Digitalis Toxicity

Cardiac GlycosidesCardiac GlycosidesDigitalisDigitalis

Dr. Ragaa DarwishDr. Ragaa Darwish Prof. Forensic Prof. Forensic Medicine &ToxicologyMedicine &Toxicology

Learning ObjectivesLearning Objectives

1. Define the nature of digitalis1. Define the nature of digitalis2. Identify sources & modes of exposure2. Identify sources & modes of exposure3.List the indications for digoxin use.3.List the indications for digoxin use.4. Recognize the pathophysiology of DT4. Recognize the pathophysiology of DT5. Identify the physical S & S of 5. Identify the physical S & S of

toxicitytoxicity.. 6. Describe initial management of 6. Describe initial management of

digitalis toxicity. digitalis toxicity.

What is a cardiac What is a cardiac glycoside ?glycoside ?It is a It is a naturally occurring drug whose naturally occurring drug whose

action includes both beneficial and action includes both beneficial and toxic effects on the heart. Cardiac toxic effects on the heart. Cardiac Glycosides areGlycosides are composed of two composed of two structural features : structural features :

-the -the sugarsugar (glycone) moiety (glycone) moiety

+ + -the -the non-sugarnon-sugar (aglycone) (aglycone)

m.m.

53

Cardiac Glycoside PlantsCardiac Glycoside Plants

Foxglove (Digitalis purpurea)

Lily of the valley (Convallaria majalis)

Oleander (Nerium oleander)

Red squill (Urginea maritima)

Yellow oleander (Thevetia peruviana)

Cardiac GlycosidesCardiac Glycosides::Digitalis purpura,lanata Digitalis purpura,lanata

OleanderOleander

Lily of valleyLily of valley

MedicationsMedications

The most common cardiac glycoside The most common cardiac glycoside

medication ismedication is :: DigoxinDigoxin from digitalis purpurafrom digitalis purpura Other active principles:Other active principles:

Digitoxin Digitoxin

from digitalis lanatafrom digitalis lanata

Digitalis Glycosides in Clinical UseDigitalis Glycosides in Clinical Use

Lipid SolubilityOral AbsorptionPlasma BindingHalf LifeRoute of Elimination

Medium High75% >90%20-40% >90%1.6 days 7 daysKidney Liver

Digoxin Digitoxin

What are the beneficial cardiac What are the beneficial cardiac effects of digoxin?effects of digoxin?

Uses: Uses: 1- 1- CCardiac tonic in HFardiac tonic in HF

Uses:Uses: 2-2- Antiarrhytmic :Antiarrhytmic : Atrial Flutter,Atrial Flutter, Atrial Atrial

FibrillationFibrillation

Atrial flutterAtrial flutter

Atrial fibrillationAtrial fibrillation

In a therapeutic dosage, the In a therapeutic dosage, the effects of digoxin include:effects of digoxin include:

• • Increased myocardial Increased myocardial contractilitycontractility

• • Decreased AV conduction rate Decreased AV conduction rate

• • Decreased heart rate Decreased heart rate

DigoxinDigoxin has the has the narrowest narrowest therapeutic rangetherapeutic range of any of any

commonly used medicationcommonly used medication

Role Preparation For NAs: Handling Medicines Calls

Narrow Therapeutic Range Drugs

CARBAMAZEPINE

CICLOSPORIN

DIGOXIN

LITHIUM

PHENYTOIN

THEOPHYLLINE

WARFARIN

Circumstances of Digoxin Circumstances of Digoxin Toxicity...Toxicity...Chronic Toxicity:Chronic Toxicity: Patients who are taking digoxin Patients who are taking digoxin

therapeutically. therapeutically.

Acute Toxicity:Acute Toxicity: Patients who have taken an overdose:Patients who have taken an overdose:

- deliberatly- deliberatly- accidentally- accidentally

- ingested a plant - ingested a plant containing card. glycosidescontaining card. glycosides

Role Preparation For NAs: Handling Medicines Calls

How medicines are handled by the body

ABSORPTION DISTRIBUTION

METABOLISM

ELIMINATION

Kidney

Liver

BloodGut wall

PHARMACODYNAMICSPHARMACODYNAMICS

Absorption:Absorption: GIT. GIT. Metabolism:Metabolism: Liver. Liver.

Excretion:Excretion: -Renal (mainly), -Renal (mainly),

Rexcretion:Rexcretion: -Enterohepatic -Enterohepatic circulationcirculation

in bile (small).in bile (small).

Diagram of first pass effectDiagram of first pass effect

liver

gut

biliary tract

to circulation

metabolised drug

portal vein

unmetaboliseddrug

Diagram of entero-hepatic Diagram of entero-hepatic circulation circulation

liver

gutunconjugateddrug

biliary tract

to circulation

conjugated drug

bacteria

portal vein

MECHANISM OF MECHANISM OF ACTION:ACTION:

Inhibits NaInhibits Na++-K-K+ + ATPase ATPase in cell membranes,in cell membranes,

and Interfere with Naand Interfere with Na++--KK+ + PumpPump

Active Transport: Na-K Pump - Active Transport: Na-K Pump - Step 1Step 1

Three sodium ions from inside the Three sodium ions from inside the cell first bind to the transport cell first bind to the transport protein. protein.


Then a phosphate group is transferred Then a phosphate group is transferred from ATP to the transport protein causing from ATP to the transport protein causing it to change shape and release the sodium it to change shape and release the sodium ions outside the cell. ions outside the cell.


Then a phosphate group is transferred Then a phosphate group is transferred from ATP to the transport protein causing from ATP to the transport protein causing it to change shape and release the sodium it to change shape and release the sodium ions outside the cell. ions outside the cell.


Two potassium ions from outside the Two potassium ions from outside the cell then bind to the transport cell then bind to the transport protein. protein.


* * High High conc. of Na+ conc. of Na+

outside the celloutside the cell

** High High conc of K+ conc of K+

inside the cellinside the cell

As the phosphate is removed, the protein As the phosphate is removed, the protein assumes its original shape and releases the assumes its original shape and releases the potassium ions inside the cell. potassium ions inside the cell.

MECHANISM OF ACTION:MECHANISM OF ACTION:

The end result The end result (intracellularly)(intracellularly) is is sodium sodium calciumcalcium

ACTIONACTION

+ve +ve InotropicInotropic effect effect ( (ContractionContraction):): Increases Contractility → Increases Contractility → ↑↑ COP COP ((NaNa++--

KK++Pump)Pump)

-ve -ve ChromotropicChromotropic Effect Effect ( (RateRate):): Increases Vagal Tone → Increases Vagal Tone → ↓↓ Heart Rate Heart Rate

-ve -ve DromotropicDromotropic Effect Effect ((ConductionConduction):): * *Depresses Depresses Conduction Velocity of the heart Conduction Velocity of the heart

(Slows AV node conduction )(Slows AV node conduction )

What are the "normal" ECG What are the "normal" ECG changes with digoxin?changes with digoxin?

Prolonged PR intervalProlonged PR intervalShortened QT interval Shortened QT interval ST segment depression ST segment depression Inverted T wave Inverted T wave

Digitalis toxicityDigitalis toxicity

The usual effects of digoxin are The usual effects of digoxin are amplifiedamplified ↑↑Excitability →Excitability →ectopic beatsectopic beats

↑↑AutomaticityAutomaticity → → tachyarrythmiastachyarrythmias ↓↓ Heart Rate Heart Rate →the heart rate →the heart rate slows further.slows further. ↓↓ conduction (through AV) →conduction (through AV) →

further slows further slows →→ Sinus bradycardia Sinus bradycardia → → AV blockAV block

Predisposing Factors to Predisposing Factors to ToxicityToxicity

Patient : old, renal failure, hepatic Patient : old, renal failure, hepatic dysfunction.dysfunction.

Electrolyte abnormalitiesElectrolyte abnormalities

↓ ↓ KK++ ↓ Mg ↓ Mg+ + + + ↑Na ↑Na++ ↑Ca ↑Ca++++ Drug interactionsDrug interactions

AntibioticsAntibiotics: erythromycins, tetracyclines: erythromycins, tetracyclines

They destroy gut flora that normally They destroy gut flora that normally metabolize digoxin before it is metabolize digoxin before it is absorbed→↑serum digoxinabsorbed→↑serum digoxin

QuinidineQuinidine: competes with digoxin for : competes with digoxin for myocardial receptor sites→displaces dig from myocardial receptor sites→displaces dig from bindbind

K-depleting diureticsK-depleting diuretics

CalciumCalcium

DIGOXIN TOXICITY DIGOXIN TOXICITY TOXIDROMETOXIDROMEAsymptomatic period: Asymptomatic period: min - hrsmin - hrs

GIT:GIT: AnorexiaAnorexia, nausea, vomiting, cramps., nausea, vomiting, cramps.

CNS:CNS: -Altered mental status: -Altered mental status:

(disorientation, confusion, drowziness, (disorientation, confusion, drowziness, lethargy)lethargy)

-Headache, diziness, fatigue, weakness, -Headache, diziness, fatigue, weakness,

-hallucinations, agitations, seizures -hallucinations, agitations, seizures (very rare).(very rare).

Occular:Occular: Blurred vision, photophobia, Blurred vision, photophobia,

abnormal color perception, toxic amblyopia, abnormal color perception, toxic amblyopia,

xanthopsia (seeing yellow-green halos).xanthopsia (seeing yellow-green halos).

Occular:Occular:

Visual disturbancesVisual disturbances are probably are probably the the hallmarkhallmark of digitalis toxicity. of digitalis toxicity.

blurred or double visionblurred or double vision sensitivity to light (photophobia)sensitivity to light (photophobia) toxic amblyopiatoxic amblyopia color vision disturbances where color vision disturbances where

things start to look green or things start to look green or yellow yellow

vision of a yellow "halo" around vision of a yellow "halo" around lights or xanthopsia (blind spots)lights or xanthopsia (blind spots)

Toxidrome cont.Toxidrome cont.

Cardiovascular:Cardiovascular: CHF exacerbationCHF exacerbation Slow full pulse, Slow full pulse, Hypotension, shock, asystole Hypotension, shock, asystole All types of arrhythmias. All types of arrhythmias.

There are many types of There are many types of arrythmias: arrythmias:

excitant,excitant,

SuppresSuppressantsant

CombinCombined.ed.

Suppressant:Suppressant: Sinus Sinus BradycardiaBradycardia, SA Block, AV Block, SA Block, AV Block

Excitant:Excitant: PVCs, VT, V Fib PVCs, VT, V Fib

AT, A Fl, A FibAT, A Fl, A Fib

Combined:Combined: Atrial Atrial TachycardiaTachycardia ++Atrial-ventricular Atrial-ventricular

BlockBlock

ACUTEACUTE CHRONICCHRONIC

AgeAge YoungYoung ElderlyElderly

IntentionIntention IntentionalIntentional AccidentalAccidental

GIGI N,V, anorexia , D, N,V, anorexia , D, abd pain abd pain

LessLess

CNSCNS LessLess Headache , fatigue , Headache , fatigue , weakness, dizziness, weakness, dizziness, confusion ,visual,comaconfusion ,visual,coma

Electrolyte/Electrolyte/RenalRenal

Hyperkalaemia,Hyperkalaemia,normal renal normal renal functionfunction

Hypokalemia,Hypokalemia, Normal NormalRenal insufficiencyRenal insufficiency

CardiacCardiac Bradyarrhythmia, Bradyarrhythmia, SVTSVT

Ventricular Ventricular dysrhythmiadysrhythmia

Management Management DiagnosisDiagnosis Circumstantial evidence.Circumstantial evidence. History → Cardiac medicationHistory → Cardiac medication

Clinical PictureClinical Picture

ECG → Combination of excitant+ ECG → Combination of excitant+ suppressant suppressant (Diagnostic) e.g. (Diagnostic) e.g. Sinus Sinus tachycardia+ Blocktachycardia+ Block Prolonged P-R Prolonged P-R +depressed S-T+depressed S-T

LaboratoryLaboratory

Laboratory Laboratory

Glucose determinationGlucose determination Complete Blood CountComplete Blood Count Serum PotassiumSerum Potassium

Serum Magnesium and Serum Magnesium and CalciumCalcium

Serum BUN and CreatinineSerum BUN and Creatinine Serum DigoxinSerum Digoxin

Serum PotassiumSerum Potassium

Hyperkalemia: Hyperkalemia: ↑ K↑ K Seen in Seen in Acute toxicityAcute toxicity correlates better than dig serum correlates better than dig serum

level.level. if serum K > 5.5 meq/L prognosis if serum K > 5.5 meq/L prognosis

poorpoor Hypokalemia:Hypokalemia: ↓ K↓ K

Common in Common in Chronic toxicityChronic toxicity Patients taking diureticsPatients taking diuretics Contributes more to digoxin Contributes more to digoxin

toxicitytoxicity

SerumSerum Digoxin Digoxin

*Therapeutic serum level: *Therapeutic serum level: 0.6 - 2.0 0.6 - 2.0 ng/ml.ng/ml.

About 2/3of people will experience About 2/3of people will experience symptoms of toxicity at a blood level symptoms of toxicity at a blood level over 2.0 ng/mL.over 2.0 ng/mL.

* * Digoxin needs betw 6 and 8 hours to Digoxin needs betw 6 and 8 hours to distribute itself within the body, so adistribute itself within the body, so a level that is drawn < 6 hours after level that is drawn < 6 hours after ingestion may give an extremely high ingestion may give an extremely high value that value that does not mean toxicitydoes not mean toxicity . .

** Elevated levels of digoxin only Elevated levels of digoxin only confirm exposureconfirm exposure

Serum DigoxinSerum Digoxin

* * Assessed byAssessed by digoxin digoxin radioimmunoassays radioimmunoassays

(RIAs)(RIAs) ..

TREATMENTTREATMENT

Stop the drug,Stop the drug, ABCs, ABCs, D: GID to prevent absorption:D: GID to prevent absorption:

-Gastric lavage, avoid emesis-Gastric lavage, avoid emesis

-Activated charcoal, repeated-Activated charcoal, repeated --Cholestyramine (Cholestyramine (steroid-binding steroid-binding

resin) resin) 15-30gm oral /3-4 dd15-30gm oral /3-4 dd DONT regimen for altered mental DONT regimen for altered mental

status,status,

TREATMENTTREATMENT Correct K disturbanceCorrect K disturbance,,

HyperkalemiaHyperkalemia: : InsulinInsulin 20 units in 20 units in 5% 5% dextrosedextroseCalcium is contraindicated to treat hyperkalemia because ventricular tachyc fibrill may be precipit.

HypokalemiaHypokalemia: K replacement to : K replacement to achieve >4mqachieve >4mq

Replete Mg,Replete Mg, with IV magnesium with IV magnesium sulfatesulfate

Management of cardiac arrythmiasManagement of cardiac arrythmias

MonitoringMonitoring NBNB Patients with rhythm Patients with rhythm

disturbances are to be monitored disturbances are to be monitored in in ICUICU

Treatment of arrythmias:Treatment of arrythmias:

Bradycardia:Bradycardia: Early cases, Early cases, AtropineAtropine 1-2 mg IV, 1-2 mg IV, Persistent cases, Persistent cases, PacemakerPacemaker..

Ventricular arrythmias:Ventricular arrythmias:Phenytoin: Phenytoin: -Drug of choice -Action at AV node-Drug of choice -Action at AV node

-beneficial in AT + AV Block-beneficial in AT + AV Block - dose 0.5 mg/kg slowly IV at 1-2hrs - dose 0.5 mg/kg slowly IV at 1-2hrs

intervalinterval

Lidocaine:Lidocaine: - for ventricular tachycardia - for ventricular tachycardia

Mg SO4:Mg SO4: - -Consider magnesium therapy. It may be lifesaving

Quinidine:Quinidine: Contraindicated. Contraindicated.

Physiological Physiological antidote:antidote:DigibindDigibind

Digoxin Specific Antibody Digoxin Specific Antibody FFaabb: : FFragmented ragmented AAnti nti BBodyody

Binds to free DigoxinBinds to free Digoxin

Mobilizes Dig. from tissue binding sitesMobilizes Dig. from tissue binding sites

purified from sheep purified from sheep IgG,IgG,

Fab Fragments + DigoxinFab Fragments + Digoxin

Fab Fragments Digoxin ComplexFab Fragments Digoxin Complex

excreted in the urine. excreted in the urine.

Digoxin Specific Antibody Fab Digoxin Specific Antibody Fab FragmentsFragmentsIndications:Indications: -Life-threatening VT and V -Life-threatening VT and V

Fib, Fib, -Progressive Bradycardia-Progressive Bradycardia

-Hyperkalemia Serum -Hyperkalemia Serum K>5.5 meq/LK>5.5 meq/L

For an For an acute overdoseacute overdose in adults: in adults: Give 10 vials IV & repeat if indicatedGive 10 vials IV & repeat if indicated

With With chronic toxicitychronic toxicity:: Give 2 vials to an adultGive 2 vials to an adult

One vialOne vial of digibind contains 40 mg, which of digibind contains 40 mg, which neutralizes approximately 0.5 mg of digoxinneutralizes approximately 0.5 mg of digoxin

How long does it take for How long does it take for the Digibind to work?the Digibind to work?

The average onset of action for The average onset of action for Digibind isDigibind is

30 minutes . 30 minutes . 90 minutes showed complete 90 minutes showed complete

recession of all toxicity symptoms, recession of all toxicity symptoms, including ECG changes. including ECG changes.

What about hemodialysis or What about hemodialysis or hemoperfusion?hemoperfusion?

Digoxin is Digoxin is notnot cleared by either cleared by either hemodialysis or hemoperfusion hemodialysis or hemoperfusion because of because of

the drug’s large volume of the drug’s large volume of distribution and its molecular distribution and its molecular weightweight

HemodialysisHemodialysis may be initiated for may be initiated for renal failurerenal failure, but is not effective , but is not effective as a treatment for the overdoseas a treatment for the overdose

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Digitalis Toxicity