CARDIOVASCULAR SYSTEM

PHARMACOLOGY
PHARMACOLOGY II

DR E KEZIA
CARDIAC GLYCOSIDES
 Introduction

 These are glycosidic drugs having cardiac inotropic

property.
 They increase myocardial contractility and output in a
hypodynamic heart without a proportionate increase in
O2 consumption.
 Thus, efficiency of failing heart is increased.
 In contrast, ‘cardiac stimulants’ (Adrenaline, theophylline)
increase O2 consumption rather disproportionately and
tend to decrease myocardial efficiency.
 Introduction

 William Withering, a Birmingham physician, learnt that a decoction

containing ‘foxglove’ (Digitalis) with other herbals, prepared by an old
lady, relieved dropsy.
 He tried extract of foxglove alone and found it to be remarkably
effective in some cases.
 He published his classic monograph ‘An account of the Foxglove and
some of its medicinal uses: with practical remarks on dropsy and
other diseases’ in 1785 and ascribed the beneficial effect to an action
on the kidney.
 Cushney and Mackenzie, in the beginning of 20th century, established
its action on the heart and its use in congestive heart failure (CHF).
 Introduction

 Cardiac glycosides are found in several plants and in toad

skin (Bufotoxin).
 Digitalis lanata is the source of Digoxin, the only glycoside
that is currently in use.
 By convention the term, ‘Digitalis’ has come to mean ‘a
cardiac glycoside’.
 Introduction

 The most important cardiac glycoside being used in medicine is

Digoxin
 It has direct effects on myocardial contractility and
electrophysiological properties.
 In addition, it has vagomimetic action, reflex effects due to
alteration in haemodynamics and direct CNS effects altering
sympathetic activity.
 It causes a dose dependent increase in force of contraction of
heart—a positive inotropic action.
 Heart rate is decreased by digitalis. Bradycardia is more marked in
CHF patients
 Mechanisms of Action

 Digoxin inhibits membrane Na/K adenosine triphosphatase (NaK ATPase), which is

responsible for the active extrusion of Na from myocardial, as well as other cells.
 This results in accumulation of intracellular Na, which indirectly increases the
intracellular Calcium ion content via Na/Ca2 exchange and intracellular Calcium storage.
 The rise in availability of intracellular Calcium accounts for the positive inotropic effect
of digoxin.
 Slowing of the ventricular rate results from several mechanisms, particularly increased
vagal activity:
 delayed conduction through the atrioventricular node and bundle of His;
 increased cardiac output due to the positive inotropic effect of digoxin reduces reflex
sympathetic tone;
 small doses of digitalis sensitize the sinoatrial node to vagal impulses.
 The cellular mechanism of this effect is not known..
 Pharmacokinetics

 Oral absorption 60–80%

 Plasma protein binding 25%
 Time course of action Onset 15–30 min, Peak 2–5 hr, Duration 2–6 days
 Plasma t½ 40 hr
 Therapeutic concentration 0.5–1.4 ng/ml
 Toxic concentration > 2 ng/ml
 Daily maintenance dose 0.125–0.5 mg
 Daily elimination 35%
 Route of elimination Renal excretion
 Route of administration Oral, i.v.
 Uses

 The main use of digoxin is to control the ventricular rate (and hence
improve cardiac output) in patients with atrial fibrillation.
 Digoxin is usually given orally, but if this is impossible, or if a rapid
effect is needed, it can be given intravenously.
 Since the t1/2 is approximately one to two days in patients with
normal renal function, repeated administration of a maintenance
dose results in a plateau concentration within about three to six
days.
 This is acceptable in many settings, but if clinical circumstances are
more urgent, a therapeutic plasma concentration can be achieved
more rapidly by administering a loading dose.
 Uses

 Digoxin is also indicated in patients with heart failure and

atrial fibrillation.
 It is usually given only when diuretics and ACE inhibitors
have failed to control symptoms.
 Only about 50% of patients with normal sinus rhythm
(usually those with documented systolic dysfunction) will
have relief of heart failure from digitalis.
 It reduces hospitalization and deaths from progressive heart
failure at the expense of an increase in sudden death.
 Toxicity

 Toxicity of digitalis is high, margin of safety is low (therapeutic index 1.5–3).

 Higher cardiac mortality has been reported among patients with steady-state
plasma digoxin levels > 1.1 ng/ml but still within the therapeutic range during
maintenance therapy.
 About 25% patients develop one or other toxic symptom.
 The manifestations are
 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.
 Toxicity

 Cardiac-Arrhythmias, partial to complete A-V block,

severe bradycardia, atrial extrasystoles, AF or AFl.
 In about 2/3 patients showing toxicity, extracardiac
symptoms precede cardiac; in the rest serious cardiac
arrhythmias are the first manifestation
 Treatment-Further doses of digoxins must be stopped
at the earliest sign of toxicity; nothing more needs to
be done in many patients, especially if the
manifestations are only extracardiac.
 Toxicity

 Treatment
 For tachyarrhythmias caused by chronic use of digitalis and
diuretics infuse KCl 20 m.mol/hour
 For ventricular arrhythmias use Lidocaine i.v. repeated as
required. It suppresses the excessive automaticity, but does
not accentuate A-V block
 For supraventricular arrhythmias give Propranolol i.v. or orally
depending on the urgency.
 For A-V block and bradycardia Atropine 0.6–1.2 mg i.m. may
help; otherwise cardiac pacing is recommended
Precautions And Contraindications

 Hypokalemia enhances digitalis toxicity.

 Elderly, renal or severe hepatic disease patients are more susceptible to digoxin
toxicity.
 Myocardial ischaemia: severe arrhythmias are more likely.
 Thyrotoxicosis: patients are more prone to develop digitalis arrhythmias.
 Myxoedema: these patients eliminate digoxin more slowly; cumulative toxicity
can occur.
 Ventricular tachycardia: digitalis is contraindicated because it may precipitate
ventricular fibrillation.
 Partial A-V block: may be converted to complete A-V block by digoxin.
 Acute myocarditis: Diphtheria, acute rheumatic carditis, toxic carditis—inotropic
response to digitalis is poor, more prone to arrhythmias.
 Drug Interactions

 Diuretics: cause hypokalemia which increases the risk of digitalis arrhythmias; potassium
supplements should be given prophylactically.
 Calcium: synergises with digitalis → precipitates toxicity.
 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. Verapamil, diltiazem, captopril, propafenone and amiodarone also increase
plasma concentration of digoxin to variable extents.
 Adrenergic drugs: can induce arrhythmias in digitalized patients; both increase ectopic
automaticity.
 Digoxin absorption may be reduced by metoclopramide, sucralfate, antacids, neomycin,
sulfasalazine. Absorption of digoxin is increased by atropinic drugs, including tricyclic
antidepressants.
 Propranolol, verapamil, diltiazem and disopyramide: may additively depress A-V conduction and
oppose positive inotropic action.
 Succinylcholine: can induce arrhythmias in digitalized patients.