Lecture 21_Toxicology II Flashcards
Predictative toxicology
Assesses risks associated with a situation in which the toxic agent, the subject, and exposure conditions are defined. Also saves pharmaceutical industry money if toxic effects of a novel compound are caught early in drug development.
LOEL v. NOEL
- Lowest observed effect level
- No observed effect level
How has increased tech sophistication lowered LOEL?
We can now detect measurable amounts of metals, toxins and pesticides that were undetectable just a few years ago. We can also detect with greater sensitivity the effects that compounds have (in 1974 the acceptable blood level for lead in children was 40 mg/dL; in 1993 it was 10 mg/dL).
Poisonings
- Common (>2 million cases per year) with about a quarter treated at some sort of health care facility and with a fatality rate of 0.07%
Common poisons
- Cleaning substances
- Analgesics
- Cosmetics
- Cough & cold remedies
- Leaves/plant material
- Bites & venoms
Drug categories most responsible for fatalities are (in order):
- Analgesics
- Antidepressants
- Stimulants (including illegal drugs)
- Hypnotic-sedatives
- Antipsychotics
- Cardiovascular drugs
- Alcohols
Breakdown of poisonings by patient age
- 56% of cases involved children under the age of 6
- 6% involved kids aged 6-12
- 38% involved adults.
Poison vs. Antidote
- Poison: Any substance which by its chemical action may cause damage to structure or disturbance of function.
- Antidote: A remedy for counteracting the effects of a poison. This may occur by preventing, minimizing or reversing the effects of the poison.
(T/F) Poisons are drugs.
TRUE. Poisons are just a type of drug with deleterious pharmacological effect.
Principles of poisoning treatment
- Minimize systemic absorption of toxin
- Antagonize effects of toxin that has already been absorbed
- Encourage metabolic processes that reduce toxicity, while inhibiting processes that might increase toxicity
- Enhance rate of elimination of toxin from body
- Provide good clinical care during the recovery phase
Most toxins are absorbed orally (3/4). These should be either expelled or prevented from being absorbed. How is this accomplished?
- Emesis
- Gastric lavage
- Activated charcoal
- Local antidotes
Emesis
Induced vomiting can be used to remove most toxins from the stomach. Ipecac (a mixture of plant alkaloids) is most often used; it triggers emesis in 5-20 minutes by acting at the chemoreceptor trigger zone and by local g.i. irritation. Use of ipecac should not be used during coma or convulsions. Ingestions of a substance that may rapidly produce coma or convulsions, or ingestion of a caustic or corrosive substance is also not advised. Passage of toxin through pylorus (or systemic absorption) decreases the efficacy of emetics so ipecac isn’t given more than half an hour after ingestion of a liquid poison, or one hour after ingestion of a solid poison. Not thought to be a reliable means of expelling poisons and is no longer recommended by the American Academy of Pediatrics. Also misused by people with eating disorders and in cases of Munchausen by proxy.
Why is Ipecac no longer recommended by the American Academy of Pediatrics? Why is Ipecac in general not very effective?
- Ipecac is misused; occurs most frequently with bulimics.
- One of the problems with ipecac and emesis in general is (depending on how full your stomach is, and if the poison is liquid or solid) once the toxin is in the intestine, you can’t vomit it back up.
Gastric lavage
Stomach pumping! Often less effective than emesis induced by ipecac in removing solid material from the stomach. Lavage may be appropriate when emesis is not advised (eg. coma and convulsions), but extreme care must be taken to prevent tracheal aspiration of fluids. This is because you don’t want to breathe in the toxin.
Activated charcoal
This is an inert, odorless, tasteless, nonabsorbable, fine black powder that has a high adsorptive capacity. It will bind most toxins in the lumen of the g.i. tract and thus reduce poison absorption. It is administered in water (25g/100 ml water) and taken orally or by nasogastric tube. A 10:1 ratio of activated charcoal to toxin should be used. The ability of activated charcoal to prevent absorption depends on the poison and the time since ingestion. It may be helpful to add a cathartic like sorbitol to speed the passage of g.i. contents. Cathartic induces diarrhea.
Local antidotes
These are compounds that change the ionic form or alter the solubility of the poison, thus reducing its absorption ands consequently also its toxicity. Eg. Calcium (milk) or magnesium is used to counter fluoride (in mouthwash/toothpaste) poisoning.
Strong acids or bases should never be used to neutralize ingested strong bases or acids, respectively. Why not?
Reaction of strong base and strong acid yields water and salt, but is extremely exothermic!
Modification of absorption and distribution of poisons (What are the different methods for absorbing poisons?)
- Poisons taken orally
- Pulmonary route
- Dermal route
- Parenteral route
How to treat inhaled poisons.
Remove patient from site of exposure to toxic gases. This is because anything you breathe in, you can remove by breathing fresh air.
Some toxins are readily absorbed through the skin (dermal route). How do you treat these toxins?
Minimizing absorption involves washing skin and removal of contaminated clothing. Abrasion of skin may help absorption and so should be avoided.
- BONUS: Nerve gas (sarin), carbon tetrachloride, parathion, phenols, strychnine, nicotine, and tetraethyl lead are absorbed through the skin.
Parenteral route is an injection (bites and injections). How should they be treated?
- Restriction of movement of afflicted limb, will slow distribution. Keep patient calm and still (minimize blood flow). Remove restrictive clothing & jewelry due to swelling at wound site. Try to keep wound at or below heart level. Get the patient to a hospital – carry him rather than letting him walk.
- Do NOT try to cut the wound and suck out the poison – life is not a John Wayne movie! Negative pressure suction may be of some use if done quickly, but who carries such devices (and some believe they do more harm than good)?
- Application of constricting bands proximal to site of injection is also just as likely to do more harm than good (induces hypoxia).
- Identify what bit you before you go in (anti venom is specific to organism).
How can you alter the distribution of toxins using pH?
The distribution of some drugs is partially dependent on pH. The acidemia (acidification of blood) accompanying salicylate poisoning aids in the transfer of salicylate across membranes (such as the BBB). Normalizing blood pH to 7.4 reduces the amount of non-ionized salicylate, decreasing distribution into the CNS.
How can activated charcoal remove morphine from systemic circulation?
In the case of morphine, if the non-ionized form leaves blood and enters the stomach it becomes ionized and has difficulty re-entering the bloodstream. Repeated dosing with activated charcoal can thus still be used in treating morphine overdose even if it is originally administered parenterally.
What are the different antidotal therapy?
- Competitive antagonism
- Noncompetitive antagonism
- Chemical neutralization
- Metabolic inhibition
- Chelation
- Antigen-Antibody
Antidotal therapy: Competitive antagonism examples
Eg. Naloxone (Narcan) is a competitive antagonist at opioid receptors, reversibly competing with agonists for binding sites on the m and k opioid receptors. Flumazenil is a competitive antagonist of benzodiazepine receptor agonists and is used in the treatment of benzodiazepine overdose.
Antidotal therapy: Noncompetitive antagonism examples
Eg. Atropine is used to treat carbamate or organophosphate insecticide poisoning. These insecticides inhibit acetylcholinesterase activity, raising ACh levels. The effects of this excess ACh are antagonized by atropine. Noncompetitive antagonist blocks postsynaptic receptor in PSD, so that any extra neurotransmitter cannot produce an effect postsynaptically (no matter how much neurotransmitter is in the synaptic cleft).
Antidotal therapy: Chemical neutralization examples
Eg., Cyanide combines strongly with the ferric form of iron (Fe3+) in proteins such as cytochrome oxidase (important in oxidative metabolism). Treatment consists of giving patient sodium nitrite which reacts with Fe2+ in haemoglobin, to produce the Fe3+ form that reacts with cyanide bound to cytochrome oxidase. The patient is then given sodium thiosulfate which neutralizes the haemoglobin-bound cyanide to the nontoxic sodium thiocyanate.
Antidotal therapy: Metabolic inhibition examples
Eg., A metabolite of methanol (formic acid) is toxic to the retinal nerve. Treatment consists of giving the patient ethanol which competes with methanol for metabolism by alcohol dehydrogenase, decreasing the rate of formic acid production.
Antidotal therapy: Chelation examples
This type of therapy is used to treat metal poisoning. Chelating agents bind tightly to metals. Examples include dimercaprol (arsenic & mercury poisoning), EDTA (lead poisoning) and deferoxamine (iron poisoning).
Antidotal therapy: Antigen-antibody examples
Serum globulins with specific activity against a specific substance (eg. the active ingredients in snake or spider venom) are used as antitoxins. There are also antitoxins to treat C. botulinum poisoning and digoxin overdose. If you know what toxin came into your body, you can use the specific antigen against the antibody.
Excretion
Attempts to increase excretion of a toxin will only work if the compound is largely excreted unchanged in the urine and if it can be ionized. Not many toxins meet this criterion.
Enhanced renal secretion is accomplished by…
…the systemic administration of drugs that change the pH of urine (sodium bicarbonate to alkalinize, ammonium chloride to acidify). This changes the ionization of basic or acidic toxins, limiting their reabsorption from urine back into blood.
For dialysis of a poison to be successful…
…the toxin must pass freely through the dialyzing membrane and equilibrate quickly between dialysis fluid and blood. If a toxin produces quick and irreversible damage, dialysis is not a useful option.
- Decreased renal or hepatic clearance are indicators of the need for dialysis.
Toxins that respond well to treatment by haemodialysis include…
…ASA, methanol, and ethylene glycol.
How does dialysis work?
- Semipermeable membrane in dialyzer has fresh dialysate and blood going by each other (membrane is between them). It keeps things like RBC and albumin in blood, but small molecules are lost into waste container. Blood going back to patient has lower concentration of toxic molecules as a result.
