Toxicology

Question 1

Aspirin

Answer 1

• Poisoning causes uncoupling of oxidative
phosphorylation.
• Impaired ability to generate ATP
• Increased O2 use
• Increased CO2 production
• Increased heat production

• Increased glycolysis and increased peripheral demand for glucose.
• Increased glycogenolysis, gluconeogenesis, lipolysis and fatty acid oxidation.
• The increase in fatty acid oxidation leads to increased synthesis of ketone bodies.
• Salicylates also inhibit the Krebs cycle.
• This results in increased levels of pyruvate and lactate.

SE’s
• Nausea, vomiting, fever, tachypnea, tachycardia, tinnitus, hearing loss
• The first sign of salicylate toxicity: Hyperventilation and respiratory alkalosis due to medullary stimulation.
• An increased anion gap -> Metabolic acidosis follows.
• Arterial blood gas testing often reveals this mixed respiratory alkalosis and metabolic acidosis.
• With very severe poisoning, profound metabolic acidosis, seizures, coma, pulmonary edema, and cardiovascular collapse may occur.
• Vomiting and hyperpnea as well as hyperthermia contribute to fluid loss and dehydration.

Tx
• General supportive care.
• Aggressive gut decontamination including gastric lavage, repeated doses of activated charcoal, and
consideration of whole bowel irrigation.
• Intravenous fluids are used to replace fluid losses.
• Moderate intoxication: IV sodium bicarbonate to alkalinize urine and promote salicylate excretion.
• Severe intoxication: Hemodialysis.

Question 2

Acetaminophen

Answer 2

• Initially, the patient is asymptomatic or has mild gastrointestinal upset.
• Later fulminant liver failure occurs, leading to hepatic encephalopathy and death.
• The metabolism of acetaminophen involves three different pathways.

Tx
• The antidote is N-acetylcysteine.
• Increase glutathione production, and also reacts
directly with (and thereby detoxifies) NAPQI.
• Effective orally or IV.

Question 3

Amphetamines and other stimulants

Answer 3

• At usual doses: euphoria and wakefulness + sense of power and well-being.
• Higher doses: agitation, acute psychosis
hypertension, tachycardia, tachyarrhythmias.
• Seizures and muscular hyperactivity may cause
hyperthermia and rhabdomyolysis.
• Pupils dilated, skin warm and sweaty.

Tx
Symptomatic, no specific antidote
• Acidification of urine with ammonium chloride.
• For HT: phentolamine or nitroprusside.
• For tachyarrhythmias: propranolol or esmolol.
• For seizures: IV benzodiazepines.
• Very high body temperatures: neuromuscular paralysis.

Question 4

Anticholinergics

Answer 4

• Anticholinergics, mushrooms 
• Antihistamines
• Antidepressants - TCAs
• Antipsychotics 
• Antiparkinsons
• Many of them have other potentially toxic effects as well: 
– Antihistamines can cause seizures
– TCAs can cause severe CV toxicity.

Tx
• Specific antidote: Physostigmine.
• Physostigmine should not be given to a patient with TCA overdose because it can aggravate
cardiotoxicity, resulting in heart block or asystole.
• Agitated patients: benzodiazepines or antipsychotics.

Question 5

B-blockers

Answer 5

• In overdose, they block both β1 and β2 receptors.

• The most toxic β blocker is propranolol.
– At high doses it blocks Na+ channels
– It is lipophilic: enters CNS, causing seizures and coma.

• Bradycardia and hypotension are the most common manifestations of toxicity.
• Hypoglycemia
• Partial agonists (e.g. pindolol): tachycardia and
hypertension.
• Propranolol overdose: can also cause seizures and cardiac conduction block.

Tx
• Usual agents used to raise blood pressure and heart rate, such as β-agonists and atropine, are generally ineffective.
• IV Glucagon is a useful antidote.
• Increases cAMP in cardiac cells, but through stimulation of glucagon receptors, not β receptors.

Question 6

Ca2+ channel blockers

Answer 6

• Depress sinus node automaticity and slow AV node conduction.
• They also reduce cardiac output and blood pressure.
• Antidote: Ca2+ IV. Restores depressed cardiac contractility.
• Glucagon & epinephrine increase blood pressure in patients with refractory hypotension. They also increase the heart rate.

Question 7

TCAs

Answer 7

• TCAs are antagonists at muscarinic receptors.
• TCAs are also α-blockers: vasodilation.
• TCAs have quinidine-like depressant effects (blockade of fast Na+ channels in the heart): slowed conduction and depressed cardiac contractility.

TREATMENT OF TCAs OVERDOSE
• Norepinephrine for hypotension.
• Antidote for quinidine-like cardiac toxicity: sodium bicarbonate. Rapid increase in extracellular sodium overcomes sodium channel blockade.
• NOT Physostigmine.

Question 8

MAOI

Answer 8

TREATMENT
• For hypertension: phentolamine or labetalol.

SEROTONIN SYNDROME
• Administration of an irreversible MAOI with a
serotonergic agent may result in a serotonin syndrome.
• Serotonin syndrome is the result of overstimulation of 5-HT1A and 5-HT2 receptors.
• It includes hyperthermia, muscle rigidity and myoclonus and hyperreflexia. It may be fatal.
• SSRIs, second-generation antidepressants, Linezolid, tramadol, meperidine, sumitriptan, lithium, ondensetron, St. John’s wort are few examples.

TREATMENT FOR SEROTONIN SYNDROME
• Cyproheptadine (a 5HT2 receptor antagonist).
• Rigidity, seizures, and agitation are treated with benzodiazepines.

Question 9

Neuroleptic malignant syndrome

Answer 9

• Hyperthermic disorder seen in some patients who use antipsychotic agents.
• Characterized by muscle rigidity, hyperthermia,
metabolic acidosis, and confusion.
• A mnemonic used to remember the features of NMS is FEVER.

F - Fever
E – Encephalopathy
V – Vitals unstable
E - Elevated enzymes (elevated CPK) 
R - Rigidity of muscles

• Bromocriptine and dantrolene for moderate to severe NMS.
• Bromocriptine is the antidote.
• Dantrolene most beneficial when profound rigidity is present
• If temperature ≥40

Question 10

Sulfonylureas and meglitinides

Answer 10

• TREA TMENT
• Concentrated glucose bolus.
• IV octreotide may be given if 5% glucose infusions do not maintain satisfactory glycemia.
• Octreotide is a long-acting analog of somatostatin. It antagonizes pancreatic insulin release.
• Diazoxide is an alternative to octreotide. It also inhibits insulin release.

Question 11

CO

Answer 11

Clinical Effects
Headache and tightness in the temporal area; confusion
and loss of visual acuity;
tachycardia, tachypnea, syncope, and coma; convulsions, death due to respiratory failure.
• Prolonged hypoxia can result in irreversible damage to the brain and the myocardium.

TREA TMENT
• With room air at 1 atm, the elimination half-life of CO is
about 320 minutes.
• With 100% O2 it is about 80 minutes.
• With hyperbaric O2 it is about 20 minutes.

Question 12

Irritant solvents

Answer 12

• Mechanism of Toxicity
Corrosive effect on upper and lower airways
• Clinical Features
Cough, stridor, wheezing, pneumonia
• Treatment:
100% oxygen