Toxicology part 1 Flashcards
These cards will go through drugs and their associated toxic effects. First we will start off with common drugs. Aspirin, which is a Salicylate, what is the MOA for the toxic effects?
Salicylic Acid:
- -central stimulation of the respiratory center results in hyperventilation, leading to respiratory acidosis
- -secondary consequences from hyperventilation include dehydration and compensatory metabolic acidosis
Salicylates are known to cause metabolic acidosis primarily due to increased production of endogenous acids rather than the salicylate itself. What are the processes that contribute to the acidosis state?
- Salicylates are weak acids
- Increased renal excretion of bicarb as a compensatory response for respiratory alkalosis
- Uncouple oxidative phosphorylation: impaired ability to generate ATP, increased O2 use, increased CO2 production and increased heart production and hyperflexia
- Increased fatty acid oxidation = ketone bodies
- Inhibit key dehydrogenase in the Krebs cycle, results in increased levels of pyruvate and lactate
- Impair renal function leading to accumulation of sulfuric acid and phosphoric acid
What are the toxic doses for Salicylates for acute and chronic?
Acute Ingestion: 150-200mg/kg of aspirin will produce mild intoxication ; severe intoxication after 300-500mg/kg
Chronic Intoxication: ingestion of more than 100mg/kg/d for 2 days or more
What are the signs of acute vs chronic intoxication with aspirin?
Acute:
–vomiting followed by hyperpnea, tinnitus and lethargy. Mixed respiratory alkalmeia and metabolic acidosis
–sever intoxication: coma, seizures, hypoglycemia, hyperthermia and pul edema
–death due to resp failure
Chronic:
–confused elderly persons
–often overlooked dx due to nonspecific presentation
–morbidity and mortality rates are much higher than after an acute overdose.
What is the treatment approach for Salicylate poisoning?
A. Emergency Medicine: ABCDE of ER (air, breathing, circulation)
B. Enhanced elimination of Salicylates:
–Urinary Alkalinization: IV sodium bicarb is given to alkalinize the urine: used for moderate intoxication
–Hemodialysis: used for severe intoxication
Next common drug to discuss is Acetaminophen (APAP). It is an active ingredient in OTC meds. It relieves pain and fever. What is the MOA for APAP toxicity?
Fatal Hepatic Necrosis (renal tubular and hypoglycemic coma can also occur)
- -APAP is converted to inactive glucuronide and sulfate conjugates, with a fraction being oxidized to N-acetyl-p-benzoquinoneimine (NAPQI)
- -NAPQI is detoxified by conjugation with glutathione, in a reaction catalyzed by glutathione S transferase
- -When high doses are consumed, the glucuronidation and sulfation pathways become saturated, large amounts of NAPQI are formed, and the body’s glutathione stores become depleted. The unconjugated NAPQI then can damage cellular proteins and lead to death of hepatocyte.
Besides the liver failure what are other consequences of APAP toxicity?
- Renal failure: metabolized APAP to toxic metabolite
- Lactic Acidosis: and altered mental status
- Severe liver damage: diminished glucuronidation and sulfation. Plasma levels of glucorinide metabolite becomes undetectable
- Acute Alcohol ingestion is not a risk factor for hepatotoxicity and may even be protective by competing with APAP for CYP2E1
- Chronic Alcoholism appears to be an increased risk for hepatotoxicity following ingestion of multiple supratherapeutic doses of acetaminophen. It acts by induction of CYP2E1, which results in the shunting of a greater fraction of APAP through the CYP2E1 pathway and enhanced generation of NAPQI.
What are the toxic doses for APAP?
Acute Ingestion:
- -of more than 200mg/kg in kids and 6-7g in adults
- -margin of safety is lower in patients with induced CYP microsomal enzymes
- -High risk patients include alcoholics and patients taking inducers of CYP2E1 such as Isoniazid
What is the treatment for APAP toxicity?
Gastric Lavage in all cases
Antidote is N-acetylcysteine (supplies cysteine as a precursor for increased glutathione production)
–AE: skin rash, nausea, vomiting, diarrhea and anaphylactoid reactions
Liver transplant in patients with fulminant hepatic failure
Next commonly abused drug are stimulant drugs. Including methamphetamine, MDMA or ecstasy and cocaine. What are the effects from these drugs?
Euphoria and Wakefulness and a sense of power
Higher Doses: restlessness, agitation and acute psychosis may occur, accompanied by HTN and tachycardia
What is the treatment for Amphetamines and Other stimulant toxicity?
NO specific Antidote
–tx acidification of urine by administration of ammonium chloride to enhance rate of elimination
HTN is treated with a parenteral vasodilator such as phentolamine or nitroprusside
Seizures managed by IV benzodiazepines (lorazepam or diazepam)
For very high body temps: neuromuscular paralysis
Next anticholinergic intoxication can occur. what are common drugs that have anticholinergic activity?
Antihistamines Antipsychotics Antispasmodics Skeletal Muscle Relaxants TCAs
What is the classical presentation for anticholinergic syndrome?
Skin Flushing (red as a beet) Hyperthermia (hot as a hare) Dry mucus membranes (dry as a bone) Blurred vision and dilated pupils (Blind as a bat) Confusion and delirium (mad as a hatter)
What is the treatment for Anticholinergic Syndrome?
A. Emergency Medicine: ABCs
–agitated patients: benzos or antipsychotics (Haloperidol)
B: Specific Drugs
–Physostigmine: crosses the BBB ; should not be given to a patient with suspected TCA overdose because it can aggravate cardiotoxicity, resulting in heart block or asystole.
–Neostigmine: does not cross the BBB
C: Enhanced Elimination:
–hemodialysis, hemoperfusion, peritoneal dialysis
Next drug are beta blocker intoxication. What is the clinical presentation?
- Cardiac Disturbances
- EKG normal QRS duration with increased PR intervals
- -Most common is Propranolol intoxication: at high doses it blocks Na channels (Class I effects) leading to QRS widening and ventricular arrhythmias - CNS
- -convulsions, coma and respiratory arrest - Bronchospasm:
- -pre-existing asthma or chronic bronchospastic dz - Hypoglycemia and Hyperkalemia
