heart failure abnormality of cardiac contraction &/or relaxation result in common symptoms of...
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HEART FAILUREAbnormality of cardiac contraction &/or
relaxation result in common symptoms of shortness of breath and tiredness, so the heart became unable to meet body requirement.
HF classificationAcute & chronicLeft & right sidedSystolic & diastolic
Main causes
I. Coronary artery disease
II. Hypertension
III. Valvular heart disease
IV.Cardiomyopathy
V. Corpulmonale
Factors aggravating heart failure
1. Myocardial ischemia or infarct.2. Dietary sodium excess.3. Arrhythmias.4. Intercurrent illness (eg. infection).5. Conditions associated with increased metabolic demand
(eg. pregnancy, thyrotoxicosis, excessive physical activity).
6. Administration of drug with negative inotropic properties or fluid retaining properties (e. NSAIDs, corticosteroids).
7. Alcohol.
New classification of heart failure
Stage A: Asymptomatic with no heart damage but have risk factors for heart failureStage B: Asymptomatic but have signs of structural
heart damageStage C: Have symptoms and heart damageStage D: End stage disease
Compensatory changes in heart failure
I. Activation of SNS.
II. Activation of RAS.
III. Increased heart rate.
IV. Release of ADH.
V. Release of atrial natriuretic peptide.
VI. Chamber enlargement.
VII.Myocardial hyperatrophy.
Goals of treatment
•To improve symptoms and quality of life.
•To decrease likelihood of disease progression.
•To reduce the risk of death and need for hospitalization.
1. Drugs increasing the strength of the cardiac muscle contraction
• i.e., drugs with positive inotropic action
2. Diuretic agents.
• decrease extracellular fluid volume (decrease preload and congestion - oedema)
• antagonize aldosteron receptors
3. ACE inhibitors (reduce both preload and after load).
4. Other vasodilators (hydralazine)
5. -blockers(carvidolol).
6. Antiarrhythmic agents occasionally are required to normalize cardiac rate and rhythm.
Drugs Classes used in the heart failure treatment
Diuretics
ReduceReduceFluidFluid
VolumeVolume
Vasodilators
DecreaseDecreasePreloadPreload
andandAfterloadAfterload
Inotropes
AugmentAugmentContractilitContractilit
yy
Natriuretic Peptide
DecreaseDecreasePreloadPreload
andandAfter load; After load;
Reduce Reduce Fluid Fluid
VolumeVolume
DecreaseDecreasePreloadPreload
andandAfter load; After load;
Reduce Reduce Fluid Fluid
VolumeVolume
Drugs increasing the strength of cardiac contraction
Drugs with direct positive inotropic effectsIncrease in contractility ↑ CO improve perfusion of
organs
Drugs
1) Cardiac glycosides.
2) Phosphodiesterase inhibitors.
3) Sympathomimetic agents.
4) Calcium sensitizers.
Ion movements during the contraction of cardiac muscle ATPase = adenosine triphosphatase
(according to Lippincott´s Pharmacology, 2006)
Often called digitalis or digitalis glycosidesSource: medicinal plants
Digitalis purpurea and alba (purple and white foxglove) their medical use goes 3000 years ago.
o Chemically similar compounds that can increase the contractility of the heart muscle and are therefore they had been widely used in treating heart failure.
o The drugs have a low therapeutic index.Agents
Digoxin – clinically used Digitoxin Oubain
1.cardiac glycosides
DigoxinEnhances LV function, normalizes baroreceptor-mediated
reflexes and increases cardiac output at rest and during exercise.
Recommended to improve clinical status of patients with heart failure due to LV dysfunction and should be used in
conjunction with diuretics, ACE inhibitors and beta-blockers.Also recommended in patients with heart failure who have
atrial fibrillation.Digoxin initiated and maintained at a dose of 0.25 mg daily.
It cause inhibition of Na/K-ATPas &also caused vagal stimulation.
1. Mechanical effects - increase in cardiac contractility intracellular Na+ increased intracellular Ca2+ content increased release of calcium from sarcoplasmatic reticulum.
2. 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 after depolarization (DAD) - Ca2+ from stores - may reach threshold - premature ventricular depolarization or „ectopic beat“.
3. ANS system mediated effects: central stimulation of nervous vagus
decreased SA pacemaker activity.
decreased AV conductanc→ decreased HR .
Pharmacological action
o Oral absorption: 65-80 %, parenteral administration for emergencies
o Wide distribution into the organ/tissues including CNS
o 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
DigoxinDigitoxin
Half-life36 hours164 hours
Therapeutic plasma concentration
0.5 - 2 ng/mL10 - 25 ng/mL
Toxic plasma concentration 2 ng/mL 35 ng/mL
Daily dose (slow loading or maintenance)
0.125 - 0.5 mg0.05 - 0.2 mg
Rapid digitalizing dose0.5 - 0.75 mg every 8 h for 3 doses
0.2 - 0.4 mg every 12 h for 3 doses
Pharmacokinetics
A comparison of the properties of digoxin and digitoxin
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 MI 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 syndrome.
Indications
Cardiac effects a) bradycardia, decreased or blocked AV conduction
b) AV junctional rhythm
c) premature ventricular depolarization, bigeminia rhythm (complex of normal and premature ventricular beats) ventricular fibrillation
o GIT: anorexia, nausea, vomiting (nausea etc. can be among the first warning signs of toxicity .)
o CNS: headache, fatigue, confusion, agitation, blurred vision, alteration of colour perception, and haloes on dark objects.
o Gynecomastia in men upon prolonged use.
Adverse effects
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, spironolacton - displace digoxin from protein increase digoxin by 50-75 % (it may be necessary to reduce dose)
Potassium-depleting diuretics and corticosteroids
Diseases Hypothyroidism, hypoxia, renal failure, and myocarditis are predisposing
factors to digitalis toxicity
Factors predisposing to digitalis toxicity
o 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
o Hypercalcemia – increased Ca loading of cardiomyocytes
o hypernatremia, hypomagnesemia, and alkalosis
Factors predisposing to digitalis toxicity
Drugs interacting with digoxin and other digitalis glycosides
Increased digitalis concentration may occur during
concurrent therapy
Enhanced potential for cardiotoxicity
Decreased levels of blood potassium
AmiodaroneErythromycin
QuinidineTetracyclineVerapamil
CorticosteroidsThiazide diuretics
Loop diuretics
Fab-fragments against digoxin largely increase renal excretion of digoxin (antidote).
KCl administration.
phenytoin may be used to suppress the ventricular arrythmia.
Atropine may be used to antagonize concomitant bradycardia.
Treatment of severe acute intoxication (overdose)
Amrinone and Milrinone
o Phosphodiesterase inhibitors III (heart specific subtype) increase the intracellular concentration of cAMP increase in
intracellular Ca, and therefore cardiac contractility .
o 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).
o 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.
2.PHOSPHODIESTERASE III Inhibitirs
Dopamine act on alpha , beta & dopaminergic receptors ,while Dobutamine act on B,D &less on alpha receptors
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
Dopamine preferred in cases of HF associated with hypotension .
Dobutamine preferred in HF with normal BP.
Diminished effects after long-time infusions and possible worsening upon withdrawal
Ibopamine (pro-drug, - beta1, beta2, D1 and D2 effects, does not increase HR)
3 .BETA1-ADRENERGIC AGONISTS
(according to Lippincott´s Pharmacology, 2006)
Sites of action by -adrenergic agonists on heart muscle
Levosimendan(simdax)
No increase intracellular Ca2+ - in contrast to previous agents.
it increase calcium sensitivity to myocyte by binding to cardiac troponine C so increase myocardial contractility.
Also it have vasodilatory effect mediated by opening of vascular ATP-sensitive K-channel.
No major proarrhythmogenic effects
Indication: i.v. for treatment acute decompositions of CHF., it give 6-12 Mg\kg(loading dose)over 10 min. followed by 0.05-0.2Mg\kg\min. as continuous infusion.
Adverse reactions: hypotension, headache
4 .CALCIUM SENSITIZERS
Angiotensin Converting Enzyme Inhibitors :
they first line in all pt. with chronic HF.They decrease PVR(after load),decrease salt &water
retention by suppress aldosteron(decrease preload),also decrease sym. activity by suppressing
NE release.Decrease remodeling effect on heart.
decrease in the progression of chronic HF.decreased hospitalization.enhanced quality of life.
renin
Angiotensinogen Angiotensin I
Other pathways Angiotensin II
Receptors
AT1 AT2
Vasoconstriction Proliferative Action
VasodilatationAntiproliferative
Action
ACE
ACE InhibitorContraindications
Renal artery stenosis (relative).Hyperkalemia. Renal insufficiency. Arterial hypotension.Cough.Angioedema.
AlternativesHydralazine + ISDN, AT-II inhibitor .
Guidelines to ACE Inhibitor TherapyAll patients with symptomatic heart failure and those in
functional class I with significantly reduced left ventricular function should be treated with an ACE inhibitor, unless
contraindicated or not tolerated.
ACE inhibitors should be continued indefinitely.
In very severe heart failure, hydralazine and nitrates added to ACE inhibitor therapy can further improve cardiac
output.
B-blocker in CHFB-blockers give protection against catecholamine
myocyte toxicity.we should start slowly& then up titrate gradually
&watching adverse effects.B-blockers add only to existing therapy include ACEI
&diuretic &(in some studies) digoxin & idealy not give for pt. with class 3 &4.
only carvidolol& metaprolol are approved in USA.carvidolol reduce mortality more than metaprolol
DiureticsIndicated in patients with symptoms of heart failure
who have evidence of fluid retention.Enhance response to other drugs in heart failure such
as beta-blockers and ACE inhibitors.Therapy initiated with low doses followed by
increments in dosage until urine output increases and weight decreases by 0.5-1 kg daily.
.decrease venous return(preload)so decrease edema, decrease cardiac size &increase pump function.
The Future of HF Pharmacotherapy Management
1) natriuretic peptides (Nesiritide, ularitide, carperitide).
2) Levosimendan (inotrope/vasodilator).
3) Vasopressin Receptor Antagonists(Tolvaptan)&IV Conivaptan (dual vasopressin blocker).
4) Endothilin-1 receptor antagonists (Tezosentan).
Nesiritide(natrecore)It recombinant DNA from human B-type natriuretic peptide.
It bind to NP-A receptor which activate guanylate cyclase that convert GTP to cGMP which act as 2nd messenger &induce it s
biological action. Advantages
Rapid symptomatic improvementTheoretical antagonism of RAAS activation
Disadvantages Minimal indirect effect in increasing cardiac output
Incompatibilities; cannot be infused through same IV catheter as heparin (no heparin-coated catheters), insulin,
bumetanide, enalaprilat, hydralazine, or furosemide.Associated with clinically significant hypotension .
Associated with increased serum creatinine concentration.
Vasopressin Antagonists Currently in DevelopmentTolvaptan—Oral selective V2-receptor antagonist
Treatment of decompensate heart failureLixivaptan—Oral selective V2-receptor antagonistConivaptan—Intravenous dual V1a/V2-receptor
antagonist
Treatment of euvolemic hyponatremia in hospitalized patients (FDA approved Dec. 30 2005 Vaprisol®)
Receptor
SubtypeSite of Action Activation Effects
V1A
Vascular smooth muscle PlateletsLymphocytes and monocytesHepatocytes
VasoconstrictionPlatelet aggregationCoagulation factor releaseGlycogenolysis
V1BAnterior pituitaryACTH and -endorphin release
V2Renal collecting duct
cellsFree water absorption
AVP-Receptor Subtypes
Arginine Vasopressin (AVP)aka Antidiuretic Hormone
VASCULAR SMOOTH MUSCLE CELL HEART DISTAL TUBULES
V1AV1A V2
• Vasoconstriction
• Coronary Vasoconstriction• Myocyte Hypertrophy
• Water Retention
• Increased after load and wall stress• LV hypertrophy• Ischemia• Increased preload, hyponatremia, edema
Conivaptan Usage in Patients With Heart Failure
Combined V1a/V2-receptor antagonismIn patients with heart failure, IV conivaptan resulted
in1.Significant reductions in PCWP and right atrial
pressure (RAP)2.No change in CI, HR, MAP, PVR, SVR
3.Dose-dependent increase in urine output
Endothilin antagonast (Tezosentan & Bosentan)
They antagonize ET-A & ET-B endothilin receptors so lead to inhibition of vasoconstricted effect caused by
endogenous endothilin. They decrease both systolic and diastolic arterial
pressure. They metabolite by cytochrome P450 system in liver.
Thank you