Lash - Toxicology I Flashcards
Toxicology:
Toxicology: study of harmful effects of chemicals on biological systems.
Toxicokinetics:
Absorption, distribution, metabolism and excretion (ADME) of toxins, toxic doses of therapeutic agents, and their metabolites
Toxicodynamics:
The injurious effects of these substances on vital functions
o A chemical produces toxic effects on a biological system whenever it reaches a critical concentration in the target tissue.
Route of Exposure (4)
Route of Exposure: can influence the response to a given dose
o Ingestion (GI tract) o Inhalation (lungs) o Topical (skin) o IV (generally have the greatest and most rapid effect when administered this way)
Toxicity rating chart for chemicals in general
Practically nontoxic > 15 g/kg More than 1 quart
Slightly toxic 5 - 15 g/kg Between pint and quart
Moderately toxic 0.5 - 5 g/kg Between ounce and
quart
Very toxic 50 - 500 mg/kg Between teaspoonful
and ounce
Extremely toxic 5 - 50 mg/kg Between 7 drops and
teaspoonful
Super toxic < 5 mg/kg A taste (< 7 drops)
Durations of exposure: (3)
(1) Acute exposure- a single exposure or multiple exposures over 24-hr period;
(2) Subacute exposure- multiple exposures over 24-hr to 3 month period;
(3) Chronic exposure- multiple exposures over period of 3 months or more.
Two classes of poisons:
Cumulative: accumulate in body and cause irreversible damage
TOTAL EXPOSURE important
Non-Cumulative: readily cleared by the body and do not cause permanent damage if given in low dose
INDIVIDUAL DOSE important (total dose not important as long as individual doses are small)
Examples: aspirin and acetaminophen
Normal vs. overdose kinetics
Administration of drugs under therapeutic conditions: normally eliminated via FIRST ORDER kinetics
Overdose or poisoning: drugs often eliminated by a ZERO ORDER kinetics
o Rate of elimination independent of drug concentration present
o Occurs due to saturation of some process of elimination scheme (ie. enzymatic conversion)
Zero order rate constant (k) =
Rate independent drug interaction.
Zero order rate constant (k) = (A0-A)/t
Rate of elimination per unit time is determined as the difference between initial concentration and concentration at time x, divided by the time x
Units are mg*hour-1
Plotted as a straight line on plot of concentration vs. time
Dose-dependent elimination of toxins:
First order kinetics can be seen at low doses of drugs/toxins
At higher doses, a mixture of first order and zero order may be seen
At even higher doses, complete saturation may occur and zero order kinetics will predominate
Zero-order rate constant:
k= (Ao-A)/t
Alcohol dehydrogenase metabolism
Alcohol dehydrogenase saturated at relatively low [alcohol]
After ingesting several ounces of alcohol, it is eliminated via a zero-order kinetic process
Important Concept: increasing the dose of a toxin at levels where zero-order elimination is observed can produce a DISPROPORTIONATE increase in the blood level of the toxin
Why? Because rate of toxin degradation does not increase to accommodate.
Aspirin metabolism
Rapidly hydrolyzed to salicylate by plasma esterases
Salicylate –> Salicyluric acid (conjugated to glycine)
Metabolic step changes from first order to zero order above a dose of 1g of aspirin (ie. only takes 3 tablets to saturate system)
How do heavy metals exert toxic effects?
Toxic Effects: exerted by their combination with one or more reactive groups that are essential for physiological function
o Example: amino acid groups that play a critical role in catalysis (binding of metals can lead to inhibition of catalytic activity)
3 types of lead poisoning:
Acute inorganic, chronic inorganic, organic
Acute Inorganic Lead Poisoning:
Symptoms:
Diagnosis:
Symptoms: severe GI distress progressing to CNS abnormalities (stupor, convulsions, coma, encephalopathy) and eventually death
Diagnosis: difficult because similar symptoms to appendicitis, peptic ulcer and pancreatitis.
Chronic Inorganic Lead Poisoning:
Symptoms:
Most characteristic finding:
Symptoms: weakness, anorexia, nervousness, tremor, weight loss, headache, GI symptoms, recurrent abdominal pain, extensor muscle weakness WITHOUT sensory disturbances
Most characteristic finding= wrist drop
Organic Lead Poisoning:
Cause:
Symptoms:
Cause: tetraethyl or tetramethyl lead in gasoline (organic lead)
- Highly volatile and lipid soluble so it is readily absorbed through the skin and respiratory tract
- No longer a component of gasoline so much less organic lead in the environment
Symptoms: acute CNS disorders but few hematological abnormalities
- Symptoms may progress rapidly and cause hallucinations, insomnia, headache and irritability
Half life of lead in blood? Bones? Circulating lead is associated with?
Blood: 2 mo.
Bones: 20 years
RBCs
2 tests to diagnose lead poisoning:
Blood Tests:
Lead: toxic concentration is >0.5mg/mL (>80μg%)
Primary screening Erythrocyte Protoporphyrin (FEP): concentration >1.1mg/mL (>190μg%) indicates lead toxicity
Builds up due to inhibition of ferrochelatase enzyme in the heme biosynthesis pathway
Urine Tests:
Lead: toxic concentration is >0.15mg/L
Most patients with lead toxicity have urine lead concentrations of 0.15-0.30mg/L
δ-ALA: concentration >19mg/L indicates lead toxicity
Builds up due to inhibition of δ-aminolevulinate dehydratase enzyme in the heme biosynthesis pathway
Biochemical effects of Pb: (3)
Inhibition of several sulfhydryl-containing enzymes involve in heme synthesis
Increased urinary levels of δ-ALA, coproporphyrin, and porphyrin
Causes anemia (hypochromic, microcytic) by inhibiting Hb synthesis in bone marrow and increasing the fragility of RBCs
Treatment of Pb poisoning:
Prevention of further exposure and supportive measures
Maintain fluid and electrolyte balance
Medications:
Diazepam (seizures)
Mannitol and dexamethasone (cerebral edema)
Three common chelators employed to treat lead poisoning:
Dimercaprol
CaNa2EDTA
- First two usually combined initially
D-Penicillamine
- Oral, given after above combination, used for long term treatment
Biosynthesis pathway of Heme
Succinyl CoA + Glycine ↓ (δ-ALA Synthase)* ↓ δ-Aminolevulinate (ALA) ↓ (δ-ALA Dehydratase)** ↓ Porphobilinogen ↓ (Porphobilinogen deaminase) (Uroporphyrinogen III cosynthase) ↓ Uroporphyrinogen III ↓ (Uroporphyrinogen decarboxylase) ↓ Coproporphyrinogen III ↓ (Coproporphyrinogen oxidase)* ↓ Protoporphyrin IX ↓ (Ferrochelatase + Fe2+)** ↓ Heme
(Lead poisoning: increase in δ-ALA, coproporphorin, protoporphyrin)
Forms of mercury:
Organic Mercurials (ie. methylmercury):
Elemental Mercury:
Inorganic Mercury:
Diagnosis of mercury poisoning: (2)
Elevated serum creatinine and BUN (kidney damage)
Hair analysis for mercury (chronic intoxication)
Organic Mercurials (ie. methylmercury):
More completely absorbed through the GI tract than inorganic forms (most dangerous)
- Short chain organic mercurials are also volatile and may be toxic via inhalation; predominantly distributed to the CNS
Elemental Mercury:
Poorly absorbed from GI tract, but is quite volatile and can be absorbed through the lungs; rapidly oxidized in the body to form inorganic mercury
Inorganic Mercury:
Most of it is excreted from the body over a 1 week period (via the urine), but kidneys and brain retain mercury for longer periods
Mercury
Biochemical effects: (3 points)
covalent bonds with:
corrosive due to:
Mercuric ion forms covalent bonds with sulfhydryl group of intracellular proteins (results in toxicity)
Mercury is corrosive due to ability to precipitate proteins on contact
Can cause toxic effects even at very low concentrations (inactivate sulfhydryls and interfere with cellular metabolism)
Treatment of mercury poisoning (acute): (3)
Removal from exposure
Chelation treatment with dimercaprol
If renal damage, hemodialysis will be required
Treatment of mercury poisoning (chronic): (3)
Chelation treatment with oral penicillamine or N-acetlpenicillamine required
DMSA (2,3-dimercaptosuccinic acid) may also be useful
Monitor mercury levels to assess removal by chelators (important)
