A20. Drugs used for treatment of heart failure II: Positive inotropic agents. Pharmacotherapy of acute heart failure. Flashcards
Name the Cardiac glycoside drugs.
Names of drugs to know:
- Digoxin
- Digitoxin
- Ouabain
What are the indications for cardiac glycoside use?
- Chronic HF from stage II or up
- Atrial flutter: risk of too quick conduction thru AV node. (Digoxin can transfer from 1 ectopic foci to multiple
ectopic foci, can change to A-fib to help reduce the ventricular rate.) - Atrial fibrillation if ventricular rate is too high
What are the contraindications for cardiac glycoside use?
absolute:
- hypertrophic cardiomyopathy
- some cases of WPW (stimulates anterograde conduction → vtach)
- AV block
- Diastolic HF
- suspected digitalis intoxication
relative: - sinus bradycardia or sick sinus syndrome
- other negative chronotropes (verapamil, diltiazem, amiodarone)
- circumstances w/ ↑ digitalis sensitivity (hypokalemia)
- renal failure (digoxin CI, but digitoxin is allowed)
MOA of Cardiac Glycosides:
Cardiac glycosides causes Postive inotropy. some differences in compounds but MOA is the same.
MOA: inhibit Na/K ATPase → intracellular [Na] ↑. Slows down or reverses [Na]/[Ca2+] exchanger. intracellular [Ca]
increases (dangerous, calcium initiates apoptotic processes)
▪ More Ca2+ is stored away in SR to prevent dangerous effects of calcium
• Resting potential becomes less negative, threshold gets closer
• AP → release of calcium from SR. Current is proportional to contraction strength. more calcium → more
troponin C gets activated → more actin-myosin binding → more filaments slide → more contractility
(inotropy)
o should inhibit only small amounts of Na/K ATPase. easily overdose. narrow therapeutic window, patient needs
regular monitoring o Other mechanisms:
• Parasympathomimetic effect: stimulate vagus nerve. would be ideal for HF but can contribute to AV block and arrhythmias
• Arrhythmogenic:
▪ Bradycardia
▪ ventricular extrasystoles: lower threshold potential and some extra spikes in threshold potential from calcium fluctuations (delayed after depolarizations) - if reach threshold, then VES
• hypoxic regions in particular become sources of ectopic beats
• ventricular bigeminy is a particular sign of digitalis toxicity
• ectopic focus might become autonomous: bigeminy may turn into trigeminy or even
ventricular tachycardia, or more than 1 ectopic foci → fibrillation ▪ atria:
• M2 receptors in atria muscle (Gi GPCR) - opens K channel → hyperpolarization (different effect than in ventricles)
• Extra K current may contribute to faster repolarization of atrial wall → desynchronization of atrial wall → possibly atrial fibrillation
Pharmacokinetics of Cardiac Glycosides?**
- long half-lives:
- digoxin = 40 hours
- digitoxin = 1 week - most drugs are given daily. so determine the dosage by:
- give loading dose, then add maintenance dose that is equal to excreted amount
- loading dose is actually given in 3 doses
- sometimes still need drug-free days to make sure not overdosed
▪ digoxin
• loading: 1-1.5 mg
• maintenance: 0.25 mg/day ▪ digitoxin: better bioavailability
• loading: 0.8-1.2 mg
• maintenance: 0.07-0.1mg / day
• digoxin is not metabolized, excreted by kidney. if renal impairment, it’s CI
• digitoxin is partly metabolized by liver, but metabolite is digoxin, which is then excreted mainly by liver in
bile, but is continuously reabsorbed (enterohepatic circulation) due to near-perfect bioavailability. keeps
half-life very long
digitalis binds to potassium-binding site. potassium competes for same site, and so hyperkalemia counteracts
digitalis action
• hypokalemia potentiates the effect. drugs that cause hypokalemia (thiazide diuretics, loop diuretics, insulin)
• so it’s particularly important here to control patient’s potassium concentration
o other ions:
• Calcium: synergistic with digitalis. hypercalcemia → digitalis is stronger
• Magnesium: opposite. Hypermagnesia inhibits, hypomagnesia potentiates
▪ magnesium is essential for ATPase enzyme function
What are the side effects of using cardiac glycosides?
SE
o signs:
• ECG: scooped ST segments, T inversion, bigeminy
▪ treat with 1B type: e.g. lidocaine, phenytoin for vent tachycardias. bradycardia treated with atropine. ▪ must check potassium level and normalize it
• if severe overdose (e.g. intentional overdose) digitalis-binding antibodies can be used - digiban: digitalis- binding antibodies.
• may “see the world in yellow” - everything turns yellow
• abdominal pain
• men: gynecomastia. contains steroid core that has mild anti-androgenic action
What is the MOA of Digoxin?
Digoxin is derived from the foxglove plant.
MOA: Inhibts Na+/K+ATPase, resulting in a increased intracellular sodium concentration. Increased intracellular sodium promotes calcium influx at the Na/Ca2+ exchanger. Increased cardiac contractility due to the positive inotropic effects.
What are the indications for Digoxin use?
- Symptomatic treatment of Chronic systolic HF. Only used for symptomatic relief, does not decrease mortality.
- Direct stimulation of vagus nerve allows for treatment of Atrial arrhythmias. (Antiarrhythmics)
** Patients presenting will have HF and A.Fib, labs show elevated K+
What are the adverse effects of taking Digoxin?
- Hyperkalemia with acute digoxin toxicity.
- It may induce various arrhythmias
- Chronic digoxin use may cause scooped concave ST segments on EKG.
- Bradycardia due to parasympathetics activity of the SA node.
5 Heart block due to digoxin toxicity
(Contraindicated in SA node heart block, or in use with caution in Beta blockers). - GI symptoms: nausea, vomiting, and abdominal pain.
- Side effects of Xanthopia (objects appear yellow)
- Hypokalemia will excerabate digoxin toxicity. Loop diuretics can cause hypokalemia, along with diarrhea or vomiting may occur.
- Renal insufficiency can make digoxin toxicity worse and will precipitate digoxin rise, long half life of digoxin, increased susceptibility of toxicity. Many arrhythmics inhibit renal clearance of digoxin, increasing suceptibility of toxicity.
*** Digoxin immune fab is used to reverse toxicity.
What are cardiac glycosides?
Cardiac Glycosides are positive inotropic Plant-derived agents (glycoside = structure contains sugars). These drugs are going out of fashion, but still may have some use.
???
Patients feel subjectively better on these drugs, improves QoL. But higher risk of arrhythmias and death from cardiac reasons. However, overall mortality doesn’t change. difficult to weigh benefit/risk. I think they’re outdated and don’t recall the cardiology department ever suggesting them, it’s frustrating that the pharma department spends so much time on it.
