University of Lahore Islamabad Campus AssignmentSubject: Clinical Pharmacy
DigoxinIntroductionDigoxin, 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 cannotbe controlled by other medication.Mechanism of actionDigoxin binds to a site on the extracellular aspect of the α-subunit of the Na+/K+ ATPasepump in the membranes of heart cells (myocytes) and decreases its function. This causesan increase in the level of sodium ions in the myocytes, which then leads to a rise in thelevel of calcium ions. Because there is a sodium/calcium exchanger which depends onsodium gradient to pump out calcium, digoxin reduces such concentration gradient andsubsequently calcium efflux, thus increasing calcium concentration in myocardiocytesand 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 extrusionof Ca2+ by the sodium-calcium exchanger that relies on the high Na+ gradient. This effectcauses 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 nervoussystem, leads to a decrease in heart rate. Increased amounts of Ca2+ are then stored in thesarcoplasmic reticulum and released by each action potential, which is unchanged bydigoxin. This leads to increased contractility of the heart.Digoxin also increases vagal activity via its action on the central nervous system, thusdecreasing the conduction of electrical impulses through the AV node. This negativelychronotropic 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 strokevolume, relative to body need,with inability of the cardiac output to keep pace withvenous return i.e heart is unable to pump all the blood coming to itEpidemiologyCongestive 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 overthe age of 65, this increases to 6–10% in total population.EtiologyMyocardial Dysfunction • Myocardial infarction • Hypertension • Myocarditis • CardiomyopathyVentricular volume over load • Valvular incomptence e.g mitral and aortic
Ventricular outflow obstruction • Systemic or Pulmonary Hypertension • Aortic or Pulmonary stenosisVentricular inflow obstruction • Mitral or tricuspid valve stenosis • Constrictive Cardiomyopathy • Restrictive CardiomyopathyObligatory high cardiac output • Anemia • Thyrotoxocosis • Beri Beri • Patent ductus arteriousus(PDA)Altererd ryhthm • Atrial fibrillationPathophysiologyDecreased cardiac outputDecreased cardiac output due to decrease heart function results in diminished arterialtree. Therefore blood supply of the organ is reduced which may leed to ischemia.Damming of BloodHeart fails to pump the whole blood coming to it resulting in blood damming back intovenous system, accumualtion of deoxygenated blood in the tissue venous system mayproduced disturbed organ function.
Compensatory MechanismAs the heart beguns to fails a number of local compensatory mechanism are activated in aattempt 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 approvesinsufficient to maintain the cardiac output heart dillates.Compensatory Heart Failure: -According to Frank’s Starling Law increase length of cardiac muscles fibres increase theforce of contraction. If the dillated ventricle is able to maintain cardiac output this stage iscalled heart failure.Decompensatory Heart FailureWhen the heart come dillated beyond the point at which adequate myocardial contractile,tension can be generated dillation no longer results increase contractality resulting inprogressively decrease cardiac output this stage is called Decompensatory heart failure.In this stage venous circulation increases due to decrease pumping capacity of heartresulting in accumulation of venous return in the heart or in tissues draining the heart.Clinical ManifestationSymptoms • 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 HepatomegalyDiagnosis • 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 ArrhythmiasCardiac Arrhythmias are deviatin from normal heart beat pattren.They includeabnormalities of impulse formation such as heart rate or site of impulse origin andconduction disturbances. Which disrupt the normal sequence of normal atrial andventricular activation ElectrophysiologyConduction systema).Two Electrical Sequences that cause the heart chambers to fill with blood and contractare 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 impulsemake up the conduction system of the heart: - 1. SA node 2. AV node 3. Bundle of His 4. Purkinje fibreMyocardial Action potentialIt consist of five phases in which depolarization and repolarization results from changesin the electrical potential across the cell membrane caused by exchange of sodium ionalongwith 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 arrythmiasThese 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 disordersPathophsiology: -Abnormal impulse formation abnormal impulse conduction or combination of both maygive rise to arrythmias.Abnormal impulse formation may stem from: - 1. Depressed automatacity as in escapes beats bradycardia 2. Increased automatacityas in premature beats tachcardia and extra systole 3. Depolarization triggers activity to sustain ectopic firingAbnormal Impulse Conduction results from: 1. A conduction block or delay 2. 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 ofvital organs. Specific pathophysiology consequences depend on the type of thearrythmias present.
Clinical ManifestationSign and symptoms • Chest pain • Anxiety and confusion from reduce brain perffusion • Dyspnea • Abnormal pulse rate rhythm, or amplitude • Reduce B.P • Palpitation • Weakness • Convulsion • HypotensionDiagnostic test result • ECG only an ECG can definitely identify an arrythmias • EP testing • Electrolyte abnormalities of lab findings, most common hypokalemia and hyperkalemia.
Atrial FibrillationAtrial fibrillation (AF or A-fib) is the most common cardiac arrhythmia (abnormal heartrhythm) and involves the two upper chambers (atria) of the heart. Its name comes fromthe fibrillating (i.e. quivering) of the heart muscles of the atria, instead of a coordinatedcontraction. It can often be identified by taking a pulse and observing that the heartbeatsdont occur at regular intervals. However, a stronger indicator of AF is the absence of Pwaves on an electrocardiogram (ECG) which are normally present when there is acoordinated atrial contraction at the beginning of each heart beat. Risk increases with age,with 8% of people over 80 having AF. Atrial flutterAtrial 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 (230–380beats per minute) and falls into the category of supra-ventricular tachycardias. While thisrhythm occurs most often in individuals with cardiovascular disease (e.g. hypertension,coronary artery disease, and cardiomyopathy), it may occur spontaneously in people withotherwise normal hearts. It is typically not a stable rhythm, and frequently degeneratesinto 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 theBritish physician Sir Thomas Lewis (1882–1945) and colleagues.
Dose & AdministrationTo treat the above mentioned indication digoxin widely used with proper monitoring, thedose of digoxin for each patient has to be tailored according to age lean body weight andrenal function. The difference in bioavailability in IV and oral fromulation must beconsidered when changing from one dosage to another for e.g if patient is switched fromoral 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 throughelimination.Emergency parentral loading:-0.5-1mgNeonates,Infants and Children upto to 10 yearsIV Loading DoseNeonates (<1.5kg) 20microgram/kg over 24 hoursNeonates(1.5 to 2.5 kg) 30microgram/kg over 24 hoursNeonates upto to 2 years 35microgram/kg over24hours2 to 5 years 35microgram/kg over 24 hours5 to 10 years 25microgram/kg over 24 hours
Oral Loading DoseNeonates (<1.5kg) 20microgram/kg over 24 hoursNeonates(1.5 to 2.5 kg) 30microgram/kg over 24 hoursNeonates upto to 2 years 45icrogram/kg over24hours2 to 5 years 35crogram/kg over 24 hours5 to 10 years 25microgram/kg over 24 hoursThe loading should be administred in divided doses with approximately half of totalgiven dose first and further fractions of the total dose at intervals of 4-8 hours for oral and4-8hours Infusion for 10-20mis for IV.Maintenasnce DoseNeonates: daily dose = 24percent of 24 hours loading dose IV&oral2-upto 10 years: daily dose=25percent of 24hours loading dose IV&oralTherapeutic Range: 0.8-1.0ng/mlPrecautions and monitoring effectsSerum electrolyte balance should be monitoring for Precautionory measurement to ensurepatient safety and eficacy. • Potassium antagonize the digoxin • Calcium ions acts synergestically with digoxin • Magnesium levels inversely related to digoxin activity
Serum Digoxin LevelSerum level of digoxin is monitored to evaluate the : - • Absorption • Distribution • Elimination • Drug Interactions • Efficacy and toxicitySample 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 becausedigoxin 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 upsetIf notice other effects not listed above, one should consult concerning docter orPharmacist.
Drug Interactions:Serum level of digooxin may be INCREASED by concomitant administration of thefollowing • Prazosin • Quinidine • Spirolactone • Tetracycline • Erythromycin and possibly other antibiotics • Gentamicin • Itraconazole • Quinine • Trimithoprim • Alprazolam • Atropine • Indomethacin etcSerum levels of digoxin may be REDUCED by concomitant administration of thefollowing: - • Antacids • Kaolin Pectin • Some bulk forming laxative • Sulphasalazine • Neomycin • Rifimpcin • Cytostatic • Phenytoin • Metoclopramide • Penicillamine • Adrenaline • Salbutamol
• Cholestyramine.Available Brands in Pakistan Till 2008Lanoxin……..GSKTabs and injDigox………..Platinum PharmaceuticalsTabsDigoxin………Global PharmaceuticalsTabsDoxin…………Xenon PharmaceuticalsSyrup 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