Clinical Toxicology

Cardio toxicology

4th Year Clinical Toxicology

Department of Pharmacy
School of Health Sciences
UNZA

Andrew M Bambala
bambalaandrew@gmail.com
 General Outline
 Introduction and Principles of Toxicology

 Specific poisons (Gases, Pesticides heavy metals)

 Drug overdose (Aspirin, paracetamol, Quinine, Digitalis, Alcohol, Opioids

benzodiazepines, herbal medicine toxicity)

 Drug abuse, drug dependence and its management

QUININE
Introduction
• Quinine comes from the Cinchona bank (Cinchona officinalis)

• Named after a woman-The 2nd countess of Chinchon in Peru c.1742.

• First effective treatment against Plasmodium Falciparum

• Quinine causes Cinchonism (nausea, vomiting and tinnitus) in overdose

• Blindness which is delayed and sometimes not noticed until the morning after the acute
toxicity has resolved
Toxicokinetics
• Rapid absorption with a 70% bioavailability

• Highly protein bound in adults but less so in the pediatric population (Increased risk in
children)

• Elimination half life is >24 hours in overdose and largely via

 Hydroxylation with 20% being excreted in the urine unchanged

Toxic Mechanism:
• Quinine is an optical isomer of quinidine

• The mechanism like quinidine however, quinine less potent cardiotoxin.

• Class 1A antidysrhythmic with both sodium and potassium blocking properties

thereby prolonging the QRS and QT intervals.
Toxic Mechanism:
• Type 1A agents depress the fast sodium-dependent channel, slowing phase zero of
the cardiac action potential.

• At high concentrations, this results in reduced myocardial contractility and excitability

and severe depression of cardiac conduction velocity.

• Repolarization is also delayed, resulting in a prolonged QT interval that may be

associated with polymorphic ventricular tachycardia (torsade de pointes).
Toxic Mechanism:
• In overdose, it is toxic to the retina which can result in permanent blindness.

• Recent evidence indicates a direct toxic effect on photoreceptor and ganglion

cells.
 Toxic levels
• Toxic effects involve the cardiovascular and central nervous systems, the eyes, and other
organ systems

• The minimum toxic dose is approximately 3–4 g in adults; 1 g has been fatal in a child.

• Mild intoxication (>1g ) produces nausea, vomiting, and cinchonism (tinnitus, deafness,
vertigo, headache, and visual disturbances).
Toxic levels
• Severe intoxication <5-10g may cause ataxia, confusion, obtundation, convulsions, coma,
blindless and respiratory arrest.

• Massive intoxication, quinidine-like cardiotoxicity (hypotension, QRS- and QT-interval

prolongation, atrioventricular [AV] block, and ventricular arrhythmias) may be fatal.

• Children: ingestion of 600mg (two tablets) in a child <6 years can potentially cause life-
threatening toxicity.
Clinical effects:

• Cinchonism: Nausea, vomiting, tinnitus, vertigo and hearing loss.

Resolves once blood quinine concentrations fall.

• Cardiovascular: Hypotension, Sinus tachycardia, QRS widening

• prolongation of the PR and QT intervals

• Wide-complex tachycardias and Torsades de points.

• Usually occur within 8 hours of overdose

• Resolve once blood concentrations of quinine fall.

Clinical effects:
• CNS: Drowsiness and confusion in larger ingestions.

• Eyes: Retinal toxicity occurs 9–10 hours after ingestion and includes blurred vision,

• Impaired colour perception, constriction of visual fields, and blindness.

• The pupils are often fixed and dilated

• Onset of visual disturbance is delayed, approximately 6 – 8 hours post ingestion.

• Complete and permanent blindness can occur in severe cases however, recovery of
minor disturbances usually resolves over weeks
Clinical effects
• Hematotoxic effects
• Hemolysis (in G6PD-deficient patients) Black-water fever (intravascular hemolysis)
(rare and fatal in quinine-sensitized persons)

• Other toxic effects

• hypokalemia, hypoglycemia
Quinine is a potent stimulant release of insulin from the pancreatic beta cells
• Congenital malformations when used in pregnancy.
Diagnosis
• Screening: • Specific:
• 12 lead ECG, • Serial ECGs
• Glucose ???
• BUN (blood urea nitrogen)
• Creatinine • EUC -Electrolytes (sodium, potassium
• Arterial blood gases and chloride),
• Paracetamol levels???
• Formal visual field mapping
• Quinine blood levels are generally not
available in a clinically useful time.
Management
Emergency and supportive measures

• Maintain an open airway and assist ventilation if necessary

• Treat coma, seizures, hypotension and arrhythmias if they occur

• Seizures: IV benzodiazepines.

• Avoid types Ia and Ic antiarrhythmic drugs; they may worsen cardiotoxicity.

• Continuously monitor vital signs and the ECG for at least 6 hours after ingestion
Management
Specific Treatment
• Wide-complex tachydyshythmias:
• Urgent serum alkalisation with sodium bicarbonate

• aiming for QRS <100ms or a pH>7.45

• followed by intubation and hyperventilation

• aiming for a pH 7.45 –7.55

Management
• Specific Treatment ; Torsades de pointes:

• Magnesium sulfate 10 mmol (0.05 mmol/kg in children) IV over 15 minute

• Correct hypoxia, hypokalemia, hypoglycemia and hypocalcemia

• If heart rate is <100 beats/minute commence an isoprenaline infusion IV at 1-10

microgram/min (0.05-1.0 microgram/kg/min in children)
Management
• Decontamination:

• Activated charcoal maybe given to the alert and cooperative patient.

• An antiemetic maybe required to assist administration.

Management
• Enhanced Elimination

• Because of extensive tissue distribution (volume of distribution is 3 L/kg)

• Dialysis and hemoperfusion procedures are ineffective.

• Acidification of the urine may slightly increase renal excretion but does not
significantly alter the overall elimination rate and may aggravate cardiotoxicity

• Antidote; None available.

Management

• Children who have ingested >600mg of quinine must be observed and monitored for 6
hours post ingestion.

• If asymptomatic with a normal ECG they are medically cleared.

• All patients with a deliberate overdose require 6 hours observation and cardiac
monitoring.

• If asymptomatic with a normal ECG they are medically cleared.

DIGITALIS
DIGITALIS

• The term “digitalis” is used to designate the whole group of glycosides

• Digitalis glycosides are found in Digitalis purpurea and Digitalis lanata.

• Digoxin is the most used digitalis preparation.

• It is used in the management of congestive heart failure and atrial fibrillation

• Toxicity could be

• Accidental in children

• Suicidal
Toxic dose
• Acute ingestion as little as 1 mg of digoxin in a child or 3 mg of digoxin in an adult can
result in serum concentrations well above the therapeutic range.

• The bioavailability of digoxin ranges from 60–80%; more than 90% is absorbed

• The volume of distribution (Vd) of digoxin is very large (5–10 L/kg)

Toxic dose
• Narrow therapeutic index

• Not metabolized by the CYP 450 system thus not known for induction or inhibition effects
on CYP450 enzymes

• Peak effects occur after a delay of 6–12 hours. The elimination half-life of digoxin is 30–
50 hours

• Amiodarone, verapamil, quinidine, (by displacing tissue binding sites and depressing
renal digoxin clearance) increase plasma levels of digoxin
Mode of toxicity:

• Chronic digoxin poisoning

• Long standing treatment in elderly patients with preexisting renal and cardiac disease
• Large doses of digoxin relative to age, changing renal function, concurrent diuretic

administration may produce hypokalemia and hypomagnesemia.

• Chronic toxicity hypokalemia may be seen due to the concomitant use of K+

losing diuretics
Mechanism of toxicity
1. Cardiac glycosides produce

• reversible inhibition of sodium-potassium (Na+-K+)-ATPase pump,

• which causes increased intracellular sodium and decreased intracellular potassium.

• Inhibition of Na+-K+-ATPase in skeletal muscle results in increased extracellular
potassium and contributes to hyperkalemia.
Mechanism of toxicity
2. Direct effects and potentiation of vagal tone
• result in slowing of the sinus rate and decreased sinus and atrioventricular (AV) node
conduction velocity

• resulting in bradycardia and heart blocks with toxic doses

Mechanism of toxicity
3. Increased atrial and ventricular automaticity occurs

• because of accumulation of intracellular calcium,

• enhanced diastolic depolarization, and development of after depolarizations.

• These effects are augmented by hypokalemia and hypomagnesemia.

.
Mechanism of toxicity
• 4. Prolongation of refractory period in AV node,
• shortening of refractory periods in atria and ventricles,

• and decrease resting membrane potential (increased excitability)

• leading to various types of arrhythmias atrial or ventricular, bradyarrhythmia, or
tachyarrhythmias
 Clinical presentation
1. Cardiac manifestations (the most frequent) include palpitations, bradycardia, any
degree of heart block, atrial and ventricular arrhythmias.

• Hypotension and shock may ensue.

2. Gl symptoms (the first symptoms to evolve) include nausea, vomiting, abdominal pain,
diarrhea, and anorexia.
Clinical presentation

3.Visual effects include blurred vision, abnormal color perceptions of yellow or yellow-green
halos may occur.

4. Others: headache, fatigue and weakness.

5. Hyperkalemia may occur in acute toxicity. (in chronic toxicity hypokalemia may be seen
due to the concomitant use of K+ losing diuretics).
Investigations

• 1. Electrolytes:
• Hyperkalemia is an early predictor of need for antidotal therapy.

• Hypokalemia exacerbates chronic toxicity.

• Hypercalcemia and hypomagnesemia exacerbate cardiac glycoside toxicity.

Why ??
Investigations
2. Digoxin level:

• Therapeutic blood level is 0.6 – 2.1ng/ml.

• Concentrations exceeding 15ng/ml carry a serious prognosis.

• 3. Renal functions:

• Renal impairment impairs elimination of glycosides.

Investigations
• 4. Electrocardiogram (ECG) and continuous cardiac monitor

• Look for bradycardia, heart block, atrial or ventricular tachyarrhythmias.

• Nonspecific ST segment sagging and T wave

• abnormalities are consistent with digitalis treatment.

• Peaked T waves may occur in hyperkalemia.

Management
I. Emergency measures (ABCD).

II. Prevent further exposure: Stop digoxin medications.

III. Continuous cardiac monitoring.

IV. Elimination:
Management
• Gastric lavage is of limited value.

• Gastric lavage increases vagal tone and may precipitate or worsen arrhythmias.

• Consider pretreatment with atropine if gastric lavage is performed

• Activated charcoal. Because of the enterohepatic circulation of digoxin and digitoxin,

multiple-dose charcoal (1 g/kg) may be beneficial.

• Cholestyramine will interrupt the enterohepatic circulation.

Antidote

• Digoxin immune fab or Digoxin-specific antibody is an antidote for overdose of

digoxin

• Made from immunoglobulin fragments from sheep that have already been
immunized with a digoxin derivative, digoxindicarboxymethoxylamine (DDMA)

• Brand names include Digibind (GlaxoSmithKline) and DigiFab (BTG plc)

• binds to digoxin and other cardiac glycoside the inactive complex that is
formed is excreted rapidly in the urine.
Antidote
• Effective for digoxin poisoning with any of one of ;

• Hemodynamically unstable arrhythmia

• End organ damage

• digoxin level > 4 ng/ml if chronic ingestion

• digoxin level > 10 ng/ml if acute ingestion

• potassium > 5 mEq/L and symptomatic

• The onset of action of Fab fragments may take 30-60 minutes.

• Monitor potassium level as hypokalemia may occur due to reactivation of Na-K-ATPase.

Management
Treatment of complications:

• Atropine may be used in bradyarrhythmia's.

• Phenytoin or Lidocaine for ventricular arrhythmias.

• Magnesium sulfate reverse digoxin-induced arrhythmias.

• Cardiac pacing (temporary pacemaker) in serious heart block if Fab fragments are not
immediately available.
Management
• Glucose, insulin, sodium bicarbonate, may be used to facilitate redistribution of potassium
intracellularly in life-threatening hyperkalemia (> 6.5 mEq/L) if Fab fragments are not
immediately available.

• Avoid the following:

• Calcium preparations, Quinidine and procainamide, Calcium channel blockers, beta-
blockers.

• Because of the large volume of distribution, diuresis, hemodialysis and hemoperfusion do

not increase clearance. These procedures may lead to fluid imbalance and exacerbate
CHF.
 THANKS

17th August, 2020 Andrew Bambala