Introduction To Principals Of Toxicology Flashcards
What is the primary determinant of drug/substance toxicity?
The dose of the substance.
- almost everything can be toxic at the right dose
Toxic dose vs Lethal dose
Toxic dose (TD50) = the minimal dose of a product that produces toxic effects in 50% of subjects
Lethal dose (LD50) = the minimal dose of a product that kills 50% of subjects
legally a poison must have an LD50 of less than 50mg/kg
Therapeutic index
LD50/ED50
ED50 = effective dose = the minimal dose required for 50% of subjects to experience therapeutic effects
the larger the number, the safer the drug
is a measure of relative safety as well
botulinum toxin has the lowest LD50 of any drug on the market currently
What are extra toxicological terms and definitions that are used?
TLV = threshold limit value
- concentration below which there is no expected adverse effects over a 40hr week
ALD = average lethal dose
- estimated number from accidental deaths in humans
STEL = short term exposure level
- 4x a day which the average being equal to the TLV
What are the safeguards for poisoning?
Airway = get an ET tube and monitor for vomit aspiration
Breathing = supplemental O2 via canal or bags as needed
Circulation = ECG and pulses and BP
Get antidotes if present and able
- glucose/insulin = diabetic shock or hypoglycemia
- naloxone = narcotic overdose
Consider dialysis, N-Acetylcistine and activated charcoal, apomorphine/ipecac as needed to remove/reduce drug exposure
What are the common substances used to induce emesis in toxicity cases?
Apomorphine
Ipecac (methylcephaeline/ cephaeline)
Contraindications to emesis
- ingestion of petroleum hydrocarbons (will induce chemical pneumonitis)
- caustic acid/alkali agents
- seizing or comatose patients
What is gastric lavage?
Tubs is inserted through nose or stomach and irrigate substances out of the stomach
Activated charcoal
Oral administrative agent that binds/chelates numerous toxins and prevents absorption
- almost always induces emesis
- **contraindicated in caustic agents and petroleum hydrocarbons again (induces emesis and causes pneumonitis)
Extra info:
- is known to inactivate ipecac so dont use together
- **in order to achieve maximum effect, must administer within 30 min-2 hrs of ingested poison
Cathartics
Liquid substances that promote very rapid movement and elimination of poison through the GI tract while chelating the poison substances
- induces watery diarrhea very quickly
includes sorbitol, magnesium citrate/sulfate
Pralidoxime
chelating agent that is used for organophosphate poisoning (cholinergic toxidrome such as insecticides, sarin, tabun, etc.)
***administered w/ atropine to block muscarinic effects of parasympathetic nervous system.
Cyanide
Binds to cytochrome c oxidase and mitochondrial membranes of all cells and prevents ETC and cellular respiration
- really hits CNS and cardiac tissues the hardest and causes toxicity to these systems
LD50 = 2 mg/kg and produces death in 1-15 minutes
antidote = give amyl nitrate/sodium nitrite and sodium thiosulfate with oxygen and whole blood. This causes methemoglobin to be produces and combines with cyanide to chelate it and allow it to be eliminated
Botulinum toxin
most potent poison known and very rapidly absorbed
Prevents ACh release form nerve terminals by cleaving SNARE proteins.
- induces respiratory depression to kill
Treatment = lavage/emesis/charcoal or anti-toxin (type A/B/E) if time frame doesnt allow for the previous
- **also always remember your ABCs to seat up safety net
Heavy metals
All pharmacological heavy metals are chelators
- BAL/EDTA/DMSA/DMPS/EDTA
- **most commonly used are BAL (British anti-lewisite (dimercaprol)) and DMSA (dimercaptosuccinic acid (succimer))
DMSA (succimer)
Used to treat arsenic/mercury or lead poisoning
ADRs
- chills/fever/diarrhea/nausea/vomiting
Dosage
- children 1-11 yrs = 10mg/kg every 8 hrs for 5 days. Then every 12 hrs for 14 days (total 19 days)
- adults and children > 12 yrs = 10 mg/kg every 8 hrs for 5 days
Trivalent antitoxin (A/B/C)
Used for botulinum toxicity
- contains neutralizing antibodies against the most common human botulinum forms
Dosage = 10 mL vial diluted 1:10 with isotonic saline and administered via IV drip infusion
- usually does not require additional doses since the dose antibodies far exceed the serum levels
More details about Cyanide antidote
Requires a “kit” that includes amyl nitrate, sodium thiosulfate and sodium nitrate
1) sodium nitrate MOA: oxidizes hemoglobin iron intro the ferric state and converts it to methemoglobin. Cyanide has highest affinity to bind to methemoglobin
* * must be careful with dosage though because too much methemoglobin causes hypotension and hypoxia
2) sodium thiosulfate MOA: reacts with cyanmethemoglobin (methemoglobin + cyanide) to produce thiocyanate + hemoglobin
- essentially takes the cyanide from hemoglobin
- thiocyanate is very easily excreted via urine
Alcohol (ethanol) as an antidote
Used for ethylene glycol/methanol and isopropyl alcohol poisoning
Ethanol competitively inhibits the above substances from being converted into toxic metabolites
- also often need to give hemodialysis in conjunction to ensure safety
Normal conversion
1) any alcohol -> acetaldehyde/formaldehyde
- uses alcohol dehydrogenase (slowly)
- ** this is where ethanol can be used to inhibit
Ethylene glycol specifics
Gets metabolized by alcohol dehydrogenase into 4 toxic metabolites
- glycoaldehyde
- glycolate
- glycolic acid
- glyoxylate
produces high anion gap metabolic acidosis with hypocalcemia and lactic acidosis
in addition, metabolites will bind with calcium to form calcium crystals and induces nephrotic syndrome and renal failure
Antidote therapy
1) IV ethanol (maintain around 100/150 mg/dL)
2) fomepizole (blocks alcohol dehydrogenase)
- **drug of choice for both ethylene glycol and methanol toxicity
- 15 mg/kg initially IV then 10-15 mg/kg every 12 hrs until normal levels are achieved
3) hemodialysis is a must for symptomatic patients
4) can consider giving any of the following as well as adjuvants (#1-3 are required though)
- sodium bicarbonate = corrects acidosis
- pyridoxine = inhibits metabolism of glycolic acid -> oxalic acid
- thiamine = inhibts metabolism as well
Carbon monoxide poisoning
Common means of suicide attempts
- auto exhaust or industrial emissions
carbon monoxide has 210x greater affinity for Hb than does O2 = produces carboxyhemoglobin which cant bind oxygen
Symptoms: (based off of levels of carboxyhemoglobin)
- 20-30% = headache and exertional dyspnea
- 40-60% = severe neurological symptoms and cherry red apperance
- > 60% = coma and convulsions
Treatment
- artificial respiration with pure O2 to promote displacement of CO
- hyperbaric oxygen chamber, if symptomatic
Warfarin review
Blocks all vitamin K- dependent cofactors
- 2/7/9/10/protein C and S
ADRs
- hemoptysis
- excessive bruising
- spontaneous bleeding
- bloody stools/urine
- if toxic levels = severe hemorrhages and very elevated INR
reversal of toxic dosing of warfarin = injection of vitamin K and FFP with prothrombin complex as needed
Naloxone vs naltrexone review
Naloxone
- acts on mu/Kappa/delta receptors to block effects of opiods
- duration of action though = 45 minutes
- usually given in emergency situations
- always induces withdrawal
Naltrexone
- same MOA but has longer duration of action
- 24-72 hrs
- usually given after emergency
Methemoglobinemia antidote
- methemoglobinemia is high levels of methemoglobin (which present with Fe3+ ferric iron instead of Fe2+ ferrous iron.*
- cant bind oxygen
Causes = nitrates, sulfa drugs, genetic causes (G6PD, PK deficiency, methemoglobin reductase deficiency, etc.)
becomes cyanotic skin at 10-15%, lethal is 70%
Antidote = methylene blue!!
- MOA = causes direct chemical reactions to reverse the iron state back to ferrous which can bind oxygen
- does = 1-2 mg/kg via IV
- toxic effects = serotonin syndrome (be careful in patients using serotonin medications)
What is the one weird opioid that presents abnormal to the common opioid toxidrome
Meperidine
Presents with dilated pupils (miosis) and increased HR
- this is due to anti muscarinic effects (only one to have this)
