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Digoxin lecture 8 - health and f

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Digoxin lecture 8 - health and f Powered By Docstoc
					    Digoxin
Pharmacokinetics
     Moayyad J. Al Omar
     Clinical Pharmacist
               Action and uses
Digoxin is the most widely used of the digitalis
glycosides
Its primary actions on the heart are those of
increasing the force of contraction and decreasing
conduction through the atrioventricular node
Currently, its main role is in the treatment of atrial
fibrillation by slowing down the ventricular response
although it is also used in the treatment of heart
failure in the presence of sinus rhythm
The primary method of monitoring its clinical
effect in atrial fibrillation is by measurement of
heart rate but knowledge of its
pharmacokinetics can be helpful in predicting a
patient's dosage requirements
An oral digoxin loading dose of approx. 1.0 to 1.5
mg/70 kg can be administered
Maintenance dose of 0.25 mg/ day
Because it has a relatively long elimination half-
life; digoxin tablets are given once daily
    Serum Concentration-response
           Relationship
< 0.5 micrograms/litre: no clinical effect

0.7 micrograms/litre: some positive inotropic and
conduction blocking effects

0.8-2 micrograms/litre: optimum therapeutic range

2-2.5 micrograms/litre: increased risk of toxicity, although
tolerated in some patients

> 2.5 micrograms/litre: gastrointestinal, cardiovascular
system and central nervous system toxicity
                 Distribution
Digoxin is widely distributed and extensively
bound in varying degrees to tissues throughout the
body
This results in a high apparent volume of
distribution
Digoxin volume of distribution can be estimated
using the equation: 7.3 l/kg (lean body weight
(BWt)) which is derived from population data
Distribution is altered in patients with renal
impairment, and a more accurate estimate in these
patients is given by:



                           (298)(ClCr as ml/min)
Vd Digoxin
 (L/70kg) =      226   +
                            29 + ClCr as ml/min
A two-compartment model best
describes digoxin disposition with a
distribution time of 6-8 hours
Clinical effects are seen earlier after intravenous
doses, since the myocardium has a high blood
perfusion and affinity for digoxin
Sampling for TDM must be done no sooner than 6
hours post-dose, otherwise an erroneous result will
be obtained
Factors affecting Vd
                 Elimination
Digoxin is eliminated primarily by renal excretion
of unchanged drug (60-80%), but some hepatic
metabolism occurs (20-40%)
The population average value for digoxin clearance
is:

digoxin clearance (ml/min) (non CHF) =
    0.8 x BWt + (creatinine clearance
               (ml/min))
However, patients with severe congestive heart
failure have a reduced hepatic metabolism and a
slight reduction in renal excretion of digoxin:

digoxin clearance (ml/min) (CHF) =
0.33 x BWt + (0.9 x creatinine clearance
               (ml/min))
Lean body weight should be used in these
equations
Cl CHF(mL/min) =
 (0.33 mL/kg/ min) (Weight in kg) +
        (0.9)(Clcr as mL/min)
                   Absorption
Digoxin is poorly absorbed from the
gastrointestinal tract, and dissolution time affects the
overall bioavailability
The two oral formulations of digoxin have
different bioavailabilities:
           F (tablets) =0.65
           F (liquid) = 0.8
Oral bioavailability (F) ranges from 0.5 - 0.9
(average ~ 0.70)
Food decreased rate, but not extent, of absorption.
F is decreased with co-administration with:-
           - Charcoal
           - Antacids
           - Cholestyramine
           - Kaolin-pectin
           - Metoclopramide
                     Half-life
t1/2 is approximately two days in normal renal
function
In anephric patients, the half-life increases to
approx 4 – 6 days
           Practical implications
•Using population averages it is possible to predict serum
concentrations from specific dosages, particularly since
the time to reach the steady state is long
•Population values are only averages, and individuals
may vary
•In addition, a number of diseases and drugs affect
digoxin disposition
•As can be seen from the preceding discussion,
congestive heart failure, hepatic and renal disease all
decrease the elimination of digoxin
•In addition, hypothyroidism increases the serum
concentration (decreased metabolism and renal
excretion) and increases the sensitivity of the heart to
digoxin
•Hyperthyroidism has the opposite effect
•Hypokalaemia, hypercalcaemia, hypomagnesaemia
and hypoxia all increase the sensitivity of the heart to
digoxin
•There are numerous drug interactions reported of
varying clinical significance
•The usual cause is either altered absorption or clearance
Plasma concentrations are meaningful
when obtained at least four hours after
an intravenous dose or six hours after
an oral dose
                 Time to Sample
Plasma samples for routine digoxin level monitoring are
ideally obtained 7 to 14 days after a maintenance regimen is
initiated or changed
Patients with end-stage renal disease it may take l5 to 20
days to achieve steady state
Plasma samples obtained within 24hours of an initial
loading dose may help confirm the relationship between the
digoxin plasma concentration and pharmacologic response or
establish the apparent volume of distribution
Monitoring parameters
   •Digoxin serum level
   Obtain level within 24 hours of digitalization,
   weekly until stable, and at steady state
   •BUN and serum creatinine
   Measure every two days, or every day in
   unstable renal function
   •Weigh patient daily
   •Measure and monitor urine output daily
   •Monitor apical pulse daily
Special situations requiring care in
Digoxin dosage
      Age
         - Children
         - Elderly
      Renal impairment
      Electrolyte disturbance
         - Potassium
         - Magnesium
         - Calcium
         - Sodium
      Severe heart disease
      Thyroid disease
      Lung disease with hypoxaemia
      Pregnancy
Factors which predispose to digoxin toxicity:
         o Hypokalemia
         o Hypomagnesemia
         o Coronary artery disease
         o Cor pulmonale
         o Uncorrected hypothyroidism
         o Renal dysfunction
         o Interacting drugs which decrease digoxin
         clearance (quinidine, spironolactone, and
         verapamil)
Factors which predispose to suboptimal
  clinical response:
      o Hyperkalemia
      o Uncorrected hyperthyroidism
      o Interacting drugs which delay or prevent
        oral absorption (antacids, cholestyramine,
        metoclopramide)
   Factors that alter sensitivity to digoxin:
A. Electrolytes:
          Hypokalemia
          Hypomagnesemia
          Hyperkalemia (may provoke AV block)
          Hypercalcemia
B. Respiratory Acidosis
C. Hypokalemia itself is arrhythmogenic- it decreases
the ERP of purkinje cells, increases automaticicty. Digoxin and both
hypo- and hyperkalemia also depress AV nodal conduction leading to
ventricular automaticity
E. Endocrinopathy: Hypo- or Hyperthyroidism

F. Underlying Cardiac Disease: Ischemic cardiomyopathy,
   Amyloid ccardiomyopathy

G.Autonomic Tone: Increased SNSdecreased sensitivity,
   Increased PNSincreased sensitivity

H.Renal Insufficiency: Decreases digoxin clearance and
   decreases volume of distribution
I. Drugs:
INCREASE serum levels-
     Propafenone, quinidine, verapamil, amiodarone,
  erythro, tetracyline, omeprazole
VARIABLE effect on serum levels-
     Thyroxine, cyclosporine, captopril, diltiazem,
  nifedipine
DECREASE serum levels-
     Cholestyramine, antacids, kaopectate, bran,
  sulfasalazine, neomycin
             Drugs that alter Digoxin clearance
Drug                      Effect on Cp   Mechanism(s)

Spironolactone            increase       Inhibition of tubular secretion.

                                         Increased renal tubular secretion,
Amiloride                 ?
                                         decreased extrarenal clearance.

Nifedipine                increase       ?
                                         Decreased renal and extrarenal
Verapamil                 increase
                                         clearance.
Aminodarone               increase       ?

Rifampin                  decrease       ? Enhanced Metabolism.
                          increase
Diazepam                                 ? Decreased renal clearance.

                                         Reduced tissue binding, decreased
Quinidine                 increase
                                         clearance.
? Nonsteroidal            increase
                                         ? Reduced renal clearance in canines.
Antiinflammatory agents
           Drugs that alter Digoxin levels

Reduced Digoxin levels Increased Digoxin levels
                          Antibiotics (in certain
Cholestyramine
                          individuals)
Antacid gels              Quinidine

Kaolin/pectin             Quinine

Neomycin                  Hydroxychloroquine

Sulphasalazine            Aminocdarone

Para-aminosalicylic acid Verapamil
Vasodilators, eg.
                          Diltiazem
Hydralazine
Rifampicin                Frusemide

Antineoplastic            Spironolactone

                          Triamterene

                          Amiloride

                          Indomethacin
          Drugs which increase Digoxin levels
Drug                                          Expected increase in Digoxin level (%)



Antiarrhythmics Amiodarone Quinidine          100 100 - 120


Calcium antagonists Diltiazem Nifedipine
                                              20 - 60a 0 - 45b 70
Verapamil


Aldosterone antagonist Spironolactone         35


a This interaction is highly variable with a mean increase of 30% (Chaffman & Brogden
1985). b This interaction is controversial. The likelihood of clinically significant
interaction is low (Freedman 1986).
Digoxin dosing flow chart
A.Initial dosing

  1. Estimate Volume of Distribution (Jusko
  Equation)
  Vd = 226 + [(298 x CrCl) / (29.1 +
  CrCl)] x (BSA / 1.73)
  where CrCl = normalized creatinine clearance
  (ml/min)
  BSA = Body surface area (square meters)
2. Calculate Loading Dose
LD = Vd x Cp/F.S

Where;
Vd = Volume of distribution (liters)
Cp = target serum level (mcg/l)
F = bioavailability factor;
     •IV Push = 1
     •Capsules= 0.95
     •Elixir = 0.8
     •Tablets = 0.75
Loading doses are always administered in divided
doses so that the patient can be evaluated for toxicity
and efficacy in the course of receiving the total
loading dose
If the patient appears to develop toxicity, the
remainder of the calculated dose is withheld
The procedure is to give one-half of the calculated
loading dose initially, followed by one-fourth in
six hrs; the remaining fourth is administered six
hrs after the second dose
Six hrs is the usual interval between doses since it is
the approximate time required for Digoxin to be
absorbed and distributed
Even following an IV injection, two to four hrs are
required for a single dose of Digoxin to exhibit its
full effect
3. Estimate Clearance (Koda-Kimble)
Cl = [(A x CrCl) + B] x C
Where;
A = 0.88, for patient with Acute CHF,
otherwise=1
B = 23, for patient with Acute CHF,
otherwise=40
Otherwise means not Acute CHF
C = correction factor for interacting drugs;
     Quinidine = 0.65
     Spironolactone = 0.75
     Verapamil = 0.7
4. Calculate Maintenance Dose
MD = (Cl x Cp x tau) / F

Where;
Cl = Clearance (liters/hour)
Cp = target serum level (mcg/l)
tau = dosing interval (hours)
F = bioavailability factor
5. Estimate steady-state trough level

Cpss = (MD x F) / (Cl x tau)

Where;
MD = Maintenance dose (mcg)
F = bioavailability factor
Cl = Clearance (liters/hour)
tau = dosing interval (hours)
B. Adjust maintenance dose
 1. Estimate Volume of Distribution (Jusko
 Equation)
2. Calculate digoxin clearance

Cl = [(MD x F) / Cp] / tau
Where;
MD = Maintenance dose (mcg)
 F = Bioavailability factor
 Cp = Actual steady-state serum digoxin
 concentration (mcg/l)
 tau = Dosing interval (hours)
3. Calculate Maintenance Dose

MD = (Cl x Cp x tau) / F.S

Where
  Cl = Digoxin clearance (l/hr)
  Cp = target serum level (mcg/l)
  tau = dosing interval (hours)
  F = bioavailability factor
The following equation could be used to
adjust the dose after checking the
plasma concentration
        Dnew = Dold /(Css. new/ Css. old)
4. Estimate steady-state trough level
  Cpss = (MD x F) / (Kel x Vd x
  tau)
Where;
 MD = Maintenance dose (mcg)
  F = bioavailability factor
  Kel = Elimination rate (1/hours)
  Vd = Volume of distribution (liters)
  tau = dosing interval (hours)


                  Cl
            Kel =
                  Vd
 Clinical Toxicity:
 Toxic effects occur at levels 2 to 3 times those
considered therapeutic, though most data involves
patients with target levels between 1.0 and 2.0 ng/ml
  In large studies, the incidence of clinical toxicity at
therapeutic levels varies between ~1% and 6%
  Hypokalemia is the greatest factor predisposing to
toxicity at levels below 2 ng/ml
  In the presence of subtherapeutic levels, digoxin
toxicity is a diagnosis of exclusion
Non-cardiac symptoms-
Fatigue, blurred vision, disturbed color perception,
anorexia, nausea, vomiting, diarrhea, abdominal
pain, headache, dizzyness, confusion, delirium, and
hallucinations
Massive overdose can lead to hyperkalemia (Na+-
K+-ATPase inhibition impairs K+ entry into cells)
The mortality associated with digoxin toxicity is due
to adverse cardiac effects
Cardiac findings-
1) Increased Ectopy
-frequent VPCs or Bigeminy, or more concerning VT
or VF
-Bidirectional VT (can be confused with Bigeminy)
with alternating polarity (should always raise
suspicion of dig toxicity)
-AV junctional rhythms (escape rate if <50-60 bpm,
accelerated JR if 60-120 bpm)
2) Enhanced Vagal Activity
-Sinus Bradycardia
-1st degree AVB
-2nd degree AVB- Wenckebach, Mobitz type I (Mobitz
type II is VERY rarely 2nd to digoxin toxicity)
-3rd degree AVB
-A-fib and A-flutter are VERY rarely/never caused by
digoxin toxicity though they may be associated with
some degree of AVB and possibly a junctional or
ventricular escape rhythm
3) Increased Ectopy and Enhanced Vagal Activity
-Atrial Tachycardia plus AV block, AV nodal
Wenckebach
Symptoms and signs of digitalis
intoxication:
Cardiac:
     - Brady- and tachyarrhythmias
     - Worsening cardiac failure
Gastrointestinal:
     - Anorexia
     - Nausea, vomiting
     - Diarrhoea
     - Abdominal pain
Neurological:
     - Fatigue, malaise
     - Headache
     - Drowsiness
     - Neuralgic pain
     - Convulsions
     - Aphasia
Vision:
     - Blurred vision
     - Altered colour vision
     - Amblyopia, diplopia
     - Ascotomata
Psychiatric:
     - Confusion
     - Delirium
     - Hallucinations
Other:
     - Gynaecomastia
     - Skin rashes
 Treatment of toxicity:
  · Dosage adjustment and clinical monitoring for
noncardiovascular effects and cardiovascular effects
such as slow ventricular response in atrial
fibrillation, frequent junction beats or ventricular
ectopy, 1st degree AVB and accelerated junctional
rhythm
  · Temporary pacing and atropine may be needed for
sinus arrest or exit block, 2nd or 3rd degree AVB.
  · Potassium (even with a normal K+)
supplementation for atrial, AV and ventricular
ectopic rhythms
· Magnesium supplementation useful especially in A-
fib with rapid ventricular response via accessory
pathway
· Antiarrhythmic therapy with lidocaine or phenytoin
for worsening ventricular rhythms
· Electrical cardioversion can precipitate malignant
rhythm disturbances in the setting of digoxin toxicity
and should be used with caution
· In overdose situations, activated charcoal should be
given if within 6 to 8 hours.
· Hemodialysis and hemoperfusion are of limited
utility in removing digoxin. Though there is an
experiemental technique using Digoxin-specific Fab-
coated beads in hemofiltration column
                                        Examples
A 50 year old male patient (70kg) with heart failure and renal impairment (serum creatinine 0.44 mmol/L)
is to be commenced on Digoxin:-
(i) Estimate the oral daily dose that would maintain the average Digoxin plasma concentration at 1.5ng/ml.
(ii) How long will it take to achieve steady-state levels?
Suggest an oral loading dose protocol for this patient?




A 62 year old woman weighing 45kg was admitted to the hospital for possible Digoxin toxicity.
Her serum creatinine was 0.17mmol/L and her dosing regimen at home was 0.25mg Digoxin
daily for many months, for heart failure.
The Digoxin plasma concentration on admission was reported to be 3.5ng/ml.
(i) How long will it take for the Digoxin level to fall from 3.5 to 2.0 ng/ml?
(ii) How do the patient’s actual and predicted clearances of Digoxin compare?
(iii) What daily dose should she receive to maintain an average plasma level of 1.5ng/ml
Use of Digoxin-Specific Antibody Fragments:
·    Antibody Fab fragments purified from sheep IgG bind to circulating digoxin.
         Fab affinity for digoxin > Na-K-ATPase affinity for digoxin 
                                   Rapid decrease in extracellular [Digoxin] and efflux of digoxin out of cells
                       Fab-Digoxin complexes are rapidly excreted by kidneys- elimation T1/2 15-20 hours
·     Dosing-
Each vial contains 40mg of Digoxin-Specific Fab that neutralizes 0.6mg of digoxin
Acute Ingestion Dose (# Vials) = [Ingested Dose (mg) x 0.8]/0.6
Chronic Ingestion Dose (# Vials) = [serum level (ng/ml) x weight (kg)]/100
                                   Infuse in 0.9% saline over 15-30”; repeat if necessary
Serum Digoxin levels are inaccurate for 2 weeks after dosing




 ·       Indications-
 Ø       Life-threatening arrhythmia (VT, VF, progressive bradycardia, high-degree AVB)
 Ø       Serum Digoxin >10 ng/ml
 Ø       Large Ingestion (10 mg in adults, 4 mg in children)