Heart failure drugz Flashcards
heart failure
progressive clinical syndrome, impairs the ventricle to pump blood/contract (has a problem filling), heart is not meeting metabolic demand, CO and Ejection fraction decreases
heart failure compensation
activation of the SNS and the RAAS,
SNS: B1 increases the heart rate and the FOC, alpha 1 is a vasoconstrictor and raises the pressure increases mean arterial pressure (CO doesn’t contribute)
RAAS: ang 2 vasoconstricts and increases pressure, aldosterone causes a retention of sodium and water, this increases pressure and increases contraction (symptoms start to decreases)
digoxin MOA
cardiac glycoside, inhibits the Na+/K+ on the cardiac myocyte, this causes an increase in Na+ intracellular conc and Ca2+ removal from the cell, because there is more Ca2+ the calcium will bind to troponin more in the sarcoplasmic reticulum and cause a conformational change allowing for the cross bridge formation– contraction
what effect does digoxin have on K+
digoxin and K+ bind near the same site on the Na+/K+ pump so an increase of K+ will decrease digoxin activity and K+ decrease will decrease K+ (diuretic and digoxin is tricky)
what is the overall effect of digoxin
vagomimetic effect, allows slowing of AV node, good for patients who have superventricular tachycardias such as atrial fibrillation, parasympathetic effect
pharmacokinetics of digoxin
renally cleared, some excretion by PGP, extremely good absorption from the GI tract, 36 hour half life, TI range is narrow, takes awhile to get the patient to steady state because of the long half life
AE of digoxin
N/V, vision disturbances (alpha 1 receptor), yellow tinge, AV nodal block (vagomimetic effect), ventricular arrhythmias (dose too high and goes the other way), fatique
drug interactions of digoxin
diuretics: hyperkalemia (dec digoxin) hypokalemia (inc digoxin)
bblockers and non-dhp: AV nodal block, dec contract
macrolide antibiotics: inc bioavailability
amiodarone, propafenone, verapamil, spironolactone: inc digoxin levels (PGP substrates?)
role of aldosterone in heart failure
HF increases aldosterone, increases stifness due to an increase of collagen levels. decreases FOC, decreases pumping ability
pharmacokinetics of spirnolactone (Cancerone and spirolactone t1/2, PB, bioavailability)
food increases the bioavailability, canerone half life 10-23 hours and spirolatone half life 7-20 hours, PB 91-98%
AE of spirnolactone
N/V/D, gynecomastia, irregular menses, impotence
drug interactions with spirnolactone
ACEI and ARBS: hyperkalemia
digoxin: hyperkalemia decreases digoxin effects
milrinone use
Acute decompensated heart failure
milrinone MOA
inhibits PDE-3 (dec cAMP, dec cGMP), cardiac and VSM effects, inodilator (like ionotropic contraction, inc FOC), prevents the breakdown of cAMP to AMP enhancing the effects of the SNS (inc contractility, inc heart rate, vasodilation)
milrinone pharmacokinetics (onset, t1/2, how it is cleared, admin)
onset of action 5-15 minutes, t1/2 2.5 hours, primarily renally cleared by active tubular secretion, IV only, no pharmacokinetic interactions
AE of milrinone
hypotension, arrhythmias (inc SNS), thrombocytopenia
nesiritide uses
acute decompensated heart failure, recombinant B-type natriuretic peptide (relaxing and dec volume) released in response to volume overload, results in: natriuresis, diuresis and vasodilation
nesiritide MOA
nesiritide binds NPR-A which is a cell surface receptor with intrinsic guanalyl cyclase activity. activation inc cGMP levels in target tissues including smooth muscle cells. inc cGMP mediates its effects including increased natriuresis and diuresis as well as vascular smooth muscle relaxation in both the venous and aterial systems. dec preload and TPR (afterload)
nesiritide pharmacokinetics (onset and t 1/2)
onset: 15 mins
t1/2 18 mins
no pharmacokinetic interactions
elimination of nesiritide
- binding to a cell surface receptor NPR-C and cellular internalization and degradation
- proteolytic cleavage by neutral endopeptidases
- renal filtration
AE nesiritide
hypotension, GI
Vasopressin use
Cardiac arrest, non-adrenergic peripheral vasoconstrictor used to increase blood flow to the heart and brain, not trying to fix anything with heart failure meds, just making the symptoms better
Vasopressin MOA
Binds to G protein coupled receptors resulting in peripheral vasoconstriction and water reabsorption in the renal collecting ducts - want to direct blood to heart and break, don’t worry about other places, V1 receptor is Gq coupled receptor located on the vascular smooth muscle, vasopressin causes vasodilation of cerebral and coronary vessels increase in NO causes relaxation
What happens in VSM when a Gq coupled receptor is activated
Vasoconstriction
T1/2 vasopressin
17-35 mins
How is vasopressin cleared
Rapidly cleaved by proteases
AE of vasopressin
N/V, abdominal cramps
V2 receptor - vasopressin
This receptor is on the basolateral side of the collecting duct and activation of this Gs coupled receptor leads to activation of adenylyl cyclase. This results in an increased cAMP level and activity of PKA which promotes the insertion of water channel containing vesicles into the apical membrane - dec endocytosis and inc permeability of water across the apical membrane
ADH antagonists - uses
Heart failure - associated with hypervolemic hyponatremia, inc fluid and dec Na
Tolvaptan MOA
V2 selective
Tolvaptan admin
PO/IV
Tolvaptan PB
99
Tolvaptan t 1/2
12 hours
Tolvaptan metabolism
3A4 substrate and PGP substrate inhibitor
Tolvaptan AE
Dry mouth, thirst, urinary frequency, constipation, and hyperglycemia
Tolvaptan drug interactions
CYP3A4 and PGP inhibitors/ inducers
Digoxin: may increase digoxin levels
Conivaptan MOA
V1a/V2 antagonists
Conivaptan admin
IV
Conivaptan T1/2
5-8 hours
Conivaptan metabolism
3A4 substrate and inhibitor, PGP inhibitor
Conivaptan AE
Orthostatic hypotension, fever, hypokalemia, local injection site reactions
Conivaptan drug interactions
3A4 inhibitors/inducers inc levels of simvastatin, digoxin, amlodipine, and Midazolam, PGP substrates
Why aren’t vaptan drugs used much?
Mortality rates are higher, not as successful as others- used for position specific
Ivabradine brand name
Corlanor
Ivabradine uses
Chronic heart failure, stable symptoms, resting HR > 70bpm, on max dose beta blockers
Ivabradine effect on Na+ channels
Affects funny channels and lengthens the 4 phase of the AP, doesn’t affect Ca2+ channels, allows more filling and better pumping
PK importance with Ivabradine
Food delays absorption and increases plasma exposure 20-40%
Metabolism of ivabradine
CYP 3A4 mediated oxidation
AE Ivabradine
Bradycardia, hypertension, atrial fibrillation (inc risk), temporary vision disturbances (light flashes), avoid in pregnancy and severe hepatic impairment
Valsartan/sacubritil brand name
Entresto
Valsartan/subuctril MOA
Valsartan blocks tha AT1 receptor and sacubitril is a prodrug that exhibits the enzyme neprisylin, neprisylin degrades atrial and brain natriuretic peptides —- dual acting angiotensin receptor - neprisylin inhibitor (ARNi), 1:1 combination
PB valsartan/sacubritil
95%
Metabolism of valsartan/sacubritil
Minimal P450 interactions, sacubitril: inhibitor of OATP1B1 and OATP1B3 (inc ATP
Drug interactions of valsartan/sacubritil
Dual block of RAAS, K+ sparing diuretics, NSAIDS, lithium
AE entresto
Angioedema, hypotension, hyperkalemia, cough, dizziness, renal failure, avoid in pregnancy, lactation, and severe hepatic impairment
Frank starling effects of entresto
nesiritide dec preload and workload, digoxin and milrinone inc
