22) Toxic substances Flashcards
father of modern toxicology
Paracelsus
positive screens require drug confirmation method with…
Definitive or reference method (GC-MS or LC-MS)
2 steps of toxic drug test
- screening test; qualitative
- confirmatory test; quantitative
a cutoff value is ———- than the detection limit, but —— enough to detect drug use within a reasonable time frame
higher
low
————– are not always specific for the drug tested.
Immunoassays
significant factors the CLS should be familiar in reference to drug abuse screening
Detection limit
Specificity (lack of)
Cutoff values
Interpreting positive versus negative results
3 types of invalid urine specimens
- adulteration
- dilution
- substitution
A specimen containing a substance that is not a normal constituent or containing an endogenous substance at a concentration that is not a normal physiological concentration
adulterated urine
Creatinine and specific gravity values that are lower than expected for human urine
dilute urine
Creatinine and specific gravity values that are so diminished or so divergent that they are not consistent with normal human urine
substituted urine
A specimen is considered to have been adulterated if it meets specific criteria established by the Substance Abuse and Mental Health Administration (SAMHSA):
- pH…
- nitrite…
- 5 substances present
- pH <3 or ≥11
- Nitrite concentration ≥ 500 ug/mL
- Chromium (VI)
- Halogens (bleach, iodine, fluoride)
- Glutaraldehyde
- Pyridine
- Surfactant
creatinine concentration is <2 mg/dL and the specific gravity is ≤1.0010
OR
≥1.0200 on both the initial and confirmatory tests on two separate aliquots
substituted urine
Creatinine concentration is 2-20 mg/dL
and
Specific gravity is 1.0010-1.0030 on a single aliquot.
dilute urine specimen
urine adulteration test strip reactions
- Creatinine
- nitrite
- glutaraldehyde
- pH
- specific gravity
- bleach
- pyridinium chlorochromate
- oxidants
Intect® 7
AdultaCheck®
Alere Toxicology PLC
urine adulteration test strips
3 major effects of acetaminophen
- anti-inflammatory
- analgesic
- antipyretic
Toxic doses, described as 2-3 times the maximum therapeutic dose, cause a serious and potentially fatal hepatotoxicity.
acetaminophen
mechanism of acetaminophen’s liver toxicity
saturation of enzymes catalyzing the normal conjugation reaction and results in the drug being metabolized by mixed function oxidases which produces a toxic metabolite that causes necrosis in the liver.
Blood samples should be obtained after 4 hours to ensure absorption is complete
acetaminophen
Not useful if the time of ingestion is unknown or unreliable
acetaminophen levels
Most commonly consumed drug in the world
aspirin
indications for aspirin use
- Cardiovascular disorders
- Colonic and rectal cancer
- Alzheimer’s disease
- Radiation-induced diarrhea
Repeated ingestion of fairly large doses
Syndrome associated with tinnitus (a high- pitched buzzing noise in the ears), vertigo, decreased hearing, and occasionally nausea and vomiting
salicylism
Follows an acute viral illness in children
Involves the liver and central nervous system (CNS)
Has a 20-40% mortality outcome.
Reye’s syndrome
(aspirin)
Causes several metabolic changes in the body (3 types of acid-base disorder)
salicylate poisoning
3 ways aspirin can cause acid-base disturbances
- resp alkalosis; hyperventilation
- resp acidosis; respiratory depression, decreased serum bicarb
- metabolic acidosis; accumulation of pyruvic acid, lactic acid, acetoacetic acid
Excessive elevation of body temperature >106.7°F
hyperpyrexia associated with aspirin poisoning
Can increase the effect of warfarin by displacing it from plasma proteins in addition to its effect on platelets
aspirin
Trinder reaction
aspirin
90% metabolized, 5-10% excreted unchanged in expired air and urine
ethanol
Metabolism of ethanol in the liver involves successive oxidations:
- First to acetaldehyde by the enzyme alcohol dehydrogenase
- Then to acetic acid by aldehyde dehydrogenase
- The intermediate metabolite acetaldehyde is a reactive and toxic compound that may contribute to the hepatotoxicity
can barely walk, vomiting, possibility of LOC
0.20 - 0.249%
alcohol poisoning
0.25 - 0.399%
onset of coma, death with alcohol
> 0.4%
The effect of CO on the oxygen dissociation curve is a shift to the ——-, which decreases the release of oxygen in the tissue
left
———- is formed via interaction of CO with nitric oxide (NO) release by platelets
Peroxynitrite
CO normal ranges and criticals
normal: 0-3%
smokers: 5-10%
critical: >60%
treatment of cases when COHb >20%
Hyperbaric oxygen therapy
Act by releasing monoamines from nerve terminals in the brain
amphetamines
effects of amphetamines
- Locomotor stimulation
- Euphoria and excitement
- Anorexia
———- are a class of drugs whose effects mimic those of stimulated sympathetic nervous system.
Sympathomimetics
(amphetamines)
Class of drugs that form the largest group of hypnotics and sedatives
barbiturates
Reversibly depress the activity of all excitable tissues
barbiturates
Anti anxiety properties of ——– are inferior to those exerted by the ————–.
barbiturates
benzodiazepines
Hypnotic doses increase the total sleep time and alter the stages of sleep in a dose-dependent fashion
barbiturates
Can form alcohols, ketones, phenols, or carboxylic acids, all of which may appear in the urine
barbiturates
Represent the most widely prescribed drugs due to their principal pharmacological effects
benzos
Act selectively on GABA receptors, which mediate fast inhibitory synaptic transmission throughout the CNS
benzos
High lipid solubility causes them to accumulate gradually in body fat
benzos
Completely metabolized and are excreted as glucuronide conjugates in the urine
benzos
Catalepsy: Retention of fixed unnatural postures
THC
highly lipophilic and therefore are sequestered in body fat, and excretion continues for several days after a single dose
THC
Pharmacological effects lie in its ability to inhibit catecholamine uptake by the noradrenaline and dopamine transporters.
cocaine
Euphoria, garrulousness, increased motor activity, and a magnification of pleasure
cocaine
Illegal use: Uses hydrochloride salt
cocaine
Primary adverse effects include cardiac dysrhythmias and coronary or cerebral thrombosis.
cocaine
Qualitative screening test in urine is designed to detect the metabolite benzoylecgonine.
cocaine
A long-acting μ-receptor agonist
methadone
Causes miosis or constriction of the pupils in most patients
methadone
Widely used as a drug to treat morphine and diamorphine addicts.
methadone
Applies to any substance, whether endogenous or synthetic, that produces morphine-like effects that are blocked by antagonists such as naloxone hydrochloride (Narcan)
opioid
Synthetic, morphine-like drugs with nonpeptidic structures
opiate
An extract of the poppy Papaver somniferum that has been used for centuries to produce euphoria, analgesia, sleep, and to prevent diarrhea
opium
Federal DHHS guidelines and DOT regulation currently limit drug testing for opiates to…
heroin, morphine, and codeine
In the clinical lab, Immunoassays for opiates are designed primarily to detect morphine and codeine at a cutoff concentration of —– ng/mL
300
Treatment for opiate overdose may include administration of ———– by IV
naloxone
Brand name Sernyl, street name “angel dust”
Phencyclidine/PCP
Affect thought, perception, and mood without causing marked psychomotor stimulation or depression.
Phencyclidine/PCP
Drugs with a chemical resemblance to known neurotransmitters (——–)
Drugs unrelated to monoamine neurotransmitters (———)
LSD
PCP
Primary mechanism of action is to block the uptake of amines by nerve terminals for binding sites on the transport protein.
Tricyclic Antidepressants (TCA)
Most ———– lead is absorbed, but only 20-70% ———- lead is absorbed
inhaled
ingested
Adults retain <1%, where children <2 years old retain 30%
lead
hemolytic anemia
Acute, high-level lead exposure
hypochromic microcytic anemia
chronic lead exposure
Current biomarker for assessment of lead exposure is…
venous whole blood lead with or without measured fluorinated ethylene propylene (FEP)
ferrochelatase
ALA dehydratase
lead inhibition
Competes with ethanol for alcohol dehydrogenase (ADH), and ethanol is used as an antidote.
methanol
Methanol is metabolized by ADH to form ———— (instead of acetaldehyde with ethanol) which converts to ———–.
Causes severe metabolic acidosis.
formaldehyde
formic acid
Methanol conversion not only takes place in the liver, but also the….
retina
blindness can occur
Central scotoma (island-like blind spot), blurred vision, tunnel vision, or diplopia
methanol
2 treatments for methanol poisoning
ethanol
hemodialysis
Metabolized to glycoaldehyde, glycolic acid, glyoxylic acid, and ultimately oxalic acid.
ethylene glycol
———- induces metabolic acidosis during ethylene glycol poisoning
———- leads to CaOx in urine
Glycolic acid
Oxalic acid
3 stages of ethylene glycol poisoning
- neurologic
- cardiopulmonary
- renal (>24 hours)
tx for ethylene glycol
ethanol or fomepizole
hemodialysis when severe
Many ERs have a wood’s lamp that provides a long-wavelength UV radiation to detect ——————-
additive in radiator fluid
fluorescein
Oxidized to a ketone (acetone) and no further
ketonemia without acidosis
isopropanol
Tricyclic structure, with two benzene rings linked by sulfur and a nitrogen atom
Antipsychotics
phenothiazines
Class of compounds referred to as anticholinesterase agents.
Organophosphate and Carbamate Compounds
Used extensively in agricultural insecticides, in pesticides, and as potential chemical warfare “nerve gas.”
Organophosphate and Carbamate Compounds
Testing is available to measure serum butyrylcholinesterase (pseudocholinesterase) activity to diagnose acute ingestion or monitoring chronic exposure
Organophosphate and Carbamate Compounds
“Liquid ecstasy, liquid X, liquid XE, Georgia home boy, scoop, fantasy”
Gamma-hydroxybutyrate (GHB)
Structurally similar to the inhibitory neurotransmitter γ-aminobutyric acid (GABA)
Cause deep, short-lived coma (1-4 hours long)
Gamma-hydroxybutyrate (GHB)
Usually have spontaneous recovery with no recollection of taking drug due to anterograde amnesia
Gamma-hydroxybutyrate (GHB)
Nonbarbiturate anesthetic compound structurally similar to PCP
ketamine
Primarily affects the cerebral cortex and locus coeruleus
LSD
Blood levels in the range of ng/dL or µg/kg
ultratrace metals
Incorporated into antacids and astringents
aluminum
↓ PTH and ↑ Aluminum
aluminum toxicity
Treatment of Leishmaniasis
Treatment of Schistosomiasis
antimony
Chronic workplace inhalation exposure leads to pneumoconiosis or pneumonitis (inflammation of the lungs)
antimony
Arsenobetaine and arsenocholine
nontoxic forms of arsenic
Monomethyl arsine (M M A)
Dimethyl Arsine (D M A)
arsenic metabolites
British anti-Lewisite
Succimer
tx for arsenic toxicity
A large percentage of absorbed ——— accumulates in the skeleton.
beryllium
Develop chronic beryllium disease or berylliosis
beryllium toxicity; workers in industry
The ——————- uses a sample of blood that measures beryllium sensitization, which represents an “allergic” reaction to beryllium.
beryllium lymphocyte proliferation test (BeLPT)
The slow release of ————- from the metallothionein (MT)-complex in hepatic cells accounts for its long biological half-life of nearly 10 years
cadmium
Chromium can enhance insulin receptors on cell membranes by binding with ——–
chromodulin
An essential metal in vitamin B12
cobalt
Associated with several metalloproteins and is essential for selective reduction-oxidation reactions
copper
Inborn error of metabolism caused by a defective gene that regulates the metabolism of copper in the body
Menkes Syndrome
An inherited autosomal recessive trait characterized by a defect in the metabolism of copper
Wilson disease
s/s of Wilson disease
- Kayser-Fleischer rings in the eyes (copper deposits)
- Both plasma copper and ceruloplasmin will be decreased
- Nonceruloplasmin-bound fraction of copper is increased, allowing copper to be deposited in the skin, eyes, brain, and kidneys
Result of a gene defect that is characterized by an absence of ceruloplasmin
progressive neurodegenerative condition that results in tremors
Aceruloplasminemia
Serves as an important constituent in several metalloenzymes that function to facilitate specific enzymatic reactions:
Superoxide dismutase
Pyruvate carboxylase
Arginase
Glycosyl transferases
manganese
Enzyme that contain metal ions in their structures and serves as an essential component or cofactor
Metalloenzyme
Chelation therapy with BAL or succimer, hemodialysis, and combinations of the 2 therapies
mercury poisoning tx
Nonmetal thought to be closely associated with vitamin E in its functions.
Selenium
Used in medicine as a bactericidal agent
Inserts itself into DNA structures, but doesn’t destroy the double helix
Inhibits fungal DNAse
silver
Permanent bluish-gray discoloration of skin, mucous membranes, and nails because of silver deposits in those tissues.
argyria
2nd to iron as the most abundant trace metal in the body
zinc
Inhaling asbestos containing dust leads to deposition of asbestos fibers in the pulmonary alveoli. (silicon)
Asbestosis