CARDIAC

GLYCOSIDES
• Cardiac glycosides are glycosidic drugs having cardiac inotropic
property.
• They increase myocardial contractility and output.
• They were the primary drugs for treatment of Congestive Heart
Failure (CHF) till the 1970s, and are still valuable when combined with
other drugs.
• Digitalis lanata is the source of Digoxin. This is the only glycoside used
currently.
MECHANISM OF ACTION
Binds and inhibits
DIGITALIS Na+K+ATPase

Increased intracellular Na+

Accumulation of Ca2+ due to diminished Ca2+ extrusion

Increased intracellular Ca2+, as it enters the cell during

depolarization through voltage sensitive L type Ca2+ channels.

Increased Ca2+ uptake and storage in the sarcoplasmic reticulum (SR)

Increased amount of Ca2+ released during each AP from SR

INCREASED
Increased availability of Ca2+ for excitation-contraction coupling thus
CARDIAC OUTPUT
increasing the myocardial contraction
 PHARMACOLOGICAL ACTIONS
1. HEART
 Digoxin has direct effect on myocardial contractility.
Force of contraction:
• Digoxin causes a dose dependent increase in force of contraction of heart – a positive
inotropic action.
• Especially seen in a failing heart, which is exquisitely sensitive.
• Systole shortened
• Diastole prolonged
Rate:
• Heart rate is decreased.
• Bradycardia is more marked in CHF patients because improved circulation (due to positive
inotropic effect) restores the diminished vagal tone and abolishes sympathetic overactivity.
2. BLOOD VESSELS
 Weak direct vasoconstrictor action
 Digoxin has no prominent effect on BP.
 Therapeutic doses of digoxin have no significant effect on coronary circulation.
3. KIDNEY
 Promptly causes diuresis in CHF patients, secondary to improvement in circulation and
renal perfusion.
 Retained salt and water is gradually excreted
4. CNS
 Digitalis has little apparent CNS effect in therapeutic dose.
 Higher doses cause CTZ activation inducing nausea and vomiting.
 Still higher doses produce hyperapnoea, central sympathetic stimulation, mental
confusion, disorientation and visual disturbances.
 Effects on the GIT are only of toxicological nature.
 PHARMACOKINETICS
PROPERTY DIGOXIN
ORAL ABSORPTION 60 – 80%
 Digoxin is concentrated in the
TIME COURSE OF ACTION
heart, skeletal muscle, liver and - ONSET 15 – 30 MINUTES
- PEAK 2 – 5 HOURS
kidney. - DURATION 2 – 6 DAYS
PLASMA T 1/2 40 HOURS
 Its t1⁄2 is prolonged in elderly THERAPEUTIC ACTION 0.5 – 1.4 ng/ml
patients and in those with renal TOXIC CONCENTRATION >2 ng/ml
insufficiency: dose has to be DAILY MAINTENANCE DOSE 0.125 – 0.5 mg
DAILY ELIMINATION 35%
reduced.
DAILY ROUTE OF RENAL EXCRETION
ELIMINATION
ROUTE ADMINISTRATION ORAL & i.v.
 ADVERSE EFFECTS
Toxicity of digitalis is high, margin of safety is low (therapeutic index 1.5–3).
The manifestations are:
1. Extracardiac:
 Anorexia, nausea, vomiting and abdominal pain are usually reported first (due to gastric
irritation, mesenteric vasoconstriction and CTZ stimulation)
 Fatigue, malaise, headache, mental confusion, restlessness, hyperapnoea, disorientation,
psychosis and visual disturbances are the other complaints.
 Skin rashes and gynaecomastia are rare.
2. Cardiac:
 Almost every type of arrhythmia can be produced by digitalis: pulsus bigeminus, nodal
and ventricular extrasystoles, ventricular tachycardia and terminally ventricular
fibrillation.
 Partial to complete A-V block may be the sole cardiac toxicity, or it may accompany other
arrhythmias.
 Severe bradycardia, atrial extra- systoles, AF or AFL have also been noted.
TREATMENT
Further doses of digoxin must be stopped at the earliest sign of toxicity.
1. Tachyarrhythmias: When caused by chronic use of digitalis and diuretics
(both induce K+ depletion)—infuse KCl 20 m.mol/hour (max. 100 m. mol) i.v. or give
orally in milder cases.
When toxicity is due to acute ingestion of large doses of digoxin, plasma K + may be
high; it should not be given from outside.
K+ is contraindicated if higher degree of A-V block is present, because complete A-V
block and ventricular asystole may be precipitated.
2. Ventricular arrhythmias: Lidocaine i.v. repeated as required is the drug of choice. It
suppresses the excessive automaticity, but does not accentuate A-V block. Quinidine,
procainamide and propafenone are contraindicated.
3. Supraventricular arrhythmias: Propranolol may be given i.v. or orally depending on
the urgency.
4. A-V block and bradycardia: Atropine 0.6–1.2 mg i.m. may help; otherwise
cardiac pacing is recommended.

PRECAUTIONS AND CONTRAINDICATIONS

(a) Hypokalemia: enhances digitalis toxicity.
(b) Elderly, renal or severe hepatic disease: patients are more susceptible to
digoxin toxicity.
(c) Thyrotoxicosis: patients are more prone to develop digitalis arrhythmias.
(d) Ventricular tachycardia: digitalis is contraindicated because it may precipitate
ventricular fibrillation.
(e) Partial A-V block: may be converted to complete A-V block by digoxin.
(f) Wolff-Parkinson-White syndrome: Digitalis is contraindicated.
INTERACTIONS
1. Diuretics: cause hypokalaemia which increases the risk of digitalis arrhythmias;
potassium supplements should be given prophylactically.
2. Calcium: synergises with digitalis → precipitates toxicity.
3. Quinidine: reduces binding of digoxin to tissue proteins as well as its renal and biliary
clearance by inhibiting efflux transporter P-glycoprotein → plasma concentration of
digoxin is doubled → toxicity can occur.
4. Adrenergic drugs: can induce arrhythmias in digitalized patients; both increase ectopic
automaticity.
5. Digoxin absorption may be reduced by metoclopramide, sucralfate, antacids,
neomycin, sulfasalazine. Absorption of digoxin is increased by atropinic drugs, including
tricyclic antidepressants.
6. Propranolol, verapamil, diltiazem and disopyramide: may additively depress A-V
conduction and oppose positive inotropic action.
USES
The two main indications of digitalis are CHF and control of ventricular rate in
atrial fibrillation/flutter.
Cardiac arrhythmias
 Digitalis can be used for controlling ventricular rate in AF and AFL, whether
associated with CHF or not, but is incapable of curing the arrhythmia.
 Can also be used for long term ventricular rate control in persistent or
permanent AF/AFL, but not preferred for rapid control of heart.
 Preferred when AF/AFL are attended by heart failure.
 Digoxin can also be combined with beta blocker/CCB, if a single drug fails to
lower the heart rate to the desired levels.
TREATMENT OF HEART
FAILURE
Heart failure occurs when cardiac output is insufficient to meet the demands of
tissue perfusion, or is able to do so only by elevating fluid pressure. It is a
progressive disease with gradually deteriorating cardiac performance.
Heart failure may primarily be due to systolic dysfunction or cardiac dysfunction.

1. Systolic dysfunction: The ventricles are dilated and unable to develop sufficient
wall tension to eject adequate quantity of blood.

2. Diastolic dysfunction: The ventricular wall is thickened and unable to relax

properly during diastole; ventricular filling is impaired because of which output is
low.
1. DIURETICS
•Almost all cases of symptomatic CHF are treated with a diuretic.
• High ceiling diuretics (furosemide, bumetanide) are the diuretics of choice for mobilizing
oedema fluid; later they may be continued in low doses.
•Addition of a metolazone/spironolactone to furosemide may overcome the resistance that
develops to high ceiling diuretics after prolonged use.

2. RAS INHIBITORS
•Cause vasodilatation, retard/prevent ventricular hypertrophy, myocardial cell
apoptosis, fibrosis, intercellular matrix changes and remodelling.
•Recommended for all grades of CHF, unless contraindicated, or if renal function
deteriorates by their use.
•ACE inhibitor therapy is generally started at low doses (to avoid initial hypotension) which
are gradually increased to obtain maximum benefit or to near the highest recommended
doses.
•ARBs are alternatives to ACE inhibitors.
3. CARDIAC GLYCOSIDES
• Digoxin is the only cardiac glycoside in use today.
• It is a positive inotropic drug, which offers symptomatic relief, primarily in systolic
dysfunction or when CHF is due to AF with rapid heart rate.
• Continued digoxin therapy is the best course in CHF patients with with atrial fibrillation
who need ventricular rate control.
• Two major limitations in its use are low margin of safety and lack of effect on
neurohumoral contributors to pathogenesis of heart failure.
4. VASODILATORS
• Direct acting vasodilators are useful in t/t of acute heart failure that occurs episodically in
advanced cases, or that follows acute MI, and are infused i.v. for short periods to tide over
crisis.
• Can be differentiated into those which
• Dilate veins (nitrates)
• Dilate arterioles (hydralazine)
• Dilate both (sod. Nitroprusside
5. BETA-ADRENERGIC BLOCKERS
• Extensive studies over the past 30 years have established the utility of β1
blockers (mainly metoprolol, bisoprolol, nebivolol) and the nonselective β +
selective α1 blocker carvedilol in mild to moderate CHF treated with ACE
inhibitor ± diuretic, digitalis.
• They afford survival benefit and are now a part of standard CHF therapy.

6. ALDOSTERONE ANTAGONIST (Spironolactone, Eplerenone)

• Rise in plasma aldosterone in CHF, in addition to its well known Na+ and water
retaining action, is an important contributor to disease progression.
• The aldosterone antagonist spironolactone is a weak diuretic, but can benefit
CHF by antagonizing the effects of aldosterone.
7. SYMPATHOMIMETIC INOTROPIC DRUGS
• Drugs with β adrenergic and dopaminergic D1 agonistic actions have positive
inotropic properties which may be utilized to combat emergency pump failure.
• Dopamine and dobutamine infused i.v. act promptly and afford additional
haemodynamic support over vasodilators, digoxin and diuretics, but benefits are
short-lasting.
• Particularly useful when heart failure is accompanied by low BP.
8. PHOSPHODIESTERASE 3 INHIBITORS
• Inamrinone (amrinone)
• is a selective PDE3 inhibitor.
• Most important actions are positive inotropy and direct vasodilation
• It increases CO and decreases peripheral vascular resistance, CVP and left ventricular
diastolic volume, accompanied by mild tachycardia and slight fall in BP.
• Thrombocytopenia is the most prominent dose related ADR, therefore seldom used.
• Milrinone
• Related to inamrinone, it has similar action but is more selective for PDE3.
• at least 10 times more potent.
• It is shorter-acting.
• Thrombocytopenia is not significant.

• Levosimendan
• Acts by sensitizing troponin C as well as by inhibiting PDE3
• Infused i.v. is primarily indicated for short term t/t of acute
decompensated severe chronic heart failure.
• Most common ADR is hypotension
9. NESIRTIDE
This recombinant brain natriuretic peptide (BNP) is being used by continuous i.v.
infusion to relieve dyspnoea and other symptoms in refractory CHF.

10. SACUBITRIL-VALSARTAN COMBINATION

Recently been approved for use in advanced heart failure to decrease the
incidence of death and acute decompensation.

11. TOLVAPTAN
Introduced recently for the correction of water retention and hyponatremia
occurring in ‘syndrome of inappropriate ADH secretion’ (SIADH) as well as in
advanced CHF.