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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.
Active Transport: Na-K Pump - Active Transport: Na-K Pump - Step 2Step 2
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.
Active Transport: Na-K Pump - Active Transport: Na-K Pump - Step 3Step 3
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.
Active Transport: Na-K Pump - Active Transport: Na-K Pump - Step 4Step 4
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.
Active Transport: Na-K Pump - Active Transport: Na-K Pump - Step 5Step 5
* * 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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