Transcript hypertension. However, pulse pressure may be used to identify

HEART FAILURE
 Abnormality 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 classification
 Acute & chronic
 Left & right sided
 Systolic & diastolic
Main causes
I. Coronary artery disease
II. Hypertension
III. Valvular heart disease
IV.Cardiomyopathy
V. Corpulmonale
Factors aggravating heart failure
1.
2.
3.
4.
5.
Myocardial ischemia or infarct.
Dietary sodium excess.
Arrhythmias.
Intercurrent illness (eg. infection).
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 failure
Stage B: Asymptomatic but have signs of structural
heart damage
Stage C: Have symptoms and heart damage
Stage 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.
Drugs Classes used in the heart failure treatment
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.
Treatments for HF
Diuretics
Reduce
Fluid
Volume
Vasodilators
Decrease
Preload
and
Afterload
Inotropes
Augment
Contractility
Natriuretic
Peptide
Decrease
Preload
and
After load;
Reduce
Fluid
Volume
Drugs increasing the strength of cardiac contraction
 Drugs with direct positive inotropic effects
 Increase 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)
1.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.
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

Digoxin
 Enhances 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.
Pharmacological action
1.
2.
3.
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 after depolarization (DAD) -  Ca2+ from stores - may reach
threshold - premature ventricular depolarization or „ectopic beat“.
ANS system mediated effects: central stimulation of nervous vagus

decreased SA pacemaker activity.

decreased AV conductanc→ decreased HR .
Pharmacokinetics
o
o
o
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
Digoxin
Digitoxin
Half-life
36 hours
164 hours
Therapeutic plasma concentration
0.5 - 2 ng/mL
10 - 25 ng/mL
Toxic plasma concentration
 2 ng/mL
 35 ng/mL
Daily dose (slow loading or maintenance)
0.125 - 0.5 mg
0.05 - 0.2 mg
Rapid digitalizing dose
0.5 - 0.75 mg every 8 h
for 3 doses
0.2 - 0.4 mg every 12 h
for 3 doses
A comparison of the
properties of digoxin
and digitoxin
Indications
 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.
Adverse effects
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
o
colour perception, and haloes on dark objects.
Gynecomastia in men upon prolonged use.
Factors 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, 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
Drugs interacting with digoxin and other digitalis glycosides
Increased digitalis
concentration may occur during
concurrent therapy
Amiodarone
Erythromycin
Quinidine
Tetracycline
Verapamil
Enhanced potential
for cardiotoxicity
Decreased levels of blood
potassium
Corticosteroids
Thiazide diuretics
Loop diuretics
Treatment of severe acute intoxication (overdose)
 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.
2.PHOSPHODIESTERASE III Inhibitirs
Amrinone
o
o
o
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.
3. BETA1-ADRENERGIC AGONISTS

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)
Sites of action by -adrenergic agonists on heart muscle
(according to Lippincott´s Pharmacology, 2006)
4. CALCIUM SENSITIZERS
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
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
ACE
Other pathways
Angiotensin II
Receptors
AT1
Vasoconstriction
Proliferative
Action
AT2
Vasodilatation
Antiproliferative
Action
ACE Inhibitor
 Contraindications
 Renal artery stenosis (relative).
 Hyperkalemia.
 Renal insufficiency.
 Arterial hypotension.
 Cough.
 Angioedema.
 Alternatives
 Hydralazine + ISDN, AT-II inhibitor .
Guidelines to ACE Inhibitor Therapy
 All 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 CHF
 B-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
Diuretics
 Indicated 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,
carperitide).
2) Levosimendan (inotrope/vasodilator).
ularitide,
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 improvement
 Theoretical 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
Development
 Tolvaptan—Oral selective V2-receptor antagonist
 Treatment of decompensate heart failure
 Lixivaptan—Oral selective V2-receptor antagonist
 Conivaptan—Intravenous dual V1a/V2-receptor
antagonist
 Treatment of euvolemic hyponatremia in
hospitalized patients (FDA approved Dec. 30 2005
Vaprisol®)
AVP-Receptor Subtypes
Receptor
Subtype
Site of Action
Activation Effects
V1A
Vascular smooth muscle
Platelets
Lymphocytes and monocytes
Hepatocytes
Vasoconstriction
Platelet aggregation
Coagulation factor release
Glycogenolysis
V1B
Anterior pituitary
ACTH and -endorphin release
V2
Renal collecting duct
cells
Free water absorption
Arginine Vasopressin (AVP)
aka Antidiuretic Hormone
V1A
VASCULAR SMOOTH
MUSCLE CELL
V1A
HEART
V2
DISTAL TUBULES
• 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 antagonism
 In patients with heart failure, IV conivaptan resulted
in
1. 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