Anti-heart failure drugs

1. Anti – Heart Failure Drugs
BME Group 1
- Settaba henry
- Kakembo Musa
- Biira Jetress
- Bukenya Fred
Presenter: Settaba Henry
Biira Jetress

2. Heart Attack, Cardiac Arrest, Heart Failure
??? What's the Difference?
Each of the statements above signifies a health crisis involving the heart.
But heart attack, cardiac arrest, and heart failure aren't the same thing. They're three
different problems with radically different causes and treatments.
 Heart Attack
 During a heart attack, blood flow to the heart is blocked, often by a blood clot or a buildup of
plaque in the arteries.
 Since the heart muscle needs oxygen to survive, when blood flow is blocked, the muscle begins
to die. Neccesiting for surgery to resolve the obstruction and restore blood flow.
 Symptoms may start slowly and persist for hours, days, or weeks before the heart attack. The
heart continues to beat, but because of the blockage, it is not receiving all the oxygen-rich blood
it requires.

3. Heart Attack, Cardiac Arrest, Heart Failure
??? What's the Difference?
 Cardiac Arrest
 In cardiac arrest, the heart stops beating and needs to be restarted.
 While a heart attack is a circulation problem, cardiac arrest is an electrical problem triggered by
a disruption of the heart's rhythm. Most heart attacks do not lead to cardiac arrest. However,
when cardiac arrest happens, a heart attack is a common cause.
 Because cardiac arrest stops the heart from beating, the brain, lungs, and other organs do
not get the blood and oxygen they need. Cardiac arrest can lead to death within minutes if
not treated.

4. Heart Attack, Cardiac Arrest, Heart Failure
??? What's the Difference?
Heart Failure
 Heart failure occurs when the heart muscle fails to pump as much blood as the body
needs. It is usually a long-term, chronic condition, but it may come on suddenly.
 In people with heart failure, the heart doesn’t pump normally, causing the hormone
and nervous systems to compensate for the lack of blood. The body may raise blood
pressure, making the heart beat faster and causing it to hold on to salt and water. If
this retained fluid builds up, the condition is called congestive heart failure.

5. Symptoms of Heart failure
•Dry, hacking cough, especially when lying down
•Confusion, sleepiness and disorientation in older
people
•Dizziness, fainting, fatigue or weakness
•Fluid buildup, usually in the legs, ankles and feet
•Increased urination at night
•Nausea, abdominal swelling, tenderness or pain
that may result from fluid in the body and backup of
blood in the liver
•Rapid breathing
•Bluish skin
•Feelings of anxiety, restlessness and suffocation
•Shortness of breath and lung congestion
•Wheezing and spasms in the airway, similar to
asthma
Note: Heart failure is usually the result of another disease, most
commonly coronary artery disease. Other causes include different forms of
heart disease, a blood clot in the lungs, problems with the thyroid gland,
heart valve disorders, kidney failure, and untreated or out-of-control blood
pressure.

6. Management of heart failure
Two major types of failure may be distinguished;
Systolic failure, with reduced mechanical pumping action (contractility) and reduced ejection
fraction.
Diastolic failure, with stiffening and loss of adequate relaxation playing a major role in reducing
filling and cardiac output.
Treatment is therefore directed at two somewhat different goals:
(1) reducing symptoms and slowing progression as much as possible during relatively stable periods
(2) managing acute episodes of decompensated failure

7. Heart failure cont…

8. Cardiac Contractility
The vigor of contraction of heart muscle is
determined by several processes that lead
to the movement of actin and myosin
filaments in the cardiac sarcomere
Ultimately, contraction results from the
interaction of activator calcium (during
systole) with the actin-troponin-
tropomyosin system, thereby releasing the
actin-myosin interaction. This activator
calcium is released from the sarcoplasmic
reticulum (SR). The amount released
depends on the amount stored in the SR
and on the amount of trigger calcium that
enters the cell during the plateau of the
action potential.

9. Anti heart failure drugs
These include the following
• Diuretics
• Aldosterone antagonists.
• Renin angiotensin system blockers
• Beta blockers.
• Inotropic agents.
• Direct vasodilators

10. Summary of drugs used to treat heart failure

11. DIURETICS
Diuretics, especially furosemide, are drugs of choice in heart failure:They reduce salt and water
retention, edema, and symptoms.
(Diuretics are medicines that help reduce fluid buildup in the body. They are sometimes called
water pills. Most diuretics help the kidneys remove salt and water through the urine. This lowers
the amount of fluid flowing through the veins and arteries. As a result, blood pressure goes down)
They therefore have no direct effect on cardiac contractility; their major mechanism of action in
heart failure is to reduce venous pressure and ventricular preload.
The reduction of cardiac size, which leads to improved pump efficiency, is of major importance in
systolic failure. In heart failure associated with hypertension, the reduction in blood pressure also
reduces afterload.

12. Diuretics cont.…
The two prototypical drugs of this group are furosemide and Ethacrynic acid.
The structures of these diuretics are shown

13. Pharmacokinetics
The loop diuretics are rapidly absorbed. They are eliminated by the kidney by glomerular
filtration and tubular secretion. Absorption of furosemide (2–3 hours) is nearly as complete as
with intravenous administration. The duration of effect for furosemide is usually 2–3 hours.
Half-life depends on renal function.
Since loop agents act on the luminal side of the tubule, their diuretic activity correlates with
their secretion by the proximal tubule.
Metabolites of ethacrynic acid and furosemide have been identified, but it is not known
whether they have any diuretic activity.
Because of the variable bioavailability of furosemide and the more consistent bioavailability of
torsemide and bumetanide, the equivalent dosages of these agents are unpredictable, but
estimates are presented in next slide

14. Pharmacodynamics
Loop diuretics inhibit NKCC2, the luminal Na+/K+/2Cl− transporter in Henle’s loop. By inhibiting this
transporter, the loop diuretics reduce the reabsorption of NaCl and also diminish the lumen-positive
potential that comes from K+ recycling. This positive potential normally drives divalent cation
reabsorption and by reducing this potential, loop diuretics cause an increase in Mg2+ and Ca2+
excretion.
Prolonged use can cause significant hypomagnesemia in some patients. Since vitamin D– induced
intestinal absorption and parathyroid hormone–induced renal reabsorption of Ca2+ can be
increased, loop diuretics do not generally cause hypocalcemia.
However, in disorders that cause hypercalcemia, Ca2+ excretion can be enhanced by treatment with
loop diuretics combined with saline infusion.
Loop diuretics have also been shown to induce expression of the cyclooxygenase COX-2, which
participates in the synthesis of prostaglandins from arachidonic acid. At least one of these
prostaglandins, PGE2, inhibits salt transport and thus participates in the renal actions of loop
diuretics.
NSAIDs (eg, indomethacin), which blunt cyclooxygenase activity, can interfere with the actions of
loop diuretics by reducing prostaglandin synthesis in the kidney. This interference is minimal in
otherwise normal subjects but may be significant in patients with nephrotic syndrome or hepatic
cirrhosis.

15. Contraindications
• Furosemide may exhibit allergic cross-reactivity in patients who are
sensitive to other sulfonamides, but this appears to be very rare.
Overzealous use of any diuretic is dangerous in hepatic cirrhosis and
borderline renal failure
• Renal failure with anuria
• Dehydration
• Known hypersensitivity to Furosemide
• hypovolemia
• Severe hypokalemia
• Severe hypernatremia

16. Vasodilators
These are effective in acute heart failure because they provide a reduction in preload (through
venodilation), or reduction in afterload (through arteriolar dilation), or both. Some evidence
suggests that long-term use of hydralazine and isosorbide dinitrate can also reduce damaging
remodeling of the heart.
Hydralazine
Hydralazine (1-hydrazinophthalazine) was one of the first orally active
antihypertensive drugs to be marketed in the U.S.; however, the drug initially was used infrequently
because of tachycardia and tachyphylaxis. With a better understanding of the compensatory
cardiovascular responses that
accompany use of arteriolar vasodilators, hydralazine was combined with
sympatholytic agents and diuretics with greater therapeutic success. Nonetheless, its role in the
treatment of hypertension has markedly diminished
with the introduction of new classes of antihypertensive agents.

17. Mechanism of Action
Hydralazine directly relaxes arteriolar smooth muscle with little effect on venous smooth
muscle. The molecular mechanisms mediating this action are not clear but may ultimately
involve a reduction in intracellular Ca2+ concentrations.
While a variety of changes in cellular signaling pathways are influenced by hydralazine, precise
molecular targets that explain its capacity to dilate arteries remain uncertain.
Potential mechanisms include inhibition of inositol trisphosphate–induced release of Ca2+ from
intracellular storage sites, opening of high-conductance Ca2+, activated K+ channels in smooth
muscle cells, and activation of an arachidonic acid, COX, and prostacyclin pathway that would
explain sensitivity to NSAIDs
Hydralazine-induced vasodilation is associated with powerful stimulation of the sympathetic
nervous system, likely due to baroreceptor-mediated reflexes, resulting in increased heart rate
and contractility, increased plasma renin activity, and fluid retention. These effects tend to
counteract the antihypertensive effect of hydralazine.

18. Pharmacological Effects
Most of the effects of hydralazine are confined to the cardiovascular system. The
decrease in blood pressure after administration of hydralazine is associated with a
selective decrease in vascular resistance in the coronary, cerebral, and renal
circulations, with a smaller effect in skin and muscle. Because of preferential
dilation of arterioles over veins, postural hypotension is not a common problem;
hydralazine lowers blood pressure similarly in the supine and upright positions.
ADMINISTRATION
Following oral administration, hydralazine is well absorbed via the GI tract.
Hydralazine is N-acetylated in the bowel and the liver, contributing to the drug’s
low bioavailability (16% in fast acetylators and 35% in slow acetylators).

19. Toxicity and Precautions
Two types of adverse effects occur after the use of hydralazine. The first, which are
extensions of the pharmacological effects of the drug, include headache, nausea,
flushing, hypotension, palpitations, tachycardia, dizziness, and angina pectoris.
Myocardial ischemia can occur on account of increased O2 demand induced by the
baroreceptor reflex–induced stimulation of the sympathetic nervous system
The second type of adverse effect is caused by immunological reactions, of which
the drug-induced lupus syndrome is the most common. Administration of
hydralazine also can result in an illness that resembles serum sickness, hemolytic
anemia, vasculitis, and rapidly progressive glomerulonephritis. The mechanism of
these autoimmune reactions is unknown

20. Cardiac Glycosides
Actions and Therapeutic Use of Digoxin.
Positive Inotropic Effect. CGs at therapeutic concentrations mildly inhibit the cardiac
Na+/K+ ATPase, causing an increase in intracellular [Na+]. Increased [Na+] inhibits Ca2+
extrusion via the NCX resulting in higher intracellular [Ca2+] and enhanced contractility.
The increased contractility and hence cardiac output provides symptomatic relief in
patients with heart failure. With the main trigger for neurohumoral activation removed,
sympathetic nerve tone and, consequently, heart rate and peripheral vascular
resistance drop.
These decreases in preload and afterload reduce chamber dilation and thereby wall
stress, a strong determinant of myocardial O2 consumption. Increased renal perfusion
lowers renin production and increases diuresis, further decreasing preload.

21. Electrophysiological Actions
CGs at therapeutic concentrations shorten action potentials by accelerating the
inactivation of L-type Ca2+ channels due to higher [Ca2+] . Shorter action potentials
favor reentry arrhythmias, a reason that CGs promote atrial fibrillation. With the loss
of intracellular K+ and increase in intracellular Na+, the resting membrane potential
(determined largely by the K+ current, now diminished) moves to less-negative
values with two consequences.
Diastolic depolarization and automaticity are enhanced, and, due to partial
inactivation of Na+ channels, impulse propagation is strongly reduced. Both
phenomena promote reentry arrhythmias. At even higher CG concentrations, SR
Ca2+ overload reaches a point at which Ca2+ is spontaneously released at amounts
large enough to initiate Ca2+ waves and, via the NCX, depolarization of the cell.
The typical ECG signs at this stage of CG intoxication are extrasystoles and bigeminies
with a high risk of ventricular fibrillation.

22. Adverse Effects.
The most frequent and most serious adverse effects are arrhythmias.
In CG overdosing, patients exhibit arrhythmias (90%), GI symptoms (~55%), and neurotoxic
symptoms (~12%).
The most frequent causes of toxicity are renal insufficiency and overdosing.
Cardiac toxicity in healthy persons presents as extreme bradycardia, atrial fibrillation, and
AV block, whereas ventricular arrhythmias are rare.
In patients with structural heart disease, frequent signs of CG toxicity are ventricular
extrasystoles, bigeminy, ventricular tachycardia, and fibrillation.

23. Side effects cont..
In principle, however, every type of arrhythmia can be CG induced. GI adverse effects are
anorexia, nausea, and vomiting, mainly as a result of CG effects on chemosensors in the
area postrema.
Spastic contraction of the mesenteric artery can rarely lead to severe diarrhea and life-
threatening necrosis of the intestine.
Headache, fatigue, and sleeplessness can be early symptoms of CG toxicity.
Typical, albeit not too common (10%), are visual effects: altered color perception and
coronas (halos).

24. Therapy of CG Toxicity.
Severe arrhythmias, such as extreme bradycardia or complex ventricular
arrhythmias, require active therapy.
• Extreme sinus bradycardia, sinoatrial block, or AV block grade II or III:
Atropine (0.5–1 mg) IV.
If not successful, a temporary pacemaker may be necessary.
• Tachycardic ventricular arrhythmias and hypokalemia:
K+ infusion (40–60 mmol/d).
Consider that high K+ can aggravate AV conduction defects.
• An effective antidote for digoxin toxicity is antidigoxin immunotherapy. Purified
Fab fragments from ovine antidigoxin antisera (Digibind) are usually dosed by the
estimated total dose of digoxin ingested to achieve a fully neutralizing effect.

25. Treatment of heart failure by Neurohumoral Modulation
Dampening neurohumoral activation and its deleterious consequences on the heart,
blood vessels, and kidney is the cornerstone of heart failure therapy.
Therapy consists of ACEIs/ARBs, β blockers, and MRAs. Further activation of the
natriuretic peptide system adds benefit.
Angiotensin-Converting Enzyme Inhibitors
Angiotensin II, the most active angiotensin peptide, is largely derived from
angiotensinogen in two proteolytic steps.
First, renin, an enzyme released from the kidneys, cleaves the decapeptide AngI from
the amino terminus of angiotensinogen (renin substrate). Then, ACE removes a
carboxy-terminal dipeptide (His9 -Leu10) from AngI, yielding the active octapeptide,

26. Mechanism of Action
AngII interacts with two heptahelical GPCRs, AT1 and AT2 , and has four major
cardiovascular actions that are all mediated by the AT1 receptor:
• vasoconstriction
• stimulation of aldosterone release from the adrenal glands
• direct hypertrophic and proliferative effects on cardiomyocytes and fibroblasts,
respectively
• stimulation of NE release from sympathetic nerve endings and the adrenal medulla

27. Inhibitors of the Renin-Angiotensin System
Drugs that interfere with the RAS play a prominent role in the treatment of
cardiovascular disease. Besides β1 blockers that inhibit renin release, the following
three classes of inhibitors of the RAS are utilized therapeutically
1. ACE inhibitors
2. Angiotensin receptor blockers
3. Direct renin inhibitors
All of these classes of agents will reduce the actions of AngII and lower blood pressure,
but each has different effects on the individual components of the RAS

28. Enalapril.
Enalapril maleate is a pro-drug that is hydrolyzed by esterases in the liver to produce
enalaprilat, the active dicarboxylic acid.
Enalaprilat is a potent inhibitor of ACE with a Ki of 0.2 nM. Enalapril is absorbed rapidly when
given orally and has an oral bioavailability of about 60% (not reduced by food). Although peak
concentrations of enalapril in plasma occur within an hour, enalaprilat concentrations peak
only after 3–4 h.
Enalapril has a t 1/2 of about 1.3 h, but enalaprilat, because of tight binding to ACE, has a
plasma t 1/2 of about 11 h. Elimination is by the kidneys as either intact enalapril or
enalaprilat. The oral dosage of enalapril ranges from 2.5 to 40 mg daily, with 2.5 and 5 mg
daily appropriate for the initiation of therapy for heart failure and hypertension, respectively

29. Adverse Effects of ACE Inhibitors
In general, ACE inhibitors are well tolerated. The drugs do not alter plasma concentrations of uric acid or
Ca2+ and may improve insulin sensitivity and glucose tolerance in patients with insulin resistance and
decrease cholesterol and lipoprotein
(a) levels in proteinuric renal disease. Hypotension. A steep fall in blood pressure may occur following
the first dose of an ACE inhibitor in patients with elevated PRA. Care should be exercised in patients
who are salt depleted, are on multiple antihypertensive drugs, or have congestive heart failure.
(b) Cough. In 5%–20% of patients, ACE inhibitors induce a bothersome, dry cough mediated by the
accumulation in the lungs of bradykinin, substance P, or PGs. Thromboxane antagonism, aspirin, and
iron supplementation reduce cough induced by ACE inhibitors. ACE dose reduction or switching to
an ARB is sometimes effective. Once ACE inhibitors are stopped, the cough disappears, usually
within 4 days.

30. Adverse Effects of ACE Inhibitors cont..
c) Hyperkalemia. Significant K+ retention is rarely encountered in patients with normal renal
function. However, ACE inhibitors may cause hyperkalemia in patients with renal insufficiency
or diabetes or in patients taking K+-sparing diuretics, K+ supplements, β receptor blockers, or
NSAIDs.
d) Acute Renal Failure. Inhibition of ACE can induce acute renal insufficiency in patients with
bilateral renal artery stenosis, stenosis of the artery to a single remaining kidney, heart failure,
or volume depletion owing to diarrhea or diuretics.

31. Adverse Effects of ACE Inhibitors cont..
e) Fetopathic Potential. If a pregnancy is diagnosed, it is imperative that ACE
inhibitors be discontinued as soon as possible. ACE inhibitors and ARBs have been
associated with renal developmental defects when administered in the third
trimester of pregnancy, and potentially earlier.
The fetopathic effects may be due in part to fetal hypotension. This possible adverse
effect should be discussed with any woman of childbearing potential, as should the
necessity of appropriate birth control measures.
f) Skin Rash. The ACE inhibitors occasionally cause a maculopapular rash that may
itch, but that may resolve spontaneously or with antihistamines.

32. Other Side Effects
Extremely rare but reversible side effects include dysgeusia (an alteration in or loss
of taste)
neutropenia (symptoms include sore throat and fever)
glycosuria (spillage of glucose into the urine in the absence of hyperglycemia)
anemia, and hepatotoxicity.

33. Drug Interactions
Antacids may reduce the bioavailability of ACE inhibitors; capsaicin may worsen
ACE inhibitor–induced cough NSAIDs, including aspirin, may reduce the
antihypertensive response to ACE inhibitors; and K+-sparing diuretics and K+
supplements may exacerbate ACE inhibitor–induced hyperkalemia. ACE inhibitors
may increase plasma levels of digoxin and lithium and hypersensitivity reactions to
allopurinol