FPPP -Toxicology

median lethal dose

dose that produces lethal effect in 50% of tested population, often abbreviated as LD50

5 spectrum of undesired effects

allergic reactions, idiosyncratic reactions, immediate vs delayed toxicity, reversible vs irreversible toxic effects, local vs systemic toxicity

chemical allergy

is an immunologically mediated adverse reaction to a chemical and is dose-related for a given individual.

examples of idiosyncratic reactions

succinylcholie and methemoglobin-inducing chemicals; unrelated to chemical’s MOA such as gynaecomastia caused by cimetidine

where does delayed toxicity happen?

can be seen in carcinogenic chemicals(years) and organophosphorus pesticides (weeks) to inhibit the neuropathy target esterase (NTE)

what determines the toxic effects whether reversible or irreversible ? examples of irreversible effects ?

the ability of the exposed tissue to regenerate. carcinogenic and teratogenic effects are irreversible effects once they occur.

the difference between local and systemic toxicity

local effects occur at the site of first contact of chemicals.

systemic effects require absorption and distribution of a toxicant from its entry point to a distant site to produce damages, some of the organs are referred as target organs of a particular chemical.

4 factors affecting the spectrum of undesired effects of chemicals (ADME)Toxicokinetics

absorption, distribution, metabolism, elimination

Toxicokinetics - absorption

is the transfer of the toxins from the site of exposure to systemic circulation.

3 factors affecting the rate of absorption of the toxin

toxin concentration, surface area of exposure, lipid solubility of the toxin

distribution

toxins enter the extracellular space and reach their sites of action.

vessel-rich organs like kidneys and livers tend to accumulate toxins more than less-perfused tissues such as fats and bones.

the presence of tight junctions in the blood brain barrier prevents toxins from entering the brain unless the toxins are lipophilic or toxins are taken up by active transport systems.

metabolism (toxication and detoxication) examples

methanol is metabolised into formic acid which can cause blindness

paracetamol is metabolised into toxic metabolites which can cause liver damage.

detoxication

the toxin is converted to an inactive metabolite or a metabolite of a reduced activity

toxication

the drug is metabolised into a more toxic compound than the parent drug

drug interaction

toxic effects occurs when the toxic agents or its metabolite reach appropriate sites in the body past a harmful concentration and for a sufficient duration of time.

what happen when the toxin binds to the drug target receptor

binding of toxins to the target receptor will lead to a series of secondary biochemical events leading to organ dysfunction, cell injury or dysregulation of ?

elimination

liver and kidneys which are major excretory organs efficiently remove highly hydrophilic toxins from the body.

which toxin are removed slowly?

highly lipophilic and non-volatile toxins can be accumulated by repeated exposure because they are removed very slowly

presystemic elimination

toxins are eliminated when it is transferred from the site of exposure to the systemic circulation

management of poison

prevent further absorption, increase elimination, antidotes, supportive care

how to prevent further absorption of poison? 4 ways

emesis - induce vomiting using ipecac syrup

gastric lavage - wash out stomach contents by repetitive instilling and withdrawal of fluid usually 90% saline

chemical adsorption with activated charcol

prevention of transdermal absorption - wash

one of the method to increase elimination is - urinary pH manipulation, explain how it is done— urinary pH plays an important role in drug ionization

drugs are mainly acidic or basic

thus they are ionized with varying degrees depending on urine pH.

when drugs are ionized, reabsorption is reduced thus increasing excretion

urine pH can be adjusted to promote excretion of drugs

urine alkalinisation — for excretion of acidic drugs and reabsorption of alkaline drugs

acidic drugs such as aspirin, phenobarbital — urine is alkalinised with sodium bicarbonate

drug is ionized, reabsorption is reduced, increase drug elimination

urine acidification - excretion of alkaline drugs and reabsorption of acidic drugs

basic drugs such as chloroquine, quinine—acidify urine with ammonium chloride or ascorbic acid

drug is ionized, reabsorption is reduced and excretion of drug is promoted.

what is the antidote for opioid overdose (heroin, morphine, codeine) ?

naloxone - reverses respiratory depression caused by opioids (AI)

what is the antidote for paracetamol (acetaminophen) overdose?

N-acetylcysteine - prevent liver damage (AI)

what is the antidote for benzodiazepine overdose (diazepam, midazolam) ?

flumazenil - reverses sedative effects (AI)

what is the antidote for poisoning by anti-acetylcholinesterase agents like malathion or parathion ? which are organophosphate insecticides

atropine - block acetylcholine activity caused by organophosphate insecticides

what is the antidote for atropine toxicity ?

physostigmine - reverses anticholinergic effects (AI)

what is the antidote for poisoning ?

methanol - competes with methanol for alcohol dehydrogenase, reducing toxic metabolites

what is the antidote for digitalis (eg, digoxin) toxicity ?

digoxin immune fab

what is the antidote for beta-blocker overdose?

glucagon

what is the antidote for heparin overdose?

protamine sulfate

what is the antidote for iron poisoning

desferrioxamine

what is the antidote for carbon monoxide poisoning

oxygen

what are the signs and symptoms of overdose?

CNS depression, respiratory depression, bradycardia, hypotension, cold,clammy skin, flaccid skeletal muscles, pin-point pupils, coma

how does naloxone treat opioid overdose?

it is administered intravenously (IV)

acts as a competitive antagonist for opioid receptor

has a quick onset of action approximately 30 seconds

explain the pathophysiology of paracetamol poisoning

paracetamol is converted by CYP450 into a toxic metabolite

toxic metabolite is detoxified by glutathione

hence paracetamol overdose depletes the supply of glutathione

when glutathione is depleted, toxic metabolite binds to hepatocytes causing cell death

how does N-acetylcysteine treat paracetamol poisoning ?

N-acetylcysteine binds to toxic metabolite

this maintains the concentration of glutathione

the liver is therefore protected

antidote is most efficacious if given within 8 hours after ingestion of paracetamol

flumazenil for benzodiazepine overdose

administer flumazenil intravenously

competitive antagonist for GABA receptor

has quick onset of action approximately 1-2 minutes

atropine is antidote for anticholinesterase agents

atropine antagonizes the autonomic and CNS effects

binds to acetylcholine (ACh) receptor site and prevents ACh from binfing

antagonizes the cholinergic effects

how does CO cause poisoning the body ?

CO binds to hemoglobin to form carboxyhemoglobin

carboxyhemoglobin cannot transport oxygen

CO further increases the affinity of oxygen for the remaining oxygen-binding sites of the hemoglobin

oxygen is prevented from being released at the tissues leading to hypoxia

sources from carbon monoxide

car exhaust, charcol grills, wood-burning stoves

what are the symptoms of carbon monoxide poisoning ?

headache, dyspnea, lethargy, confusion, drowsiness, high levels of exposure can result in seizures, death and coma

how does oxygen treat CO poisoning ?

administer 100% pure oxygen

oxygen competes with CO and displaces it from the heme group of hemoglobin

how does ethanol against methanol poisoning

ethanol competes with methanol to bind alcohol dehydrogenase and

inhibits the metabolism of methanol to to produce toxic metabolite formic acid

how supportive care should be done, what are the basic principles of supportive care in poisoning ?

ABC approach

maintain open airway

provide adequate ventilation and oxygenation

maintain adequate circulation