Toxicity

Kinetics

• LD50: “lethal dose” that causes death in 50% of the population exposed

  • TD50: toxic dose for 50% of population

• LD99: lethal dose that causes death in 99% of the population exposed

  • TD99

Routes of Exposure

• GI

  • lipid soluble

    • more toxic, more easily absorbed in membranes

  • water soluble

• Respiratory

  • small molecules

  • lipid and water soluble

• Skin/mucous membranes

  • small molecules

  • lipid soluble

Harmful Effects

• drug-induced toxicity

  • functional change

    • occur at the therapeutic dose

    • reversible with discontinuation of druge

    • “like a drug allergy”

  • structural change

    • produce gross or histologic lesions

    • instantly recognizable

    • prevent further damage, can’t reverse damage already occur

  • biochemical change

    • do no produce gross or histologic lesions

    • effects can be dose related

• intentional administration

  • stuff in there that should be there but either too much or available

  • “not malicious”

  • food additivies

  • insecticides

  • doses and concentrations are established

• unintentional administration

  • should not have been there

  • chemicals

  • non-food botanicals

  • no doses or concentrations established

• expected or normal effects

  • usually dose dependent

  • caustic/corrosive

  • specific toxicologic action

  • exaggerated pharmacologic action

• abnormal effects

  • immune mechanisms

    • possible drug allergy

• normal effects

  • caustic/corrosive

    • classified as irritants

  • asphyxiants

    • ex. carbon monoxide

  • specific actions

    • botulism toxin

    • teratogens

    • mutagens

    • carcinogens

• teratogens

  • thalidomide: limb abnormalities

    • indication: insomnia and nausea, leprosy

    • given to pregnant women

    • inhibit the ability of new blood vessels to be formed

  • ethyl alcohol: growth retardation, craniofacial defects

  • diethylstilbestrol: carcinoma in young women

    • women who experienced many miscarriages

    • thought to help maintain pregnancy

    • carcinoma in ovaries

  • cocaine: limb and urinary tract defects, congenital heart disease

  • organic Hg: cerebral palsy

  • trimethadione: cleft palate, heart disease

    • antiepileptic

    • mental development problems

    • used if an epileptic patient wants a pregnancy

  • aminopterin: hydrocephalus

• toxicity associated with normal concentrations

  • toxicity due to individualization

  • toxicity due to malfunction in mechanisms terminating action of the agent

    • leads to accumulation of drug

    • impaired elimination

      • competition by other drugs

      • state of health of patient

  • toxicity due to action on wrong target

  • toxicity due to synergism with other drugs

Abnormal Effects

• hypersensitivity reactions

  • allergies to…

    • typically have to have a prior exposure

  • does not always require prior exposure

• prior exposure

  • hapten system: compound combines with carrier (protein or cell)

    • allergic reaction after it reacts to the drug

  • normally non-antigenic compound now “big enough” to be recognized by the immune system on subsequent exposure

• types of reactions

  • type 1: histamine release

  • type 2: cytotoxicity

  • type 3: immune complex formation

  • type 4: delayed-cellular response

Biochemical Effects

• barriers to absorption (translocation)

• biotransformation mechanisms

  • species variation

• receptor variability

Antidotes

• stragtegy

  • time depends upon route of exposure

  • reduce exposure

  • interfere with translocation (absorption)

    • activated charcoal (absorption)

    • gastric lavage (water for water-soluble)

    • emetics (+/-)

    • decontamination shower

  • formation of less toxic compounds

  • ion trapping

  • switch metabolism to less toxic product

  • increase rate of elimination

    • dialysis

    • transfusion

    • diuresis

    • chelation of heavy metals

  • elevate the threshold for toxicity

    • maintenance therapy

    • specifics

      • antagonism

        • the antidote is competing for the same receptor as toxin

Acetaminophen toxicity

• high dose leads to the production of NAPQI due to glutathione

• treatment is N-acetylcysteine

  • uses sulfation in addition to glutathione

• phases

  • phase 1 (0-24 hours): loss of appetite, nausea, vomiting, general malaise

  • phase 2 (24-72 hours): abdominal pain, increased liver enzymes

  • phase 3 (72-96 hours): liver necrosis, jaundice, encephalopathy, renal failure, death

  • phase 4 (>4 days to 2 weeks): complete resolution of symptoms and organ failure

OP intoxication

• insecticides

• nerve gas

• inhibits acetylcholinesterase

  • reversible or irreversible

  • excess of ACh because the enzyme breaks done ACh

• atropine

  • binds to muscarinic receptors, competes with ACh

    • calms down the parasympathetic system

• pralidoxime

  • reactivates AChE

Specifics

• alcohols

  • interfere with metabolism

  • ethylene glycol → glycolaldehyde → glycolate → calcium oxalate crystals → renal failure

  • methanol → formaldehyde → formic acid → retinal injury and permanent blindness

  • antidote: fomepizole

• carbon monoxide → antidote: oxygen (± hyperbaric chamber)

• cyanide → antidote: hydroxocobalamin, sodium nitrite, and sodium thiosulfate

• iron → antidote: deferoxamine

• lead → succimer (dimer-captosuccinic acid, DMSA), dimercaprol, calcium disodium edetate