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drugs used to treat congestive heart failure (Positive inotropic drug -…
drugs used to treat congestive heart failure
cardiac decompensation
congestive heart failure = cardiac decompensation
the condition, in which the cardiac output is insufficient to meet the circulatory needs of the body
there is no proper tissue perfusion
compensatory mechanism is targeted in treatment of congestive heart failure
digitoxin / digoxin is still good drug in the end-stage of heart failure, but not the best choice in early stage
Factors determening cardiac working capacity
Preload
cardiac filling pressure (end-diastolic volume)
determined by venous return
increased venous return is not always good
venous pressure↑ -> stroke volume↑ -> elongation of cardiac muscle fibers until certain length
at first, heart can pump more blood, but finally, stroke volume decreased (irreversible)
Drugs
Nitrates: dilate both artery and vein
Afterload
resistance against ventricular systolic force
α1 blocker or Ca2+ channel blocker : for vasodilation
Intrinsic myocardial contractility
all factors determining how strong the heart muscle can contract
IC Ca2+ concentration
the only factor that we can regulate (pharmacologically important)
increase IC Ca2+ concentration -> increase contractility
problem : positive bathmotropic effect -> risk for arrhythmia
O2 concentration
cannot do something chronically
glucose concentration
availability of ATP
decreased stroke volume -> several compensatory mechanisms
compensatory
mechanisms
activate sympathetic system – constriction of the vessels (increase preload and afterload)
β1 activation on the kidney – renin secretion for (RAAS)
angiotensin2 – direct vasoconstriction
aldosterone – salt/water retension (increase venous return = increase preload)
all these mechanism -> cause remodeling of the heart muscle (fat and connective tissue replace cardiac muscle)
Treatment
decrease these compensatory mechanisms (to decrease preload and afterload)
sympathetic tone
heart
CArdioselective beta blocker
Partial agonist of Beta receptor for elderly
Vessel
Alpha1 blocker
Ca2+ channel blocker
nitrate
RAAS
ACE inhibitor
Angiotensin receptor inhibitor
Aldosterone receptor antagonist
Diuretic
Positive inotropic drug - for end stage of heart failure
Drugs
natural derivative from foxglove
digoxin
digitoxin
General structure
steroid based + lactone ring = genin (aglycon
responsible for binding to target – Na/K ATPase
sugar residue
prolong the action
increase the solubility of the genin part
OH-group
increase water solubility
MOA
Na/K ATPase inhibition and increased IC Ca2+
Na/K ATPase inhibition -> no Na+ outflow -> no Na+ inflow via Na/Ca exchanger -> Ca2+ stay within cell
-> Ca2+ from sarcoplasmic reticulum(Ryadonie receptor)↑ -> IC Ca2+↑ -> contractility↑
Cardiac glycosides increase the output force of the heart and decreases its rate of contractions by acting on the Na-K ATPase pump, they are used for treating congestive heart failures and cardiac arrhytmias. Found on foxglove plants
Pharmacological effect
cardiac effects
positive inotropic action
myocardial contractility↑ -> better pump function
decreased venous stasis
Increase diuresis
edema↓
heart size ↓
MOA
inhibition of Na/K ATPase Æ Ca2+ from sarcoplasmic reticulum(Ryadonie receptor)↑ -> IC Ca2+↑ Æ contractility↑
positive bathmotropic effect
arrhythmia
ectopic activity -> as cardiac glycosides intoxication
negative chronotropic effect
heart rate↓ (beneficial for coronary filling)
negative dromotropic effect
AV conduction↓
Mechanism of action in negative chronotropic and dromotropic effects
Vagal tone
Na/K ATPase is present in vagal nuclei
neuron also very sensitive to Ca2+ concentration
cardiac glycosides can get into the CNS -> stimulate vagus.n -> acetylcholine acts on M2 in pacemaker cells
atropine is good for glycosides intoxication-induced bradycardia
extra cardiac effect
kidney
renin release↓ via inhibition of the Na/K ATPase -> beneficial effect (decrease decompensation effects)
GIT
nausea / vomiting / constipation via stimulation of the vagal nuclei and the CTZ -> side effects
CNS
disorientation / hallucinations / disturbance in the color vision -> side effects
Vessel
smooth muscle contraction via inhibition of Na/K ATPase -> side effects
Pharmacokinetics
Absorption
orally administerable polar compound
lipophilicity increases the absorption
Distribution
widely distributed in the body, but acts predominantly in the heart
plasma binding
digoxin(60%)
digitoxin(97%)
Metabolism/excretion
digoxin
70-80% excreted unchanged through the kidney
digitoxin
metabolized in the liver -> biliary excretion as glucuronide -> enterohepatic circulation -> accumulation
Dosing
oral or parentral
accumulation in the myocardium
T1/2
digoxin (36h)
digitoxin( 4-5days)
loading dose
digoxin (1.8mg)
digitoxin (1.2mg)
maintaining dose
substitution of the eliminated amount
digoxin 0.5mg/day (40%)
digitoxin 0.1 mg/day (7%)
Side effect/toxicity
toxicity is really great because of very narrow therapeutic index
cardiac side effects and toxic effects
bradycardia
Slow AV conduction
Ventricle extra systole
Ventricular tachycardia
Ventricular fibrilation
Extra-cardiac side effect and toxic effect
GIT
Anorexia
Nausa
Vomiting
CNS
Headache
Weakness
Dizziness
Sleeping disorder
Visual disturbance
Convulsion
Hallucination
intoxication with cardiac glycosides
reasons
overdose
plasma K+↓(binding site)
plasma Ca2+↑
renal failure
myocardial hypoxia
Therapy
stop administration
anti-digoxin antibody
K+ administration
block vagal tone with atropine
Drug interaction
pharmacokinetic
kinidin/ verapamil / amiodarone / propafenon
release digoxin from tissue stores
reduce digoxin excretion
displacement from plasma protein binding
Pharmacodynamic
Ca2+
potentiation
K+
Antagonism
Clinical use
for end-stage of heart failure -> give positive inotropic effect
slowing ventricular rate in rapid, persistent atrial fibrilation or atrial tachycardia.
Contraindication
Slow AV conduction patient
Sinus bradycardia
Ventricular extra systole / WPW syndrome
Hypertrophic cardiomyopathy
Previous AMI (risk of rupture
Renal failure patient
Drugs which increase IC cAMP
Beta 1 agnoist
dobutamine
positive inotropic effect without tachycardia -> β1 stimulation
Used I.V. infusion in acute (reversible) heart failure
dopamine
strong positive inotropic effect -> β1 stimulation
renal vasodilation -> D1 receptor stimulation
for cardiogenic shock
Phosphodiesterase inhibitors
in acute cases with i.v.
inhibition of cAMP degradation in cardiac muscle -> IP3↑ -> IC Ca2+↑ -> contractility↑
Inhibiting cAMP degradation in SM will lead to myosine light chain activation causing a vasodilator effect
(theophylline)
aminophylline
Narrow therapeutic range
Amrinone
Only acute treatment
Side effect
Thrombocytopenia
Liver function disorders
Hypoxia induced myocardium damage
Milrinone
20 times more effective than amrinon
No thrombocytopenia
Ca 2+ sensitizers
binding to troponin C and increase its Ca2+ sensitivity without increasing IC Ca2+
non-arrhythmogenic and “energy saving” positive inotropic drugs (safe)
administered orally
levosimendane
Ca2+ dependent binding to troponin C -> no prolong relaxation
activates ATP-dependent K+ channel (present in vein) -> dilate veins