Congestive Heart Failure - Drugs Used in CHF

Congestive Heart Failure

Congestive heart failure (CHF), or heart failure, is a condition in which the heart is unable to pump sufficient blood to meet the metabolic demand of the body and also unable to receive it back because every time after a systole.

Classification of CHF

1. BY EJECTION FRACTION


Reduced ejection fraction(<40-50%)- systolic heart failure

Preserved ejection fraction(>40-50%)- diastolic heart failure

2. BY TIME COURSE


Chronic heart failure(CHF)

Acute heart failure (Cardiogenic Shock)

3. ANATOMICALLY 


Left sided- LHF

Right sided- RHF(CHF)

4. BY OUTPUT


High output failure-Thyrotoxicosis, Paget's disease, Anemia, Pregnancy, A-V fistula

Low output failure 


Sign & Symptoms of CHF

  • Shortness of breath (dyspnea)
  • Fatigue and weakness
  • Swelling in your legs, ankles and feet
  • Rapid or irregular heartbeat
  • Reduced ability to exercise
  • Persistent cough or wheezing with white or pink blood-tinged phlegm
  • Increased urinate at night
  • Swelling of your abdomen 
  • Weight gain from fluid retention
  • Lack of appetite and nausea
  • Difficulty concentrating or decreased alertness
  • Sudden, severe shortness of breath and coughing up pink, foamy mucus
  • Chest pain if  heart failure is caused by a heart attack

Key Indicator for Diagnosing Heart Failure


Ejection Fraction (EF)


Ejection Fraction (EF) is the percentage of blood that is pumped out of your heart during each beat.

Pathophysiology of CHF


Compensatory Mechanisms

• Sympathetic nervous system stimulation

• Renin-angiotensin system activation

• Myocardial hypertrophy

• Altered cardiac Rhythm




Classification of Drugs used in CHF


1. Inotropic drugs:


(a) Cardiac glycosides: Digoxin, Digitoxin, Ouabain 

(b) Sympathomimetics: Dobutamine, Dopamine

(c) Phosphodiesterase III inhibitors: Amrinone

2. Diuretics:


(a) High ceiling diuretics: Furosemide, Bumetanide 

(b)Thiazide like diuretics: Hydrochlorothiazide, Metolazone, Xipamide 

3. Aldosterone antagonist:

Spironolactone, Eplerenone


4. Inhibitors of Renin-Angiotensin system-


(a) ACE-inhibitors: Enalapril, Ramipril

(b) Angiotensin (AT receptor) antagonists: Losartan 

5. Vasodilators-


(a) Venodilators: Glyceryl trinitrate

(b) Arteriolar dilator: Hydralazine

(c) Arteriolar + Venodilator: Sod. Nitroprusside

6. β-Adrenergic blockers:


Metoprolol, Bisoprolol, Carvedilol


7. Others-


(a) Metabolic cardioprotectives: Trimetazidine

(b) Calcium sensitizers: Levosimendan

(c) Levocarnitine

(1) Inotropic drugs

(a)Cardiac Glycosides

If a sugar molecule is joined together with a  non sugar molecule by a ether linkage it is called a glycoside.

Sugar + Nonsugar = Glycoside

Digitoxose + Steroidal Lactone = Cardiac Glycoside

Leaves of Digitalis lanata provide two – DIGOXIN and DIGITOXIN, while leaves of Digitalis Purpurea (Fox glove) are the major source of digitoxin.

Seeds of Strophanthus gratus provide two Active glycoside – STROPHANTHUS-G and OUABAIN, While seeds of strophanthus kombe yield primarily STROPHANTHIN-K.

Digoxin


A cardiac glycoside extracted from foxglove leaves (Digitalis sps.) is the most important Inotropic agent.

Increase the contractile force.

Particularly indicated in patients with atrial fibrillation.

MOA- Inhibits the Na+/K+-ATPase, which is responsible for Na+/K+ exchange across the muscle cell membrane ------>  increased [Na+]in ------> increased [Ca2+]in -----> increased force of myocardial contraction.

• Positive inotropic effect (without increasing of oxygen consumption)

• Positive batmotropic effect

• Negative chronotropic effect 

• Negative dromotropic effect

Extracardiac effect: 


Blood Vessels- Has direct vasoconstrictor effect, there is no prominent effect on BP as it is secondary to the improvement in circulation.

Kidney- Diuresis occurs due to improvement in renal perfusion, which brings about a shift of oedematous fluid into circulation.

GIT- The effect include anorexia, diarrhea, nausea and vomiting (stimulation of CTZ)

CNS Effect- These include disorientation, hallucination (in elderly), visual disturbance and aberrations of colour perception.

Pharmacokinetic profile of three typical cardiac glycosides


Therapeutic uses

1) Congestive heart failure- Drug of choice for “low out put HF” due to HT, IHD or arrhythmias. 

2) Paroxysmal supraventricular tachycardia- it’s a arrhythmia due to reentry phenomenon taking place at SA or AV node. They frequently respond to digitalis favorably, because of reflux vagal activation which slow the conduction of impulses.

3) Atrial Flutter and Atrial Fibrillation- As it decreases conduction velocity and increases ERP of AV node.

4) Dilated Heart-As it is helpful in restoring cardiac compensation.  

Side effects

Extracardiac Side effects

• GIT- Anorexia, nausea, vomiting, diarrhoea and abdominal cramps.

• CNS- Headache, fatigue, neuralgia, blurred vision, loss of colour perception.

• Endocrinal- Gyanecomastia in males (very rare)

Management of extracardiac side effects requires no more than reducing the dose of digoxin.

Cardiac side effects and Management of toxicity: 

Include bradycardia, partial or complete heart block, atrial or ventricular extrasystoles, coupled beats, ventricular fibrillation and fatal cardiac arrhythmias.

If severe intoxication- administration of digitalis antibodies, e.g., Digibond Fab fragments (Digitalis immune Fab.)

These antibodies are raised against digoxin. These also recognize digitoxin and Ouabain

Contraindications:

Hypokalemia

renal impairment

MI- When HF is accompanied with atrial flutter & fibrillation 

Hypothyroidism

Myocarditis or grossly damaged myocardium

Hypomagnesemia

Hypercalcemia and 

Pulmonary disease

Ventricular fibrillation

Patient must be advised not to take nonprescription cough or cold medications, antacids, laxatives, or antidiarrheals without consulting the physician.

Pregnancy 

(B) Sympathomimetics 


They improve cardiac performance through positive inotropic effect and lead to an increase in intracellular cAMP which results in the activation of protein kinase. 

Slow Ca2+ channels are then phosphorylated by protein kinase which increases Ca2+ flow into the myocardial cell causing increased force of contraction of heart muscles.

Dobutamine


The most commonly used inotropic agent other than digitalis. 

On heart, dobutamine has more selective inotropic than chronotropic effect without any significant change in peripheral resistance and BP.

Its half life is about 2 min and therefore must be given by I.V. (5-10 µg/kg/min.) 

It ↑ CO, therefore urinary output, and stroke volume with affecting HR, TPR or BP. 

Tolerance may develop on repeated use.

As it ↑ BP it should be avoided in patients with history of HT.

Dopamine


When given by I.V. infusion in low dose (2-5 µg/kg/min.) acts on D1 receptor in kidney and causes dilatation of renal blood vessels resulting in an increase in GFR, renal blood flow and urinary output.

In therapeutic doses (5-10 µg/kg/min.), also stimulate β1 receptors resulting in an increase in CO but the TPR is unchanged.

In high doses (above 10 µg/kg/min.) it then activates α1 receptors also, which causes vasoconstriction with an increase in TPR and pulmonary pressure.

Adverse effects include nausea, vomiting, tachycardia, ectopic beat, HT in high dose.

(C) Phosphodiesterase III inhibitors


Amrinone and Milrinone are the two phosphodiesterase inhibitors. 

They inhibiting the enzyme phosphodiesterase, increase the stay cAMP with in the myocardial cell as a result -------> sustained rise of Ca2+ concentration in these cells occurs -------> rise of cardiac contractility.

Both are also called “Inodilators” because they increase cardiac contractility and at the same time produce vasodilatation.

Thrombocytopenia is the most prominent and dose related side effects, but is mostly transient and asymptomatic.

Nausea, diarrhoea, abdominal pain, liver damage, fever are the other side effects.

Dose


Amrinone: 0.5 mg/kg bolus inj. Followed by 5-10 µg/kg/min. IV infusion (Max. 10 mg/kg in 24 hr.)

Milrinone: 50 µg/kg IV bolus followed by 0.4 – 1.0 µg/kg/min. infusion. 

Diuretics

They generally cause natriuresis and water removal  ------>   this leads to removal of fluid from the body  ------>   leading to reduction of volume of blood + other ECF components (= reduction of overload) reduction of  ------> 

Pulmonary congestion (dyspnea) + Peripheral congestion (peripheral edema) + Preload

High ceiling diuretics - (FUROSEMIDE, BUMETANIDE)

High ceiling diuretics act principally on the ascending limb loop of Henle. 

They are high potency diuretics and are effective even when there is renal insufficiency.

IV furosemide promptly increases systemic venous capacitance and produces rapid symptomatic relief in acute left ventricular failure.

Adverse effects- Acute fluid loss, hypotension, Hypokalemia, Hypomagnesimia, Hyperuricemia, Ototoxicity

Dose- Furosemide (LASIX): 20-80 mg, tab. orally


Thiazide diuretics - (Hydrochlorothiazide)


Act principally on the early distal tubule of the nephron and are of moderate potency. 

Thiazide diuretics become inefficient in presence of renal insufficiency. 

Thiazide however cannot be used where the GFR is < 50 ml/min.

AEs- Hypokalemia, Metabolic defects, Volume depletion, Hypersensitivity reaction.

Dose- Hydrochlorothiazide (Esidrex) 25-100 mg/day   

Aldosterone antagonist - (Spironolactone, Eplerenone)


These enhances Diuresis by promoting Na+ and Water excretion (While retaining K+) and prevents Myocardial as well as vascular fibrosis which is responsible for pathological remodeling of the heart.
 
AEs: Hyperkalemia is a major risk during the therapy and require serum K+ monitoring. Gynaecomastia may occur in male patients, after long term use.

Dose:  25-50 mg OD orally

Inhibitors of Renin-Angiotensin system 

ACE inhibitor

These drugs not only block the conversion of Ang-I to Ang-II but also prevent the breakdown of bradykinin to vasodilatation. 

They also decrease aldosterone secretion and hence reduce salt and water retention, so CO improves.

They also cause natriuresis and most imp. 

They Prolong the survival by preventing pathological remodeling of the heart and blood vessels.

Most commonly used ACEIs


Enalpril (2.5 mg BD and worked up to 10 mg BD) 

Lisinopril (2.5 - 5 mg OD, worked up to 20 mg OD) 

Ramipril (2.5 mg OD, worked up to 10 mg OD) 

AEs- Hypotension after first dose, dry cough, angioneurotic oedema, foetal hypotension with a risk of foetal malformation if administer during II or III trimester of pregnancy, hyperkalemia.

DIs- Non systemic antacid reduce the BA of ACEIs, NSAIDs may impair the hypotensive effects of ACEIs by blocking bradykinin-mediated vasodilatation etc.

Angiotensin (AT1 receptor) antagonists 
Losartan

ARAs stimulate renin release and increases circulating Ang II levels, resultant increased amount of Ang II would now stimulate AT2 receptor which are lying unblocked causes vasodilatation.

Dose- 25-50 mg OD

AEs- 

Cause foetal toxicity 

Precipitate renal failure in patients with bilateral renal artery stenosis.

Hyperkalemia in patients with renal failure 

First dose hypotension in rare cases may occur


Vasodilators


These agents reduce pulmonary congestion and increase cardiac out put by reducing preload and/or after load. 

They also prevent remodeling of the heart. 

The nitrate receptors presents on smooth muscle. 

The nitrate receptors possess –SH groups which reduce nitrates to nitrite and nitric oxide (NO). 

The NO itself gets converted to an intermidiate- reactive nitorsothiol which activates intracellular guanylate cyclase (GC) to convert GTP to cGMP results in vascular smooth muscle relaxation. 

Nitorglycerine


In patients of HF with dyspnoea, venodilators like or long-acting nitrates are preferred because these may reduce the filling pressure and ultimately the pulmonary congestion.

Dose-

Route                          Dose (mg)                   Onset (min)              Duration (hrs) 

Sublingual                      0.5                                 2-5                          0.25-0.5

Oral                               5-15                             20-30                             4-8

Ointment (2%)                -                                 15-30                             3-8

Transdermal         5-10 mg/24hr                       30-40                       Max. 24 hr

AEs- Throbbing headache, flushing of face, palpitations, dizziness, Tolerance develop rapidly if used orally in sustained release form, or transdermally or by I.V. infusion without drug free interval.

DIs- Sildenafil and other vasodilator potentiate the hypotensive action of nitrates (Inhibit the metabolizing enzymes PDE-IV and potentiate further release of cGMP), sudden death occures.

Arteriolar dilator
Hydralazine


Vasodilatation due to hydralazine is partly endothelium dependent and may involve generation of nitric oxide and stimulation of cGMP, increase in intracellular levels of cGMP are associated with vascular smooth muscle relaxation.Hydralazine (25-50 mg BD orally) and is generally not employed BY I.V. route because the onset of action is hardly different than that of oral

AEs- Headache, tachycardia, nausea, nasal congestion, and anginal attack (due to tachycardia), prolong use in High doses it causes reversible disseminated lupus erythematosus like syndrome 

Arteriolar + Venodilator
(Sod. Nitroprusside)


Sod. Nitroprusside activates guanylyl cyclase either directly or through release of nitric oxide. 

This results in an increase in the intracellular levels of cGMP which provides vascular smooth muscle relaxation.

Patients having severe chronic failure benefitted by combination of arteriolar + venodilator, And useful in patients in whom ACEIs are contraindicated or are not tolerated. 

Dose- It is powerful parenterally administered vasodilator, the onset effect is rapid (30 sec.) after I.V. infusion (0.3 µg/kg/min, slowly raised to 0.5 µg/kg/min) and disappear within 10 min after discontinuation.

AEs- Other than headache, nausea and vomiting Which quickly dissipate after the infusion is stopped. 

β-Adrenergic blockers: 
Metoprolol, Bisoprolol, Carvedilol


As a general rule β- blockers are contraindicated in CHF. 

Because HF patients have a decreased CO since CO is equal to stroke volume (SV) multiplied by heart rate (HR), an increase HR would be necessary to maintain an adequate CO in the presence of decreased SV as observed in HF. 

As a result, a decrease in HR and cardiac contractility produced by β- blockers would be expected to produce acute cardiac decompensation, in patients with HF. 

β- blockers like Metoprolol, Bisoprolol, carvedilol, improve ventricular function and prolong the survival in HF patients. 

Doses-

Metoprolol- 50-100 mg OD orally

Bisoprolol- 2.5-10 mg OD orally

Carvedilol- 6.25 mg BD orally, increased to 12.5 mg BD

AEs-

Bronchoconstriction

Sudden withdrawal of β- blockers  is very dangerous most imp. Cause seems to be up regulation of β- adrenoceptors due to use of β- blockers.

Person who use insulin or oral antidiabetic tab. Are susceptible to develop hypoglyemia.

Occasionally can produce some CNS symptoms like depression and sleep disturbance. 

Rash, urticaria rarely. 

Can mask some symptoms of hyperthyroidism.

Absolute CIs- Severe bradycradia, pre existance gross block in the conducting system and overt left ventricular failure, Asthma, COPD, Depression, Active peripheral vascular disease.

Other drugs
Metabolic cardioprotectives: Trimetazidine

It prevents the degradation of membrane unsaturated fatty acids by lipid peroxidation and 
thus reduce myocardial O2 demand. 

It also inhibit the superoxide cytotoxicity to protect the myocardium from the harm full effect. but can cause parkinsonism.

Dose- 20-60 mg OD tab. and cap.

Calcium sensitizers 
Levosimendan


It increases sensitivity of troponin in the Heart to calcium. 

This results in increased myocardial contractility. 

It is  infused i.v. for short treatment of severe heart failure.

Levocarnitine


It is a N-containing amino acid in muscle, which has antioxidant activity. It is indicated in cardiomyopathy and muscle dystrophy caused by carnitine deficiency.

Preparations containing Coenzyme Q10 (a part of the mitochondrial redox system), stimulate ATP synthesis and improve myocardial contractility in CHF.

Non Pharmacological

Activity

Routine modest exercise for class I-III– For euvolemic patients

Regular isotonic exercise such as walking or riding a stationary-bicycle ergometer

Diet


Restriction of sodium (2-3 g daily) is recommended in all patients, Extra < 2g reduction in moderate to severe cases.

Fluid restriction (<2 L/day) if hyponatremia (<130 meq/L)

Caloric supplementation- with advanced HF and unintentional weight loss or muscle wasting (cardiac cachexia) 

Reduce or eliminate alcohol and caffeine

Quit Smoking

Surgical measures


Cardiac Resynchronization

Implantable Cardiac Defibrillators

Intraaortic balloon counter pulsation

Percutaneous and surgically implanted LV assist devices

Biventricular Pacing

Cardiac transplantation

Novel agents in HF


Newer InotropeS

– Cardiac myosin activators- Omecamtive mecarbil 

– Na/K-ATPase inhibitors- Istaroxime

– Ryanodine receptor stabilizers- JTV-519(K 201),S107,S44121

– SERCA2a activators- MYDICAR

Vasodilators- Relaxin 

Neuregulins- recombinant human NRG-1β2 

Novel RAAS blockers-

– Direct renin inhibitors- Oral Aliskiren,IV Remikiren, IV Enalkiren 

– Angiotensin receptor & neprilysin inhibitors- LCZ696, AHU377 ,Candoxatril, Ecadotril 

– Aldosterone blockers - 

Dual ACE/NEP Inhibition – Vasopeptidase Inhibitors

Dual NEP & ECE(endothelin converting enz.) inhibitors – GGS34043, GGS34226, GGS26303, SLV306

Triple enzyme inhibitors of ECE/NEP/ACE – GGS26670 

Dual dopamine D2-α2 agonist – Nolomirol

Dopamine β-Hydroxylase inhibitor – Nepicastat

Adenosine A1 receptor antagonists – BG9719,BG9928

Carnitine palmitoyl transferase-1(CPT-1) inhibitors – Etoxomir, Oxenicine

Matrix Metalloproteinase (MMP) Inhibitors– Batimastat, ilomastat, marimastat and prinomastat

Immune modulator – CelacadeTM

Cardiac  Myosin Activators 
(Omecamtive Mecarbil)


They accelerate transition of actin-myosin complex from a weakly bound to strongly bound configuration 


↑ myosin head interaction with actin ↓ nonproductive ATP hydrolysis

↑duration of systole ----> ↑stroke vol - ---->improvement 
in myocardial systolic function in absence of arrythmogenesis & ↑ O2 consumption.

Currently under phase 2 trial.


Istaroxime

MOA- 


Inhibition of sodium/potassium adenosine triphosphatase (Na+/K+ ATPase).

Drug is under phase 2 trial.

Vasodilators - Serelaxin


Recombinant human relaxin- 2

Relaxin- circulating peptide found in pregnant women 

Regulates systemic vasodilation 

Improves dyspnea significantly

Dose 30 μg/kg/day infusion

Currently under phase 3 trial.

SERCA 2a activators


Improved systolic and diastolic functions, improved ventricular metabolic reserve, and reducing the likelihood of ventricular arrhythmias during ischemia-induced Ca2+ overload 

Currently under phase 3 trial.

Ryanodine receptor stabilizers (JTV519 )


preserve left ventricular systolic and diastolic function 

prevents left ventricular remodeling 

Neuregulins


Recombinant human NRG-1β2  infusion improve cardiac structure and function by 90 days 

Increase in cardiac output as well as vasodilator effect   

Currently under phase 3 trial.

Novel blockers of the renin–angiotensin aldosterone system


Direct renin inhibitors


Oral Aliskiren,IV Remikiren, IV Enalkiren

Reduce increased plasma renin activity directly independent of plasma levels of BNP, background effect of beta blockers & ACEI.

MOA- inhibit conversion of Angiotensinogen to angiotensin-I

Drawback- hyperkalemia, hypotension

Angiotensin receptor and neprilysin inhibitors 
(Candoxatril, Ecadotril)


Atrial natriuretic peptide, B, C and exogenous D- type,  possess differing degrees of hemodynamic, neurohormonal, renal and cardiac effects 

Novel approaches to aldosterone blockade Non-steroidal mineralocorticoid receptor antagonists

PF3882845 -greater blood pressure reduction and renal protection 

BR-4628  -dihydropyridine (DHP) structure 

Aldosterone synthase inhibitors


There is induction of aldosterone synthase (CYP11β2) or angiotensin II in the failing ventricle 

FAD286 - improved cardiac hemodynamic parameters, preventing progressive LV remodeling 

LCI699 - reduction in blood pressure 

Triple Enzyme Inhibitors of ECE/NEP/ACE


GGS 26670

Improved LV function and reduced LV collagen accumulation better than either ACE alone or ECE-NEP inhibition

Dual Dopamine D2- Adrenoceptor agonist


Nolomirole


Inhibits catecholamine release from sympathetic nerve endings and also inhibits the release of TNF from cardiac tissue

Significantly reduces hypertrophy and attenuates signs and symptoms

Dopamine-Hydroxylase Inhibitor 


DBH catalyses the conversion of dopamine (DA) to norepinephrine (NE) in sympathetic nerves 

Nepicastat- reduce norepinephrine synthesis. 

Phase 2

Adenosine A1 receptor antagonists


BG 9928, BG 9719

Protects renal function and exerts additive natriuretic effects without excessive potassium loss

Carnitine Palmitoyl Transferase-1 (CPT-1) Inhibitors


CPT-1 helps in metabolism of fatty acid which is a source of energy production in heart 

Etoxomir, Oxfenicine

dilation, prevents ventricular remodeling.

Matrix Metalloproteinase (MMP) Inhibitors


Enhanced expression of MMP triggers signaling cascade of cardiac remodeling

Batimastat, ilomastat, marimastat and prinomastat, PG-53072

Prevent ventricular dysfunction and delay heart failure progression 

Immune modulator


CelacadeTM

Prevents chronic inflammation and apoptotic cell death by activating physiological immune system’s IL -10 mediated anti-inflammatory process.

Improve quality of life in patients of NYHA class III or IV heart failure.

Reduce the risk of death and hospitalization due to chronic heart failure

Can CHF prevented


CHF can't always be prevented, but there are many things can do to help.

Try preventing CHF by practising good heart health. 

This will also guard against heart attack, stroke, and coronary artery disease. 

Tips to follow include:

Control high blood pressure

Eat a healthy diet• Exercise

Control blood sugar levels (especially if you have diabetes) 

Maintain good blood cholesterol levels

Quit smoking

Drugs Used in Congestive Heart Failure Notes PDF



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