Toxicology - Mata Flashcards
What is a toxic response?
• Change from normal state
o Could be on molecular, cellular, organ or organism level
What are the 4 types of toxic response?
- Local vs systemic
- Reversible vs irreversible
- Immediate vs delayed
- Graded (individual) vs quantal (population)
Graded (individual) vs quantal (population) response
- Degrees of the same damage vs. all or none
- Quantal dose-response is extremely important in toxicology and used to determine the median toxic (TD) or lethal (LD) dose of a substance
Dose Response Curve
Shows therapeutic index or dose at which 50% of people given drug will have a therapeutic effect
ED50
Median Effective dose at which 50% of the population responds
TD50
Median Toxic dose at which 50% of the population responds
LD50
Median Lethal dose at which 50% of the population responds
Therapeutic Index
LD50/ED50
On Target Adverse Drug Effects - Intended Tissue
- Dose too high
* Chronic activation or inhibition effects
On Target Adverse Drug Effects - Unintended Tissue
- Correct receptor, but incorrect tissue
- Dose too high
- Chronic activation of inhibition effects
Off Target Adverse Drug Effects
For both intended and unintended tissues
• Incorrect receptor is activated or inhibited
Subtoxic damage
In response to moderate or high doses or drug
What can you do to intervene?
- Reduce absorption of toxin
- Reduce or increase metabolism
- Increase excretion of toxin
- Neutralize toxic effect
GI Decontamination
• Activated charcoal
o Effectively absorbs all drugs or toxic chemicals
• Gastric lavage
o Use after ingestion of:
• Sustained release drugs
• Xenobiotics not absorbed by activated charcoal
Reducing formation of toxic metabolites
Administer agent that alters the production of a toxic metabolite
Reducing formation of toxic metabolites - Acetaminophen Example
• Metabolized by P450 to a reactive metabolite that induces hepatotoxicity
• Greater risk to chronic alcoholics or patients taking drugs that alter P450
• Mechanism of antidote
o Replenishes glutathione and reacts directly with NAPQI
Reducing formation of toxic metabolites - Methanol and ethylene glycol Example
• Metabolized to form highly toxic acids
• Mechanism of antidote
o Fomepizole competitively inhibits alcohol dehydrogenase, an enzyme which catalyzes the metabolism of ethanol, ethylene glycol, and methanol to their toxic metabolites
Increase renal elimination
• Works for weak acids by enhancing increasing urinary pH (ion trapping)
• Antidote
o Sodium bicarbonate (IV)
• Produces urine alkalization (alkaline diuresis)
Increase GI elimination
• GI excretion can be enhanced by increasing adsorption of toxin into the lumen
• Antidote
o Multiple doses of activated charcoal
• Increases the intestinal diffusion of drug in blood → drug in lumen
Neutralizing toxic effects of xenobiotics
• Antidote: Antagonists
o Prevent binding of toxins with its target site
o Prevent binding of endogenous chemical with its target site
Treatment of drug or chemical toxicity
• Antidote: Chemical inactivation
o Bind directly to toxin
• Chelation of heavy metals
o Examples: lead, mercury and iron poisoning
• Antidote: Antitoxin (antibodies to venoms)
o Bind directly to toxic protein from bites of poisonous animals
