HF Drugs Flashcards
Which beta blockers are indicated in HF?
Bisoprolol, Metoprolol XL, Carvedilol, Nebivulol
Why does HF cause edema?
- Increased venous pressures lead to decreased GFR => Increased fluid retention
- Reduced CO leading to increased sympathetic activity and reduced blood pressure => Decreased renal blood flow. This causes renin secretion => AngII / Aldosterone - mediated Na, fluid retention
What is ARNi?
ARNi - Angiotensin Receptor / Neprilysin inhibitor
Physiologically, when there is HF, the heart secretes NT-proBNP and BNP. BNP promotes vasodilation, natriuresis, diuresis. It therefore antagonizes RAAS and helps in HF.
BNP and other natriuretic peptides are broken down by neprilysin, so in that sense neprilysin is bad for HF.
Neprilysin also breaks down AngII, so in that sense neprilysin is good for HF (AngII increases blood pressure).
Neprilysin also breaks down bradykinin, which has no effect on HF, but bradykinin does make you cough.
Sacubitril -> Neprilysin inhibitor, thereby prolonging the activity of BNP (but also stops the inhibition of AngII and bradykinin)
Valsartan -> AT1 (AngII Type 1 Receptor blocker), thereby reducing the activity of RAAS)
ADR of ARNi?
ADR - Hypotension (BNP activity, RAAS blockage), Hyperkalemia (RAAS blockage), Renal failure, Cough (Bradykinin accumulation), Angioedema
Outline reabsorption at thick ascending limb
Na / K / 2Cl COTRANSPORTER on the apical surface. This takes up all these electrolytes.
There is an open K+ channel protein that allows K efflux, creating a positive electrical gradient.
This allows Mg and Ca reabsorption paracellularly
Name loop diuretics
Sulfonamide, Furosemide, Bumetanide, Ethacrynic acid
MOA of loop diuretics
MOA - Inhibit luminal Na/K/2Cl cotransporter in the thick ascending limb. They also induce renal PG synthesis and hence NSAIDs like aspirin and indomethacin interfere with loop diuretic activity.
Furosemide also increases renal blood flow.
By blocking the cotransporter, it is easy to see why there would be hypomagnesemia and hypocalcemia.
PK of loop diuretics?
PK - Rapid absorption, or extremely rapid action if given IV (much faster than thiazides!). Lasts 2-3h and eliminated by the kidneys themselves through filtration and later tubular secretion as well.
Indications for loop diuretics?
Indications - Acute pulmonary oedema (other oedema too), acute hyperkalemia, acute renal failure,
anion overdose (toxic ingestion of bromide, fluoride, iodide) because then the uptake of these anions is reduced; these anions sometimes use the same NaKCl cotransporter that furosemide blocks
ADR of loop diuretics?
ADR - Hypokalemic metabolic acidosis, Hyperuricemia, Hypomagnesaemia, Ototoxicity. Because of the ototoxicity, avoid using it with aminoglycosides!
Which LoH is water ONLY?
Descending. Ascending is then NaCl active reabsorption. It has the NaKCl cotransporter
Name the potassium-sparing diuretics
Spironolactone, Eplerenone, Triamterene, Amiloride
SE -> Inhibit aldosterone receptor activity
TA -> Inhibit apical Na+ channel protein activity
These both act on the principal cells!
Are potassium-sparing diuretics given together?
NO, it would be inhibiting the same pathway.
How do potassium-sparing diuretics actually spare the potassium?
Diffusion of Na+ through the apical channel protein creates an electrical gradient that allows K+ efflux. Blocking this channel reduces the secretion of K+ through this pathway.
Indications of PSD?
Diuretic usage
Hyperaldosteronism!!!
PK of PSD?
Spironolactone has a slow onset (several days before the full effect is achieved)
Triamterene is metabolised in the liver. Shorter T1/2 and given more frequently than amiloride. Amiloride is just excreted unchanged.
Indomethacin is used in _ for neonates?
PDA closure in neonates
Indomethacin is also a painkiller, sometimes used in gouty arthritis
ADR of PSD?
Hyperkalemia, Metabolic acidosis
Gynecomastia (only in spironolactone though because as a mineralocorticoid blocker it also blocks testosterone receptors)
Acute renal failure (when triamterene and indomethacin given together)
Kidney stones with triamterene
How is hydralazine used in HF?
Direct arteriolar vasodilator by inhibiting the IP3-induced release of Ca. This reduces the TPR, but increases preload
It is combined with ISDN to be used in HFrEF
Hydralazine PK?
Given orally - 20-30 min onset with 2-4h action
Used in primary Htn when first-line meds are not suitable. PO.
Acute onset severe peri/post-partum htn, starts acting in around 15min. IV delivery - 5-30 minute onset with 2-6h duration
Peak plasma at 2.5h with T1/2 7h
ADR of Hydralazine?
C/I in _?
ADR, C/I -
Reflex tachycardia, flushing, hypotension
HILS! - Hydralazine-Induced Lupus Syndrome:
Arthralgia, myalgia, serositis, fever that occurs in 5.8% pts, dose-dependent severity, happens in long-term (>6mo) usage.
C/I in CAD. The reflex sympathetic activation may increase CO, leading to increased myocardial oxygen demand and consequent ischaemia
Ivabradine vs. ISDN/ISMN; Which one used in HF?
BOTH! Lol
Ivabradine reduces the workload of the heart by reducing HR and hence CO and hence oxygen demand.
ISDN/ISMN reduces the preload (venodilation) and afterload (TPR because dilates the arteries too) thereby reducing the workload of the heart
What is digitalis?
Digitalis refers to the group of drugs derived from the foxglove plant, including cardiac glycosides.
This contains the subsets digoxin and digitoxin
When are cardiac glycosides used?
End-stage HF, when the aim of the treatment is to increase cardiac output
What is the MOA of digitalis drugs?
Cardiomyocytes have Na/K ATPase (Kicks out Na and takes in K) and Na/Ca exchangers (kicks out Ca and takes in Na).
Digitalis inhibits Na/K ATPase activity. This causes increase of intracellular Na, because less Na is being actively removed.
This reduces the rate of activity of the Na/Ca exchanger because there is a less steep Na concentration gradient between intracellular and extracellular fluid.
This reduces the rate of Ca efflux, leading to stronger systolic contractions
What is the difference between digoxin and digitoxin?
Digoxin is not extensively metabolised, and up to 2/3 is excreted unchanged by the kidney.
Digitoxin is extensively metabolised by the liver before being excreted via feces.
Digitoxin has MUCH greater T1/2, DOA, and protein binding too.
Both are PO and have a large Vd
How do cardiac glycosides reduce preload and afterload?
An increase in the CO causes increased carotid sinus firing (because of increased blood pressure) as well as increased renal blood flow.
The increase in carotid sinus firing reduces sympathetic activity; increases parasympathetic activity as well!
The increase in renal blood flow reduces RAAS activation because of reduced renin release.
Reduced sympathetic activity and reduced RAAS activity help to reduce both the preload and the afterload.
Electrical effects of digoxin?
Reduced QT, Reduced ST, Inverted T wave.
Since digoxin increases PS activity, there is reduced AV conduction as well. This increases the PR interval and reduces the ventricular rate
What are the indications for digoxin?
Late-stage heart failure
Systolic dysfunction
Atrial fibrillation
Digoxin ADR?
- Dysrhythmia becomes progressively more severe in electrical conduction pathologies like AV block, Afib, Vfib
- GI effects like NV and ANOREXIA
- CNS headache, fatigue, confusion, blurred vision
How is digoxin toxicity managed?
- Discontinue digoxin therapy
- Correct any electrolyte balances, particularly K+ and Mg2+
- Antiarrhythmics like lidocaine and propanolol in cases of increased automaticity
- Antibodies against digoxin do exist! Such as FAB fragments, “Digibind”
