Drugs Used in the Drugs Used in the

Management ofManagement of

CONGESTIVE HEART CONGESTIVE HEART

FAILUREFAILURE

Aims and ObjectivesAims and Objectives

Congestive Heart Failure is one of the

common causes of death and disability,

and is among the syndromes

commonly encountered in clinical

practice.

Decreased cardiac out-put, a salient

feature of heart failure, is associated

with edema, ascites, pericardial and

plural effusion, reflex sympathetic over

activity, oliguria and dyspnoea.

Different classes of drugs i.e. Diuretics,

Vasodilators, Renin Angiotensin system

blockers and -Adrenergic agonists and

antagonists, which are used in the

management of congestive heart failure, will

be discussed.

This lecture deals with various aspects of

the Pharamacology of Digoxin and related

drugs (positive inotropic agents).

The role of other classes of drugs will be

briefly reviewed in context of the treatment of

heart failure.

_______________________________________

ETIOLOGY

Hypertension, Coronary Infarction; Congenital

Heart Disease. Cardiomyopathy

NOTE

Before initiating drug therapy for Heart

Failure, it is important to eliminate or mitigate

potentially reversible causes of cardiac

dysfunction i.e., Myocardial Ischemia, Valvular

heart disease, Hypertension, Intracardiac or

Intravascular Shunts, Cardiac Arrhythmias,

and Hyperthyroidism.

Cardiovascular

Consequences

of Heart Failure

PRELOAD AFTERLOAD

Signs and SymptomsSigns and SymptomsREDUCED STROKE VOLUME

(MAIN FEATURE)

1. BACKGROUND SYMPATHETIC ACTIVITY INCREASEDI. Tachycardia

II. Constriction of peripheral arterioles and veins (3 to 4 fold increase in peripheral resistance)

2. OLIGURIA

3. FLUID AND WATER RETENTION

i. Peripheral Edema

ii. Ascities

iii. Pleural and pericardial effusion

4. PULMONARY EDEMA

i. Dyspnoea

ii. Cyanosis

iii. Paroxysmal nocturnal dysponea

5. VEINS

i. Engorged

ii. Pulsations are visible in the jugular

veins in the neck

HEART

FAILURE:

Cyanosis,

Engorgement

of juglar veins,

enlargement

of liver,

ascites,

dependent

edema,

elevated

venous

pressure

WHAT TO DO UNDER THESE WHAT TO DO UNDER THESE

CONDITIONS? CONDITIONS?

INCREASE THE FORCE OF MYOCARDIAL

CONTRACTION

DECREASE THE HEART RATE

DECREASE THE AFTERLOAD

DECREASE THE PRELOAD

INDUCE DIURESIS

CLASSIFICATION CLASSIFICATION

OF OF

DRUGSDRUGS

DIGOXINDIGOXIN

CARDIAC-GLYCOSIDES

Source

Digitalis purpurea (purple fox glove)

Digitoxin, Gitoxin, Gitalin

Digitalis lanata

Digoxin, Digitoxin, Gitoxin

Strophanthus kombe

Strophanthin, a glucoside

Strophanthus gratus

Ouabain:-

(Shortest acting, given I/V in emergency)

These cardiac-glycosides are also known as

cardinolides

Apart from digitalis, strophantus other plants

including, See onion (squill), Lilly of the valley,

Milk weed or also resource of cardiac glycosides

Chinese toad skin’s glands also secrete these

Glycosides (Bufadienolides).

MAJOR EFFECTSMAJOR EFFECTS

FORCE OF VENTRICULAR

CONTRACTION

HEART RATE

DIGOXIN, THEREFORE, PRODUCES

POSITIVE INOTROPIC AND NEGATIVE

CHRONOTROPIC EFFECTS

Effects of Effects of DigoxinDigoxin

in Congestive Heart Failurein Congestive Heart Failure

FORCE OF VENTRICULAR CONTRACTION AND CARDIAC

OUTPUT INCREASE

I. BACKGROUND SYMPATHETIC ACTIVITY

DECREASED

i. HEART RATE

ii. VASOMOTOR TONE

iii. PRELOAD AND AFTERLOAD

II. RENAL CIRCULATION IMPROVED

i. RENIN, ANGIOTENSIN II, ALDOSTERONE

ii. Na+ and H2O RETENTION

iii. DIURESIS

III. HYDROSTATIC PRESSURE IN VEINS

DECREASED AND THE EXTRA FLUID

RESPONSIBLE FOR EDEMA IS DRAWN

BACK IN TO GENERAL CIRCULATION

PERIPHERAL EDEMA, ASCITIES AND

PULMONARY EDEMA

Negative Chrontropic Action Negative Chrontropic Action of of DigoxinDigoxin

I. CARDIAC OUTPUT INCREASED,

THEREFORE, DECREASE IN

BACKGROUND SYMPATHETIC

ACTIVITY

II. STIMULATION OF VAGAL CENTER

III. DEPRESSION OF SA NODE

IV. SLOWING OF AV CONDUCTION

___________________________________

INDIRECT EFFECT: I and II

DIRECT EFFECT: III and IV

DIRECT EFFECTSDIRECT EFFECTS

1. SA NODE

Spontaneous activity (Automaticity)

2. AV NODE

i. ERP

ii. Conductivity

iii. Excitability

3. HIS PURKINJE SYSTEM

i. Excitability

ii. Automaticity

iii. ERP

iv. Conductivity

Ectopic Beats, Ventricular Tachycardia,

[SIDE EFFECTS]

4. AURICLES

i. ERP

ii. Can lead to Fibrillations

iii. Flutter Fibrillations

5. VENTRICLES

ERP

EXCITABILITY: - Effect variable,

usually increases

Ventricular Arrhythmias

POSITIVE INOTROPIC POSITIVE INOTROPIC ACTION ACTION

(MECHANISM)(MECHANISM)

INHIBITION of Na+ / K+ ATPase

THERAPEUTIC USES

CONGESTIVE HEART FAILURE

ATRIAL FIBRILLATION

Even in the absence of congestive heart

failure, Digitalis may be indicated in many

cases of atrial fibrillation. The inappropriately

rapid ventricular rate in this disorder results in

great discomfort.

The aim of Digitalis therapy is to reduce the

ventricular rate.

It rarely halts atrial fibrillation. The dosage

should be adjusted to maintain the

ventricular rate in the range of 60-80/mint.

OTHER DRGUS: Propranolol, Verapamil

ATRIAL FLUTTER

To decrease the ventricular rate

AV Node: ERP

Digitalis may convert flutter in to

fibrillation. This too facilitates control of

ventricular rate

If such conversion to fibrillation occurs,

withdrawal of Digitalis may result in the

return to Sinus Rhythm*.

*Danger of Embolism. A thrombus in auricles

may dislodge due to good contraction

PAROXYSMAL TACYHCARDIA

Atrial and AV nodal paroxysmal tachycardias

are the most common tachyarrhythmias next

to atrial fibrillation.

Digitalis is successful in terminating this

type of tachycardia by virtue of its vagal

effects (I/V administration).

Note: -

1. Digoxin therapy is indicated in Severe Left

Ventricular Systolic Dysfunction.

2. Patients with mild to moderate heart failure

will often respond to ACE inhibitors and

Diuretics, and do not require Digoxin.

3. It is no longer a first line agent in the

treatment of C.H.F. Reserved for patients

who are in atrial fibrillation or patients with

sinus rhythm who remain symptomatic

despite treatment with other drugs.

ADVERSE EFFECTS

HEART

Cardiac arrhythmias which under certain

circumstances are life threatening.

Sinus bradycardia, AV–block, Atrial

Fibrillation, Ventricular Extra Systoles,

Ventricular Fibrillation.

CNS DISTURBANCES

Characteristically altered color vision

(Xanthopsia). White borders or halos may

appear on dark objects.

Fatigue, disorientation, hallucinations,

delirium.

G.I.T

Anorexia, Nausea, Vomiting, Diarrhea.

OTHER EFFECTS:

Gynecomastia due to estrogenic effects; skin

rashes; hypokalaemia.

________________________________________

Delirium:- Fluctuating impairment of

consciousness and disorientation

Hallucinations:- False perceptions having no

external stimulus (visual, auditory)

TOXICITY MANAGEMENT

1) Discontinue the drug

2)Ventricular arrhythmias: Lidocaine, Phenytoin

3) AV conduction delay: Atropine

4)Hypokalaemia : K+

5)Anti-digoxin Immuno Therapy: Injection (IV)

of antibody (fab) fragments that bind with,

and inactivate Digoxin.

________________________________________

CAUTION:- Diuretics which produce

hypokalaemia

Comparison of

Digoxin and Digitoxin

1. Amiodarone2. Erythromycin3. Quinidine4. Tetracycline5. Verapamil

Increased Digitalis

concentration may occur during

concurrent therapy

1. Corticosteroids2. Thiazide

diuretics3. Loop diuretics

ENHANCED POTENTIAL FOR CARDIOTOXICITY

Drug interactions with DIGOXIN

OTHER INOTROPIC OTHER INOTROPIC AGENTSAGENTS

I ) -ADRENERGIC AGONIST

(Dobutamine)

ATP cAMP

cAMP Phosphorylation of Ca2+ Channels

+

II.PHOSPHODIESTARASE INHIBITORS

(AMRINONE; MILRINONE)

cAMP AMP

-

Phosphodi-esterase

Inhibitors

OVERVIEWOVERVIEW

Steps in the Treatment Steps in the Treatment of Congestive Heart of Congestive Heart

FailureFailure1. Reduce work load of the heart

a) Limit activity level

b) Reduce weight

c) Control hypertension

2. Restrict sodium

3. Restrict water (rarely required)

4. Give ACE inhibitor or Digitalis *

5. Give -blockers to selected patients

6. Give vasodilators

* Many clinicians use ACE inhibitors before Digitalis.

Vasodilators for Use in Congestive Vasodilators for Use in Congestive Heart FailureHeart Failure

DRUGSDRUGS SITE OF DILATING SITE OF DILATING ACTIONACTION

Hydralazine Arterioles

Nitrates Veins and Venules

Captopril and other

ACE inhibitors,

Angiotensin receptor

blockers

Both arterioles and Veins

DRUG PERLOAD AFTERLOAD

I. Nitrovasodilators Nitroglycerin Isosorbide dinitrate

++++++

++

II. ACE inhibitors Captopril Enalapril

++++

++++

III. Angiotensin receptor antagonist

(losartan)++ ++

IV. Phosphodiesterase inhibitor

(Amrinone)

++ ++

DRUG PERLOAD AFTERLOAD

V. Direct Vasodilators

(Hydralazine)+ +++

VI. Adrenergic receptor

antagonists

Prazosin (1 antagonist)

Labetalol(1;

Nonselective )

+++

++

++

++

VII. Ca ++ channel blockers

Nifedipine + +++

QUESTIONS

1. The drugs that have been found to be

least useful in congestive heart failure:

a) Na+/K+ ATPase inhibitors

b) Calcium channel blockers

c) β-adrenoceptor agonists

d) β-adrenoceptor antagonists

e) ACE inhibitors

2. The mechanism of action of digoxin is

associated with

a) Decrease in calcium uptake by the

sarcoplasmic reticulum

b) Increase in ATP synthesis

c) Modification of the actin molecule

d) Increase in systolic cytoplasmic calcium

levels

e) Blockade of cardiac adrenoceptors

3. A 65- year old woman has been admitted to

coronary care unit with a left ventricular

myocardial infarction. If this patient develops

acute severe heart failure with marked

pulmonary edema, which one of the following

drugs would be most useful?

a) Digoxin

b) Furosemide

c) Minoxidil

d) Propranolol

e) Spironolactone

4. Which of the following is most likely to

contribute to the arrhythmogenic effect of

digoxin?

a) Increased vagal discharge

b) Increased intracellular calcium

c) Decreased sympathetic discharge

d) Increased extracellular magnesium

e) Increased extracellular potassium

Drugs used in chronic heart failure Loop diuretics, for example furosemide. Angiotensin-converting enzyme inhibitors (e.g. ramipril). Angiotensin II subtype 1 receptor antagonists (e.g. valsartan,

candesartan). β-adrenoceptor antagonists (e.g. metoprolol, bisoprolol, carvedilol),

introduced in low dose in stable patients. Aldosterone receptor antagonists (e.g. spironolactone, and

eplerenone). Digoxin especially for heart failure associated with established rapid

atrial fibrillation. It is also indicated in patients who remain symptomatic despite optimal treatment.

Organic nitrates (e.g. isosorbide mononitrate) reduce preload, and hydralazine reduces afterload. Used in combination, these prolong life in African-Americans.

Approach Recommendations Symptoms &

Signs of HF: Fatigue (low card iac output), SOB, JVP, rales, S3, edema, rad iologic congestion, cardiomegaly. Elevated BNP. CXR to r/o infection, interstitial lung disease & PPH

Ejection fraction (obtain echo or LV gated study)

40% = systolic dysfunction 40-55% = mixed systolic and diastolic dysfunction 55% = d iastolic dysfunction - treat underlying disorder (HPT/ ischaemia/pericard ial constriction/restrictive CM (card iomyopathy)/infiltrative d isorders)

Consider etiology

Ischemic-CM HPT-CM Valvu lar HD-CM (A S/AR/MR) Metabolic: hyper/hypo thyroidism / hemochromatosis/pheochromocytoma Toxins: Alcohol/ anthracyclines/cocaine/amphetamines Viral CM Id iopathic Dilated CM Other:

Identi fy triggers Acute-sudden onset Ischaemia, arrhythmia, infection, pulmonary embolis m, acute valvular pathology

Chronic-gradual onset Anemia, thyrotoxicosis, non-compliance, diet, Rx e.g. NSAID’s

Treatment: Correct triggers and precipitants of acute and chronic Heart Failure

General measures Low sodium d iet Regular exercise/activity Treat ischemia Control hypertension

D/C smoking Treat lipid abnormalit ies Treat and control diabetes Identify & Rx depression

Symptomatic therapy Diuretics-titrate to euvolemic state Maintain Ideal Body Weight (dry weight = JVP normal / trace pedal edema) Furosemide 20 - 80 mg OD-BID

HCT/Zaroxo lyn for refractory congestion Digoxin-for persisting symptoms in NSR (systolic dysfunction) or symptoms and rate

control in Afib. Dose: 0.125 mg – 0.25 mg (Lower dose in elderly: 0.0625 mg) Therapy to

improve prognosis

AACCEE IInn hhii bbii ttoorrss -- GGeenneerraall GGuu iiddeell iinnee:: SSttaarrtt lloo ww aanndd tt iitt rraattee ttoo tthhee ttaarrggeett ddooss ee uuss eedd iinn tthhee cclliinn iiccaall tt rr iiaallss oo rr tthhee MMAA XX IIMMUUMM TTOO LLEERR AATTEEDD DDOOSS EE:: CCaapptt oopprrii ll 66.. 2255--1122.. 55 mmgg 5500 mmgg BBIIDD --TTII DD EEnn aallaapprrii ll 22.. 55mmgg 1100mmgg BBIIDD†† RRaammii pprrii ll 22.. 55 mmgg 55mmgg BBII DD §§

LLiiss iinnoopprrii ll 22 ..55 mmgg 3300-- 4400 mmgg OODD

TTrraann ddoollaapprrii ll 11 44 mmgg mmgg OO DD‡‡ **QQuuiinnaapprrii ll 1100 mmgg 4400 mmgg OO DD **CCii llaa zzaapprr iill 00 ..55 mmgg 1100 mmgg OODD **FFooss iinnoopprriill 55 mmgg 4400 mmgg OODD *Perindopril 4 mg 88 mmgg OO DD **NNoo llaarrggee ss ccaallee oouu ttccoommee tt rriiaa llss †† SSoo LLVVDD//XX--SSoo LLVVDD §§ AA IIRREE //AA II RREEXX ‡‡TT RRAA CCEE Consider ISDN 5-40mg QID+Hydralazine 10-75mg QID for ACE-I/ARB intolerance VHeFT

CCoonnss iiddeerr AACCEE--II//AARRBB ccoommbbiinnaatt iioonn iinn AACCEE--II aanndd //oorr --bblloocckkeedd pp aatt iieennttss wwiitt hh wwoorrsseenniinngg HHFF oorr hhoosspp iitt aalliizz aatt iioonn

Angiotensin II receptor antagonists (ARB’s) AA CCEE-- IInnhh iibb iittoo rrss rree mmaa iinn ff iirrss tt ll iinnee tthheerraappyy AA RRBB’’ss iinndd iiccaatteedd iinn AA CCEE-- II iinn ttoo lleerraann tt ppaatt iieenn tt ss ((CCHHAA RRMM ccaannddeess aarrttaann 1166--3322 mmgg OODD )) (( VVaa ll-- HHeeFFTT // VVAA LLIIAA NNTT vvaallss aarrttaann 116600 mmgg BBII DD))

Beta-blockers-Add Beta-blocker* to ACE-inhibitor/diuretic/+/- d igoxin in stable Class II-IV CHF/LVEF 40% (*No outcome data for other beta-blockers) Bisoprolol* 1.25 10 mg OD (CIBIS II Trial) Carvedilol* 3.125 mg BID 25 mg BID (50 mg BID if weight > 85 kg) Metoprolol* 12.5 mg BID 75 mg BID (MERIT Trial)

Caution:diabetics/renal disease/elderly/ NSAIDs & COX-2 inhibitors

Aldosterone antagonist (follow K/Cr in 3-7 days/ furosemide to avoid azotemia) Spironolactone 12.5-25 mg OD added to ACE-inhib itor/diuretic/+/- digoxin in stable

Class III-IV CHF/LVEF 35%/CR<220/K<5.0 (RA LES Trial) Anti-coagulant

anti-platelet Rx ASA if CA D ( dose to ACE inhib itor interaction) Coumadin for Afib, LV thrombus, LVEF 20%, DVT or pulmonary embolism Duration of A/C therapy: Indefinite fo r Afib/recurring systemic TE or DVT/PE

Consider Internal Medicine/Cardiology or Heart Failure Clinic referral for initiation/titration of - blocker. Consider EPS referral for symptomatic sustained or non-sustained ventricular arrhythmia (LVEF 30-40%) or AICD: Prior MI/CAD (LVEF 30% with IVCD 0.12 sec: MADIT II) CHF: (NYHA II-III & LVEF <35% SCD-HeFT) Cardiac Resynchronization Therapy(CRT):(NYHA Class III-IV with reduced ejection fractions; LVEF < 35%; QRS duration 0.13 with IVCD or LBBB: MIRACLE / MUSTIC) or both CRT/AICD: (NYHA III-IV;QRS 0.12:COMPANION). EECP/Transplant for refractory CHF.