Transcript Digoxin - Fakultas Farmasi UNAND

Clinical Pharmacokinetics
of Digoxin
Dr. Muslim Suardi, MSi., Apt.
Faculty of Pharmacy
University of Andalas
1998
Digoxin
The primary cardiac glycoside
Possesses a low therapeutic index dosage
Individualization important
Uses
CHF
Because of its inotropic effects on the
myocardium
Atrial fibrillation/tachycardia
Because of its chronotropic effects on the
electrophysiological system of the heart
HEART FAILURE CLASS DESCRIPTION
I. Patients with cardiac disease but without limitations of
physical activity. Ordinary physical activity does not
cause undue fatigue, dyspnea, or palpitation.
II. Patients with cardiac disease that results in slight
limitations of physical activity. Ordinary physical activity
results in fatigue, palpitation, dyspnea, or angina.
• III. Patients with cardiac disease that results in marked
limitations of physical activity. Although patients are
comfortable at rest, less than ordinary activity will lead to
symptoms.
• IV Patients with cardiac disease that results in an
inability to carry on physical activity without discomfort.
Symptoms of CHF are present even at rest. With any
physical activity, increased discomfort is experienced.
Absorption
• Not usually administered im-ly due to erratic
absorption & severe pain at the injection site
• Oral BA, F, ranges from 0.5-0.9 ng/mL (Ẋ ~
0.70ng/mL).
• Absorption of oral digoxin from the GIT is
influenced by many different compounds
• Food decreased rate, but not extent, of
absorption.
Absorption
F is decreased by:
- Antacids
- Charcoal
- Cholestyramine
- Kaolin-pectin
- Metoclopramide
Vd
Vd is large due to the extensive tissue
binding of digoxin in the body
510 L in normal renal function
330 L in patients with RI.
Best described by a 2-comp model
Distribution
• The myocardium (target organ) behaves as
though it were in the tissue comp.
Since plasma samples are obtained from Vi (or
Vc), Cp of digoxin do not accurately reflect the
drug’s pharmacological effects until it is
completely distributed into both comp
• Digoxin levels obtained prior to complete
distribution are often misleading. Because the
initial Vd (Vi or Vc) is relatively small (~ 1/10 x
V), high plasma levels are commonly reported
soon after a dose is administered.
Distribution
• Because the heart behaves as though it
were in the second (tissue) comp, these
levels are not reflective of either
therapeutic or toxic effects.
Distribution
• When given as oral or iv doses, the Cp
digoxin–time curve follows a 2-comp
model & exhibits a long & large distribution
phase of 8-12h
• Therefore, plasma levels should be taken
>6h post-dose
• 20-30% bound - no clinical significance.
Elimination
• Digoxin is primarily eliminated unchanged
by the kidney ~75% in normal patient.
• So its Cl is predominately influenced by
renal function.
• The remainder of a digoxin dose (~25%) is
removed by hepatic metabolism or biliary
excretion
Metabolism
• Each metabolic step decreases the
cardioactivity of the molecule.
• Digoxin & its metabolites, are also present
in bile & entero-hepatic cycling occurs
Metabolite Activity
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•
•
•
•
Compared to Digoxin
Dihydrodigoxin
Dihydrodigoxigenin
Digoxigenin
Digoxigenin mono-digitoxiside
Digoxigenin bis-digitoxiside
2-6%
2%
4-21%
66%
77%
Clearance
• Digoxin Cl rate decreases in proportion to
CrCl, & this relationship will be utilized to
aid in the computation of initial doses
• Metabolic Cl of digoxin is 40mL/min in
normal patients.
• The presence of CHF reduces Cl to
20mL/min.
Renal Excretion
• Digoxin undergoes GF as well as both
tubular reabsorption & active secretion.
• ClCr approximates the renal Cl of Digoxin.
• ClT = ClR + Clm
• ClT = +40mL/min (without CHF)
• ClT = +20mL/min (with CHF)
Terminal t½
• Normal renal 1.6 days
• RI
3.5 - 6.0 days
Elimination Half-Live
• t½ = (0.693 X Vd)/Cl
• Because of the reduction in Vd in renal
failure & the variability of Cl, relationship
between renal function & t½ is not
perfectly clear-cut.
Plasma Level Monitoring of
Digoxin
Therapeutic range: 0.8 - 2.0ng/mL
1. There is considerable overlap & interpatient variability ie. many patients with
concentrations > 2ng/mL can tolerate
more digoxin without toxicity, while others
with concentrations below this may be
either close to or already showing toxicity.
2. Many factors can influence myocardial
sensitivity to digoxin
Monitoring
Hospitalized patients with severe or acute
heart failure may need to have Scr
determinations 2–3x weekly to monitor
renal function, while ambulatory patients
with stable heart failure may only need
yearly Scr measurements
Factors can Influence Myocardial
Sensitivity to Digoxin
1. Hypokalaemia, hypomagnesaemia,
hypothyroidism–sensitivity
2. Successful treatment of arterial fibrillation
may require digoxin level of 2.04.0ng/mL
Signs of Digitalis Intoxication
Cardiac
GI
Neurological
Vision
Psychiatric
Others
Digitalis Intoxication
Cardiac
• Brady- & tachyarrhythmia
• Worsening cardiac failure
GI
• Anorexia
• Nausea, vomiting
• Diarrhoea
• Abdominal pain
Digitalis Intoxication
Neurological
• Fatigue, malaise
• Headache, Neuralgic pain
• Drowsiness, Convulsions
• Aphasia
Vision
• Blurred vision
• Altered color vision
• Amblyopia, diplopia
• Ascotomata
Digitalis Intoxication
Psychiatric
• Confusion
• Delirium
• Hallucinations
Others
• Gynaecomastia
• Skin rashes
Factors that Influence
Myocardial Sensitivity to Digoxin
1.
2.
3.
4.
5.
6.
7.
8.
9.
Hypo & hyper-kalemia
Hypercalcemia
Hypo & hyper-magnesemia
Acid base disorders
Myocardial ischemia
Hypoxemia
Underlying heart disease
Automatic nervous system tone
Pulmonary disease
Special Situations Requiring
Care in Digoxin Dosage
1.
2.
3.
4.
5.
6.
7.
Age (children, elderly)
RI
Electrolyte disturbance (K, Mg, Ca, Na)
Severe heart disease
Thyroid disease
Lung disease with hypoxaemia
Pregnancy
When should Digoxin levels
be Monitored?
1. When standard doses would not be expected
to produce satisfactory effect without toxicity,
eg. RI, hypokalemia, hyper/hypo-thyroidism
2. When toxicity is suspected, eg. anorexia,
nausea, vomiting, confusion in the elderly,
visual disturbances or arrhythmias.
3. When compliance is in doubt.
4. When a digoxin-drug interaction is known or
suspected.
Side Effects
Most digoxin side effects involve:
• GIT
• CNS
• Cardiovascular system
GI-related Adverse Effects
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•
•
•
Anorexia
Nausea, vomiting
Diarrhea, abdominal pain
Constipation.
CNS Side Effects
Headache
Fatigue, insomnia
Confusion, vertigo
Visual disturbances are manifested as
blurred vision & changes in color vision or
colored halos around objects often times
involving the yellow-green spectrum.
GI & CNS Side Effects of
Digoxin
• Most of the GI & CNS side effects of
digoxin are nonspecific & could be caused
by many different things.
• Because of this, clinicians should pay
close attention to any new symptoms
reported by patients receiving cardiac
glycosides.
Cardiac Side Effects
Commonly include:
• Second/third degree atrioventricular block
• Atrioventricular dissociation
• Bradycardia
• Pemature ventricular contractions
• Ventricular tachycardia.
Toxic Effects of Digoxin
1. GI: Anorexia, nausea, vomiting
2. CNS: Weakness, lethargy
3. Visual: Blurred vision, yellow/green
tinting or halos, red-green color
blindness.
4. Cardiac: PVC’s heart block, ventricular
tachycardia.
Drug Interactions
Inhibition of P-glycoprotein, a drug efflux
pump which is found in the kidney, liver,
and intestine, appears to be involved in
the majority of digoxin interactions
Factors Influencing Digoxin
Cl & Plasma Levels
Renal disease.
Age (via renal function).
Other drugs.
Reduced Digoxin Levels
1.
2.
3.
4.
5.
6.
7.
8.
9.
Cholestyramine
Antacid gels
Kaolin, Pectin
Neomycin
Sulphasalazine
PAS
Vasodilators, eg. Hydralazine
Rif
Antineoplastic
Increased Digoxin Levels
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•
•
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•
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Antibiotics (in certain individuals)
Quinidine, quinine, hydroxychloroquine
Amiodarone
Verapamil
Diltiazem
Frusemide, spironolactone
Triamterene
Amiloride
Indomethacin
Mechanism of Interaction
• Quinidine decreases both the renal &
nonrenal Cl & also decreases the Vd of
digoxin.
• Verapamil, diltiazem, & bepridil inhibit
digoxin Cl & increase mean digoxin SS
concentrations by various degrees
• Amiodarone & propafenone are
antiarrhythmic agents that decrease
digoxin Cl
Drugs that Alter Digoxin Cl
• Drug
: Spironolactone
• Effect on Cp: Increasing
• Mechanism : Inhibition of tubular
secretion
• Drug
: Verapamil
• Effect on Cp: Increasing
• Mechanism : Decreased renal &
extrarenal Cl
INITIAL DOSAGE
DETERMINATION METHODS
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Pharmacokinetic dosing method:
CLEARANCE ESTIMATE
VOLUME OF DISTRIBUTION ESTIMATE
SELECTION OF APPROPRIATE
PHARMACOKINETIC MODEL AND
EQUATIONS
• STEADY-STATE CONCENTRATION
SELECTION BAYESIAN
PHARMACOKINETIC
Clinical Application of
Pharmacokinetic Data
Estimation of
MD
LD
Estimation of MD
Css = (F x DC) / (Cl x‫)ד‬
D/ ‫( = ד‬Css x Cl) / F
Digoxin Cl can be estimated:
Cl = ClCR + 40 mL/min (without CHF)
Cl = ClCR + 20 mL/min (with CHF)
Use TDM to individualize dosage more
accurately!
Estimation of LD
IV : LD = Vd x Cdesired
Oral : MD = LD (1 – e–k t)
• LD of digoxin are almost always
administered in divided doses, so that the
patient can be evaluated for toxicity &
efficacy prior to receiving the total LD.
Eg. 1/2 the calculated LD initially followed
by 1/4 in 6 hrs & the remaining 1/4 after a
further 6h.
Clinical Examples
A 50 year old male patient (70kg) with HF & RI
(SCr 0.44 mmol/L) is to be commenced on
digoxin
1. Estimate the oral daily dose that would
maintain the average digoxin Cp at 1.5ng/mL
2. How long will it take to achieve SS levels?
3. Suggest an oral LD protocol for this patient
Clinical Examples
A 62 year old woman weighing 45kg was admitted to
the hospital for possible digoxin toxicity. Her SCr was
0.17mmol/L & her dosing regimen at home was 0.25mg
digoxin daily for many months, for HF.
Digoxin Cp on admission was reported to be 3.5ng/mL.
1. How long will it take for the digoxin level to fall from 3.5
to 2.0 ng/mL?
2. How do the patient’s actual & predicted Cl of digoxin
compare?
3. What daily dose should she receive to maintain an
average Cp of 1.5ng/mL.
Terminology
Lethargy = keadaan mengantuk/tdk peduli
Yellow/green tinting or halos =
PVC’s heart block =
Ventricular tachycardia
Delirium = gangguan mental
Hallucinations = persepsi sensorik tanpa adanya
sumber dalam dunia luar
Gynaecomastia = perkembangan berlebihan
kelenjar susu lelaki