Heart Failure Medications Pharmacology and PKPD Flashcards
What are the Morbidity and Mortality Reducing Drugs?
RAAS Inhibition, MRAs, SGLT, BBs, Veno/Vasodilators
What are the RAAS Inhibitors?
ACEI/ARB, ARNI
Effects of RAAS Inhibitors on HF?
Arteriolar and venous dilation
Decreases aldosterone secretion
Reduces cardiac remodeling
Sacubitril increases…
BP and natriuresis
What is the indication for Entresto?
HFrEF, HFpEF, HFmrEF
MOA Sacubitril?
Neprilysin inhibitor that blocks the breakdown of BNP –> naturesis and vasodilation
MOA Valsartan?
Blocks AG II receptor (decreases RAAS cascade)
Most common ADR for Entresto?
Hyperkalemia
What happens if the 36 hour wash out period is NOT given with an ACEI?
Increase in bradykinin and angioedema
The ARNI has ______ BP lowering effects than an ACEI or ARB alone
More
Almost all _____ are renally eliminated?
ACEI
ACEI and ARBs are used for which type of HFEF?
HFrEF
MRAs Effect on HF?
Increases salt and water excretion
Reduces cardiac remodeling
Major Contraindication MRA?
Severe kidney impairment
eGFR <30mL/min/1.73m^2 or creatinine >2.5 mg/dL in men or creatinine >2 mg/dL in women
Potassium >5.0 mEq/L
Which MRA is a strong CYP3A4 inhibitor?
Eplerenone
ADR Spironolactone?
Gynecomastia, breast tenderness, impotence
ADR Eplerenone?
Increased TGs
ADRs MRAs
Dehydration, hyperkalemia, hyperatremia, dizziness
What are the SGLT inhibitors?
Empagliflozin, Dapagliflozin, Sotagliflozin
Which is the SGLT2 inhibitors?
Empagliflozin, Dapagliflozin
Which is the SGLT1/2 Inhibitor?
Sotagliflozin
SGLT Effects in HF
-Increased sodium and water excretion
-Decreased cardiac preload and afterload
-Reduces pulmonary and peripheral edema
-Improves metabolism and efficiency of cardiac muscle
MOA SGLT
Increases urine output by osmotic diuresis (glucose excretion)
Increased fibrosis
SGLTI Inhibition: decrease absorption of sodium/glucose
Major Contraindications for Dapagliflozin and Sotagliflozin?
eGFR > 25 mL/min/1.73m^2 for initiation
DO NOT need to discontinue if eGFR falls below this while on treatment
Major Contraindication for Empagliflozin?
No renal adjustments necessary
ADRs for SGLT?
Dehydration, genital mycotic infections/UTI
Hypoglycemia, euglycemic acidosis (stop surrounding surgeries)
How many days prior to surgery should you stop SGLT inhibitors due to euglycemic ketoacidosis?
3 days prior to surgery
Which dose may require an adjustment due to SGLT?
Loop Diuretic
What are the Beta-Blockers used that have mortality benefit in patients with HF?
Carvedilol, Metoprolol Succinate, Bisoprolol
Beta-Blockers effect in HF?
Reduces HR
Decreases sympathetic input to cardiac and vascular tissue
Decreases arrhythmias and sudden cardiac death in patients w/ HFrEF mainly due to decrease in sympathetic drive
Major contraindication for Beta-Blocker?
Severe bradycardia
DDI of Beta-Blockers?
Additive AV nodal blockade with Non-DHP CCB
Which are the Vaso/Venodilators associated w HF?
Hydralazine and Isosorbide Dinitrate
Effects in HF: Hydralazine
Reduces afterload –> increased cardiac output
Major Contraindication Hydralazine?
CAD (causes reflex tachycardia and can cause angina/MI)
Effects in HF: Isosorbide Dinitrate
Reduces preload –> decreases ventricular stretch
ADR Hydralazine?
Dizziness, REFLEX TACHYCARDIA, DILE
Hydralazine half life?
1.5-3 hours
Pearls for Hydralazine and combo tablet BiDil?
Need to take 3 times daily, not great for adherence!
Major Contraindication for Isosorbide Dinitrate
PDE5
ADR Isosorbide Dinitrate
Headaches, dizziness, syncope
MOA Isosorbide Dinitrate
Forms the free radical nitric oxide which in smooth muscle activates guanylate cyclase which
increases guanosine 3’5’ monophosphate (cGMP) leading to smooth muscle relaxation.
Produces a vasodilator effect on the peripheral veins and arteries with more prominent
effects on the veins.
Key PKPD Isosorbide Dinitrate
Dependent in formulation, oral bioavailability is low bc of first pass hepatic metabolism (10-20%)
Loop Diuretics Effect in HF
Increased excretion of salt and water
Reduces cardiac preload and afterload
Reduces pulmonary and peripheral edema
Loop Diuretics key note**
Improves symptoms of HF, fluid overload, SOB, that is when loop diuretics are use completely for symptom control, they do not reduce mortality in patients with HF
Major Contraindications Loop Diuretics
Anuria (no urine)
DDI Loop Diuretics
Increased risk of ototoxicity if used with aminoglycosides
BBW Loop Diuretics (Furosemide)
Potent diuretic at high doses can lead to profound fluid and electrolyte loss
Bioavailability of Loop Diuretics
Furosemide is 40-70%
The rest are 90 and above
Diuretic Resistance: What do you do if there is increased distal sodium reabsorption (chronic loop diuretic use)?
ADD Thiazide to the loop
Diuretic Resistance: Poor delivery to site of effect: reduced GFR, HF, gut enema
INCREASED dose of loop diuretic
When do you increase the threshold of diuretics?
Chronic use, AKI/CKD, HF (gut edema)
What is the ceiling dose for a loop diuretic?
Once you hit a good dose, an increase in dose 80 vs 120 won’t do anything different to the patient, so no need to go up.
Which two medications require food to ensure adequate absorption?
Ivabradine (Corlanor)
Vericiguat (Verquvo)
These drugs are also BOTH indicated for HFrEF only
MOA of Ivabradine?
Impacts the ‘funny’ channel in the SA node
DDI Ivabradine
Major substrate of CYP3A4
Major Contraindications Ivabradine
Severe hepatic impairment, acute decompensated HF, clinically significant hypotension, sick sinus syndrome, sinoatrial block, third degree AV block
ADR Ivabradine
Bradycardia, afib
MOA Vericiguat
Enhances production of cGMP by directly stimulating sGC independent of NO and enhances sGC sensitivity to endogenous NO, thereby increasing cGMP production. Increased levels of cGMP lead to smooth muscle relaxation and vasodilation
Major Contraindication Vericiguat?
Pregnancy
ADR Vericiguat?
Hypotension, anemia
DDI Vericiguat?
Category X: use in combination with PDE5 inhibitors
Pearls Vericiguat?
Formulation may include lactose
Must have a negative pregnancy test prior to initiation
Which drug is the Cardiac Glycoside?
Digoxin
Digoxin effects in HF?
Increases cardiac contractility
Increases parasympathetic tone of heart (decreases sinus rate, AV conduction)
Digoxin indication?
HFrEF, rate control for afib
MOA Digoxin
Inhibition of the sodium/potassium ATPase pump in myocardial cells results in a transient
increase of intracellular sodium, which in turn promotes calcium influx via the sodium-
calcium exchange pump leading to increased contractility.
May improve baroreflex sensitivity.
ADR Digoxin?
Arrhythmia, heart block, GI and neurological side effects
DDI Digoxin
Major substrate of PgP, minor substrate of CYP3A4
Monitoring for Digoxin?
Heart rate and rhythm
Monitoring for Digoxin…what is the serum concentration trough goal?
Ideally 0.5-0.9 ng/mL
ADR Digoxin?
Tachycardia, bradycardia, anorexia, nausea, vomiting
Distribution of Digoxin?
HIGH volume of distribution: once absorbed, it is widely distributed into the tissues, takes 6-8 hours for that
Pearls Digoxin?
Almost exclusively used for patients with HFrEF and afib
BEERS criteria (not ideal for older patients)
Heart:Serum Concentration Digoxin?
70:1
Excretion of Digoxin?
2/3 excreted unchanged by the kidneys , renal clearance is proportional to creatinine clearance, half life is 36-40 hours in normal renal function (worse in patients w bad renal function)
Digoxin Levels
Toxic effects may occur BEFORE therapeutic effects are detected
Levels must be drawn after distribution period, ideally at least 10-12 hours, levels should be drawn at steady state: 5-7 days after initiation
What are the morbidity drugs?
Diuretics, If Channel Inhibitor, Soluble Cyclase Stimulator, Cardiac Glycoside
