Therapy of Heart Failure PDF

█ Therrapy of heart h failu ure Non n-drug the erapy = life e style mo odification n: – Rest. – Dietary sodium (salt)) and fat re...

█ Therrapy of heart h failu ure Non n-drug the erapy = life e style mo odification n: – Rest. – Dietary sodium (salt)) and fat re estriction. – AAvoid stre ess, smokinng and alc ohol. – WWeight redduction. – Control of risk factors e.g. surgical correction c of valvullar diseas ses and ttreatment of hyperthhyroidism, hypertension, etc. – A gs that ↑ BP Avoid drug P: e.g. symmpathomimetics, sodiu um containning drugs, etc. Dru ug therapy y: – Positive in notropic drugs:  Carrdiac glyco osides (Diggitalis).  Dop pamine & dobutamin d ne (used for short terrm only).  Pho osphodiestterase inhi bitors: inammrinone & milrinone.. – Diuretics. – A ACEIs. – V Vasodilatoors: nitrates s and hydrralazine – Other drug gs: e.g. betta-blockerrs and spironolactonee. ▌Carddiac glycoosides: Digoxin, Digitox xin, Ouaba ain Source e and chemistry – Nattural plant derivatives s (Foxglovve plant). – Carrdiac glycoosides conntain a lacttone ring and a a stteroid (aglycone) mo oiety attachhed to sug gar molecules. – Dig goxin is thee most widely used. Pharm macokinetics of digo oxin – Dig goxin distriibutes to most m bodyy tissues and a accum mulates in n cardiac tissue. Thee concentrration of th he drug in the heart is i twice that in skeleetal muscle e and at leasst 15 timess that in plasma. – Elim mination iss renal. Do ose adjusttment should be done accord ding to creeatinine clearance. anism of action Mecha a Pos sitive inotrropic effec ct: 175  Digitalis ↑ ca ardiac con asing free intracelluular Ca2+ through ntractility by increa t + + inhiibition of membrane m e-bound N Na /K ATPase enzy yme. This result in in nhibition + + of N Na /K pum mp with sub bsequent a acellular N a and Ca2+ accumulattion of intra + 2 via: – Increase C Ca2+ releas se from the e ssarcoplasm mic reticulu um. – Displacemment of intracellula ar 2+ CCa from its bindingg sites. – Increased intracellular Naa+ prevents Ca2+ expu ulsion from m tthe cell by the Na /Ca22+ + eexchangerr. Auttonomic effects: – ↑ vagal acttivity: By direct d and iindirect meechanismss. – ↓ sympatheetic activityy due to relieve of hypo oxia & imprroved tissuue oxygenattion. Pharm macologica al effects  ↑ Contracttility and COP: C due tto +ve inottropic effec ct. This leaads to: - Improvvement of RBF R → diurresis and ↓ RAAS (i.e e. ↓ fluid reetention). - Relief of o lung con ngestion.  ↓ HR: (B r a d y c a r d i a ) d due to: - ↑ vagall tone and ↓ sympathetic activityy on the hea art. - Direct inhibition i of o the AV c conducting g system.  C Conductioon velocityy: ction: ↑ due - Intra atrial conduc e to vagal stimulation. s. - A-V conduction: ↓↓ by direcct and vagal effects.  ↑ Excitabillity and automatici a ity: le eading to o ectopic c foci a and a arrhythmia of any typ pe (bigemin ny, trrigeminy, etc.). e  E ECG changges: - Prolongged PR intterval. - Short QT Q interval. - ST seggment deprression & T T- wave in nversion.  N Normalizattion of arterial a a and v venous pressures s due to im mproved heemodynammics. 176 Therapeutic indications  The use of digoxin is now limited to cases of chronic CHF associated with atrial flutter or fibrillation (AF) because digoxin is the only drug that ↑ contractility and ↓ AV conduction in the same time.  In cases of AF alone, other drugs like verapamil or beta-blockers are preferred.  In cases of CHF without AF, other drugs like diuretics and ACEIs are preferred. Contraindications Absolute contraindications: – Heart block: because digitalis worsens AV conduction by direct and vagal effects. – Hypertrophic obstructive cardiomyopathy (HOCM): because increasing cardiac contractility will ↑ the outflow tract resistance and accelerates heart failure (see before). – Wolff-Parkinson-White (WPW) syndrome: although digitalis (and verapamil) ↓ conduction in the normal pathway, they can ↑ conduction in the abnormal pathway leading to ↑ arrhythmia (see before). – Paroxysmal ventricular tachycardia: digitalis ↑ excitability and automaticity. Relative contraindications: – All causes of bradycardia (e.g. sick sinus syndrome, hypersensitive carotid sinus, with beta-blockers or verapamil) because addition of digoxin can lead to severe bradyvardia or even heart block. – Systemic hypertension: digitalis will ↑ the strain of the LV (you must correct hypertension first by giving VDs or diuretics). – Pulmonary hypertension due to chronic lung disease: digitalis will ↑ the strain of the RV (you must correct pulmonary hypertension first by giving VDs). – Cardiac diseases:  Acute MI: digitalis ↑ the infarct size and aggravates arrhythmia.  Cardiomyopathy…. digitalis is useless. – Renal or hepatic diseases: digoxin must be avoided in renal patients while digiToxin must be avoided in hepaTic patients. – In patients likely to require cardioversion: because digitalis may lead to fatal arrhythmia if given with cardioversion. 177  Drug in nteraction ns Drug Me echanism/effect Antacids - Kaolin Bin nd digoxin in the gut and decre ease bioavaailability Choles styramine (ab bsorption) Metoclopramide e Inc crease gut motility lea ads to dec crease digo oxin absorption. Atropin ne Decrease gutt motility le eads to inc crease digo oxin absorrption Quinidine Decrease ren nal clearance of digoxin and dissplace digoxin from plasma proteins. Serum S digo oxin is incrreased. Loop ddiuretics and a Thiiazides or loop diurettics may cause hypo okalemia and a thiazid des hyp pomagnessemia whic ch can ↑ thee risk of diigitalis toxicity Dosage and adm ministratio on Initiial digitalization: – It is done by giving one o tablett 0.25 mg /day ((5 days/weeek) from the t start. – TThe Cpss will be achieved a a after 5 t½ (i.e. aafter one week w for digoxin). – Rapid (lo oading) method is done in e emergencyy conditio ons to a achieve raapid C Cpss. It is given as 2 tablets (0 0.5 mg) tw wice d daily for 2 days (2x2 2x2). Maiintenance e dose: on ne tablet (0 0.25 mg)/d day, 5 da ays/week. Precau utions durring digitalis therapyy – Nevver give diigitalis i.v. before beeing sure that t the patient ha as not receeived digitaalis during the lastt 14 days to avoid diggitalis toxic city. – Con ntinuous monitoring m of plasma K+ level. – Men ntion all the relative contraind dications. ▌Digittalis toxic city Predisposing fac ctors  Hyppokalemiaa: increases digoxin b binding an nd effect.  Hyp mia (N.B. Hypocalcem percalcem H mia renderrs digitalis less effecttive).  Presence of reenal impairment. 178 Manife estations Carrdiac: – Bradycard dia and va ariable de egree o of heart block. – Paroxysmaal atrial tac chycardia – A Any type of arrhythm mia (premaature beats, bige emeny, trigemeny, etcc.) Extrracardiac:: – T The first manifestattion is fattigue aand anorrexia, follo owed by GIT ssymptomss e.g. diarrh hea, nause ea & vomiting due to stimulatio on of CTZ. – CCNS: head dache, delirium, halluucination, and a convulsions. – VVision: yelllow visionn (chromat atopsia), diplopia, am mblyopia, sscotoma, etc. e due tto retrobullbar neuritiis. – OOthers: sk kin rash, gyynecomasttia, galactoorrhea. Manag gement  Stop digitalis administra ation.  Corrrect hypok kalemia by y giving K+ either i.v. or oral (2 gm/4 g h).  Antiarrhythmic c drugs: – Lidocaine (in ventric cular arrhyythmia): 1-2 2 mg/kg i.v. bolus tthen 1-2 mg m /min i.v.i. – Phenytoin (in ventricular arrhytthmia with heart bloc ck): 250 mgg i.v. over 10 min. – A Atropine: if there is bradycardia b a or heart block.  Speecific digittalis antibo odies (Fab b fragments; Digib bind) to bbind digitaalis and promote its reenal clearance (the m most specific therapy y). █ Othe er positiv ve inotrop pic drugs Phospphodiesteerase (PD DE) inhibittors: Inamrinone – Miilrinone  Theey inhibit PDE P enzym me (type 3) → ↑ cAMP → ↑ Ca2+ in nflux in myyocardial cells c →↑ myo ocardial coontractility..  Theey have VD D properties.  Theey are use ed only i.v. for sh hort term treatment of CHF F in patients not respponding to o digitalis. They T are n not safe forr long term m use.  Advverse effe ects includ de: thromb bocytopen nia, cardiacc arrhythmmia, increa ase liver enzzymes (hep patotoxicityy).  Milrrinone is le ess toxic thhan inamrinnone 179