Heart failure treatment

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Heart failure treatment
Martin Šterba, PharmD., PhD. Department of
Pharmacology Faculty of Medicine HK, Charles
University
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HEART FAILURE

• Inability of the heart as a pump to maintain
  adequate tissue perfusion
• Compensatory responses sympathetic and RAAS
• HF classification
• Acute chronic
• Left right sided
• Systolic diastolic
• Severity according symptom scoring NYHA I-IV
• Aim to affect both symptoms and prognosis
• Different endpoints acute vs. chronic HF
• Acute HF acute decompensation of chronic HF
• To support and maintain adequate organ perfusion
  - an imperative
• Chronic HF treatment
• Antagonize chronic overstimulation of the
  sympathetic NS and RAAS which became
  contraproductive
• To decrease preload, afterload, heart remodelling

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DRUG CLASSESS USED IN THE HEART FAILURE TREATMENT

• Drugs increasing the strength of the cardiac
  muscle contraction
• i.e., drugs with positive inotropic action
• Diuretic agents
• decrease extracellular fluid volume (decrease
  preload and congestion - oedema)
• antagonize aldosterone receptors
• ACE inhibitors (reduce both preload and
  afterload)
• Other vasodilators
• ?-blockers
• Antiarrhythmic agents occasionally are required
  to normalize cardiac rate and rhythm

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DRUGS INCREASING THE STRENGHT OF CARDIAC
CONTRACTION

• Drugs with direct positive inotropic effects
• Increase in contractility ? ? CO ? improve
  perfusion of organs
• Drugs
• Cardioglycosides
• Phosphodiesterase inhibitors
• Sympathomimetic agents
• Calcium sensitizers

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CARDIAC GLYCOSIDES

• Often called digitalis or digitalis glycosides
• Source medicinal plants
• Digitalis purpurea and alba (purple and white
  foxglove) their medical use goes 3000 years ago
• Oleander, Lilly of the Valley (Convalaria
  majalis), Sea Squill (Scilla maritima)
• Chemically similar compounds that can increase
  the contractility of the heart muscle and are
  therefore they had been widely used in treating
  heart failure
• Pharmacodynamics Na/K ATPase inhibition
• The drugs have a low therapeutic index
• Agents
• Digoxin (di JOX in) clinically used
• Digitoxin (di ji TOX in)
• Oubain

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DIGITALIS AND W. WITHERING
Digilis purpurea Purple foxglove
William Withering (1741 - 1799)
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CARDIOGLYCOSIDESChemical structure
sugar
aglycone
lactone ring
steroid
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Ion movements during the contraction of cardiac
muscle ATPase adenosine triphosphatase
(according to Lippincotts Pharmacology, 2006)
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CARDIOGLYCOSIDESEffects on the heart

• Mechanical effects - increase in cardiac
  contractility
• ? ? intracellular Na ? increased intracellular
  Ca2 content ? increased release of calcium from
  sarcoplasmatic reticulum
• Direct electrophysiological effects
• AP shortening (esp. the plateau phase) ?
  potassium conductance that is caused by increased
  intracellular calcium
• resting membrane potential is increased - made
  less negative (due to the ? Na, Ca2) in ? doses
• delayed afterdepolarization (DAD) - ? Ca2 from
  stores - may reach threshold - premature
  ventricular depolarization or ectopic beat

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CARDIOGLYCOSIDESEffects on the heart

• ANS system mediated effects
• significant parasympathomimetic effects
• central stimulation of nervus vagus
• decreased SA pacemaker activity
• decreased AV conductance
• ? decreased HR !!!
• during intoxications - increased sympathetic
  outflow may be present (sensitizing for other
  cardiac tox.)

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DIGOXINPharmacokinetics

• Oral absorption 65-80 , parenteral
  administration for emergencies
• Wide distribution into the organ/tissues
  including CNS
• Excretion
• 80 of drug unchanged in the urine mostly
  glom. filtration
• dose individualisation in renal failure according
  GF
• small amount eliminated via active transport
  renal tubules and bile interactions
  importance ??? during renal failure

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CARDIOGLYCOSIDESPharmacokinetic properties
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A comparison of the properties of digoxin and
digitoxin
(according to Lippincotts Pharmacology, 2006)

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CARDIOGLYCOSIDESIndications

• Congestive heart failure
• In association with atrial fibrillation/flutter
  (clear indication)
• Digoxin reduces hospitalizations and improves
  symptoms, however, without improving survival
  (generally poor)
• indicated in severe forms of HF in combination
  with other treatment to improve symptoms of HF
  and clinical status
• Not to be used in diastolic HF and acute IM
  related HF
• Antiarrhythmic indications
• Supraventricular arrhythmias
• ? AV conduction will help control an excessively
  high ventricular rate - improving ventricular
  filling and increasing cardiac output
• !!! Contraindicated in Wolf-Parkinson-White sy
  (AVRT)

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CARDIOGLYCOSIDESAdverse effects

• Target organs heart, CNS, GIT
• Mechanisms Na/K-ATPase inhibition, vagal
  mediated effects
• Cardiac effects
• bradycardia, decreased or blocked AV conduction
• AV junctional rhythm
• premature ventricular depolarization, bigeminia
  rhythm (complex of normal and premature
  ventricular beats) ventricular fibrillation
• GIT anorexia, nausea, vomiting (nausea etc. can
  be among the first warning signs of toxicity !!!)
• CNS headache, fatigue, confusion, agitation,
  blurred vision, alteration of colour perception,
  and haloes on dark objects
• Gynecomastia in men upon prolonged use

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CARDIOGLYCOSIDESFactors predisposing to
digitalis toxicity

• Electrolytic disturbances
• Hypokalemia !!!
• K competes with digoxin for Na/K-ATPase
  binding site
• ? hypokalemia facilitate digoxin binding and
  Na/K-ATPase inhibition, while hyperkalemia has
  the opposite effects
• hypokalemia generally makes the heart more
  imbalanced and sensitive to proarythmogenic
  stimuli
• SIGNIFICANT RISK
• patients heavily vomiting, GIT infections with
  diarrhoea
• patients receiving diuretics (loop/thiazides),
  dose effect
• PREVENTION
• co-administration of a potassium-sparing
• diuretic or supplementation with KCl
• Hypercalcemia !!! increased Ca loading of
  cardiomyocytes
• hypernatremia, hypermagnesemia, and alkalosis

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CARDIOGLYCOSIDESFactors predisposing to
digitalis toxicity

• Drugs
• Quinidine - reduces the renal clearance of
  digoxin (competition for renal excretion) and
  displaces digitalis from tissue protein ?
  increases the toxicity of digoxin
• Verapamil, amiodaron, spironolakton - displace
  digoxin from protein ? increase digoxin by 50-75
  (it may be necessary to
• reduce dose)
• Potassium-depleting diuretics, corticosteroids
  and
• other drugs
• Diseases
• Hypothyroidism, hypoxia, renal failure, and
  myocarditis are predisposing factors to digitalis
  toxicity
• TDM to well individualize the therapy and avoid
  toxicity

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CARDIOGLYCOSIDESTreatment of severe acute
intoxication (overdose)

• Fab-fragments against digoxin largely increase
  renal excretion of digoxin (antidote)
• KCl administration
• Fenytoin may be used to suppress the ventricular
  exrasystoles
• Atropine may be used to antagonize concomitant
  bradycardia

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Drugs interacting with digoxin and other
digitalis glycosides
Amiodarone Erythromycin Quinidine Tetracycline Ver
apamil
Increased digitalis concentration may occur
during concurrent therapy
Enhanced potential for cardiotoxicity
Corticosteroids Thiazide diuretics Loop diuretics
Decreased levels of blood potassium
(according to Lippincotts Pharmacology, 2006)
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OTHER POSITIVE INOTROPIC AGENTS

• Due to the mechanisms and risks, they are used
  only in
• acute HF arising from the surgery or shocks
  (cardiogenic, septic)
• severe acute decompensation of chronic HF with
  signs of organ hypoperfusion
• BETA1-ADRENERGIC AGONISTS
• PHOSPHODIESTERASE III INHIBITORS
• CALCIUM SENSITIZERS

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A. BETA1-ADRENERGIC AGONISTS

• Dobutamine and Dopamine
• Improves cardiac performance by their positive
  inotropic effects and vasodilatation (minimum
  effects on HR by dobutamine)
• Increase in intracellular cAMP ? results in the
  entry of Ca2 into the myocardial cells
  increases, thus enhancing contraction
• Could be used for bridging the severe hemodynamic
  complications
• Diminished effects after long-time infusions and
  possible worsening upon withdrawal
• Ibopamine (pro-drug, - beta1, beta2, D1 and D2
  effects, does not increase HR)

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Sites of action by b-adrenergic agonists on heart
muscle
Sites of action by b-adrenergic agonists on heart
muscle
(according to Lippincotts Pharmacology, 2006)
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B. PHOSPHODIESTERASE III INHIBITORS

• Amrinone and milrinone
• Phosphodiesterase inhibitors III (heart specific
  subtype)
• increase the intracellular concentration of cAMP
  ? increase in intracellular Ca, and therefore
  cardiac contractility
• Amrinone
• given only i.v. mainly for short-term
  management of acute congestive heart failure
• is associated with reversible thrombocytopenia
  (milrinone does not affect platelets)
• Milrinone showed increased mortality and no
  beneficial effects, amrinone did not reduced the
  incidence of sudden cardiac death or prolong
  survival in patients with CHF !!!!!!

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C. CALCIUM SENSITIZERS

• Levosimendan
• No increase intracellular Ca2 - in contrast to
  previous agents
• Major effects sensitizing troponin C to calcium
  and vasodilatation (also some antiischemic
  effects)
• Increased contractility without worsening Ca2
  metabolism a increased O2 demands
• No major proarrhythmogenic effects
• Indication i.v. for treatment acute
  decompensations of CHF
• Adverse reactions hypotension, headache
• ? costs !!!