HEART FAILURE DRUGS

and
DIURETICS
Prepared by:
Abraham Daniel C. Cruz, MD, MS (Pharmacology)
Instructor A
Department of Pharmacology
Far Eastern University Nicanor Reyes Medical Foundation

HEART FAILURE

Pathophysiology
Progressive and lethal disease, usually a complication of uncontrolled
hypertension, myocardial infarction, valve dysfunction, viral myocarditis,
and other conditions
1 manifestations reduced cardiac output and unfavorable
compensatory responses excessive sympathetic discharge and
salt and water retention
Long-term changes remodeling, cardiac hypertrophy, cardiac cell
apoptosis
Periods of acute decompensation complicate longer periods of slow
decline of cardiac function

Pathophysiologic Processes and Drug Targets in

Heart Failure

What is the cardiac output equation?

Cardiac output (CO) = heart rate (HR) stroke volume (SV)

What is normal CO?

5 L/min

What is the most common cause of right-sided heart failure?

Left-sided heart failure
Name three compensatory physiologic responses seen in congestive heart
failure (CHF):
1. Fluid retention
2. Increased sympathetic drive
3. Hypertrophy of cardiac muscle

Define preload
The pressure stretching the ventricular walls at the onset of
ventricular contraction; related to left ventricular end-diastolic
volume/pressure
Define afterload
The load or force developed by the ventricle during systole

Drug Groups Used in Heart Failure

Treatment of Heart Failure

Drug Group

Drugs

Beneficial Effects

Chronic failure (oral)

Diuretics

Thiazides, furosemide,
spironolactone

Reduced preload, afterload; spironolactone

reduces aldosterone effects

Cardiac glycosides

Digoxin

Positive inotropic effect

Vasodilators

Hydralazine, isosorbide dinitrate

Reduced afterload, preload

Angiotensin
antagonists

Captopril, losartan

Reduced remodeling, preload, afterload,

apoptosis

blockers

Carvedilol, metoprolol

Reduced afterload, reduced remodeling,

apoptosis

Acute failure (parenteral)

Diuretics

furosemide

Reduced pulmonary pressures, preload

1 agonists

dobutamine

Increased cardiac force, output

Vasodilators

Nitroprusside, nitroglycerin

Reduced preload, afterload

What drugs are used to decrease preload?

Diuretics; vasodilators; angiotensin-converting enzyme inhibitors (ACEIs);
angiotensin II receptor blockers (ARBs); nitrates
What drugs are used to decrease afterload?
Vasodilators; ACEIs; ARBs; hydralazine
What drugs are used to increase contractility?
Digoxin; phosphodiesterase inhibitors (amrinone and milrinone); adrenoceptor agonists

Diuretics
Useful in almost all cases of heart failure
Loop diuretics (furosemide) are particularly effective in acute
pulmonary edema and severe chronic HF
Thiazides (hydrochlorothiazide) may be adequate in mild chronic
failure
Spironolactone can reduce morbidity and mortality (see separate
section on diuretics)

How do diuretics work in CHF?

Decrease in intravascular volume thereby decrease in preload;
reduce pulmonary and peripheral edema often seen in CHF
patients

Angiotensin-Converting Enzyme Antagonists

ACE-inhibitors (captopril) reduce morbidity and mortality in patients
with severe HF
First-line agents (along w/ diuretics) in HF; used orally
Angiotensin II-receptor antagonists (losartan) are used if ACEIs are not
tolerated

Reduce remodeling and sympathetic excess in chronic HF; little or no

effect on cardiac contractility or manifestations of acute decompensation
Toxicities:
ACEIs cause cough and renal damage in the fetus (CI in pregnancy)

How do ACEIs work in CHF?

Inhibition of angiotensin-II (AT-II) production thereby decreasing
total peripheral resistance (TPR) and thus afterload; prevents left
ventricular remodeling

 Adrenoreceptor Blockers
Carvedilol and metoprolol can prolong life in chronic HF; used
orally
MOA in heart failure is unclear; may involve reduced renin and
angiotensin production and decreased cardiac cell apoptosis
Toxicities
May cause worsening of HF, AV blockade, hypotension, and sedation

How can increased sympathetic activity in CHF be counteracted?

-Blockers
What two -blockers have specific indications for the treatment of CHF?
1. Metoprolol
2. Carvedilol (mixed -/-blocker)
What classes of medications have been shown to increase survival in CHF patients?
ACEs/ARBs; -blockers

INOTROPES

 Adrenoreceptor Agonist and Dopamine

Dobutamine

1-selective agonist given parenterally for severe acute HF; short

duration of action (minutes) administered by IV infusion

Dopamine

not 1-selective; has similar benefits and toxicities in HF

Both increase cardiac force and reduce afterload increases

cardiac output
Toxicities:
Tachycardia, arrhythmias, angina

How does dobutamine work in CHF?

-Adrenergic agonist (sympathomimetic that binds to (1adrenoceptors) that increases force of contraction and
vasodilation via increased cAMP

Cardiac Glycosides - Digoxin

Steroidal molecules from Digitalis and other plants; the only important cardiac
glycoside in the US
blocks Na+, K+-ATPase and increases intracellular sodium
Decreased outside/inside sodium gradient results in less expulsion of calcium from the cell and
increased calcium stores in the sarcoplasmic reticulum
Increased release of calcium occurs increased contractility

has cardiac parasympathomimetic effect reduces AV conduction used in

atrial fibrillation
Available in oral and IV preparation; half-life 36 hours
Toxicities:
Cardiac arrhythmias, GI upset, neuroendocrine effects (rare), cardiac arrest (severe
overdose); Antidote: digoxin antibodies (Digibind)

What is the mechanism of action of digoxin?

Inhibition of the Na+/K+-ATPase pump which leads to positive inotropic action
(via increased intracellular sodium ions that exchanges with extracellular
calcium ions; resulting increase in intracellular calcium ions leads to increased
force of contraction)
What are the two digitalis glycosides?
1. Digoxin
2. Digitoxin

What are the adverse effects of digoxin?

Arrhythmias; nausea; vomiting; anorexia; headache; confusion;
blurred vision; visual disturbances, such as yellow halos around
light sources
What electrolyte disturbances predispose to digoxin toxicity?
Hypokalemia; hypomagnesemia; hypercalcemia

Digoxin can cause what types of arrhythmias?

Supraventricular tachycardias; AV nodal tachycardias; AV block;
ventricular tachycardias; ventricular fibrillation; complete heart
block
Can digoxin be used in Wolff-Parkinson-White syndrome?
No. Since digoxin slows conduction through the AV node, the
accessory pathway present in WPW is left unopposed, leading to
supraventricular tachycardias and atrial arrhythmias.

Wolff-Parkinson-White Syndrome
caused by the presence of an abnormal accessory electrical
conduction pathway between the atria and the ventricles
electrical signals traveling down this abnormal pathway (bundle of
Kent) may stimulate the ventricles to contract prematurely result
in a unique type of supraventricular tachycardia atrioventricular
reciprocating tachycardia
USE: IA or Ill antiarrhythmics
DO NOT USE: drugs that slow AV conduction digoxin, -blocker,
Ca2+-channel blocker, adenosine

How is digoxin toxicity treated?

Correction of electrolyte disturbances; antiarrhythmics; antidigoxin Fab antibody (Digibind)
What drugs can increase digoxin concentrations?
Quinidine; amiodarone; erythromycin; verapamil

What drugs can decrease digoxin concentrations?

Loop diuretics; thiazide diuretics; corticosteroids

Does digoxin therapy in CHF lead to prolonged survival?

No. It is of symptomatic benefit only, improving quality, but not
necessarily duration of life.

Phosphodiesterase Inhibitors (Bipyridines)

Amrinone, milrinone, aminophylline, theophylline
Occasionally used parenterally for acute decompensation of HF; duration
of action varies from 2 to 8 hours
Increase inward calcium influx in the heart during the action potential
Inhibit phosphodiesterase increase cAMP in cardiac tissue and
vessels
Toxicities
1 - cardiac arrhythmias; aminophylline and theophylline seizures
Reason PDE inhibitors are used infrequently

How do amrinone and milrinone work in CHF?

Inhibits phosphodiesterase (PDE) thereby increasing cAMP levels;
increased cAMP leads to increased intracellular calcium; increased
intracellular calcium leads to increased force of contraction;
increased cAMP also leads to increased vasodilation
What are the side effects of the PDEIs?
Milrinone may actually decrease survival in CHF; amrinone may
cause thrombocytopenia.

Vasodilators
Nitroprusside and nitroglycerin

Administered IV for acute decompensation

Nesiritide synthetic form of the endogenous brain natriuretic peptide; used IV for
acute HF; vasodilator with diuretic properties
Isosorbide dinitrate and hydralazine
Used occasionally for chronic HF

Vasodilators reduce afterload (increasing ejection fraction) and preload (reduction in

myocardial oxygen requirement)
Toxicities:
Nitrovasodilators - orthostatic hypotension
ALL tachycardia
Nesiritide renal damage

What is the mechanism of action of nesiritide?

Recombinant B-type natriuretic peptide that binds to guanylate
cyclase receptors on vascular smooth muscle and endothelial
cells, thereby increasing cyclic guanosine monophosphate
(cGMP) levels; increased cGMP leads to increased relaxation of
vascular smooth muscle

New Drugs for Heart Failure

LCZ696 - Angiotensin ReceptorNeprilysin Inhibitor
Valsartan + sacubitril (AHU377)
Neprilysin breaks down natriuretic and other vasoactive peptides
Inhibition results in lowering of BP and promotes sodium excretion

Compared to ACE inhibition, there is a greater reduction in:

CV death as hospitalization for HF
Overall mortality
Symptoms improved function

Possible risks from long term therapy (still under study all in vitro)
Alzheimers disease
Prostate and breast cancer

Investigational Positive Inotropic Drugs

Istaroxamine

Act like glycosides but also facilitates sequestration of calcium ions by

the sarcoplasmic reticulum less arhythmogenic than digitalis

Levisomendan

Sensitizes the troponin system to calcium; also inhibits

phosphodiesterase may also cause vasodilation

Omecamtiv, mecarbil

Activates cardiac myosin and prolongs systole without increasing

oxygen consumption of the heart

Diuretics and Other Drugs Acting

on the Kidney

Which renal tubular segment is responsible for the majority of sodium

reabsorption?
Proximal convoluted tubule (>60%)

Electrolyte Changes Produced by Diuretic Drugs

Drug Group
Carbonic anhydrase inhibitors
Loop diuretics
thiazides
K+-sparing diuretics

NaCl

Urine
NaHCO3 K+

Body pH

Ca++

Acidosis
Alkalosis
Alkalosis
Acidosis

What class of drugs are used to counteract the fluid retention caused
by hydralazine?
Diuretics

Carbonic Anhydrase Inhibitors

Acetazolamide; used for glaucoma, altitude sickness, and to reduce
metabolic alkalosis
Block carbonic anhydrase in the brush border and cytoplasm of
proximal tubule cells and other tissues (eye and brain)
Orally active; some members of the group (dorzolamide) are available
in topical form for glaucoma; duration of action: 8 12 hours
Toxicities:
Oral: GI upset, paresthesias, hepatic encephalopathy (if with severe hepatic
impairment)
Cross-allergenicity with sulfonamides

Carbonic Anhydrase Inhibitors

Carbonic Anhydrase Inhibitors

MOA: carbonic anhydrase inhibition, results in:
H+ formation inside PCT cell
Na+/H+ antiport
Na+ and HC03- in lumen
Diuresis

Give two examples of carbonic anhydrase inhibitors (CAIs):

1. Acetazolamide
2. Dorzolamide
What is the mechanism of action of CAIs?
Increased excretion of sodium and bicarbonate

What metabolic disturbance may be caused by CAIs?

Metabolic acidosis

What are CAIs used for?

Altitude sickness (decreases cerebral and pulmonary edema);
glaucoma (decreases aqueous humor formation thereby
decreasing intraocular pressure); metabolic alkalosis; to
enhance renal excretion of acidic drugs

Loop Diuretics
Furosemide, ethacrynic acid; used for conditions associated with moderate or
severe hypertension or fluid retention (heart failure, cirrhosis, nephrotic syndrome)
Most efficacious diuretics currently available
Block Na+/K+/2Cl- symporter in the ascending limb of the loop pf Henle
Indirect effect: increase calcium and magnesium excretion
Useful in the management of severe hypercalcemia; must be given with saline infusion to prevent
hemoconcentration

Orally active but can also be used IV; duration of action: 2 4 hours
Toxicities: hypokalemia, ototoxicity, renal impairment
Effects are diminished by NSAIDs
All are sulfonamides EXCEPT ethacrynic acid

Loop Diuretics

Loop Diuretics
MOA: Na+/K+/2Cl- transporter inhibition, results in:
intracellular K+ in TAL
back diffusion of K+
positive potential
reabsorption of Ca2+ and Mg2+
diuresis

What is the site of action of loop diuretics?

Loop of Henle (thick ascending limb)

Give examples of loop diuretics:

Furosemide; bumetanide; ethacrynic acid; torsemide

Which loop diuretic can be given safely to patients with allergy to sulfonamide
antimicrobials?
Ethacrynic acid

What transporter (in the thick ascending loop of Henle) is inhibited by loop
diuretics?
Na+/K+2Cl- transporter
True or False? Loop diuretics increase calcium excretion.
True

What are the adverse effects of loop diuretics?

Hypersensitivity; hypocalcemia; hypokalemia;
hypomagnesemia; metabolic alkalosis; hyperuricemia;
ototoxicity
Which loop diuretic is the most ototoxic?
Ethacrynic acid

Thiazides
Hydrochlorothiazide and others; for mild to moderate hypertension, mild heart
failure, chronic calcium stone formation, and nephrogenic diabetes insipidus
Block Na+/Cl- symporter in the distal convoluted tubule; increase calcium
reabsorption decreased concentration in urine
Orally active; almost exclusively used by this route; duration of action is 8 12 hrs
Toxicities
Potassium wasting (most important), may also raise blood glucose, lipids, and uric acid; may
cause significant hyponatremia
Sulfonamides can cause cross-allergenicity
NSAIDs can reduce thiazide efficacy

Thiazides

Thiazides
MOA: Na+/Cl- transporter inhibition results in:
luminal Na+ and Cl- in DCT
diuresis

What is the name of the most common thiazide diuretic used in the
treatment of HTN?
Hydrochlorothiazide (HCTZ)
What are the immediate/acute effects of thiazide diuretics?
Increased sodium, chloride, and water excretion which leads to
decreased blood volume

What are the chronic effects of thiazide diuretics?

Decreased TPR

What is the site of action of thiazide diuretics?

Distal convoluted tubule of nephron

What transporter (in the distal convoluted tubule) is inhibited by thiazide

diuretics?
Na+/Cl- transporter

Give examples of thiazide diuretics:

HCTZ; chlorothiazide; chlorthalidone
Thiazide diuretics may be ineffective in patients with creatinine clearances of
less than what?
50 mL/min

With regard to blood concentrations, state whether each of the following

electrolytes will be increased or decreased in patients on thiazide diuretic
therapy:
Calcium - Increased
Magnesium - Decreased
Potassium - Decreased
Sodium - Decreased
With regard to increased renal calcium reabsorption, what are thiazide diuretics
sometimes used for?
Treatment of calcium stones in the urine

What are the adverse effects of HCTZ?

Hypercalcemia; hypokalemia; hypomagnesemia; hyperglycemia;
hyperuricemia; pancreatitis; metabolic alkalosis; StevensJohnson syndrome; hyperlipidemia
Patients allergic to what class of antimicrobials may also be sensitive
to thiazide diuretics?
Sulfonamides

Potassium-Sparing (Aldosterone Antagonist)

Diuretics
Used to prevent potassium wasting by other diuretics
Spironolactone and eplerenone
particularly effective in treating heart failure and other high-aldosterone conditions
Block cytoplasmic aldosterone receptor; weak antagonism of androgen receoptors
Eplerenone more selective for mineralocorticoid receptor

Amiloride and triamterene

Block sodium channels in the collecting tubule

Orally active; duration of action is 12 72 hours

Toxicities
Hyperkalemia (major), GI upset
Spironolactone antiandrogen effects

Potassium-Sparing (Aldosterone Antagonist)

Diuretics

Name three potassium-sparing diuretics:

1. Spironolactone
2. Triamterene
3. Amiloride
What is the mechanism of action of spironolactone?
Aldosterone receptor antagonist

Where in the kidney is the aldosterone receptor found?

Basolateral membrane of the principal cell in the collecting duct

Where in the kidney does triamterene and amiloride work?

Sodium ion channel on the luminal side of the principal cell in
the collecting duct
What are the adverse effects of spironolactone?
Hyperkalemia; metabolic acidosis; gynecomastia

Triamterene is often used in combination with what other diuretic?

HCTZ
Spironolactone is used to treat what conditions?
HTN; CHF; ascites
Amiloride is used to treat what conditions?
HTN; CHF; lithium-induced diabetes insipidus

What diuretic blocks mineralocorticoid receptors and also inhibits the synthesis
of aldosterone and androgens (e.g. testosterone)?
Spironolactone
Name a potassium sparing diuretic that does not have anti-androgen side
effects:
Epleronone, which has increased specificity for the mineralocorticoid
receptor when compared to spironolactone
How is nephrogenic diabetes insipidus treated?
Thiazide diuretics in combination with amiloride; chlorpropamide;
clofibrate

Osmotic Diuretics
Mannitol; for acute glaucoma, increased ICP, protects kidney from
solute overload due to crush injury or chemotherapy
Small, non-absorbable molecule; osmotically inhibits resorption of
water in water-permeable portions of the nephron
Given IV; duration of action: 1 2 hours
Toxicities
Headache, GI upset, hypotension, mild hyponatremia, followed by
hypernatremia

What is the mechanism of action of mannitol?

Acts as an osmotic diuretic, thereby drawing water via increased
osmolality, into the proximal convoluted tubule, loop of Henle
(thin descending limb), and the collecting ducts
What is mannitol used for?
Decreases intraocular and intracranial pressure; prevents anuria
in hemolysis and rhabdomyolysis

Summary of the Modes of Action and Effects of the

Various Classes of Diuretics
DRUG
Acetazolamide

Ethacrynic acid,
furosemide,
torsemide

Mechanisms of
Action
Inhibition of
carbonic
anhydrase in PCT
Inhibition of
Na+/K+/2Clcotransporter in
TAL

Urinary
Electrolytes
Na+
K+
HCO3 Na+
K+
Ca2+
Mg2+
Cl-

Blood pH
Acidosis

Alkalosis

Summary of the Modes of Action and Effects of the

Various Classes of Diuretics
DRUG

Mechanisms of
Action

Urinary
Electrolytes

Na+
K+
Cl Ca2+
Block Na+ channels, Na+ (small)
block aldosterone
K+
receptors in
collecting tubule

Blood pH

Hydrochlorothiazide Inhibition of Na+/ClIndapamide

cotransporter in
Metolazone
DCT

Alkalosis

Amiloride,
triamterene,
spironolactone,
Eplerenone

Acidosis

Antidiuretic Hormone Agonists

Vasopressin, desmopressin (analogue of vasopressin)
for pituitary deficiency diabetes insipidus
Collecting ducts are responsive to vasopressin and insert additional water
channels (aquaporins) into the luminal membrane facilitate water resorption
restores urine concentrating power to normal

NOT useful for nephrogenic diabetes insipidus

Does not respond to pituitary peptides; treated INDIRECTLY with thiazides
urine osmolality is increased but not to normal maximal levels
Thiazides decrease blood volume lead to compensatory water
reabsorption from proximal tubule reduces urine volume

Antidiuretic Hormone Agonists

Duration of action
Vasopressin and desmopressin 4 8 hrs
Thiazides up to 12 hours

Toxicities
Vasopressin and desmopressin rarely cause vasoconstriction
with hypertension or coronary spasm
Thiazides hyponatremia, hyperlipidemia, hyperuricemia

Antidiuretic Hormone Antagonists

Demeclocycline prevents hyponatremia in SIADH; MOA unclear
can cause iatrogenic diabetes insipidus (like lithium) by blocking
ADH-like peptides
Used orally; duration of action 10 16 hrs
Toxicities:
Like other tetracyclines disorders of developing bones and teeth in
children; rash, GI upset, hepatic dysfunction

Antidiuretic Hormone Antagonists

Conivaptan
Antagonist at V1a, V2 receptors
Clinical applications: SIADH, hyponatremia
PK: administered parenterally
Toxicities: infusion site reactions
Tolvaptan like conivaptan but more selective for V2 receptors

New Antidiabetic Agent

Canagliflozin, dapagliflozin
inhibitor of subtype 2 sodium-glucose transport protein (SGLT2) responsible for 90% of the glucose reabsorption in the kidney
(SGLT1 for the remaining 10%)
causes about 100 g of blood glucose per day to be eliminated
through the urine (450 kcal)
additional water is eliminated by osmotic diuresis lowers BP
can cause weight loss as the body metabolizes adipose tissue to
replace the lost glucose

THANK YOU!!!