Toxicology Flashcards
Drug testing process
Earliest analysis is toxic effects followed by IND application
Clinical trials
- Phase 1: Healthy volunteers; safety concerns and dosages
- Phase II: diseased PTs., toxic effects
- Phase III: large number of PTs., effectiveness, rare side effects
- Phase IV: post marketing research, verification
- ANDA: generic release
- Phase IV: research
Orphan drugs
Drugs for diseases that have that effect Less than 200,000 people
Dosage adjustment equation
Body Surface Area(M^3)/1.73 x adult dose
Category A,D and X
A - no known risks to fetus
D - risk to fetus, therapeutic effect may justify use
X - significant risk to fetus: Do not use in pregnant pt
Schedules
- I: High potential for abuse/dependency no therapeutic value: heroine, PCP et al
- II: High potential for abuse/dependency; Written prescription only, No refills
- III: Moderate potential for abuse; Written or oral prescription, 5/6mo refills
- IV: Limited potential for abuse; Written or oral prescription, 5/6mo refills
- V: Limited potential for abuse; Prescription or OTC
Recall classes
- I: serious health effects or death: contaminated Abx
- II: temporary or medically reversible adverse health consequences:
- III: Not likely to cause any health effects: quantity packaging error
Dialysis of toxins
Primarily a function of volume of distribution
- High Vd indicates low chance of success and visa versa
ABC’s of poison treatment
Airway, breathing, circulation, dextrose
- Alcohol: thiamine (avoids Warneke’s encephalopathy)
- Opioid: Naxalone (narcan)
- Benzodiazepine antagonist (flumazenil)
Assess exposure especially if anyone else may have been affected
Poison treatment physical exam
Vitals, eyes, mouth, CNS, abdomen, skin
Decontamination
- Activated charcoal: superior to emesis and gastric lavage
- Emesis and gastric lavage: especially if < 1 hour postexposure
- Cathartics: laxatives or whole bowel irrigation
Acetaminophen toxicity
P450 converts acetaminophen to NAPQI which is then typically converted to an excreta bowl conjugate via glutathione
- In an acetaminophen glutathione gets overloaded, and the toxic NAPQI builds up and causes hepatotoxicity
- N-acetylcystine, a glutathione precursor is administered to handle the toxic metabolite overload
Cyanide poisoning
Two treatment options:
- nitrates -> methemoglobin + methylene blue -> hemoglobin
- hydroxycolobamin -> cyanocolobamin (soluble excretory product)
Nicotine poisoning
Nicotinic receptors are preganglionic autonomics; Sympathetic and parasympathetic activation. Stimulation followed by inactivation
- insecticide is highly toxic -> coma, resp arrest, HTN, arrythmias,
- Trt: symptomatic; usually if pt survives 4 hours recovery is good
Halogenated aliphatic hydrocarbons
Carbon tetrachloride, chloroform
- chloriform is a CNS depressant
- carbon tet is hepatotoxic
- trt: support/symptomatic
Heavy metal toxicity: Arsenic
Toxin and toxicant (natural and man made)
- MOA: Interferes with oxidative phosphorylation, cell signaling and gene expression
- clinical effects: often seen in manufacturing processes and water supplies/aquatic sources
~ pancytopenia
~ Gastroenteritis
~ Cardiovascular: shock/arrhythmias
~ CNS: encephalopathy, peripheral neuropathy
Heavy metal toxicity: lead
Organic and inorganic forms
Inorganic: deposits in bone (X-ray diagnosis)
- MOA: interferes with essential cations
- Clinical affects: CNS and peripheral neuropathy, HTN, repro toxicity
- can be excreted in breast milk
Organic:
- MOA: hepatic dealkylation (fast) trialkylmetabolites (slow)
- clinical findings: encephalopathy
Heavy metal toxicity: elemental mercury
- MOA: enzyme inhibition, membrane alteration
- clinical findings: tremor, behavioral changes, gingivostomatitis, acrodynia; high dose pneumonitis
- Higher tissue distribution then the other mercury types
Heavy-metal toxicity: inorganic Mercury
- MOA: inhibits enzymes; alters membranes
- clinical findings: Acute tubular necrosis, GI
Heavy metal toxicity: organic mercury
- MOA: alters enzymes, microtubules and neuronal structure
- clinical findings: CNS and birth defects
Heavy metal chelators
Dimercaperol Succimer Penicillamine Calcium EDTA Ferroxamine Unithiol Dferoxamine
Dimercaperol
Arsenic and inorganic/elemental mercury
- in cases of severe lead poisoning, add it to calcium EDTA
- not H2O soluble (admin with 10% peanut oil)
- succimer and unithiol superior agents
Succimer
Use in children with blood [lead] > 45 ng/dl and adults
- arsenic and mercury poisoning
- water soluble
- prodrug: binds cystines to form mixed disulfides
- comparable to parenteral EDTA, and is used more commonly now
- does not affect other Ca, Zn, Mn
Calcium EDTA
- primarily lead
- zinc, manganese, certain heavy radionuclides
- 1 hour 1/2 life
- nephrotoxicity if not careful (hydration, low adequate dose)
Ferroxamine
Iron and aluminum
Unithiol
- increases excretion of mercury, arsenic and lead
- associated with sever allergic rxns, Stevens-Johnson syndrome
Penicillamine
- D is less toxic than L isomer
- readily absorbed in the gut
- copper chelators: Wilson’s disease
Deferoxamine
- Iron chelator
- in combo with dialysis useful for treatment of aluminum toxicity in renal failure
- IM/IV
- can cause hypotension and increased susceptibility to yersinia enterocolitica
Chlorinated hydrocarbons (4) ABCD
- insecticides: DDT, Benzine Hexachlorides, cyclodienes, toxaphens
DDT
- Poor dermal absorption
- prevents inactivation of Na channels -> depol of neurons
- inhibits Ca transport -> increases neuronal excitability
- symptomatic treatment
bipyridyl herbicide: paraquat
Oral toxicity
- free radical production
- initially GI irritation hematemesis, bloody stools
- accumulation in lungs-> edema, alviolitis, progressive fibrosis
- treat with activated charcoal, gastric lavage and symptomatic care; PROMPT IS KEY
Chlorophenoxy herbicides
- increased risk of Hodgkin’s lymphoma
- 2,4 D: large doses req for coma/hypotonia. Symptoms last weeks
-2,4,5D: coma more muscular effects - TCDD: by product of combustion of organic + chlorine
~ MOA: Aryl Hydrocarbon receptor
~ forest fires, bleaching, waste incineration
~ agent orange
~ Chloracne
~ human tumor promoter
Organophosphates
- MOA: AChE inhibition-> hypercholinergic effect: DUMBELS
- trt: atropine and pralidoxamine (AChE agonist)
Carbamate insecticides
- less toxic, effects more transient
- pralidoxamine is not indicated
Venomous vs. non venomous snakes
- triangular head
- pits AND nostrils
- elliptical pupil
- undecided scales on underside of tail
Jimsom weed
- all parts toxic
- contains atropine, scopolamine, hyocyanamine
- anticholinergic effect: mydriasis, flushed dry skin, agitation, tachycardia, hyperthermia, hallucinations
Death cap mushroom
- amanitin: inhibits RNA Pol II -> hepatocellular necrosis
- death may occur 4-9 days after infection
Alcohol toxicity treatment
Administration of thiamin helps avoid Wernecke’s encephalopathy
Opioid overdose treatment
Naxalone (Narcan)
SO2
- combustion of fossil fuels: colorless irritant
- clinical: bronchospasm, pulmonary edema
- trt: support
NO2
- waste fires and silage on farms: brown irritant
- clinical: bronchial irritation, pulmonary edema
- trt: support
CO
- causes tissue hypoxia; HA followed by confusion, deteriorating visual acuity, coma, seizures, death
- Trt: pure O2; hyperbaric oxygen therapy may help
Aromatic hydrocarbons
Benzene, toluene, xylene
- CNS depression, ataxia, coma
- industrial, chemistry settings
- trt: support
Rotenone
Plant insecticide
- irritant: dermatitis, GI irritation
- trt: symptomatic
Pyrethrum
- plant alkaloid insecticide
- most commonly irritation: contact dermatitis, CNS excitation -> seizures
- trt: generally support, anticonvulsant
Glyphosate
Irritant
Trt: Support
PCB (polychlorinated biphenyls)
- bioaccumulate in food chain, electrical equipment manufacturing
- dermatotoxic, screws with liver enzymes
TDCC
by-product of combustion of organic + chlorine
~ MOA: Aryl Hydrocarbon receptor
~ forest fires, bleaching, waste incineration
~ agent orange
~ Chloracne
Membrane depressant cardiotoxic drugs OD
- tricyclic antidepressants, quinidine
- trt: bicarbonate, sodium
Fluoride OD
- calcium channel blockers
- give calcium
Short acting beta-blockers OD
- theophylline, caffeine, metaproterenol
- esmolol
Methanol, ethaleneglycol OD
Ethanol, fomepizol easier to use
Benzo OD
Flumazenil
- Cind: seizures, benzo dependance
Delirium caused by anticholinergic agents
Phyostigmine
B-blocker OD
Glucagon
Fomepezil
Methanol/ethylene glycol antidote
Previously healthy patient presents to the emergency room after burning refuse. He is suffering from headaches, nausea, dizziness and is cyanotic and upon admission begins to seize. His breath has a distinct odor of bitter almonds.
Diagnosis: cyanide poisoning
- cytochrome C oxidase inhibition
Trt: hydroxycolobamin or nitrates/sodium thiosulfate followed by methylene blue.
45-year-old man previously healthy reports to the ED with Bright cherry red skin on his extremities, nausea/vomiting dizziness, confusion. The wife reports that he was working out in his shop and had a small kerosene heater burning when she found him.
Diagnosis: CO poisoning (looks just like cyanide poisoning: clues in history)
Trt: 100% O2 and hyperbaric therapy
