart failure.
• Normal EF: 55% to 70%
• Mild HF EF 35% to 39%
• HF-rEF. EF of less than 35%,

Common signs and symptoms of HF

• Shortness of breath (Dyspnoea,Orthopnoea and PND)
• Feeling tired (fatigue) and leg weakness while active.
• Swelling ankles, legs and abdomen; weight gain.
• Dizziness , confusion, difficulty concentrating, fainting.
• palpitations
• A dry, hacking cough

Epidemiology

• The current Global prevalence of HF is 64.34 million cases (8.52 per 1,000 inhabitants),
• accounting for 9.91 million years lost due to disability (YLDs)
• 346.17 billion US $ expenditure.
• Affects 10% of people over 65 year
• Approximately 1 million new HF cases diagnosed annually, and the prevalence continues to rise.
• The lifetime risk of developing HF is 20% for Americans ≥40 years of age.

• Prevalence 2% in developed countrie eg in india 1.87 %

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Epidemiology

• Although aetiologies and clinical Xtics have been studied in Sub-Saharan Africa, there are actually no population studies providing insight into prevalence or incidence.
• Affects over 50% of people with 85+ years
• Approx 10% of patients with HF die each yr in Nigeria
• Mortality rates for HF remain approximately 50% within 5 years of diagnosis

Main causes

• Coronary artery disease

• Hypertension

• Valvular heart disease

• Cardiomyopathy

• Cor pulmonale

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Aetiology

• It is a common end point for many diseases of cardiovascular system

• It can be caused by :

-Inappropriate work load (volume or pressure overload)

-Restricted filling

-Myocyte loss

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Causes of left ventricular failure

• Volume over load: Regurgitate valve high output status

• Pressure overload: Systemic hypertension

Outflow obstruction

• Loss of muscles: Post MI, Chronic ischemia Connective

tissue diseases, Infections, Poisons

(Alcohol,cobalt,Doxorubicin)

• Restricted Filling: Pericardial diseases, Restrictive

cardiomyopathy, Tachyarrhythmia

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Background – Cardiac Function

• Cardiovascular function based on
• Cardiac pumping ability
• Pace-making electrical signals
• Force of contraction
• Height of ventricle discharge pressure
• Integrity of vasculature
• Presence of blockage
• Muscular tone/structural integrity
• Pressure drop needed to move blood to and through capillary beds
• Blood volume/composition
• Water, electrolyte, iron balances
• Lipid and protein composition

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Cardiac Function

• Dependent upon
• Adequate amounts of ATP
• Adequate amounts of Ca⁺⁺
• Coordinated electrical stimulus

Adequate Amounts of ATP

• Needed to:
• Maintain electrochemical gradients
• Propagate action potentials
• Power muscle contraction

Adequate Amounts of Calcium

• Calcium is ‘glue’ that links electrical and mechanical events.

Coordinated Electrical Stimulation

• Heart capable of automaticity
• Two types of myocardial tissue
• Contractile
• Conductive
• Impulses travel through ‘action potential superhighway’.

Pathophysiology of Cardiac Performance

• Hemodynamic changes

• Neurohormonal changes

• Cellular changes

Hemodynamic changes

• From hemodynamic stand point, HF can be secondary to systolic dysfunction or diastolic dysfunction

1.Preload: is the volume of the blood that fills the ventricles in

diastole, when it is increase, it causes the overfilling of the heart

which increase the work load.

• Starling Law: within limits, the Ventricular performance is related to the degree of myocardial stretching
• When Lt Ventricular performance (eg stroke volume or CO) is plotted as a function of LV function curve….therefore when preload is increase lead to increase in ventricular stretching and will enhance the ventricular function.
• The limit is End Diastolic Pressure (EDP) of 15mmHg when plateau of performance.

Pathophysiology of Cardiac Performance

• On the other hand marked stretching causes deterioration of ventricular function and EDP of 20mmHg or more result in pulmonary congestion
• In HF, preload usually increase because of increase in blood volume and venous return
• Reduction of preload is the goal of salt restriction and diuretic therapy
• Vasodilators also reduce preload by redistributing the blood into peripheral veins away from the heart.

Pathophysiology of Cardiac Performance

2. Afterload – is the systemic vascular resistance against which the heart must pump the blood. This is frequently increase in CHF which leads to decrease CO.

This set the stage for the use of drugs that decrease arterial tone in CHF

3. Contractility: in patient with low output failure, there is reduction in the intrinsic contractility of myocardium resulting in reduction of pump performance; here comes the role of +ve inotropic drugs

4. Heart Rate: which is the major determinant of CO (ie CO ₌ S.V. x Ht rate). The heart rate increase as the SV decrease, this is the 1^st compensatory mechanism

Neurohormonal changes

1. Neuro - hormonal reflex involves:

a). The sympathetic nervous

b). The renin–angiotensin–aldosterone system

These compensatory mechanism increase the work of the heart and can further contribute to the decline in the cardiac function.

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Pathophysiology of Cardiac Performance

CO

Carotid sinus firing Renal blood flow

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Sympathetic Discharge renin angiotensin11 and aldosterone

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Forces Rate Preload Afterload *Remodeling

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* Remodeling: change the shape (geometry) of the ventricles

Pathophysiology of Cardiac Performance

2. Myocardial Hypertrophy: Is the most important intrinsic compensatory mechanism, the increase in myocardial mass helps to maintain cardiac performance in the phase of pressure or volume overload.

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However, after initial beneficial effect, hypertrophy can lead to ischaemic changes, impairment of diastolic filling and alteration in ventricular geometry (remodeling) due to proliferations of abnormal myocardial cells and connetctive tissues which die at the accelerated rate leaving the remaining myocardial cells subject to even greater overload.

Cellular changes

• Changes in Ca+2 handling.

• Changes in adrenergic receptors:

• Slight ↑ in α1 receptors

• β1 receptors desensitization → followed by down regulation

• Changes in contractile proteins

• Program cell death (Apoptosis)

• Increase amount of fibrous tissue

 Symptoms

• Orthopnea, paroxysmal nocturnal dyspnea

• Low cardiac output symptoms

• Abdominal symptoms: Anorexia,nausea,

abdominal fullness, Rt hypochondrial pain

NYHA Classification of heart failure

• Class I: No limitation of physical activity

• Class II: Slight limitation of physical activity

• Class III: Marked limitation of physical activity

• Class IV: Unable to carry out physical activity

without discomfort

New classification of heart failure: ACC/AHA guidelines, 2001

• Stage A: Asymptomatic with no heart damage

but have risk factors for heart failure

• Stage B: Asymptomatic but have signs of

structural heart damage

• Stage C: Have symptoms and heart damage

• Stage D: Endstage disease

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Drug Used to treat CHF

Cardiac inotropic agents

• Inotrope: Drugs that affect the force of contraction of myocardial muscle,independent of changes in heart rate and loading conditions
• Positive or negative
• Term “inotrope” generally used to describe positive effect

Other Cardiac inotropic agents

1). Cardiac Glycosides (Digoxin, Digitoxin, Ouabain)

2). Sympathomimetics (Β₁ -adrenergic agonist:

- Naturally occuring: Epinephrine, Norepinephrine, Dopamine

- Synthetic: Dobutamine, Dopexamine, Phenylephrine, Metaraminol, Ephedrine

3). Phosphodiesterases inhibitors (amrinone,milrinone)

4). Diuretics (Loop diuretics eg Frusamide, K+ sparing diuretics eg Spironolactone)

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5). Angiotensin converting enzyme inhibitors(ACI) – Captopril, Enalapril, Lisinopril

6) Angiotensin Receptor Blockers (ARB) – Candesartan, Losartan, Valsartan

7)Beta Blockers - Artenolo,Bisoprolol , Carvedilol

8) Calcium channel Blockera:Diltiazem

Verapamil

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Other possible medications that might be prescribed

• Anticoagulants (blood thinners) �These drugs may be prescribed if heart failure patient is with atrial fibrillation, or have another problem with your heart where adding this drug is indicated. 
• Anticoagulants are not used to treat heart failure without the presence of atrial fibrillation.
• Cholesterol lowering drugs (statins)�May prescribe this class of medication if you have high cholesterol or have had a heart attack in the past. 

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Pharmacology: Cardiac Glycosides

Digoxin

Cardiac glycosides come from the plants of foxglove family (Digitalis spp) & related plant

Two types in clinical use –Digoxin and Digitoxin

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Digoxin -Chemistry

• Possess a common mol. Moiety
• Quabain is similar to Digitalis but has short activity
• The basic structure of glycosides consists of three components;
• A sugar moiety
• A steroid moiety &
• A lactone
• The sugar moiety consists of unusual 1 -4 chains linked monosaccharides
• A steroid nucleus containing an unsaturated lactone at C- 17 position and Glycosides residue at C-3
• The lactone ring is essential for activity and can retain biological activity even when the steroids is removed.

Digoxin –Mechanism of Action

• Act by inhibiting Na+/K+ ATP-ase in myocytes (Cardiac cells), this leads to a transient increases intracellular concentration of Na+ leading to increases influx of Ca++ via Na/Ca2+ exchanger.
• This result in increase contractility (Positive inotropic effect)
• Increased parasympathetic (Vagal) tone and decreased sympathetic effect on the heart this suppressed AV node conduction increasing refractory period, thereby decrease conduction velocity and result in decreased heart rate.

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1. Regulation of cytosolic calcium concentration:

• By inhibiting the Na+/K+-adenosine triphosphatase (ATPase) enzyme, digoxin reduces the ability of the myocyte to actively pump Na+ from the cell.
• This decreases the Na+ concentration gradient and, consequently, the ability of the Na+/Ca2+-exchanger to move calcium out of the cell.

• When Na+/K+-ATPase is markedly inhibited by digoxin, the resting membrane potential may increase (−70 mV instead of −90 mV).

Digoxin –Mechanism of Action�

2. Increased contractility of the cardiac muscle:

• Digoxin increases the force of cardiac contraction, causing cardiac output to more closely resemble that of the normal heart.

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Digoxin –Mechanism of Action

3. Neurohormonal inhibition:

• Low-dose digoxin inhibits sympathetic activation with minimal effects on contractility.Increase CO through their +ve inotropic effect.
• They slow heart rate by relieving the sympathetic tone & through their vagotonic effects
• They reduce the heart size by relisving Frank –Starling relationship
• They increase cardiac efficiency by increasing CO, force of cardiac contractility, decrease O2 consumption ( decrease heart size & rate).

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Digoxin –Mechanism of Action

• Blood Pressure – Remain unchanged following the administration of cardiac glycosides
• In CCF, the CO is reduced but the total peripheral resistance is increased, & these effects are reversed by cardiac glycosides
• Cardiac glycosides bring about diuresis by increasing both CO & renal blood flow; the latter in turn reverses the renal compensatory mechanism activated in CCF.
• Consequently, the production of aldosterone is reduced , sodium retention is reversed, & the excretion of oedematous fluid.

Digoxin: Pharmacokinetic

• Administered orally or IV in urgent situations
• Absorption varies from zero to nearly 100%.
• Distributed widely to tissues, including the central nervous system.
• Digoxin is not extensively metabolized in humans – Almost two thirds is excreted unchanged by the kidneys.
• Its renal clearance is proportional to creatinine clearance, and
• Its T1/2 = 36–40 hours in patients with normal renal function – give once daily
• Because digitalis: low margin of safety of the drug (lethal dose is only 5 – 10 times the minimum effective dose).

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Digoxin: Pharmacokinetic

Administration and Dosage

• You should not exceed then safety therapeutic range, the slow approach of digitalization is safest method.
• If a more rapid effect is needed, then you can give a loading dose divided into 3 -4 doses over 24 hours then followed by maintenance dose
• Slow digitalization or maintenance doses of digoxin is 0.125mg while loading dose is o.5 – 0.75mg every 8 hours (3 daily) then followed by maintenance dose.
• Digoxin can be used IV. But its dangerous.

Digoxin

Clinical Utility

• Decreases morbidity

• Does not decrease mortality

• Improves symptoms

• CHF refractory to other drugs

• Can be combined with other drugs

• Withdrawal of digoxin in stable patients carries considerable risk

Digoxin Toxicity�

• This is frequent and may be fatal
• Toxicity may result from
• Overdose
• Decrease in metabolism and excretion
• Hypokalaemia (stemming from the use of thiazides diuretics, diarrhea & vomiting)
• SA and AV blocks –conduction disturbances
• Arrhythmias occurring de novo
• Atrial/Ventricular ectopic
• CHF exacerbation

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�Digoxin Toxicity – Several Manifestations�

• Gastrointestinal- Anorexia, nausea, vomting abdominal pain and diarrhoea
• Psychiatric – Delirium, fatique, malaise, confusion, dizinness and abnormal dreams
• Headache
• Visual – blurred or yellow vission,halos
• Pulmonary disease
• Renal insufficiency
• Hyperestrongenism

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Drug - Drug Intractions

• Increased Risk of Hypotension - in patients on antihypertensives, Nitrates, or Acute ingestion of Alcohol
• Hypokalaemia: increase Digoxin toxicity, and increase risk of arrythmias
• Decreases Lithium excretion resulting in Lithium toxcicity
• May increase risk of Methotreaxate toxicity
• Reduces the effects of Furosemide when given with sucralfate, cholestyramine or colestipol
• Increases risk of Salicylate toxicity (with use of high dose salicylate therapy)

Digoxin Contraindications�

• The following agent are C/I

• Quinidine – Displaces digoxin from binding sites
• Bretylium: should not be used because it releases Norepineprine
• Carotid sinus stimulation: should be discouraged as it may precipitate ventricular fibrillation.
• Ventricular fibrillation
• Digoxin toxicity

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Antidigoxin Antibodies

• The antidigoxin or the antidigoxin antibodies (Digibind) have been used to control digoxin intoxication

β Stimulants : Dopamine

• Peripheral doperminergic receptor agents are useful in the the treatment of CCF
• Two type of Dopamine Receptors ( D1 &2)
• Dopamine: -2 (D1) receptor are located at various sites within the sympathetic nervous system & their activation results in inhibition of sympathetic NS.
• D1 receptor however, are located in vascular smooth muscles, mesentry,cerebral & coronary vascular beds

The pharmacologic response to D2 & D1 receptors are hypotension, bradycardia,diuresis & naturesis

β Stimulants : Dopamine

• Dopamine stimulates alpha & beta –adrenergic receptors
• Dopamine use in CHF is limited because it causes nausea & vomiting, becomes inactive when giving orally
• Increases afterload ( alpha –adrenergic mediated peripheral vasoconstriction), & enhances O2 demand on Lt Ventricles
• Dobutamine: (selective β1 agonist) has been widely used in heart failure (has strong inotropic effects).
• Availlable only for paerenteral use

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β Stimulants : Dopamine

• It increases cardiac output together with a decrease in ventricular filling pressure.
• Tachycardia may occur so angina or arrhythmias must be considered in patients with CAD.
• Tachyphylaxis may be seen with any β-stimulant.
• Dopamine is also used in acute heart failure and is helpful if blood pressure should be raised

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β Stimulants : Dopamine

• Ibopamine: which is active orally, is capable of iliciting peripheral & renal vasodilation & a +ve inotropic effects
• Ibopamine is converted to Epinine which is an active drug.
• Fenoldopam: active orally, D1 receptor agonist.
• It is more potent than dopaminein causing renal vasodilation without having adrenergic,cholinergic or histaminergic properties.

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Phosphodiesterase inhibitors

• Bipyridines :Two successful bipyridines are: Inamrinone and Milrinone.
• Bipyridines that inhibit phosphodiesterases, are used in heart failure.
• Inhibition of phosphodiesterase increases cAMP and increases contractility and vasodilation.
• The bipyridines increase myocardial contractility by increasing inward calcium flux in the heart during the action potential

Milrinone

• Milrinone is a type 3 phosphodiesterase inhibitor that increases inotropy, chronotropy, and lusitropy,
• Act via cyclic guanosine monophosphate (cGMP) to increase the intramyocardial adenosine triphosphate (ATP).
• It is a potent vasodilator agent, a venous and arterial vasodilator, and it is used in patients with pulmonary hypertension.
• Milrinone can be used in the presence of a beta-blocke

Phosphodiesterase inhibitors

• Although they have positive inotropic effects, most of their benefits derive from vasodilation.
• Inamrinone and milrinone are used only for acute heart failure or severe exacerbation of chronic heart
• Milrinone is thought to create less tachycardia, because it does not directly stimulate beta-receptors

Diuretics

Thiazides:

• chlorothiazide & hydrochlorothiazide (HCTZ)

Loop Diuretics

• furosemide, bumetanide

Potassium Sparing Diuretics

• spironolactone

Mechanism

• Water follows Na⁺
• 20-25% of all Na⁺ is reabsorbed into the blood stream in the loop of Henle
• 5-10% in distal tubule & 3% in collecting ducts
• If it can not be absorbed it is excreted with the urine
• ⇓ Blood volume = ⇓ preload !

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Diuretics

• They reduce venous pressure and ventricular preload.
• This results in reduction of edema and cardiac size, which improves pump efficiency.
• Aldosterone may cause myocardial and vascular fibrosis and baroreceptor dysfunction in addition to its renal effects.
• For this reason the aldosterone antagonists, spironolactone and eplerenone, decrease morbidity and mortality in severe heart failure.(M.H.Farjoo Jan. 2007)

Side Effects of Diuretics

• electrolyte losses [Na⁺ & K⁺ ]
• fluid losses [dehydration]
• myalgia
• N/V/D
• dizziness
• hyperglycemia

ACE Inhibitors

Angiotensin I

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ACE

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Angiotensin II

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1. potent vasoconstrictor

- increases BP

2. stimulates Aldosterone

- Na⁺ & H₂O

reabsorbtion

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RAAS

Renin-Angiotensin Aldosterone System

• Angiotensin II = vasoconstrictor
• Constricts blood vessels & increases BP
• Increases SVR or afterload

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ACE-I blocks these effects decreasing SVR & afterload

ACE Inhibitors

• Aldosterone secreted from adrenal glands causing
• sodium & water reabsorption (retention)
• Increase blood volume
• Increase preload
• causes cardiac hypertrophy & remodeling (by collagen deposition & fibrosis) 
• Inhibits degradation of Bradykinin (potent vasodilator, cough, angioedema)

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ACE-I blocks this and decreases preload

ACE Inhibitors & ARBs

• These drugs reduce peripheral resistance and afterload.
• They also reduce salt and water retention and in that way reduce preload.
• The reduction in tissue angiotensin also reduces sympathetic activity.
• These drugs reduce the long-term remodeling of the heart and vessels

Calcium Channel Blockers (CCB)

• diltiazem
• verapamil
• nifedipine

CCB Action

• diltiazem & verapamil
• decrease automaticity & conduction in SA & AV nodes
• decrease myocardial contractility
• decreased smooth muscle tone
• decreased PVR
• nifedipine
• decreased smooth muscle tone
• decreased PVR

Side Effects of CCBs

• Cardiovascular
• hypotension, palpitations & tachycardia
• Gastrointestinal
• constipation & nausea
• Other
• rash, flushing & peripheral edema

Vasodilators

• diazoxide
• hydralazine
• minoxidil
• sodium Nitroprusside

Mechanism of Vasodilators

• Directly relaxes arteriole smooth muscle
• Decrease SVR = decrease afterload

Side Effects of Vasodilators

• Hydralazine: Reflex tachycardia
• Sodium nitroprusside
• Cyanide toxicity in renal failure
• CNS toxicity = agitation, hallucinations, etc.

Goals of Pharmacotherapy

Relief of congestion/low cardiac output symptoms & restoration of cardiac performance:

-Inotropic drugs-digoxin,butamine,amrinone/milrinone.

-Diuretics: furosemide, thiazides.

-Vasodilators: ACE inhibitors/AT1 antagonist, hydralazine, nitrate.

-Beta blockers: metoprolol,bisprolol,carvedilol

Arrest/reversal of disease progression & prolongation of survival

• ACE inhibitors/AT1 antagonist (ARBs).
• Beta-blockers
• Aldosterone antagonist- spironolactone

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TREATMENT OBJECTIVES

• Survival
• Morbidity
• Exercise capacity
• Quality of life
• Neurohormonal
• changes Progression of CHF
• Symptoms

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Thank you! Any ?????

References

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1. Drugs Used in Heart Failure By M.H.Farjoo M.D., Ph.D.Shahid Beheshti University of Medical Science
2. Heart Failure Dr Vallish.K. BHARDWAJ DNB 3rd YR
3. Pharmacotherapy of Heart Failure Dr. Ashutosh Tiwari PG Resident, IInd Year Pharmacology Department SAIMS Indore 14/02/201LKY5
4. Text book of Pharmacology, by Rang/Dale/Ritter
5. A Textbook of Clinical Pharmacology by Gillies/Rogers/Spector/Trounce

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