Drugs for Heart Failure Flashcards
Captopril: MOA
competitive inhibitor of
angiotensin- converting
enzyme (ACE)
Captopril: Effects
None emphasized
- prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor and mitogen for cardiovascular remodeling
- lowers levels of angiotensin II --> ↑ plasma renin activity and ↓ aldosterone secretion
- lowers blood pressure
Captopril: Clinical Applications
none emphasized
- hypertension
- acute hypertension
(urgency/emergency) - heart failure with
reduced ejection
fraction (HFrEF)
(ACCF/AHA) - LV dysfunction following
MI - diabetic nephropathy
- off-label: aldosteronism
(diagnosis), delay the
progression of
nephropathy and
reduce risks of
cardiovascular events
HT + DM
Captopril: Pharmacokinetics
t1/2: ~1.7 hrs,
longer in renal
impairment
Captopril: Toxicities
- cough
- angioedema
another early ACEI, a prodrug with active form (enalaprilat) available for IV
enalapril (enalaprilat)
now widely used ACE inhibitor, longer half life permitting 1X/day dosing
benazepril
now widely used ACE inhibitor, longer half life permitting 1X/day dosing
lisonopril
losartan: MOA
competitive NONPEPTIDE
ANGIOTENSIN II RECEPTOR
ANTAGONIST
losartan: Effects
- blocks the
vasoconstrictor and aldosterone-secreting
effects of angiotensin II - does not affect
the response
to bradykinin!!
losartan: Clinical Applications
none emphasized
- treatment of diabetic
nephropathy - HT, alone or in
combination with other
antihypertensives - heart failure if intolerant
of ACE inhibitors - off-label: Marfan
syndrome
losartan: Pharmacokinetics
none emphasized
extensive
first-past
metabolism
losartan: Toxicities
none emphasized
- adverse effects more
common in those with
diabetic nephropathy - hypotension, first-dose
hypotension,
orthostatic hypotension - fatigue , dizziness ,
fever - hypoglycemia,
hyperkalemia - diarrhea, gastritis,
nausea, weight gain - anemia
- weakness , back/knee
pain - cough (< ACEI)
bronchitis, nasal
congestion
t1/2 ~ 6 -10 hrs, noteworthy in that NOT A PRODRUG requiring activation, excreted primarily in feces as uncharged drug
valsartan
t1/2 5-9 hrs, noteworthy for its relatviely IRREVERSIBLE BINDING
candesartan
valsartan/sacubitril: MOA
- sacubitril is a prodrug that inhibits neprilysin (neutral endopeptidase [NEP])
- valsartan is an
ARB - drugs are co-
crystalized
valsartan/sacubitril: Effects
- neutral endopeptidase blockade leads to increased levels of peptides, including natriuretic peptides
- valsartan
antagonizes AT1-
receptors
valsartan/sacubitril: Clinical Applications
heart failure
valsartan/sacubitril: Pharmacokinetics
none emphasized
- twice daily
dosing - LBQ657 has t1/2
of ~ 11 hrs - valsartan has t1/2
of ~9 hrs
Valsartan/Sacubitril: Toxicities
Common - hypotension - hyperkalemia - increased serum creatinine
also - orthostatic hypotension - dizziness, falling - decreased Hct, Hgb - angioedema (~ 2% of black patients, <1% of others) - renal failure -cough
Carvedilol: MOA
none emphasized
a racemic mixture, is a nonselective beta- and alpha- adrenergic blocker
Carvedilol: Effects
not in table
• Used to prevent down-regulation of the β
in the heart as a result of excessive sympathetic stimulation during heart failure
- keeps heart responsive to sympathetic drive
- protects against dysrhythmias
- reduces renin secretion
- reduces myocardial oxygen consumption
- limits heart muscle remodeling and reduces necrosis and apoptosis of myocardial cells
• LOW DOSES are used at least initially, with caution in patient that
is stable
Carvedilol: Clinical Applications
• If clinically stable, it is recommended for:
- recent or remote history of MI or ACS and reduced ejection fraction (rEF; <40%)
- rEF to prevent symptomatic HF
Carvedilol: Clinical Applications (not in table)
•should be administered only to clinically stable patients
- patients with diastolic heart failure will benefit from a lower heart rate
- β-blockers should be given to all patients with
symptomatic CHF and LVEF < 40% unless contraindications…- bronchospastic disease
- symptomatic bradycardia or heart block
- unless contraindications, carvedilol should also be
given along with ACE inhibitors to all patients with left ventricular systolic dysfunction caused by
myocardial infarction to reduce mortality
Carvedilol: Common Adverse Effects
– allergy
– chest pain, discomfort, tightness, or heaviness
– dizziness, lightheadedness, or fainting
– generalized swelling or swelling of the feet, ankles, or lower legs
– pain
– shortness of breath
– bradycardia
– weight gain
– angina/heart attack if abruptly discontinued
Ivabradine: MOA
none emphasized
selective and specific inhibition of the hyperpolarization -activated cyclic nucleotide-gated (HCN) channels (f-channels) within the sinoatrial (SA) node of cardiac tissue
Ivabradine: Effects
none emphasized
disrupts I(f) (“funny” current) to prolong diastole and slow HR
Ivabradine: Clinical Applications ***
• treatment of resting HR ≥70 bpm in patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction ≤35%, who are in sinus rhythm with:
- maximally tolerated
doses of beta blockers
(or) - contraindication to
beta-blocker use
Ivabradine: Pharmacokinetics
none emphasized
Given PO
Ivabradine: Toxicities
none emphasized
• bradycardia • hypertension • increases risk of atrial fibrillation • heart block • sinoatrial arrest
Spironolactone: MOA
- competitive
antagonist of
aldosterone
receptors,
Spironolactone: Effects
K+-sparing
diuretic
– decreases myocardial fibrosis
– reduces early morning rise in heart rate
– reduces mortality and morbidity in patients with severe
heart failure
Spironolactone: Clinical Use
• cardioprotective, antifibrotic, and antiarrhythmic effects
have been proven in animal experiments
• effects on morbidity and mortality have been
demonstrated in randomized clinical trials
• APPROVED FOR TREATMENT OF SYMPTOMATIC HEART FAILURE WITH REDUCED SYSTOLIC FUNCTION but…
- most underutilized of all classes of medications for
heart failure, primarily because of fear of hyperkalemia
Furosemide: MOA
directly Inhibits reabsorption of sodium and chloride in the thick ascending limb of the loop of Henle (TAL) by BLOCKING THE Na+-K+-2Cl- cotransporter
Furosemide: Effects
none emphasized
causes increased excretion of water, sodium, potassium, chloride, magnesium, and calciu
Furosemide: Clinical Applications
• management of edema associated with - heart failure - hepatic disease - renal disease
• acute pulmonary edema by decreasing preload
- decreases EC vol
- rapid dyspnea relief due in part to PG-mediated venodilation (faster than
fluid excretion)
• treatment of HYPERTENSION (alone or combined with other antihypertensives) - unlike thiazides, also works in patients with low GFR
Furosemide: Toxicities
• hypokalemia • hyponatremia • hypocalcemia • hypomagnesemia • hypochloremic metabolic alkalosis • hyperglycemia • hyperuricemia • increased cholesterol and triglycerides • ototoxicity: vertigo, hearing impairment, tinnitus • ± reversible • SULFONAMIDE, so risk of hypersensitivity
sulfonamide similar to furosemide with longer t1/2, better oral absorption and some evidence that it WORKS BETTER IN HEART FAILURE
torsemide
sulfonamide similar to furosemide, but MORE PREDICTABLE ORAL ABSORPTION
bumetanide
NON-SULFONAMIDE LOOP DIURETIC reserved for those with sulfa allergy
ethacrynic acid
hydrochlorothiazide (HCTZ): MOA
blockade of
Na+-Cl-
cotransporter
hydrochlorothiazide (HCTZ): Effects
• also increases
urinary
excretion of K+,
and Mg2+
• i.e., K+ - losing
hydrochlorothiazide (HCTZ): Clinical Applications
• management of mild- to-moderate HYPERTENSION, ALONE OR IN COMBINATION with other antihypertensive agents - NOT EFFECTIVE IN PATIENTS WITH LOW GFR
• treatment of edema
(adjunct role)
• off-label: CALCIUM
NEPHROLITHIASIS;
nephrogenic diabetes
insipidus
hydrochlorothiazide (HCTZ): Pharmacokinetics
none emphasized
well absorbed
via oral administration
hydrochlorothiazide (HCTZ): Toxicities
• hypokalemia • hypomagnesemia • hyponatremia • hypochloremic metabolic alkalosis • SULFONAMIDE drug, so hypersensitivity reactions possible
similar to HCTZ, but poor oral absorption
chlorothiazide
similar to HCTZ, but half-life of 40-60 hrs… prolonged/stable response with
proven benefits is reason it is preferred by some hypertension specialists
chlorthalidone
another long-acting thiazide diuretic, this is a favorite of cardiologists for use as an adjunct diuretic in the treatment of congestive heart failure
metolazone
nitroglycerin: Effects
produces a vasodilator effect on the peripheral veins and arteries with MORE PROMINENT EFFECTS ON THE VEINS
nitroglycerin: Clinical Applications
none emphasized
• treatment or prevention of angina pectoris
• acute decompensated heart failure (especially when associated with acute myocardial infarction)
• perioperative hypertension
(especially during
cardiovascular surgery)
• induction of intraoperative
hypotension
• Intra-anal administration (Rectiv ointment): treatment of moderate-to- severe pain associated with chronic anal fissure
• off-label uses for short-
term for GI and pulmonary
arterterial smooth muscle
relaxation
similar drug with slower onset of action, administered orally for prevention of angina and for heart failure with reduced ejection fraction.
isosorbide dinitrate
hydralazine: MOA
• old drug but mechanism of action remains incompletely understood…
• recent study of isolated mesenteric resistance arteries from pregnant rats indicated:
- endothelium dependent - hyperpolarizes - requires activation of COX - mediated by prostacyclin (PGI2) receptor
Hydralazine: Effects
DIRECT VASODILATION OF ARTERIOLES (with
little effect on veins) –> decreased
systemic
resistance
Hydralazine: Clinical Applications
• Management of moderate to severe hypertension - NOT recommended for the initial treatment of hypertension by JNC8
• off-label:
- heart failure with
reduced ejection fraction if intolerance to ACEI or ARB
- HEART FAILURE with
reduced ejection fraction NYHA Class III-IV (self-identified African-American) - HYPERTENSIVE
EMERGENCY IN PREGNANCY - postoperative
hypertension
Hydralazine: Toxicities
• ANGINA PECTORIS, FLUSHING, orthostatic hypotension, palpitations, PERIPHERAL EDEMA, TACHYCARDIA, vascular collapse; increases intracranial pressure
• pruritus
•drug-induced lupus-like
syndrome
Digoxin: MOA
inhibition of the
Na+ - K+ ATPase
pump in myocardial
cells
Digoxin: Effects
- Increased
contractility - direct suppression
of AV node
conduction
- positive inotropic effect, enhanced vagal tone, and decreased ventricular rate to fast atrial arrhythmias
Digoxin: Clinical Applications
- control of ventricular
response rate in adults
with chronic atrial
fibrillation
- treatment of mild-to- moderate (or stage C as recommended by the ACCF/AHA) HEART FAILURE in adults and pediatric PATIENTS TO INCREASE MYOCARDIAL CONTRACTILITY
Digoxin: Pharmacokinetics
• administered orally
• t1/2: 36-48 hrs, increased as cardiac output and renal function decrease… so NEEDS A LOADING DOSE
• widely distributed, CROSSES THE PLACENTA, but long history of “safe” use in pregnant women with supraventricular tachycardia
Digoxin: Noncardiac Adverse Effects
– anorexia, nausea, vomiting, salivation
– excessive urination
– fatigue, visual disturbances (blurred vision, HALOS, YELLOWISH OR GREENISH TINGE TO OBJECTS)
Digoxin: Drug Interactions
– diuretics… the “biggie”; diuretics cause HYPOKALEMIA, WHICH LEADS TO INCREASED DIGOXIN BINDING, WHICH LEADS TO INCREASED DIGOXIN TOXICITY
– ACE inhibitors and ARBs - can increase plasma K+ levels, decreasing
digoxin effects
– sympathomimetics - beneficial interaction on contractility, detrimental
effects on arrhythmias
– quinidine, spironolactone, verapamil, propafenone and alprazolam are
among a range of drugs that interfere with clearance of digoxin
– cholesterol-binding resins block digoxin absorption from GI tract
