18B02: Exam Report

Compare and contrast amiodarone and digoxin.

82% of candidates passed this question.

Most Candidates had a good structure for answering this question; a table was commonly used. Marks were awarded for indications and an explanation of the mechanism of action of both drugs, which was generally well explained. The pharmacodynamic effects were often listed in a  general manner and more detail would have achieved a higher mark, including a list of the ECG effects. Some detail on the pharmacokinetics and adverse effects of the drugs was expected and this section was generally well answered. Better answer noted digoxin levels and potential drug interactions.

G7iii / 18B02: Compare and contrast amiodarone and digoxin

Amiodarone

Digoxin

Comparison

Chemical

Amiodarone

Iodinated benzofurane derivative

37% iodine by weight

Resembles thyroxine structure

Class III anti-arrhythmic

Digoxin

A cardiac glycoside naturally occurring in many plants

Basic structure → steroid nucleus with a glycose & aglycone portion

 Glycose → glucose → required to fixate the glycoside to cardiac muscle

 Aglycone → influences PD effects

Comparison

Use

Amiodarone

  1. Ventricular tachyarrhythmias
  2. SVTs

Digoxin

  1. Treatment of heart failure
  2. Slow ventricular response rate

Comparison

Presentation

Amiodarone

Clear, colourless vial 50mg/mL

PO tablets 100/200mg

Digoxin

Clear colourless vial 0.25mg/ml

PO tablets

Comparison

Dose

Amiodarone

300mg/30min IV load

Then 1500mg/24hrs infusion

PO → load 900mg/day for 2/52

      → maintenance 200mg/day

Digoxin

Load: IV 0.5mg/30mins or 10mcg/kg

Maintenance: 0.125 – 1mg/day

Comparison

Route

Amiodarone

PO/IV → Rapid IV infusion risks circulatory collapse

Digoxin

PO/IV

Comparison

Onset

Amiodarone

IV → suppression of arrhythmia < 1hr

PO → suppression of arrhythmia 72hrs

Digoxin

IV: 15 mins

PO: 1 – 6hrs

Comparison

DoA

Amiodarone

4 hrs

Digoxin

Days

t ½ 40hrs w normal renal fn

Comparison

MoA

Both prolong PR

Opposing effects on QT

Amiodarone

All 4 V-W class actions

1) Blocks K+ channels

  • Prolongs effective refractory period
  • ∴ prolongs AP duration & QT interval

2) Na+ channel blockade

  • ↓slope of Ph 0
  • ↓amplitude AP
  • ↓conduction velocity ( – CHRONO) so there is slower transmission of AP
  • Especially slows conduction through His Purkinje & Ventricles

3) Anti-adrenergic

  • Non-competitive block of α & β adrenoreceptors
  • ↓HR
  • ↓AV Nodal conduction

4) Ca2+ channel block

  • Mild direct -ve inotrope

Digoxin

Myocardial → DIRECT → MECHANICAL

  • Inhibits Na/K/ATPase (binds directly)
  • ↑intrac. Na+
  • ↓activity of Na+/Ca2+ exchanger
  • ↑intrac. Ca2+
  • Causes further release of Ca2+ from SR = ↑force of contraction

 Myocardial → DIRECT → ELECTRICAL

  • Inhibits Na/K/ATPase
  • Which is essential for maintaining normal RMP/ion concentration

= ↑automaticity

  • RMP becomes less negative (depol easier) 2° ↑intrac. K
  • AP shortens 2° ↑K conductance
  • ↑slope of Ph 4
  • ↓slope Ph 0 because less Na gradient (this is the only ∆ that doesn’t ↑automaticity)

 Myocardial → INDIRECT → ↑PARASYMP ACTIVITY

  • Sensitizes CAROTID SINUS BARORECEPTORS
  • Activates vagal nuclei
  • Facilitates muscarinic transmission at cardiac cell

→ CHOLINERGIC INNERVATION MORE PRONOUNCED IN ATRIA →

∴ affect atria & AV node movement

  • – VE CHRONO / -VE DROMO

 Peripheral vascular effects

  • Inhibition of Na/K/ATPase of vascular sm m → depolarization → smooth muscle contraction → VC →  = ↑PreL & SVR

ECG Effects

Amiodarone

  • Prolong PR interval
  • Widened QRS
  • QT prolongation

Digoxin

Prolonged PR

Scooped out ST

T waves ↓amplitude ST inversion

Shortened QT

No effect on QRS

Comparison

Both prolong PR

Opposing effects on QT

PD

Amiodarone

CVS

  • Prolongs refractory period in all cardiac tissue

→ ↓HR

→ May cause AV block

→ Prolonged QT risks TdP

  • Mild negative inotropy
  • Potent vasodilation → CA but also ↓BP
  • Irritates veins

Digoxin

CVS

  • ↑myocardial contractility
  • ↓HR
  • ↑SVR

 RENAL: ↑renal perfusion & mild diuresis

Comparison

Dig often given when +inotropy required

PK

Amiodarone

A

Incomplete

Highly variable

OBA 20 – 90%

Titrated on an individual basis

D

Huge tissue affinity

Myocardial concentration x 10 that of plasma

∴ not a good relation b/w plasma [  ] & PD effects

Large VD 70L/kg

Extensive PPB > 99%

Not removed well in HD

M

Liver metabolism to desmethylamiodarone which is active & has a longer t ½ cf. amiodarone

E

Small renal excretion mainly in bile & faeces

Elimination is v. long ~30 days

Digoxin​

A

75% OBA

Peak plasma in 1 – 2hr

D

PPB 25%

VD 6L/kg

Tissue affinities:

  • Heart → 15 – 30x plasma levels
  • Skeletal m. → 50% less cardiac levels (principle reservoir)
  • Fat → minimal accumulation

M

Minimal

E

Excreted by kidneys unchanged

Depends on CrCl

t ½ B = 2 days!

Comments

Amiodarone notoriously variable in absorption with wide tissue distribution

Both drugs are not removed by dialysis

Digoxin requires renal dosing

Amiodarone has much longer lasting effects

AE

Amiodarone

CVS

  • Irritant to veins
  • Bradycardia → resistant to atropine
  • Prolongs QT → risks TdP
  • Potent VD → risks cardiovascular collapse → esp. with rapid IV bolus
  • Complete AV block

Resp

  • Pulmonary fibrosis secondary to alveolitis
  • Pulmonary toxicity is dose-related → esp. >400mg/day for >4wks

CNS

  • Sleep disturbance
  • Headache
  • Peripheral neuropathy
  • Tremors/proximal skeletal m. weakness

Ocular

  • Corneal microdeposits → virtually all patients
  • Halo development in peripheral fields
  • Optic neuritis may progress to blindness

Dermatologic

  • Blue slate skin
  • Photodermatitis esp. to sun-exposed areas

GI

  • Fatty infiltration of liver
  • ↑transaminases
  • Hypersensitivity hepatitis

Endocrine

  • 5% pats → hyper/hypo-thyroidism
  • More likely with pre-existing thyroid disease
  • Hyperthyroidism → from release of iodine during metabolism
  • Hypothyroidism → when Amiodarone inhibits peripheral deiodination of T4 → T3

Pregnancy

  • Amiodarone & its metabolite demethylamiodarone (DEA) are found in placenta & breast milk
  • Can cause infant hypothyroidism
  • Amiodarone inhibits P450 enzyme & ↑levels of drugs: statins, digoxin, warfarin
  • WARFARIN needs to ↓ 1/3 of dose with amiodarone
  • Erythromycin → also prolongs QT interval = ↑risk TdP

 NOTE: K+ channel blocking takes days to become evident

∴ only if you need urgent rate control for AF, do you give amiodarone IV

Initial action = ↓ventricular rate in RAF without reverting to SR

↓

Then the K+ blocking takes place & reverts to SR seen

Digoxin

TOXIC EFFECTS → Na/K/ATPase inhibition

CVS

  • Heart block (AV conduction delayed)
  • Arrhythmias (↑slope 4, ↑Ca2+ intrac) → any arrythmia but VF most common cause of death from dig toxicity

CNS

  • Insomnia
  • Agitation
  • Confusion
  • Delirium
  • Xanthopsia (seeing yellow)

GI: anorexia, N&V (stimulations CTZ)

RISK FACTORS:

  • Renal impairment
  • Elderly
  • ↓K
  • ↑Ca2+
  • ↓Mg2+

Drug Interactions

Both drugs have high number of drug interactions

Amiodarone displaces the small amount of PPB of Digoxin

Amiodarone also inhibits p450

Increasing plasma digoxin x 50%