Digoxin

Clinical Pharmacy

University of Lahore

Islamabad Campus

Assignment

Subject: Clinical Pharmacy

DigoxinIntroduction

Digoxin, also known as digitalis, is a purified cardiac glycoside extracted from the plant, Digitalis lanata. Digoxin is widely used in the treatment of various heart conditions, namely cardiac arrythmias atrial fibrillation, atrial flutter and cardiac failure that cannot be controlled by other medication.

Mechanism of action

Digoxin binds to a site on the extracellular aspect of the α-subunit of the Na+/K+ ATPase pump in the membranes of heart cells (myocytes) and decreases its function. This causes an increase in the level of sodium ions in the myocytes, which then leads to a rise in the level of calcium ions. Because there is a sodium/calcium exchanger which depends on sodium gradient to pump out calcium, digoxin reduces such concentration gradient and subsequently calcium efflux, thus increasing calcium concentration in myocardiocytes and pacemaker cells. The proposed mechanism is the following: inhibition of the Na+/K+

pump leads to increased intracellular Na+ levels, which in turn slows down the extrusion of Ca2+ by the sodium-calcium exchanger that relies on the high Na+ gradient. This effect causes an increase in the length of Phase 4 and Phase 0 of the cardiac action potential, which when combined with the effects of digoxin on the parasympathetic nervous system, leads to a decrease in heart rate. Increased amounts of Ca2+ are then stored in the sarcoplasmic reticulum and released by each action potential, which is unchanged by digoxin. This leads to increased contractility of the heart.

Digoxin also increases vagal activity via its action on the central nervous system, thus decreasing the conduction of electrical impulses through the AV node. This negatively chronotropic effect is important for its clinical use in different arrhythmias.

Therapeutic and Clinical Indication

Congestive Cardiac failure Cardiac arrhythmias Artrial Fibrillation and flutter associated with CHF and Cardiac Arrythmias

Congestive Cardiac Failure ( CHF)

Congestive heart failure is clinical syndrome resulting from deficient cardiac stroke volume, relative to body need,with inability of the cardiac output to keep pace with venous return i.e heart is unable to pump all the blood coming to it

Epidemiology

Congestive Heart Failure is a common, costly, disabling and potentially deadly condition. In developing countries, around 2% of adults suffer from heart failure, but in those over the age of 65, this increases to 6–10% in total population.

Etiology

Myocardial Dysfunction

Myocardial infarction Hypertension Myocarditis Cardiomyopathy

Ventricular volume over load

Valvular incomptence e.g mitral and aortic

Ventricular outflow obstruction

Systemic or Pulmonary Hypertension Aortic or Pulmonary stenosis

Ventricular inflow obstruction Mitral or tricuspid valve stenosis Constrictive Cardiomyopathy Restrictive Cardiomyopathy

Obligatory high cardiac output

Anemia Thyrotoxocosis Beri Beri Patent ductus arteriousus(PDA)

Altererd ryhthm

Atrial fibrillation

Pathophysiology

Decreased cardiac output

Decreased cardiac output due to decrease heart function results in diminished arterial tree. Therefore blood supply of the organ is reduced which may leed to ischemia.

Damming of Blood

Heart fails to pump the whole blood coming to it resulting in blood damming back into venous system, accumualtion of deoxygenated blood in the tissue venous system may produced disturbed organ function.

Compensatory Mechanism

As the heart beguns to fails a number of local compensatory mechanism are activated in a attempt to maintain normal cardiac output such compensatory methods are;

Increased sympathetic activity: It leads to increase the heart rate and increased force of contraction of cardiac

muscles that leads to increase cardiac output. Hypertrophy of cardiac muscles: It is a compensatory mechanism to eject all the venous blood that comes to the

heart. Dillation of heart chambers;

When the combination of increased sympathatic activity and hypertrophy approves insufficient to maintain the cardiac output heart dillates.

Compensatory Heart Failure: -

According to Frank’s Starling Law increase length of cardiac muscles fibres increase the force of contraction. If the dillated ventricle is able to maintain cardiac output this stage is called heart failure.

Decompensatory Heart Failure

When the heart come dillated beyond the point at which adequate myocardial contractile, tension can be generated dillation no longer results increase contractality resulting in progressively decrease cardiac output this stage is called Decompensatory heart failure.In this stage venous circulation increases due to decrease pumping capacity of heart resulting in accumulation of venous return in the heart or in tissues draining the heart.

Clinical Manifestation

Symptoms

Dyspnea Orthropnea Paroxysmal nocturnal dyspnea Fatigue Sudden death

Signs

Tachycardia Third heart sound Fine crypts at lung bases Cardiomegaly Pleural effusion Edema of dependant part Distened neck veins Tender Hepatomegaly

Diagnosis

ECG: show depression of ST segment ETT :when history is suggestive of angina but ECG is normal ETT is performed

for diagnostics Heart Scan :It shows schemic area in myocardiam Angiography: It provides information about the extent and site of coronary artery

stenosis usually performed bypass surgery. Echocardiography Chest X-ray etc

Cardiac Arrhythmias

Cardiac Arrhythmias are deviatin from normal heart beat pattren.They include abnormalities of impulse formation such as heart rate or site of impulse origin and conduction disturbances. Which disrupt the normal sequence of normal atrial and ventricular activation

Electrophysiology

Conduction system

a).Two Electrical Sequences that cause the heart chambers to fill with blood and contract are initiated by the conduction system of the heart: -

1. Impulse formation, 2. Impulse transmission

b). Four main structures composed of tissue that can generate or conduct electric impulse make up the conduction system of the heart: -

1. SA node2. AV node3. Bundle of His4. Purkinje fibre

Myocardial Action potential

It consist of five phases in which depolarization and repolarization results from changes in the electrical potential across the cell membrane caused by exchange of sodium ion alongwith activity of calcium ions: -

1. Phase 0 (rapid depolarization)2. Phase 1 (Early rapid repolarization)3. Phase 2 (Plateau)4. Phase 3 (Final rapid repolarization)5. Phase 4 (Slow depolarization)

Classification of arrythmias

These are generally classified by origin: -

1. Supraventricle arrythmias: stem from enhance automaticity of the SA node or another pacemaker region above the bundle of His or from reentry conduction

2. Ventricular arrythmias: They occur below the bundle of His when an ectopic pacemaker trigers of ventricular contraction before the SA node fires, for example from a conduction disturbance or ventricular irrtability.

Etiology: -

Heart diseases for example CAD, VHD etc. MI Toxic doses of acrdioactive drugs Vagal Stimulation Hyperkalemia / hypokalemia COPD Increased sympathetic tone Thyroid disorders

Pathophsiology: -

Abnormal impulse formation abnormal impulse conduction or combination of both may give rise to arrythmias.

Abnormal impulse formation may stem from: -

1. Depressed automatacity as in escapes beats bradycardia2. Increased automatacityas in premature beats tachcardia and extra systole3. Depolarization triggers activity to sustain ectopic firing

Abnormal Impulse Conduction results from: 1. A conduction block or delay2. Reentry occurs when an impulse is rerouted through certain region in ehich it has

already travels thus impulse depolarizes the same tissue more then ones producing the additional impulse.

Hence arrythmias may decrease cardiac output reduce B.P and disrupt perfusion of vital organs. Specific pathophysiology consequences depend on the type of the arrythmias present.

Clinical Manifestation

Sign and symptoms

Chest pain Anxiety and confusion from reduce brain perffusion Dyspnea Abnormal pulse rate rhythm, or amplitude Reduce B.P Palpitation Weakness Convulsion Hypotension

Diagnostic test result ECG only an ECG can definitely identify an arrythmias EP testing Electrolyte abnormalities of lab findings, most common hypokalemia and

hyperkalemia.

Atrial Fibrillation

Atrial fibrillation (AF or A-fib) is the most common cardiac arrhythmia (abnormal heart rhythm) and involves the two upper chambers (atria) of the heart. Its name comes from the fibrillating (i.e. quivering) of the heart muscles of the atria, instead of a coordinated contraction. It can often be identified by taking a pulse and observing that the heartbeats don't occur at regular intervals. However, a stronger indicator of AF is the absence of P waves on an electrocardiogram (ECG) which are normally present when there is a coordinated atrial contraction at the beginning of each heart beat. Risk increases with age, with 8% of people over 80 having AF.

Atrial flutter

Atrial flutter (AFL) is an abnormal heart rhythm that occurs in the atria of the heart. When it first occurs, it is usually associated with a fast heart rate or tachycardia (230–380 beats per minute) and falls into the category of supra-ventricular tachycardias. While this rhythm occurs most often in individuals with cardiovascular disease (e.g. hypertension, coronary artery disease, and cardiomyopathy), it may occur spontaneously in people with otherwise normal hearts. It is typically not a stable rhythm, and frequently degenerates into atrial fibrillation (AF). However, it does rarely persist for months to years.

Atrial flutter was first identified as an independent medical condition in 1920 by the British physician Sir Thomas Lewis (1882–1945) and colleagues.

Dose & Administration

To treat the above mentioned indication digoxin widely used with proper monitoring, the dose of digoxin for each patient has to be tailored according to age lean body weight and renal function. The difference in bioavailability in IV and oral fromulation must be considered when changing from one dosage to another for e.g if patient is switched from oral IV formulation the dosage should be reduced by approx. 33%,

Adults and Childrens Over 10 years: -

Rapid oral loading; 0.75-1.5mg single dose

Slow oral loading; 0.25-0.75mg should be given daily for one week by an appropriate mention dose.Clinical reponse should be seen within a week.

Maintenance Dose: -

It should be based upon the % of the body stores of digoxin, lost each day through

elimination.

Emergency parentral loading:-

0.5-1mg

Neonates,Infants and Children upto to 10 years

IV Loading Dose

Neonates (<1.5kg) 20microgram/kg over 24 hours

Neonates(1.5 to 2.5 kg) 30microgram/kg over 24 hours

Neonates upto to 2 years 35microgram/kg over24hours

2 to 5 years 35microgram/kg over 24 hours


Oral Loading Dose

Neonates (<1.5kg) 20microgram/kg over 24 hours

Neonates(1.5 to 2.5 kg) 30microgram/kg over 24 hours

Neonates upto to 2 years 45icrogram/kg over24hours

2 to 5 years 35crogram/kg over 24 hours


The loading should be administred in divided doses with approximately half of total

given dose first and further fractions of the total dose at intervals of 4-8 hours for oral and

4-8hours Infusion for 10-20mis for IV.

Maintenasnce Dose

Neonates: daily dose = 24percent of 24 hours loading dose IV&oral

2-upto 10 years: daily dose=25percent of 24hours loading dose IV&oral

Therapeutic Range: 0.8-1.0ng/ml

Precautions and monitoring effects

Serum electrolyte balance should be monitoring for Precautionory measurement to ensure

patient safety and eficacy.

Potassium antagonize the digoxin

Calcium ions acts synergestically with digoxin

Magnesium levels inversely related to digoxin activity

Serum Digoxin Level

Serum level of digoxin is monitored to evaluate the : -

Absorption

Distribution

Elimination

Drug Interactions

Efficacy and toxicity

Sample should be taken 6-8 hours after oral dose and 3-4 hours IV dose,

This monitoring is done to ensure safety, efficacy, patient compliance and care because

digoxin is narrow therapeutic drug.

Digoxin Toxicity: -

Its fairly common occurrence is due to narrow therapeutic range (0.8-1.0ng/ml)

Signs of toxicity: -

Anorexia

Fatigue

Headache and malaise

Nausea and vomiting

Mental confusion and disorientation

Cardiac Effects: -

a. Premature ventricular contraction and ventricular trachycardia and fibrillation

b. SA and AV block

c. Atrial Trachycardia with AV block

Treatment of toxicity: -

Discontinuation

To counter hypokalemia potassium suppliment should be administered and

potassim level should be monitored in the serum.

Arrythmias are treated with lidocaine (100mg bolus followed by infusion, 25-

50mg/minutes to a max. of one gram)

Cholestyramine for prevevevtion of absorption and re-absorption of digoxin in the

bile

Patient with high serum level of digoxin for example in sucidal overdose purifies

digoxin specific FAB one vial(38mg) will bind 0.6mg of digoxin.

Side effects:

Diarrhea

loss of appetite

Drowsinesss

headache

muscle weakness

fatigue may occur as your body adjusts to the medication.

confusion,

visual disturbances (blurred vision or yellow/green halos around objects)

fast/slow/irregular heartbeat

skin rash

breast enlargement

severe stomach upset

If notice other effects not listed above, one should consult concerning docter or

Pharmacist.

Drug Interactions:

Serum level of digooxin may be INCREASED by concomitant administration of the

following

Prazosin

Quinidine

Spirolactone

Tetracycline

Erythromycin and possibly other antibiotics

Gentamicin

Itraconazole

Quinine

Trimithoprim

Alprazolam

Atropine

Indomethacin etc

Serum levels of digoxin may be REDUCED by concomitant administration of the

following: -

Antacids

Kaolin Pectin

Some bulk forming laxative

Sulphasalazine

Neomycin

Rifimpcin

Cytostatic

Phenytoin

Metoclopramide

Penicillamine

Adrenaline

Salbutamol

Cholestyramine.

Available Brands in Pakistan Till 2008

Lanoxin……..GSK

Tabs and inj

Digox………..Platinum Pharmaceuticals

Tabs

Digoxin………Global Pharmaceuticals

Tabs

Doxin…………Xenon Pharmaceuticals

Syrup

Refrences

Coomprehensive Pharmacy Review 7TH Edition

Essentials of Medical Pathology 2nd Edition

Pakistan Drug Manual 2008

GlaxoSmithKline United Kingdom

www.wilipedia.org

www.drugs.com

Good and Gillman Pharmacology and Clinical Basis of Therapeutics 11th

Edition

Health & Medicine

Digoxin