Theophylline & Digoxin Chapt February 16, 2005 Dr. Kranitz slides by Scott Gunderson PGY-2

Theophylline

Theophylline Narrow therapeutic window Narrow therapeutic window Toxic range considered > 20 µg/ml Toxic range considered > 20 µg/ml In 2000 In exposures to aminophylline/theophylline 1146 exposures to aminophylline/theophylline 18 deaths 18 deaths Most overexposures are unintentional in adults Most overexposures are unintentional in adults Toxicity may result in cardiac, neurologic, and metabolic abnormalities Toxicity may result in cardiac, neurologic, and metabolic abnormalities

Pharmacology Mechanism of action not completely understood Mechanism of action not completely understood Traditional theory Traditional theory Inhibition of phosphodiesterase which converts cAMP to AMP Inhibition of phosphodiesterase which converts cAMP to AMP Other theories include alterations in Other theories include alterations in Binding of cAMP, cGMP phosphodiesterase inhibition, prostaglandin antagonism, intercellular calcium, or catecholamine release. Binding of cAMP, cGMP phosphodiesterase inhibition, prostaglandin antagonism, intercellular calcium, or catecholamine release.

cAMP-PKA Active MLCK Inactive Ca Calmodulin Actin + Myosin-LC Actin-Myosin-LC P Myosin Light Chain Phosphatase Ca Calmodulin-MLCK active Cross Bridge Cycling Power Stroke ADP + P i ATP Actin-Myosin-LC P (Relaxed) Head Detachment Recock Head 90 o MLCK-P Inactive and Ca ++ -Calmodulin Insensitive cAMP (Relaxes Smooth Muscle) Ca ++ + Calmodulin (Contracts Smooth Muscle) ATP ADP-P ATP frame.htm#slide0032.htmPharmacology AMP phosphodiesterase

Pharmacology Orally absorbed Orally absorbed peak levels in 90 – 120 minutes peak levels in 90 – 120 minutes Enteric or SR peak in hours Enteric or SR peak in hours Daily preparations have erratic peaks Daily preparations have erratic peaks IV IV Peak within 30 minutes Peak within 30 minutes Not useful for acute exacerbations in adults, but may have a role for children Not useful for acute exacerbations in adults, but may have a role for children IM and PR IM and PR Not recommended Not recommended

Pharmacology 60% protein bound 60% protein bound Metabolism Metabolism 85-90% hepatic P450 system 85-90% hepatic P450 system 10-15% urinary excretion 10-15% urinary excretion First order elimination kinetics First order elimination kinetics T 1/2 is 4-8 hours T 1/2 is 4-8 hours Brochodilation at 15 µg/ml Brochodilation at 15 µg/ml

Pharmacology Elimination affected by: Elimination affected by: Cigarette use, diet, P450 meds Cigarette use, diet, P450 meds Theophylline acts as an adenosine antagonist and may interfere with pharmacologic stress tests Theophylline acts as an adenosine antagonist and may interfere with pharmacologic stress tests

Toxic effects Cardiovascular, neurologic, metabolic, and GI toxic effects Cardiovascular, neurologic, metabolic, and GI toxic effects Symptoms do not always correlate to serum- level Symptoms do not always correlate to serum- level Life threatening effects may occur with out warning Life threatening effects may occur with out warning

Cardiovascular Atrial automaticity increases Atrial automaticity increases Sinus tachycardia, PAC’s, atrial tachycardia, MAT, atrial fibrillation, atrial flutter Sinus tachycardia, PAC’s, atrial tachycardia, MAT, atrial fibrillation, atrial flutter All occur more frequently with levels greater than 20 µg/ml All occur more frequently with levels greater than 20 µg/ml Ventricular automaticity increases Ventricular automaticity increases PVC’s and self-limited ventricular tachycardia PVC’s and self-limited ventricular tachycardia Sustained V-tach Sustained V-tach Elderly may occur at levels of µg/ml Elderly may occur at levels of µg/ml Young intentional overdoses may go over 100 µg/ml without life threatening cardiac events Young intentional overdoses may go over 100 µg/ml without life threatening cardiac events Hypotension Hypotension

Neurologic Side effects including therapeutic levels Side effects including therapeutic levels Agitation, headache, irritability, sleeplessness, tremors, muscular twitching Agitation, headache, irritability, sleeplessness, tremors, muscular twitching Toxic levels Toxic levels Seizures, hallucinations, psychosis Seizures, hallucinations, psychosis

Seizures Generalized tonic clonic and focal seizures Generalized tonic clonic and focal seizures Incidence increases with higher levels Incidence increases with higher levels Seizures at lower levels correlate to a possible neurologic causes Seizures at lower levels correlate to a possible neurologic causes Epileptics are particularly susceptible to theophylline induced seizures Epileptics are particularly susceptible to theophylline induced seizures

Metabolic Dose dependent rise in circulating catecholamines Dose dependent rise in circulating catecholamines Increases glucose, free fatty acids, insulin, and WBC’s Increases glucose, free fatty acids, insulin, and WBC’s Hypokalemia Hypokalemia Inversely proportional to theophylline level Inversely proportional to theophylline level May be compounded by hypokalemia from beta- agonists May be compounded by hypokalemia from beta- agonists

Gastrointestinal Nausea and vomiting Nausea and vomiting Direct CNS effect Direct CNS effect Most frequent and usually earliest symptom Most frequent and usually earliest symptom 25% of patients with levels greater than 20 µg/ml 25% of patients with levels greater than 20 µg/ml GERD, GI bleeding, and epigastric pain may also occur GERD, GI bleeding, and epigastric pain may also occur

Treatment Gastric emptying with lavage Gastric emptying with lavage Ingestion within 1-2 hours Ingestion within 1-2 hours Not indicated if dose will not put level over 30 µg/ml (appox. 10 mg/kg) Not indicated if dose will not put level over 30 µg/ml (appox. 10 mg/kg) Avoid ipecac Avoid ipecac Lowers seizure threshold Lowers seizure threshold Activated charcoal Activated charcoal Multiple dose Multiple dose Initial dose is 1gm/kg Initial dose is 1gm/kg Repeat dose at 2 and 4 hours at 1gm/kg up to 50gms Repeat dose at 2 and 4 hours at 1gm/kg up to 50gms

Treatment Cathartics Cathartics Enhance passage Enhance passage Sorbitol solution 70%, 100cc with charcoal Sorbitol solution 70%, 100cc with charcoal Antiemetics Antiemetics Ranitidine 50 mg IV Ranitidine 50 mg IV Metoclopramide mg/kg Metoclopramide mg/kg Whole bowel irrigation Whole bowel irrigation Controversial Controversial

Treatment Hemodialysis Hemodialysis Indicated for life threatening levels Indicated for life threatening levels Controversial at high levels without significant adverse reactions Controversial at high levels without significant adverse reactions Hemoperfusion Hemoperfusion Charcoal hemoperfusion with hemodialysis increases elimination rate. Charcoal hemoperfusion with hemodialysis increases elimination rate. Recent studies indicate that complication rate is higher and adds little clinical efficacy Recent studies indicate that complication rate is higher and adds little clinical efficacy

Treatment Hypotension Hypotension Treat with fluids and pressers Treat with fluids and pressers Phenylephrine may also be used Phenylephrine may also be used Beta-blockers – particularly propranolol reverses the vasodilatation Beta-blockers – particularly propranolol reverses the vasodilatation Cardiac arrhythmias Cardiac arrhythmias Beta-blockers, verapamil, digoxin, lidocaine Beta-blockers, verapamil, digoxin, lidocaine Adenosine for SVT Adenosine for SVT Caution due to adenosine induced bronchospasm Caution due to adenosine induced bronchospasm

Treatment Seizures Seizures Standard seizure medications Standard seizure medications Benzodiazepines first line Benzodiazepines first line Barbiturates second line Barbiturates second line

Disposition Serum levels Serum levels Do not correlate well with toxicity in chronic exposures Do not correlate well with toxicity in chronic exposures Acute exposures have a more predictable course Acute exposures have a more predictable course Elderly patients with comorbidities are at increased risk 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 or > 100 µg/ml in younger patients Consider hemoperfusion and/or hemodialysis in addition and admit

Prevention Toxicity only rarely intentional Toxicity only rarely intentional Patients being started on cimetidine, macrolides, or fluoroquinolones should reduce the theophylline dose by 25% Patients being started on cimetidine, macrolides, or fluoroquinolones should reduce the theophylline dose by 25% Loading doses based on the initial theophylline level Loading doses based on the initial theophylline level

Digitalis

Epidemiology Used for centuries for SVT and CHF Used for centuries for SVT and CHF Digitalis glycosides found in Digitalis glycosides found in Foxglove, oleander, lily of the valley Foxglove, oleander, lily of the valley Potentially fatal dysrhythmias Potentially fatal dysrhythmias In 2001 In overexposures to cardiac glycosides 2977 overexposures to cardiac glycosides 652 (22%) had moderate to major morbidity 652 (22%) had moderate to major morbidity 13 (0.4%) died 13 (0.4%) died

Name the Plant Lilly of the ValleyOleanderFoxglove

Pharmacology Digoxin – most commonly used digitalis preparation Digoxin – most commonly used digitalis preparation Rapid absorption Rapid absorption Primarily renal excretion Primarily renal excretion Mechanism of action Mechanism of action Inactivation of the Na + K + ATPase pump Inactivation of the Na + K + ATPase pump When inactivated cell uses sodium-calcium exchanger increasing intracellular calcium When inactivated cell uses sodium-calcium exchanger increasing intracellular calcium

Pharmacology Increases vagal tone Increases vagal tone Toxic doses often cause bradydysrhythmias Toxic doses often cause bradydysrhythmias Automaticity increased Automaticity increased Due to delayed conduction of the electrical system Due to delayed conduction of the electrical system

Clinical Features Nonspecific cardiac dysrhythmias Nonspecific cardiac dysrhythmias May be life threatening May be life threatening Any dysrhythmia or junctional escape rhythm with an AV block consider digoxin toxicity Any dysrhythmia or junctional escape rhythm with an AV block consider digoxin toxicity PVC’s PVC’s Frequent PVC’s are the most common dysrhythmia Frequent PVC’s are the most common dysrhythmia Bi-directional V-tach Bi-directional V-tach Rare, but relatively specific for digitalis toxicity Rare, but relatively specific for digitalis toxicity

Digitalis Effect

Digoxin Toxic Dysrhythmias Bradycardia with AV block Bradycardia with AV block

Digoxin Toxic Dysrhythmias Second degree AV block, Type I – Wenckebach Second degree AV block, Type I – Wenckebach Atrial tachycardia with AV block Atrial tachycardia with AV block

Digoxin Toxic Dysrhythmias A. Fib with a regular ventricular rate A. Fib with a regular ventricular rate PVC’s PVC’s

Digoxin Toxic Dysrhythmias Ventricular Tachycardia Ventricular Tachycardia Bifascicular Ventricular Tachycardia Bifascicular Ventricular Tachycardia

Clinical Features Other symptoms: Other symptoms: Gastrointestinal distress Gastrointestinal distress Dizziness Dizziness Headache Headache Weakness Weakness Syncope Syncope Seizure Confusion Disorientation Delirium Hallucinations Visual changes (yellow-green halos)

Laboratory Evaluation Potassium Potassium Acute poisoning of the Na + K + ATPase pump causes elevated potassium levels 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 level may be a better prognostic indicator in acute poisoning than the digoxin level Potassium less elevated in chronically poisoned patients Potassium less elevated in chronically poisoned patients

Laboratory Evaluation Digoxin level Digoxin level Therapeutic levels 0.5 – 2.0 ng/µl Therapeutic levels 0.5 – 2.0 ng/µl With signs of toxicity therapeutic level does not exclude toxicity With signs of toxicity therapeutic level does not exclude toxicity Acute exposures Acute exposures Digoxin absorbed into the plasma then redistributed to the tissues Digoxin absorbed into the plasma then redistributed to the tissues Serum levels most reliable at 6 hours Serum levels most reliable at 6 hours Renal and hepatic function, and electrolytes must also be evaluated. Renal and hepatic function, and electrolytes must also be evaluated.

Acute vs. Chronic Acute Acute Asymptomatic for several hours Asymptomatic for several hours GI symptoms often occur first GI symptoms often occur first Bradydysrhythmias or supraventricular with AV block Bradydysrhythmias or supraventricular with AV block Severity correlates with K + not with digoxin level Severity correlates with K + not with digoxin level High 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 Elderly on digoxin and diuretics May mimic influenza or gastroenteritis May mimic influenza or gastroenteritis Mental status change Mental status change Many dysrhythmias, but ventricular more common than in acute Many dysrhythmias, but ventricular more common than in acute K + often low and digoxin is a poor predictor K + often low and digoxin is a poor predictor

Differential Diagnosis Bradydysrhythmias Bradydysrhythmias Calcium channel blockers overdoses Calcium channel blockers overdoses Beta-blockers overdoses Beta-blockers overdoses Class IA antidysrhythmic overdoses Class IA antidysrhythmic overdoses Clonidine overdoses Clonidine overdoses Organophosphate poisoning Organophosphate poisoning Cardiotoxic plants Cardiotoxic plants Sinus node disease Sinus node disease

Factors Enhancing Toxicity Electrolyte abnormalities Electrolyte abnormalities Hypokalemia, hypomagnesemia, and hypercalcemia Hypokalemia, hypomagnesemia, and hypercalcemia Cardiac hypersensitivity with myocardial disease or ischemia Cardiac hypersensitivity with myocardial disease or ischemia Decreased renal, hepatic, or thyroid function Decreased renal, hepatic, or thyroid function Drugs Drugs Antidysrhythmic, spironolactone, indomethacin, clarithromycin, erythromycin Antidysrhythmic, spironolactone, indomethacin, clarithromycin, erythromycin

ED Care Remember in acute ingestion may be initially asymptomatic Remember in acute ingestion may be initially asymptomatic Initiate Initiate Continuous cardiac monitoring, IV’s, frequent reevaluations Continuous cardiac monitoring, IV’s, frequent reevaluations Extended observation at least 12 hours Extended observation at least 12 hours

Dysrhythmia Treatment ABC’s ABC’s Correct hypoxia, hypoglycemia, and electrolytes Correct hypoxia, hypoglycemia, and electrolytes Atropine and cardiac pacing Atropine and cardiac pacing Antidysrhythmias Antidysrhythmias Lidocaine and phenytoin Lidocaine and phenytoin Both decrease ventricular automaticity Both decrease ventricular automaticity Phenytoin increases conduction through AV node therefore often considered the DOC for bradydysrhythmias Phenytoin increases conduction through AV node therefore often considered the DOC for bradydysrhythmias Bretylium shown clinical use but animal studies do not support it. Bretylium shown clinical use but animal studies do not support it. Class IA antidysrhythmics are contraindicated as they slow AV nodal conduction Class IA antidysrhythmics are contraindicated as they slow AV nodal conduction

Dysrhythmia Treatment Electrocardioversion Electrocardioversion May induce ventricular fibrillation so only as last resort 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 Digoxin specific Fab fragment is the treatment of choice for life-threatening dysrhythmias that do not respond to conventional therapy

Dysrhythmia Treatment Hyperkalemia Hyperkalemia Glucose, insulin, and sodium bicarbonate Glucose, insulin, and sodium bicarbonate Potassium-binding resins Potassium-binding resins Avoid Calcium Avoid Calcium Calcium may promote cardiac toxicity Calcium may promote cardiac toxicity

GI Decontamination & Elimination Activated charcoal Activated charcoal Gastric lavage Gastric lavage Not routinely recommended as it may increase vagal tone Not routinely recommended as it may increase vagal tone Ipecac, cathartics, diuresis, hemodialysis, hemoperfusion Ipecac, cathartics, diuresis, hemodialysis, hemoperfusion No role in increasing elimination No role in increasing elimination

Digoxin-Specific Fab Antibody Sheep IgG antibody to digoxin Sheep IgG antibody to digoxin Remove digoxin from plasma and tissue Remove digoxin from plasma and tissue Clinical improvement within 1 hour in 90% of patients Clinical improvement within 1 hour in 90% of patients Indications Indications 1. Ventricular dysrhythmias 2. Unresponsive hemodynamically significant bradydysrhythmias 3. Hyperkalemia > 5.5 mEq/L with suspected digoxin toxicity

Digoxin-Specific Fab Antibody Adverse effects Adverse effects Cardiogenic shock reported in patients dependent on digoxin for inotropic support Cardiogenic shock reported in patients dependent on digoxin for inotropic support Increased ventricular response to A. Fib Increased ventricular response to A. Fib Hypokalemia from rapid digoxin removal Hypokalemia from rapid digoxin removal Rare hypersensitivity reactions Rare hypersensitivity reactions

Digoxin-Specific Fab Antibody Dosage Dosage Calculate total body load Calculate total body load Based on amount ingested Based on amount ingested Total body load = amount ingested x 0.8 Total body load = amount ingested x 0.8 Based on digoxin concentration Based 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 vials Calculate number of vials Digibind vials (40mg) required = total body load/0.6 Digibind vials (40mg) required = total body load/0.6 DigiFab vials (40mg) required = total body load/0.5 DigiFab vials (40mg) required = total body load/0.5

Digoxin-Specific Fab Antibody Digoxin levels Digoxin levels Most lab assays measure both bound and unbound digoxin Most lab assays measure both bound and unbound digoxin Free digoxin will go to zero minutes after infusion Free digoxin will go to zero minutes after infusion Total serum digoxin level increases times Total serum digoxin level increases times Complex is eliminated by renal excretion Complex is eliminated by renal excretion

Disposition Admit all patient with signs of toxicity or a large ingested dose to monitored floor Admit all patient with signs of toxicity or a large ingested dose to monitored floor Contact poison control for further help Contact poison control for further help All patients receiving Fab should go the ICU All patients receiving Fab should go the ICU

References Tintinalli, Judith E., Emergency Medicine a Comprehensive Study Guide. Sixth edition. McGrw-Hill Companies, Inc Chapter Theophylline & Digitalis Glycosides. Pages Tintinalli, Judith E., Emergency Medicine a Comprehensive Study Guide. Sixth edition. McGrw-Hill Companies, Inc Chapter Theophylline & Digitalis Glycosides. Pages Bear’s Physiology Site. Kirksville College of Osteopathic Medicine. files/frame.htm#slide0032.htm. Accessed February 12 th, Bear’s Physiology Site. Kirksville College of Osteopathic Medicine. files/frame.htm#slide0032.htm. Accessed February 12 th, files/frame.htm#slide0032.htm files/frame.htm#slide0032.htm

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) Cardiac dysrhythmias b) Seizures c) Hallucinations d) Nausea and vomiting

Questions 3. Digitalis works by shutting down the: a) Na + K + ATPase pump b) Calcium pump c) Calcium sodium exchanger d) Hydrogen ion pump 4. Hyperkalemia is more common in which digitalis toxicity a) Acute b) Chronic

Questions 5. Which antidysrhythmic is contraindicated in digitalis toxicity: a) Lidocaine b) Magnesium c) Amiodarone d) Procainamide e) Phenytoin