TREATMENT OF CONGESTIVE HEART

FAILURE (CHF)

DIGITALIS GLYCOSIDES AND OTHER POSITIVE INOTROPIC

AGENTS

Common Diseases Contributing to CHF

- Cardiomyopathy Hypertension Myocardial ischemia & infarction Cardiac valve disease Coronary artery disease

Clinical Features of CHF

Reduced force of cardiac contraction

Reduced cardiac output Reduced tissue perfusion

Edema (congestion) Increased peripheral

vascular resistance

Important definitions :

Afterload: pressure exerted on the left ventricle during systole which is dependent on the peripheral vascular resistance.

Preload : end-diastolic pressure when the ventricle has become filled.(depend on venous return, venous pressure, and blood volume)

Congestive Heart Failure Events

The heart can’t eject blood , so it remains inside the heart after

systole

The heart can’t eject blood , so it remains inside the heart after

systole

As compensation mechanism the heart

will increase the incoming volume of

blood so the heart can eject more blood

As compensation mechanism the heart

will increase the incoming volume of

blood so the heart can eject more blood

Dilated heart ischemia of

cardiomyocytes ↓contraction

Dilated heart ischemia of

cardiomyocytes ↓contraction

↑ afterload

↑ preload

Which type of drugs do we choose to treat this disease

β blockers to decrease

sympathetic activity.

EspeciallyHR to

increase diastolic time

To refill left ventricle

ACEI or ARB to inhibit the action of anigiotensin

Diuretics to relieve the edema

Positive inotropic drugs to increase

contractility

Used in acute or decompensated HFUsed in acute or decompensated HF

CARDIOTONIC DRUGS Cardiac Glycosides

Mechanism of the beneficial positive inotropic pharmacodynamic effect

The principal beneficial effect of digitalis in CHF is the increase in cardiac contractility (+ve inotropism) leading to the following:

o increased cardiac output o decreased cardiac size (via ↓EDV & ↓ ESV)o decreased venous pressure and blood volumeo diuresis and relief of edema (due to ↑ CO &

↓capillary permeability)o Decrease O2 consumption.

Cardiac glycosides: drugs used in treatment of CHF and cardiac arrhythmia

Physiology of contractionAs you know 1st the cell

depolarizes then contraction occurs

In depolarization In depolarization

Ca++ will enter the cellCa++ will enter the cell

Ca++ will trigger the release of Ca++ from the sarcoplasmic reticulum

Ca++ will trigger the release of Ca++ from the sarcoplasmic reticulum

In repolarization In repolarization

Ca++ will return to the sarcoplasmic reticulumCa++ will return to the sarcoplasmic reticulum

Intracellular Ca++ leaves by means of Na/Ca exchangerIntracellular Ca++ leaves by means of Na/Ca exchanger

Intracellular Na leavs by means of

Na/ K ATPase

Intracellular Na leavs by means of

Na/ K ATPase

continued

Na/Ca exchanger depends on Na electricgradient

Inside the cell outside

NaLess Na

More Na

KNa/K ATPase

Na

CaNa/Ca exchanger

This exchanger operates bidirectionally

In depolarization

Ca++ in Na+ out

In repolarization

Ca++ out Na+ in

Mechanism of action of cardiac glycosides

Pharmacological Actions of Digitalis Glycosides

Inotropism. Digitalis exerts positive inotropic effect both in the normal and failing heart via inhibition of Na+-K+ATPase at the cardiac sarcolemma.

I. Cardiac output (CO) Digitalis increases the stroke volume and hence the

CO No increase in oxygen Consumption

Decreased EDV & hence the dilated cardiac muscle

II. Heart Rate

Digoxin can decrease heart rate by : 1- slowing SA nodal firing rate

2- slowing AV conduction.3- increase refractory period.

III.Venous Pressure

IV.Diuresis

V. Myocardial Automaticity/Conductivity

Therapeutic Uses of Digitalis Glycosides

Treatment of congestive heart failure which does not respond optimally to diuretics or ACEI.

Treatment of atrial fibrillation and flutter by slowing SA nodal firing rate as well as AV conduction preventing the occurrence of the life-threatening ventricular arrhythmias.

So we use digitals to treat atrial fibrillation and flutter because they slow automaticity.

Adverse Effects of Digitalis Glycosides

i. Ventricular Arrhythmias

Arrhythmias resulting from oscillatory after potentials include single and multiple ventricular premature beats and ventricular tachy-arrhythmias

Digitalis ↑ intracellular Ca

↑ Ca in sarcoplasmic reticulum (become saturated)

Result in oscillating in Ca levels inside the cell oscillatory after potential

Adverse Effects of Digitalis Glycosides

ii. CNS side-effects Stimulation of the vagal

center and chemoreceptor trigger zone (CTZ) results in nausea, vomiting, diarrhea & anorexia

Other CNS effects include blurred vision, headache, dizziness, fatigue, and hallucinations

iii. Gynecomastia Gynecomastia may

occur in men either due to peripheral esterogenic actions of cardiac glycosides or hypothalamic stimulation

iv. ↓conduction velocity (AV block)

Treatment of Digitalis Toxicity

Immediate withdrawal of digitalis

I.V. K+ supplementaion to compensate for ↓intracellular K.

This may lead to

Hyperkalemia ↓slope of phase 4 ↓ automaticity Hyperkalemia ↓slope of phase 4 ↓ automaticity

Complete AV block

(contraindicated in digitalis induced

heart block)

Complete AV block

(contraindicated in digitalis induced

heart block)

continued

Lidocaine or phenytoin is effective against K+ digitalis-induced dysryhthmias

Use digoxin’s specific Fab fragments

If that doesn’t work

If that doesn’t work (severe case or resistance to drugs)

•They are antibodies against digoxin.

•Produced from sheep(we give the sheep digoxin and then get the antibodies produced against it).

•We separate the Fab portion from Fc portion by papain

•Fab portion is not antigenic thus, it doesn’t cause allergy (not produced anaphylactic shock).

•Antibody will bind to digoxin forming a complex which can be excreted through the kidneys increasing renal blood flow

•They are antibodies against digoxin.

•Produced from sheep(we give the sheep digoxin and then get the antibodies produced against it).

•We separate the Fab portion from Fc portion by papain

•Fab portion is not antigenic thus, it doesn’t cause allergy (not produced anaphylactic shock).

•Antibody will bind to digoxin forming a complex which can be excreted through the kidneys increasing renal blood flow

Digoxin-specific Fab fragments

Digoxin-specific Fab fragments are used safely for the treatment of the life-threatening cardiac glycosides-induced arrhythmias and heart block

Digoxin-specific Fab fragments are produced by purification of antibodies raised in sheep by immunization against digoxin

The crude antiserum from sheep is fractionated to separate the IgG fraction, which is cleaved into Fab and Fc fragments by papain digestion

The Fab fragments are not antigenic and with no complement binding

They are excreted fairly rapidly excreted by the kidney as a digoxin-bound complex

Selective ß1- Adrenergic Agonists

Dobutamine (and dopamine), at doses equal to or less than 5 µg/kg/min, have selective ß1- adrenergic agonistic activity.

Beneficial effects in emergency treatment of acute CHF (decompensated ) include the following:

o 1- Increased cardiac output as a result of enhanced contractility without appreciably altering the heart rate.

o 2- Reduction of mean arterial blood pressure.o 3- Lowering of the total peripheral vascular resistance and

consequently decreasing the afterload?? Read slide #3 o 4- Reduction of ventricular filling pressure

dobutamine

receptor

G- protein Adenlyl cyclase

cAMP PKA

Phosphodiesterase III (PD-III) Inhibitors (amrinone &

milrinone)

PD-III inhibitors are suitable only for acute CHF because they can induce life-threatening arrhythmias on chronic use same ß1- Adrenergic Agonists

cAMP

Phosphodiesterase III

PD-III inhibitors

They increase Ca indirectly

They increase Ca indirectly

Dobutamine and PD-III inhibitors are taken parenteral and act in a short period

Dobutamine and PD-III inhibitors are taken parenteral and act in a short period

OTHER DRUGS OF USE IN CHF WITHOUT INOTROPIC EFFECT

Diuretics Diuretics ↓cardiac preload by inhibiting sodium and water

retention Cardiac pumping improves with the consequent reduction in

venous pressure relieving edema Thiazide (e.g., hydrochlothiazide) and loop diuretics (e.g.,

frusemide) are routinely used in combination with digitalis Potassium-sparing diuretics can be concurrently used to

correct hypokalemiao Spironolactone+Digitalis+ACEI ↓mortality because

spironolactone antagonize aldosterone which cause myocardial and vascular fibrosis

Angiotensin Converting Enzyme Inhibitors (ACEIs)

ACEIs

Action of AT1 receptor:1- vasoconstriction of veins and arteries.

2- release of aldosteron in renal cortex.

3- sympathetic activity by NE in nerve terminal.

4- hypertrophy of the heart.

Action of AT 2 receptor:1- release of NO so vasodilatation.

2- prevent hypertrophy.

Effect of ACEIs on Bradykinin

Angiotension II activate sympathetic nervous system in the brain and synapses

Angiotensin Converting Enzyme Inhibitors (ACEIs)

Ultimately both preload and afterload are reduced Clinical trials showed that the use of ACEIs in CHF has

significantly reduced morbidity and mortality

Decreased sodium and water retention

Adverse Effects of ACEIs

1. Postural hypotension 2. Hyperkalemia 3. Renal insufficiency (don’t forget that in heart failure there is renal

insufficiency caused by decrease renal blood flow but still we use ACEI)

4. Persistent dry cough 5. ACEIs are contraindicated in pregnancy ACEIs include agents like: captopril, enalapril,

lisinopril and many others

LOCATION FUNCTION

Kidney

Glomerulus Mesangial cell contraction ↓GFR

Proximal tubule Increased reabsorption of sodium

Juxtaglomerular apparatus Decreased renin secretion

Heart Inotropic effect and release of growth factors with ensuing stimulation of cardiac myocyte hypertrophy and increased extracellular matrix production

Blood vessels Vasconstriction with an increase in afterload as well as local release of growth factors

Adrenal gland Aldosterone and catecholamine release

Brain Vasopressin release, stimulation of thirst; autonomic activity and cardiovascular reflexes

Sympathetic nervous system Increased sympathetic outflow

Angiotensin II Type-1 Receptor Antagonists (ARBs)

Physiologic functions of AT1 receptors according to their location

AT-1 Receptor Blockers (ARBs)

Agents include: Losartan and Valsartan They are recently approved for treatment of CHF They have the same beneficial effect of ACEIs except they don't

increase bradykinin. They don’t cause cough They enhance AT-2 function .

AT-1 Receptor Blockers (ARBs)

ARBs have the same side-effects of ACEIs, except they don’t cause cough.

Nitrovasodilators Sodium nitroprusside I.V. infusion is used at a

dose of 0.1- 0.2 µg/kg/min only in acute CHF to lower preload and afterload.

Nitrates can be used also to decrease preload (nitrates and hydralazine were used to decrease preload and afterload).