General Principles of Toxicology

General Principles of Toxicology

Know the following definitions:

Toxicology: relation of hazardous effects of chemicals, including drugs, to biological systems
Acute toxicity: adverse effect resulting from a single, usually large, exposure to a toxin

Subacute toxicity: Somewhat acute, between acute and chronic (online med. dictionary)

Chronic toxicity: harmful effect from repeated exposures to a toxin for 3+ months

Therapeutic index: LD50/ED50

Risk: probability that injury will result from exposure to a substance for given conditions, dose, and route

Threshold limit values (TLV): maximum safe ambient air concentrations of chemicals during a workweek,a 15 minute interval, and instantaneously

Know the following general mechanisms by which drugs or chemicals can cause toxicity:

Alterations in receptor-ligand interactions

Nicotine, most drugs

Alterations in membrane function
Local anesthetics, hydrocarbons
Interference with cellular energy mechanisms
Cyanide, Pentachlorophenol
Covalent binding to biomolecules
Organophosphates, alkylating agents
Interference with calcium homeostasis
Oxalates

By causing non-lethal alterations in somatic cells
Carcinogens, e.g. aflatoxin

Alterations in ligand-activated transcription factors
Dioxins

By inducing programmed cell death (apoptosis)
Acetaminophen
· Understand the primary determinants of toxicity

Dose and dose rate
Duration of exposure: long duration: bad.
(Principle) routes of exposure: inhalation, transdermal, and oral
· Understand how the following factors modify toxicity

Biotransformation
Parathion à Paraxon
Methanol à Formaldehyde à Formic Acid (MeOH shares pathway with EtOH)
Immune function

Review the hypersensitivities, e.g. Mosby 1-9 or perhaps even your long term memory
Phototoxicity: drug intermediates accumulate in skin, exposed to UV à toxic compounds
Examples: tetracycline, sulfonamides

Age: pharmodynamics, pharmokinetics vary over a lifetime

Gender: no specifics were discussed
· Understand how to manage a poisoned patient - know the ABCD's

Airway: should be cleared of vomitus or other obstruction and an airway or ET tube inserted

Breathing:Assesed by observation and measurements of arterial gases
Intubate and mechanically ventilate if necessary
Circulation
Monitor pulse rate, blood pressure, and urinary output
Start IV and draw blood for glucose and other labs
Dextrose: to every patient with altered mental status (thinking about hypoglycemic problems)
100mg thiamine to alcoholic and malnourished to prevent Wernicke-Korsakoff’s
· Understand the importance of the history and physical examination in treating a poisoned patient
Oral history may be unreliable for a number of reasons
Be on the lookout for classical OD effects of common meds and poisons
Treat the patient, not the poison
· Understand the importance of the following laboratory analysis and procedures
Arterial blood gases
CO2: increased with hypoventilation
PO2: low with aspiration pneumonia or drug-induced pulmonary edema
Reduced with poor tissue oxygenation due to hypoxia, hypotension, or Cn poisoning
May appear normal in CO because dissolved O2 is measured, not oxyhemoglobin
Electrolyte analysis (an ion gap)
(Na+ + K+) + (HCO3
- + Cl-) (this is just major cations minus anions)
normal = 12 plus/minus 4
elevated by:
renal failure
diabetic ketoacidosis
shock-induced lactic adicosis
Drug-induced metabolic acidosis (salicylates, methanol, ethylene glycol, isoniazid, Fe)
Renal and liver function tests
Renal tests: In the UA look for:
BUN, creatinine (nitrogen load and glomerular filtration checks, respectively)
CK and myoglobin (muscle insults)
oxlate crystals: suggest ethylene glycol poisoning
Liver tests: transaminases, look at the PT
Osmolar gap: useful in alcohols poisonings; alcohols will increase the osmolar gap (K. table 59-4)
Calculated serum osmolality: [ 2Na+ + glucose/18 + BUN/3]
Osmolar gap: measured osmolality – calculated osmolality
EKG examples:
Wide QRS: tricyclics, quinidine
Long QT: quinidine, phenothiazine, tricyclics
Variable AV block, screwy rhythms: dig. overdose
Ischemic changes: hypoxemia due to CO
· Understand how toxins can be removed or elimination can be enhanced
Gastric lavage
> 30 minutes have passed since the ingestion of a corrosive material
ingestion of hydrocarbons
coma, stupor, delerium, unconsciousness, convulsions
Induced emesis (know contraindications)
Syrup of Ipecac is often used; same contraindications as above
Increased rate of excretion
Catharsis: increased clearance of intestinal contents
Sorbitol is the preferred agent (hellooooo, apple juice), MgSO4 can be used if kidneys are ok
osmotic diuretics: e.g. mannitol, urea, etc.
Altered urinary pH
Alkalination: useful for salicylate or phenobarbitol overdose
Acidification: not recommended b/c worsens renal effects of rhabdomyolysis
Peritoneal dialysis: simple and available, but inefficient for most drugs
Hemodialysis: especially useful in cases where electrolyte and fluid imbalances are present
Hemoperfusion: blood pumped from pt’s vein through a cartridge filled with adsorbent material
Especially effective for high molecular weight compounds
· Understand the importance of the following specific drugs in managing the poisoned patient
Activated charcoal: large surface area, suggested dose is 10:1 charcoal to est. weight of toxin
Good for: adsorption of many drugs and poisons
No good for: Fe, Li, K, Cn, alcohols, corrosive acids and alkali, methylcarbmate, tolbutamide
Ipecac syrup: emetic agent; use 30 ml for adults, 10-15 ml for kids, repeated q 15 minutes if necessary
Emetic contraindications still apply: not for corrosives, hydrocarbons, rapidly acting convulsants
Ammonium chloride: used to acidify the urine
Not used much clinically because of side effects, e.g. indirect kidney damage
 urinary excretion of weak organic bases
Sodium bicarbonate: urine alkalinization
 urinary excretion of weak organic acids
Magnesium sulfate: cathartic, contraindicated in renal compromise
Mannitol: used to  renal clearance of toxins (also to  intraocular and intracranial pressure)
Deferoxamine: use IV or IM; chelator of choice for Fe poisoning
Dimercaprol: single-agent therapy for arsenic and mercury, use for lead with EDTA
Edetate, calcium disodium (EDTA): efficient chelator of many di/trivalent metal ions, esp. lead
Penicillamine: chelator of Cu and Pb
used in Wilson’s cystinuria, resistant cases of rheumatoid arthritis
Succimer (Dimercaptosuccinic Acid, DMSA), analog of dimercaprol,
prevents and reverses metal-induced inhibition of sulfhydryl-containing enzymes
 urinary Pb excretion, protects against lethal effects of As,  kidney [Hg]
Acetylcysteine: acetaminophen OD antidote, give within 8-10 hours of insult
Digoxin-specific FAb antibody: binds Dig
Atropine: used for cholinesterase poisonings to block ACh binding
Pralidoxime (2-PAM): cholinesterase reactivator, given only for organophosphates
Physostigmine: suggested for antimuscarinic, anticholinergic agents, but not for TCA’s
Flumazenil: used for benzodiazepine overdoses
Cyanide antidote package: sodium nitrate, sodium thoisulfate, amyl nitrate
Glucagon: antidote for Beta-adrenoreceptor blockers, may reverse low BP, bradycardia
Ethanol: used in ethylene glycol poisoning to decrease kidney damage, in MeOH poisoning as well
Fomepizole: an alcohol dehydrogenase inhibitor used to treat MeOH and ethylene glycol accidents
Diazepam: used for chemical-induced convulsions
Pyridoxine (Vitamin B6): used for isoniazid OD
Methylene blue: used to convert methemoglobin to hemoglobin (nitrate poisoning)