Theophylline & Theophylline & DigoxinDigoxin

Chapt. 173-174Chapt. 173-174

February 16, 2005February 16, 2005

Dr. KranitzDr. Kranitz

slides byslides by

Scott Gunderson PGY-2Scott Gunderson PGY-2

TheophyllineTheophylline

TheophyllineTheophylline

Narrow therapeutic windowNarrow therapeutic window Toxic range considered > 20 Toxic range considered > 20 µg/mlµg/ml

In 2000In 2000 1146 exposures to aminophylline/theophylline1146 exposures to aminophylline/theophylline 18 deaths18 deaths

Most overexposures are unintentional in Most overexposures are unintentional in adultsadults

Toxicity may result in cardiac, neurologic, Toxicity may result in cardiac, neurologic, and metabolic abnormalitiesand metabolic abnormalities

PharmacologyPharmacology

Mechanism of action not completely Mechanism of action not completely understoodunderstood

Traditional theoryTraditional theory Inhibition of phosphodiesterase which Inhibition of phosphodiesterase which

converts cAMP to AMPconverts cAMP to AMP

Other theories include alterations inOther theories include alterations in Binding of cAMP, cGMP phosphodiesterase Binding of cAMP, cGMP phosphodiesterase

inhibition, prostaglandin antagonism, inhibition, prostaglandin antagonism, intercellular calcium, or catecholamine intercellular calcium, or catecholamine release.release.

cAMP-PKAActive

MLCKInactive

Ca4++- Calmodulin

Actin + Myosin-LC Actin-Myosin-LCP

Myosin Light Chain Phosphatase

Ca4++-Calmodulin-MLCKactive

Cross Bridge Cycling

Power Stroke

ADP + Pi

ATP

Actin-Myosin-LCP

(Relaxed) Head Detachment Recock Head 90o

MLCK-PInactive and Ca++-Calmodulin Insensitive

cAMP (Relaxes Smooth Muscle)

Ca++

+ Calmodulin

(Contracts Smooth Muscle)

ATP

ADP-P

ATP

http://www.ursa.kcom.edu/LectStreams/Other/DesMoines/SmMuscle_DesMoines_files/frame.htm#slide0032.htm

PharmacologyPharmacologyAMP

phosphodiesterasephosphodiesterase

PharmacologyPharmacology

Orally absorbedOrally absorbed peak levels in 90 – 120 minutespeak levels in 90 – 120 minutes Enteric or SR peak in 6 - 8 hoursEnteric or SR peak in 6 - 8 hours Daily preparations have erratic peaksDaily preparations have erratic peaks

IVIV Peak within 30 minutesPeak within 30 minutes Not useful for acute exacerbations in Not useful for acute exacerbations in

adults, but may have a role for childrenadults, but may have a role for children IM and PRIM and PR

Not recommendedNot recommended

PharmacologyPharmacology

60% protein bound60% protein bound MetabolismMetabolism

85-90% hepatic P450 system85-90% hepatic P450 system 10-15% urinary excretion10-15% urinary excretion

First order elimination kineticsFirst order elimination kinetics TT1/21/2 is 4-8 hours is 4-8 hours Brochodilation at 15 Brochodilation at 15 µg/mlµg/ml

PharmacologyPharmacology

Elimination affected by:Elimination affected by: Cigarette use, diet, P450 medsCigarette use, diet, P450 meds

Theophylline acts as an adenosine Theophylline acts as an adenosine antagonist and may interfere with antagonist and may interfere with pharmacologic stress testspharmacologic stress tests

Toxic effectsToxic effects

Cardiovascular, neurologic, Cardiovascular, neurologic, metabolic, and GI toxic effectsmetabolic, and GI toxic effects

Symptoms do not always correlate to Symptoms do not always correlate to serum-levelserum-level

Life threatening effects may occur Life threatening effects may occur with out warningwith out warning

CardiovascularCardiovascular Atrial automaticity increasesAtrial automaticity increases

Sinus tachycardia, PAC’s, atrial Sinus tachycardia, PAC’s, atrial tachycardia, MAT, atrial fibrillation, atrial tachycardia, MAT, atrial fibrillation, atrial flutterflutter

All occur more frequently with levels All occur more frequently with levels greater than 20 greater than 20 µg/mlµg/ml

Ventricular Ventricular automaticity increasesautomaticity increases PVC’s and self-limited ventricular PVC’s and self-limited ventricular

tachycardiatachycardia Sustained V-tachSustained V-tach

Elderly may occur at levels of 40-60 µg/mlElderly may occur at levels of 40-60 µg/ml Young intentional overdoses may go over 100 Young intentional overdoses may go over 100

µg/ml without life threatening cardiac eventsµg/ml without life threatening cardiac events HypotensionHypotension

NeurologicNeurologic

Side effects including therapeutic Side effects including therapeutic levelslevels Agitation, headache, irritability, Agitation, headache, irritability,

sleeplessness, tremors, muscular sleeplessness, tremors, muscular twitchingtwitching

Toxic levelsToxic levels Seizures, hallucinations, psychosisSeizures, hallucinations, psychosis

SeizuresSeizures

Generalized tonic clonic and focal Generalized tonic clonic and focal seizuresseizures

Incidence increases with higher levelsIncidence increases with higher levels Seizures at lower levels correlate to a Seizures at lower levels correlate to a

possible neurologic causespossible neurologic causes

Epileptics are particularly susceptible Epileptics are particularly susceptible to theophylline induced seizuresto theophylline induced seizures

MetabolicMetabolic

Dose dependent rise in circulating Dose dependent rise in circulating catecholaminescatecholamines Increases glucose, free fatty acids, Increases glucose, free fatty acids,

insulin, and WBC’sinsulin, and WBC’s HypokalemiaHypokalemia

Inversely proportional to theophylline Inversely proportional to theophylline levellevel

May be compounded by hypokalemia May be compounded by hypokalemia from from betabeta-agonists-agonists

GastrointestinalGastrointestinal

Nausea and vomitingNausea and vomiting Direct CNS effectDirect CNS effect Most frequent and usually earliest Most frequent and usually earliest

symptomsymptom 25% of patients with levels greater than 25% of patients with levels greater than

20 20 µg/mlµg/ml

GERD, GI bleeding, and epigastric GERD, GI bleeding, and epigastric pain may also occurpain may also occur

TreatmentTreatment

Gastric emptying with lavageGastric emptying with lavage Ingestion within 1-2 hoursIngestion within 1-2 hours Not indicated if dose will not put level Not indicated if dose will not put level

over 30 over 30 µg/ml (appox. 10 mg/kg)µg/ml (appox. 10 mg/kg) Avoid ipecacAvoid ipecac

Lowers seizure thresholdLowers seizure threshold Activated charcoalActivated charcoal

Multiple doseMultiple dose Initial dose is 1gm/kgInitial dose is 1gm/kg Repeat dose at 2 and 4 hours at 1gm/kg Repeat dose at 2 and 4 hours at 1gm/kg

up to 50gmsup to 50gms

TreatmentTreatment

CatharticsCathartics Enhance passageEnhance passage Sorbitol solution 70%, 100cc with Sorbitol solution 70%, 100cc with

charcoalcharcoal AntiemeticsAntiemetics

Ranitidine 50 mg IVRanitidine 50 mg IV Metoclopramide 0.5-1.0 mg/kgMetoclopramide 0.5-1.0 mg/kg

Whole bowel irrigationWhole bowel irrigation ControversialControversial

TreatmentTreatment

HemodialysisHemodialysis Indicated for life threatening levelsIndicated for life threatening levels Controversial at high levels without Controversial at high levels without

significant adverse reactionssignificant adverse reactions HemoperfusionHemoperfusion

Charcoal hemoperfusion with hemodialysis Charcoal hemoperfusion with hemodialysis increases elimination rate.increases elimination rate.

Recent studies indicate that complication Recent studies indicate that complication rate is higher and adds little clinical rate is higher and adds little clinical efficacyefficacy

TreatmentTreatment

HypotensionHypotension Treat with fluids and pressersTreat with fluids and pressers Phenylephrine may also be usedPhenylephrine may also be used Beta-Beta-blockers – particularly propranolol blockers – particularly propranolol

reverses the vasodilatationreverses the vasodilatation Cardiac arrhythmiasCardiac arrhythmias

Beta-Beta-blockers, verapamil, digoxin, blockers, verapamil, digoxin, lidocainelidocaine

Adenosine for SVTAdenosine for SVT Caution due to adenosine induced Caution due to adenosine induced

bronchospasmbronchospasm

TreatmentTreatment

SeizuresSeizures Standard seizure medicationsStandard seizure medications

Benzodiazepines first lineBenzodiazepines first line Barbiturates second lineBarbiturates second line

DispositionDisposition

Serum levelsSerum levels Do not correlate well with toxicity in Do not correlate well with toxicity in

chronic exposureschronic exposures Acute exposures have a more Acute exposures have a more

predictable coursepredictable course

Elderly patients with comorbidities Elderly patients with comorbidities are at increased riskare at increased risk

DispositionDispositionHistory of seizures or History of seizures or ventricular ventricular dysrhythmiasdysrhythmias

Monitor until normal Monitor until normal levelslevels

Level < 25 Level < 25 µg/ml and µg/ml and minor symptomsminor symptoms

Discontinue Discontinue medication and medication and dischargedischarge

Levels > 30 µg/mlLevels > 30 µg/ml Treat with activated Treat with activated charcoal and admitcharcoal and admit

Levels > 40 µg/ml in Levels > 40 µg/ml in elderly or > 100 elderly or > 100 µg/ml in younger µg/ml in younger patientspatients

Consider Consider hemoperfusion hemoperfusion and/or hemodialysis and/or hemodialysis in addition and admitin addition and admit

PreventionPrevention

Toxicity only rarely intentionalToxicity only rarely intentional

Patients being started on cimetidine, Patients being started on cimetidine, macrolides, or fluoroquinolones macrolides, or fluoroquinolones should reduce the theophylline dose should reduce the theophylline dose by 25%by 25%

Loading doses based on the initial Loading doses based on the initial theophylline leveltheophylline level

DigitalisDigitalis

EpidemiologyEpidemiology

Used for centuries for SVT and CHFUsed for centuries for SVT and CHF Digitalis glycosides found inDigitalis glycosides found in

Foxglove, oleander, lily of the valleyFoxglove, oleander, lily of the valley Potentially fatal dysrhythmiasPotentially fatal dysrhythmias In 2001In 2001

2977 overexposures to cardiac glycosides2977 overexposures to cardiac glycosides 652 (22%) had moderate to major 652 (22%) had moderate to major

morbiditymorbidity 13 (0.4%) died13 (0.4%) died

Name the PlantName the Plant

http://biology.clc.uc.edu/graphics/steincarter/florida/http://www.huntingtonbotanical.org/Shakespeare/photogallery.htm

http://www.dososos.com/availability_photos/lily_valley.html

Lilly of the Valley

Oleander

Foxglove

PharmacologyPharmacology

Digoxin – most commonly used Digoxin – most commonly used digitalis preparationdigitalis preparation Rapid absorptionRapid absorption Primarily renal excretionPrimarily renal excretion

Mechanism of actionMechanism of action Inactivation of the NaInactivation of the Na++KK++ATPase pumpATPase pump When inactivated cell uses sodium-When inactivated cell uses sodium-

calcium exchanger increasing calcium exchanger increasing intracellular calciumintracellular calcium

PharmacologyPharmacology

Increases vagal toneIncreases vagal tone Toxic doses often cause Toxic doses often cause

bradydysrhythmiasbradydysrhythmias Automaticity increasedAutomaticity increased

Due to delayed conduction of the Due to delayed conduction of the electrical systemelectrical system

Clinical FeaturesClinical Features

Nonspecific cardiac dysrhythmiasNonspecific cardiac dysrhythmias May be life threateningMay be life threatening Any dysrhythmia or junctional escape Any dysrhythmia or junctional escape

rhythm with an AV block consider digoxin rhythm with an AV block consider digoxin toxicitytoxicity

PVC’sPVC’s Frequent PVC’s are the most common Frequent PVC’s are the most common

dysrhythmiadysrhythmia Bi-directional V-tachBi-directional V-tach

Rare, but relatively specific for digitalis toxicityRare, but relatively specific for digitalis toxicity

Digitalis EffectDigitalis Effect

http://www.emedu.org/ecg/voz.php

Digoxin Toxic Digoxin Toxic DysrhythmiasDysrhythmias

Bradycardia with AV blockBradycardia with AV block

Digoxin Toxic Digoxin Toxic DysrhythmiasDysrhythmias

Second degree AV block, Type I – Second degree AV block, Type I – Wenckebach Wenckebach

Atrial tachycardia with AV blockAtrial tachycardia with AV block

Digoxin Toxic Digoxin Toxic DysrhythmiasDysrhythmias

A. Fib with a regular ventricular rateA. Fib with a regular ventricular rate

PVC’sPVC’s

http://www.tchpeducation.com/General%20Interest/Digoxin%20Toxicity/digoxin_toxicity.htm

Digoxin Toxic Digoxin Toxic DysrhythmiasDysrhythmias

Ventricular TachycardiaVentricular Tachycardia

Bifascicular Ventricular TachycardiaBifascicular Ventricular Tachycardia

Clinical FeaturesClinical Features

Other Other symptoms:symptoms: Gastrointestinal Gastrointestinal

distressdistress DizzinessDizziness HeadacheHeadache WeaknessWeakness SyncopeSyncope

SeizureSeizure ConfusionConfusion DisorientationDisorientation DeliriumDelirium HallucinationsHallucinations Visual changes Visual changes

(yellow-green (yellow-green halos)halos)

Laboratory EvaluationLaboratory Evaluation

PotassiumPotassium Acute poisoning of the NaAcute poisoning of the Na++KK++ATPase ATPase

pump causes elevated potassium levelspump causes elevated potassium levels Potassium level may be a better Potassium level may be a better

prognostic indicator in acute poisoning prognostic indicator in acute poisoning than the digoxin levelthan the digoxin level

Potassium less elevated in chronically Potassium less elevated in chronically poisoned patientspoisoned patients

Laboratory EvaluationLaboratory Evaluation

Digoxin levelDigoxin level Therapeutic levels 0.5 – 2.0 ng/Therapeutic levels 0.5 – 2.0 ng/µlµl

With signs of toxicity therapeutic level does With signs of toxicity therapeutic level does not exclude toxicitynot exclude toxicity

Acute exposuresAcute exposures Digoxin absorbed into the plasma then Digoxin absorbed into the plasma then

redistributed to the tissuesredistributed to the tissues Serum levels most reliable at 6 hoursSerum levels most reliable at 6 hours

Renal and hepatic function, and Renal and hepatic function, and electrolytes must also be evaluated.electrolytes must also be evaluated.

Acute vs. ChronicAcute vs. Chronic AcuteAcute

Asymptomatic for Asymptomatic for several hoursseveral hours

GI symptoms often GI symptoms often occur firstoccur first

Bradydysrhythmias Bradydysrhythmias or supraventricular or supraventricular with AV blockwith AV block

Severity correlates Severity correlates with Kwith K++ not with not with digoxin leveldigoxin level

High digoxin levelHigh digoxin level

ChronicChronic Elderly on digoxin Elderly on digoxin

and diureticsand diuretics May mimic influenza May mimic influenza

or gastroenteritisor gastroenteritis Mental status changeMental status change Many dysrhythmias, Many dysrhythmias,

but ventricular more but ventricular more common than in acutecommon than in acute

KK++ often low and often low and digoxin is a poor digoxin is a poor predictorpredictor

Chronic ToxicityChronic Toxicity

Elderly on digoxin and diureticsElderly on digoxin and diuretics May mimic influenza or May mimic influenza or

gastroenteritisgastroenteritis Mental status changeMental status change Many dysrhythmias, but ventricular Many dysrhythmias, but ventricular

more common than in acutemore common than in acute KK++ often low and digoxin is a poor often low and digoxin is a poor

predictorpredictor

Differential DiagnosisDifferential Diagnosis

BradydysrhythmiasBradydysrhythmias Calcium channel blockers overdosesCalcium channel blockers overdoses Beta-Beta-blockers overdosesblockers overdoses Class IA antidysrhythmic overdosesClass IA antidysrhythmic overdoses Clonidine overdosesClonidine overdoses Organophosphate poisoningOrganophosphate poisoning Cardiotoxic plantsCardiotoxic plants Sinus node diseaseSinus node disease

Factors Enhancing Factors Enhancing ToxicityToxicity

Electrolyte abnormalitiesElectrolyte abnormalities Hypokalemia, hypomagnesemia, and Hypokalemia, hypomagnesemia, and

hypercalcemiahypercalcemia Cardiac hypersensitivity with myocardial Cardiac hypersensitivity with myocardial

disease or ischemiadisease or ischemia Decreased renal, hepatic, or thyroid Decreased renal, hepatic, or thyroid

functionfunction DrugsDrugs

Antidysrhythmic, spironolactone, Antidysrhythmic, spironolactone, indomethacin, clarithromycin, erythromycinindomethacin, clarithromycin, erythromycin

ED CareED Care

Remember in acute ingestion may be Remember in acute ingestion may be initially asymptomaticinitially asymptomatic

InitiateInitiate Continuous cardiac monitoring, IV’s, Continuous cardiac monitoring, IV’s,

frequent reevaluationsfrequent reevaluations Extended observation at least 12 Extended observation at least 12

hourshours

Dysrhythmia TreatmentDysrhythmia Treatment

ABC’sABC’s Correct hypoxia, hypoglycemia, and Correct hypoxia, hypoglycemia, and

electrolyteselectrolytes Atropine and cardiac pacingAtropine and cardiac pacing AntidysrhythmiasAntidysrhythmias

Lidocaine and phenytoinLidocaine and phenytoin Both decrease ventricular automaticityBoth decrease ventricular automaticity Phenytoin increases conduction through AV node Phenytoin increases conduction through AV node

therefore often considered the DOC for therefore often considered the DOC for bradydysrhythmiasbradydysrhythmias

Bretylium shown clinical use but animal studies do Bretylium shown clinical use but animal studies do not support it.not support it.

Class IA antidysrhythmics are contraindicated as Class IA antidysrhythmics are contraindicated as they slow AV nodal conductionthey slow AV nodal conduction

Dysrhythmia TreatmentDysrhythmia Treatment

ElectrocardioversionElectrocardioversion May induce ventricular fibrillation so May induce ventricular fibrillation so

only as last resortonly as last resort Digoxin specific Fab fragment is the Digoxin specific Fab fragment is the

treatment of choice for life-treatment of choice for life-threatening dysrhythmias that do threatening dysrhythmias that do not respond to conventional therapynot respond to conventional therapy

Dysrhythmia TreatmentDysrhythmia Treatment

HyperkalemiaHyperkalemia Glucose, insulin, and sodium Glucose, insulin, and sodium

bicarbonatebicarbonate Potassium-binding resinsPotassium-binding resins Avoid CalciumAvoid Calcium

Calcium may promote cardiac toxicityCalcium may promote cardiac toxicity

GI Decontamination & GI Decontamination & EliminationElimination

Activated charcoalActivated charcoal Gastric lavageGastric lavage

Not routinely recommended as it may Not routinely recommended as it may increase vagal toneincrease vagal tone

Ipecac, cathartics, diuresis, Ipecac, cathartics, diuresis, hemodialysis, hemoperfusionhemodialysis, hemoperfusion No role in increasing eliminationNo role in increasing elimination

Digoxin-Specific Fab Digoxin-Specific Fab AntibodyAntibody

Sheep IgG antibody to digoxinSheep IgG antibody to digoxin Remove digoxin from plasma and tissueRemove digoxin from plasma and tissue Clinical improvement within 1 hour in Clinical improvement within 1 hour in

90% of patients90% of patients IndicationsIndications

1.1. Ventricular dysrhythmiasVentricular dysrhythmias

2.2. Unresponsive hemodynamically significant Unresponsive hemodynamically significant bradydysrhythmiasbradydysrhythmias

3.3. Hyperkalemia > 5.5 mEq/L with suspected Hyperkalemia > 5.5 mEq/L with suspected digoxin toxicitydigoxin toxicity

Digoxin-Specific Fab Digoxin-Specific Fab AntibodyAntibody

Adverse effectsAdverse effects Cardiogenic shock reported in patients Cardiogenic shock reported in patients

dependent on digoxin for inotropic dependent on digoxin for inotropic supportsupport

Increased ventricular response to A. FibIncreased ventricular response to A. Fib Hypokalemia from rapid digoxin Hypokalemia from rapid digoxin

removalremoval Rare hypersensitivity reactionsRare hypersensitivity reactions

Digoxin-Specific Fab Digoxin-Specific Fab AntibodyAntibody

DosageDosage Calculate total body loadCalculate total body load

Based on amount ingestedBased on amount ingested Total body load = amount ingested x 0.8Total body load = amount ingested x 0.8

Based on digoxin concentrationBased on digoxin concentration [Digoxin level (ng/mL) x 5.6L/kg x weight (kg)] / 1000[Digoxin level (ng/mL) x 5.6L/kg x weight (kg)] / 1000

Calculate number of vialsCalculate number of vials Digibind vials (40mg) required = total body Digibind vials (40mg) required = total body

load/0.6load/0.6 DigiFab vials (40mg) required = total body DigiFab vials (40mg) required = total body

load/0.5load/0.5

Digoxin-Specific Fab Digoxin-Specific Fab AntibodyAntibody

Digoxin levelsDigoxin levels Most lab assays measure both bound Most lab assays measure both bound

and unbound digoxinand unbound digoxin Free digoxin will go to zero minutes Free digoxin will go to zero minutes

after infusionafter infusion Total serum digoxin level increases 10-Total serum digoxin level increases 10-

20 times20 times Complex is eliminated by renal Complex is eliminated by renal

excretionexcretion

DispositionDisposition

Admit all patient with signs of toxicity Admit all patient with signs of toxicity or a large ingested dose to monitored or a large ingested dose to monitored floorfloor

Contact poison control for further Contact poison control for further helphelp

All patients receiving Fab should go All patients receiving Fab should go the ICUthe ICU

ReferencesReferences Tintinalli, Judith E., Tintinalli, Judith E., Emergency Medicine a Comprehensive Study Emergency Medicine a Comprehensive Study

Guide.Guide. Sixth edition. McGrw-Hill Companies, Inc. 2004. Chapter Sixth edition. McGrw-Hill Companies, Inc. 2004. Chapter 173-174. Theophylline & Digitalis Glycosides. Pages 1098-1105.173-174. Theophylline & Digitalis Glycosides. Pages 1098-1105.

Bear’s Physiology Site. Kirksville College of Osteopathic Bear’s Physiology Site. Kirksville College of Osteopathic Medicine. Medicine. http://www.ursa.kcom.edu/LectStreams/Other/DesMoines/SmMushttp://www.ursa.kcom.edu/LectStreams/Other/DesMoines/SmMuscle_DesMoines_files/frame.htm#slide0032.htmcle_DesMoines_files/frame.htm#slide0032.htm. Accessed February 12. Accessed February 12thth, 2006., 2006.

QuestionsQuestions

1.1. Intravenous administration of Intravenous administration of theophylline is an effective treatment theophylline is an effective treatment in adults with acute exacerbations of in adults with acute exacerbations of COPD or asthma. (T/F)COPD or asthma. (T/F)

2.2. The most common side effect of The most common side effect of theophylline toxicity is:theophylline toxicity is:

a)a) Cardiac dysrhythmiasCardiac dysrhythmiasb)b) SeizuresSeizuresc)c) HallucinationsHallucinationsd)d) Nausea and vomitingNausea and vomiting

QuestionsQuestions

3.3. Digitalis works by shutting down Digitalis works by shutting down the:the:

a)a) NaNa++KK++ATPase pumpATPase pump

b)b) Calcium pumpCalcium pump

c)c) Calcium sodium exchangerCalcium sodium exchanger

d)d) Hydrogen ion pumpHydrogen ion pump

4.4. Hyperkalemia is more common in Hyperkalemia is more common in which digitalis toxicitywhich digitalis toxicity

a)a) AcuteAcute

b)b) ChronicChronic

QuestionsQuestions

5.5. Which antidysrhythmic is Which antidysrhythmic is contraindicated in digitalis toxicity:contraindicated in digitalis toxicity:

a)a) LidocaineLidocaine

b)b) MagnesiumMagnesium

c)c) AmiodaroneAmiodarone

d)d) ProcainamideProcainamide

e)e) PhenytoinPhenytoin