Drugs for Heart Failure Flashcards
1
Q
Captopril: MOA
A
competitive inhibitor of
angiotensin- converting
enzyme (ACE)
2
Q
Captopril: Effects
None emphasized
A
- 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
3
Q
Captopril: Clinical Applications
none emphasized
A
- 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
4
Q
Captopril: Pharmacokinetics
A
t1/2: ~1.7 hrs,
longer in renal
impairment
5
Q
Captopril: Toxicities
A
- cough
- angioedema
6
Q
another early ACEI, a prodrug with active form (enalaprilat) available for IV
A
enalapril (enalaprilat)
7
Q
now widely used ACE inhibitor, longer half life permitting 1X/day dosing
A
benazepril
8
Q
now widely used ACE inhibitor, longer half life permitting 1X/day dosing
A
lisonopril
9
Q
losartan: MOA
A
competitive NONPEPTIDE
ANGIOTENSIN II RECEPTOR
ANTAGONIST
10
Q
losartan: Effects
A
- blocks the
vasoconstrictor and aldosterone-secreting
effects of angiotensin II - does not affect
the response
to bradykinin!!
11
Q
losartan: Clinical Applications
none emphasized
A
- treatment of diabetic
nephropathy - HT, alone or in
combination with other
antihypertensives - heart failure if intolerant
of ACE inhibitors - off-label: Marfan
syndrome
12
Q
losartan: Pharmacokinetics
none emphasized
A
extensive
first-past
metabolism
13
Q
losartan: Toxicities
none emphasized
A
- 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
14
Q
t1/2 ~ 6 -10 hrs, noteworthy in that NOT A PRODRUG requiring activation, excreted primarily in feces as uncharged drug
A
valsartan
15
Q
t1/2 5-9 hrs, noteworthy for its relatviely IRREVERSIBLE BINDING
A
candesartan
16
Q
valsartan/sacubitril: MOA
A
- sacubitril is a prodrug that inhibits neprilysin (neutral endopeptidase [NEP])
- valsartan is an
ARB - drugs are co-
crystalized
17
Q
valsartan/sacubitril: Effects
A
- neutral endopeptidase blockade leads to increased levels of peptides, including natriuretic peptides
- valsartan
antagonizes AT1-
receptors
18
Q
valsartan/sacubitril: Clinical Applications
A
heart failure
19
Q
valsartan/sacubitril: Pharmacokinetics
none emphasized
A
- twice daily
dosing - LBQ657 has t1/2
of ~ 11 hrs - valsartan has t1/2
of ~9 hrs
20
Q
Valsartan/Sacubitril: Toxicities
A
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
21
Q
Carvedilol: MOA
none emphasized
A
a racemic mixture, is a nonselective beta- and alpha- adrenergic blocker
22
Q
Carvedilol: Effects
not in table
A
• 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
23
Q
Carvedilol: Clinical Applications
A
• 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
24
Q
Carvedilol: Clinical Applications (not in table)
A
•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
25
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
26
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
```
27
Ivabradine: Effects
| none emphasized
```
disrupts I(f)
(“funny” current) to prolong diastole and slow HR
```
28
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
29
Ivabradine: Pharmacokinetics
| none emphasized
Given PO
30
Ivabradine: Toxicities
| none emphasized
```
• bradycardia
• hypertension
• increases risk of
atrial fibrillation
• heart block
• sinoatrial arrest
```
31
Spironolactone: MOA
- competitive
antagonist of
aldosterone
receptors,
32
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
33
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
34
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
```
35
Furosemide: Effects
| none emphasized
```
causes increased
excretion of
water, sodium, potassium,
chloride,
magnesium,
and calciu
```
36
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
```
37
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
```
38
sulfonamide similar to furosemide with longer t1/2, better oral absorption and some evidence that it WORKS BETTER IN HEART FAILURE
torsemide
39
sulfonamide similar to furosemide, but MORE PREDICTABLE ORAL ABSORPTION
bumetanide
40
NON-SULFONAMIDE LOOP DIURETIC reserved for those with sulfa allergy
ethacrynic acid
41
hydrochlorothiazide (HCTZ): MOA
blockade of
Na+-Cl-
cotransporter
42
hydrochlorothiazide (HCTZ): Effects
• also increases
urinary
excretion of K+,
and Mg2+
• i.e., K+ - losing
43
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
44
hydrochlorothiazide (HCTZ): Pharmacokinetics
| none emphasized
well absorbed
| via oral administration
45
hydrochlorothiazide (HCTZ): Toxicities
```
• hypokalemia
• hypomagnesemia
• hyponatremia
• hypochloremic
metabolic alkalosis
• SULFONAMIDE drug, so hypersensitivity
reactions possible
```
46
similar to HCTZ, but poor oral absorption
chlorothiazide
47
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
48
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
49
nitroglycerin: Effects
```
produces a
vasodilator effect
on the peripheral
veins and arteries
with MORE
PROMINENT EFFECTS
ON THE VEINS
```
50
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
51
similar drug with slower onset of action, administered orally for prevention of angina and for heart failure with reduced ejection fraction.
isosorbide dinitrate
52
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
```
53
Hydralazine: Effects
DIRECT VASODILATION OF ARTERIOLES (with
little effect on veins) --> decreased
systemic
resistance
54
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
55
Hydralazine: Toxicities
```
• ANGINA PECTORIS, FLUSHING,
orthostatic hypotension,
palpitations, PERIPHERAL
EDEMA, TACHYCARDIA, vascular collapse; increases intracranial
pressure
```
• pruritus
•drug-induced lupus-like
syndrome
56
Digoxin: MOA
inhibition of the
Na+ - K+ ATPase
pump in myocardial
cells
57
Digoxin: Effects
- Increased
contractility
- direct suppression
of AV node
conduction
```
- positive inotropic
effect, enhanced
vagal tone, and
decreased
ventricular rate to
fast atrial
arrhythmias
```
58
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
```
59
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
```
60
Digoxin: Noncardiac Adverse Effects
– anorexia, nausea, vomiting, salivation
– excessive urination
– fatigue, visual disturbances (blurred vision, HALOS, YELLOWISH OR GREENISH TINGE TO OBJECTS)
61
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
