Download Theophylline & Digoxin - Cleveland Clinic Hospital

Theophylline &
Digoxin
Chapt. 173-174
February 16, 2005
Dr. Kranitz
slides by
Scott Gunderson PGY-2
Theophylline
Theophylline

Narrow therapeutic window


Toxic range considered > 20 µg/ml
In 2000
1146 exposures to aminophylline/theophylline
 18 deaths



Most overexposures are unintentional in adults
Toxicity may result in cardiac, neurologic, and
metabolic abnormalities
Pharmacology

Mechanism of action not completely
understood

Traditional theory


Inhibition of phosphodiesterase which converts cAMP
to AMP
Other theories include alterations in

Binding of cAMP, cGMP phosphodiesterase inhibition,
prostaglandin antagonism, intercellular calcium, or
catecholamine release.
Pharmacology
Ca++
(Contracts
Smooth Muscle)
+ Calmodulin
MLCKInactive
AMP
cAMP (Relaxes Smooth Muscle)
phosphodiesterase
cAMP-PKAActive
MLCK-P
Ca4++- Calmodulin
Inactive and
Ca++-Calmodulin
Insensitive
ATP
Ca4++-Calmodulin-MLCKactive
ATP
Actin-Myosin-LC
Actin + Myosin-LC
(Relaxed)
P
Myosin Light Chain
Phosphatase
Head Detachment
Recock Head 90o
Cross
Bridge
Cycling
ATP
ADP + Pi
Power Stroke
Actin-Myosin-LCP
ADP-P
http://www.ursa.kcom.edu/LectStreams/Other/DesMoines/SmMuscle_DesMoines_files/
frame.htm#slide0032.htm
Pharmacology

Orally absorbed
peak levels in 90 – 120 minutes
 Enteric or SR peak in 6 - 8 hours
 Daily preparations have erratic peaks


IV
Peak within 30 minutes
 Not useful for acute exacerbations in adults, but may
have a role for children


IM and PR

Not recommended
Pharmacology


60% protein bound
Metabolism
85-90% hepatic P450 system
 10-15% urinary excretion




First order elimination kinetics
T1/2 is 4-8 hours
Brochodilation at 15 µg/ml
Pharmacology

Elimination affected by:


Cigarette use, diet, P450 meds
Theophylline acts as an adenosine antagonist
and may interfere with pharmacologic stress
tests
Toxic effects

Cardiovascular, neurologic, metabolic, and GI
toxic effects

Symptoms do not always correlate to serumlevel

Life threatening effects may occur with out
warning
Cardiovascular

Atrial automaticity increases
Sinus tachycardia, PAC’s, atrial tachycardia, MAT,
atrial fibrillation, atrial flutter
 All occur more frequently with levels greater than 20
µg/ml


Ventricular automaticity increases
PVC’s and self-limited ventricular tachycardia
 Sustained V-tach

Elderly may occur at levels of 40-60 µg/ml
 Young intentional overdoses may go over 100 µg/ml
without life threatening cardiac events


Hypotension
Neurologic

Side effects including therapeutic levels


Agitation, headache, irritability, sleeplessness,
tremors, muscular twitching
Toxic levels

Seizures, hallucinations, psychosis
Seizures

Generalized tonic clonic and focal seizures

Incidence increases with higher levels


Seizures at lower levels correlate to a possible
neurologic causes
Epileptics are particularly susceptible to
theophylline induced seizures
Metabolic

Dose dependent rise in circulating
catecholamines


Increases glucose, free fatty acids, insulin, and
WBC’s
Hypokalemia
Inversely proportional to theophylline level
 May be compounded by hypokalemia from betaagonists

Gastrointestinal

Nausea and vomiting
Direct CNS effect
 Most frequent and usually earliest symptom
 25% of patients with levels greater than 20 µg/ml


GERD, GI bleeding, and epigastric pain may
also occur
Treatment

Gastric emptying with lavage
Ingestion within 1-2 hours
 Not indicated if dose will not put level over 30
µg/ml (appox. 10 mg/kg)


Avoid ipecac


Lowers seizure threshold
Activated charcoal
Multiple dose
 Initial dose is 1gm/kg
 Repeat dose at 2 and 4 hours at 1gm/kg up to
50gms

Treatment

Cathartics
Enhance passage
 Sorbitol solution 70%, 100cc with charcoal


Antiemetics
Ranitidine 50 mg IV
 Metoclopramide 0.5-1.0 mg/kg


Whole bowel irrigation

Controversial
Treatment

Hemodialysis
Indicated for life threatening levels
 Controversial at high levels without significant
adverse reactions


Hemoperfusion
Charcoal hemoperfusion with hemodialysis increases
elimination rate.
 Recent studies indicate that complication rate is
higher and adds little clinical efficacy

Treatment

Hypotension
Treat with fluids and pressers
 Phenylephrine may also be used
 Beta-blockers – particularly propranolol reverses the
vasodilatation


Cardiac arrhythmias
Beta-blockers, verapamil, digoxin, lidocaine
 Adenosine for SVT


Caution due to adenosine induced bronchospasm
Treatment

Seizures

Standard seizure medications
Benzodiazepines first line
 Barbiturates second line

Disposition

Serum levels
Do not correlate well with toxicity in chronic
exposures
 Acute exposures have a more predictable course


Elderly patients with comorbidities are at
increased risk
Disposition
History of seizures or
ventricular dysrhythmias
Monitor until normal levels
Level < 25 µg/ml and
minor symptoms
Discontinue medication and
discharge
Levels > 30 µg/ml
Treat with activated charcoal
and admit
Levels > 40 µg/ml in elderly Consider hemoperfusion
or > 100 µg/ml in younger and/or hemodialysis in
patients
addition and admit
Prevention

Toxicity only rarely intentional

Patients being started on cimetidine, macrolides,
or fluoroquinolones should reduce the
theophylline dose by 25%

Loading doses based on the initial theophylline
level
Digitalis
Epidemiology


Used for centuries for SVT and CHF
Digitalis glycosides found in



Foxglove, oleander, lily of the valley
Potentially fatal dysrhythmias
In 2001
2977 overexposures to cardiac glycosides
 652 (22%) had moderate to major morbidity
 13 (0.4%) died

Name the Plant
Lilly of the Valley
Oleander
http://www.huntingtonbotanical.org/Shakespeare/photogallery.htm
http://biology.clc.uc.edu/graphics/steincarter/florida/
http://www.dososos.com/availability_photos/lily_valley.html
Foxglove
Pharmacology

Digoxin – most commonly used digitalis
preparation
Rapid absorption
 Primarily renal excretion


Mechanism of action
Inactivation of the Na+K+ATPase pump
 When inactivated cell uses sodium-calcium
exchanger increasing intracellular calcium

Pharmacology

Increases vagal tone


Toxic doses often cause bradydysrhythmias
Automaticity increased

Due to delayed conduction of the electrical system
Clinical Features

Nonspecific cardiac dysrhythmias
May be life threatening
 Any dysrhythmia or junctional escape rhythm with
an AV block consider digoxin toxicity
 PVC’s



Frequent PVC’s are the most common dysrhythmia
Bi-directional V-tach

Rare, but relatively specific for digitalis toxicity
Digitalis Effect
http://www.emedu.org/ecg/voz.php
Digoxin Toxic Dysrhythmias

Bradycardia with AV block
Digoxin Toxic Dysrhythmias

Second degree AV block, Type I – Wenckebach

Atrial tachycardia with AV block
Digoxin Toxic Dysrhythmias

A. Fib with a regular ventricular rate

PVC’s
http://www.tchpeducation.com/General%20Interest/Digoxin%20Toxicity/digoxin_toxicity.htm
Digoxin Toxic Dysrhythmias

Ventricular Tachycardia

Bifascicular Ventricular Tachycardia
Clinical Features

Other symptoms:
Gastrointestinal
distress
 Dizziness
 Headache
 Weakness
 Syncope

Seizure
 Confusion
 Disorientation
 Delirium
 Hallucinations
 Visual changes
(yellow-green halos)

Laboratory Evaluation

Potassium
Acute poisoning of the Na+K+ATPase pump causes
elevated potassium levels
 Potassium level may be a better prognostic indicator
in acute poisoning than the digoxin level
 Potassium less elevated in chronically poisoned
patients

Laboratory Evaluation

Digoxin level

Therapeutic levels 0.5 – 2.0 ng/µl


With signs of toxicity therapeutic level does not exclude
toxicity
Acute exposures
Digoxin absorbed into the plasma then redistributed to
the tissues
 Serum levels most reliable at 6 hours


Renal and hepatic function, and electrolytes
must also be evaluated.
Acute vs. Chronic

Acute





Asymptomatic for several
hours
GI symptoms often occur
first
Bradydysrhythmias or
supraventricular with AV
block
Severity correlates with
K+ not with digoxin level
High digoxin level

Chronic





Elderly on digoxin and
diuretics
May mimic influenza or
gastroenteritis
Mental status change
Many dysrhythmias, but
ventricular more common
than in acute
K+ often low and digoxin
is a poor predictor
Chronic Toxicity





Elderly on digoxin and diuretics
May mimic influenza or gastroenteritis
Mental status change
Many dysrhythmias, but ventricular more
common than in acute
K+ often low and digoxin is a poor predictor
Differential Diagnosis

Bradydysrhythmias
Calcium channel blockers overdoses
 Beta-blockers overdoses
 Class IA antidysrhythmic overdoses
 Clonidine overdoses
 Organophosphate poisoning
 Cardiotoxic plants
 Sinus node disease

Factors Enhancing Toxicity

Electrolyte abnormalities
Hypokalemia, hypomagnesemia, and hypercalcemia
 Cardiac hypersensitivity with myocardial disease or
ischemia
 Decreased renal, hepatic, or thyroid function
 Drugs


Antidysrhythmic, spironolactone, indomethacin,
clarithromycin, erythromycin
ED Care


Remember in acute ingestion may be initially
asymptomatic
Initiate


Continuous cardiac monitoring, IV’s, frequent
reevaluations
Extended observation at least 12 hours
Dysrhythmia Treatment




ABC’s
Correct hypoxia, hypoglycemia, and electrolytes
Atropine and cardiac pacing
Antidysrhythmias

Lidocaine and phenytoin




Both decrease ventricular automaticity
Phenytoin increases conduction through AV node therefore often
considered the DOC for bradydysrhythmias
Bretylium shown clinical use but animal studies do not
support it.
Class IA antidysrhythmics are contraindicated as they slow
AV nodal conduction
Dysrhythmia Treatment

Electrocardioversion


May induce ventricular fibrillation so only as last
resort
Digoxin specific Fab fragment is the treatment
of choice for life-threatening dysrhythmias that
do not respond to conventional therapy
Dysrhythmia Treatment

Hyperkalemia
Glucose, insulin, and sodium bicarbonate
 Potassium-binding resins
 Avoid Calcium


Calcium may promote cardiac toxicity
GI Decontamination & Elimination


Activated charcoal
Gastric lavage


Not routinely recommended as it may increase vagal
tone
Ipecac, cathartics, diuresis, hemodialysis,
hemoperfusion

No role in increasing elimination
Digoxin-Specific Fab Antibody
Sheep IgG antibody to digoxin
Remove digoxin from plasma and tissue
Clinical improvement within 1 hour in 90% of
patients
Indications




1.
2.
3.
Ventricular dysrhythmias
Unresponsive hemodynamically significant
bradydysrhythmias
Hyperkalemia > 5.5 mEq/L with suspected digoxin toxicity
Digoxin-Specific Fab Antibody

Adverse effects
Cardiogenic shock reported in patients dependent
on digoxin for inotropic support
 Increased ventricular response to A. Fib
 Hypokalemia from rapid digoxin removal
 Rare hypersensitivity reactions

Digoxin-Specific Fab Antibody

Dosage

Calculate total body load

Based on amount ingested


Based on digoxin concentration


Total body load = amount ingested x 0.8
[Digoxin level (ng/mL) x 5.6L/kg x weight (kg)] / 1000
Calculate number of vials
Digibind vials (40mg) required = total body load/0.6
 DigiFab vials (40mg) required = total body load/0.5

Digoxin-Specific Fab Antibody

Digoxin levels
Most lab assays measure both bound and unbound
digoxin
 Free digoxin will go to zero minutes after infusion
 Total serum digoxin level increases 10-20 times


Complex is eliminated by renal excretion
Disposition

Admit all patient with signs of toxicity or a large
ingested dose to monitored floor

Contact poison control for further help

All patients receiving Fab should go the ICU
References


Tintinalli, Judith E., Emergency Medicine a Comprehensive Study Guide.
Sixth edition. McGrw-Hill Companies, Inc. 2004. Chapter 173-174.
Theophylline & Digitalis Glycosides. Pages 1098-1105.
Bear’s Physiology Site. Kirksville College of Osteopathic Medicine.
http://www.ursa.kcom.edu/LectStreams/Other/DesMoines/SmMuscle_DesMoines_
files/frame.htm#slide0032.htm. Accessed February 12th, 2006.
Questions
1.
Intravenous administration of theophylline is
an effective treatment in adults with acute
exacerbations of COPD or asthma. (T/F)
2.
The most common side effect of theophylline
toxicity is:
a)
b)
c)
d)
Cardiac dysrhythmias
Seizures
Hallucinations
Nausea and vomiting
Questions
3.
Digitalis works by shutting down the:
a)
b)
c)
d)
4.
Na+K+ATPase pump
Calcium pump
Calcium sodium exchanger
Hydrogen ion pump
Hyperkalemia is more common in which
digitalis toxicity
a)
b)
Acute
Chronic
Questions
5.
Which antidysrhythmic is contraindicated in
digitalis toxicity:
a)
b)
c)
d)
e)
Lidocaine
Magnesium
Amiodarone
Procainamide
Phenytoin