Mercury

Mercury• a metal that exists in three forms:

– Elemental (liquid at room temperature)– Inorganic salts– Component of organic compounds

• Exposure: inhalation & ingestion* Ingestion – most common route of exposure* Consumption of contaminated food – major source of

exposure* Inhalation & accidental ingestion of inorganic and organic

compounds (industry) – most common reason for toxic levels.

Mercury• Each form of mercury has different toxicologic

characteristics.– Elemental mercury (Hg0)

• can be ingested without significant effects• Inhalation is insignificant because of its low vapor

pressure• largely not absorbed because of its viscous liquid

nature.− Cationic mercury (Hg2+)

• Moderately toxic• Partially absorbed (inorganic Hg)

Mercury− Organic mercury

Methyl mercury (CH3Hg+) – very toxic• Not significantly absorbed• has significant local toxicity in the

gastrointestinal tract• rapidly and efficiently absorbed by passive

diffusion

Mercury Systemic organic mercury (hydrophobic

compartments)Results in high concentrations in brain and

peripheral nerves.Organic mercury is biotransformed to the divalent

state, allowing it to bind to neuronal proteinsElimination: renal filtration of bound low molecular

weight species or free (ionized) state.Elimination rate is slow; chronic exposure exerts a

cumulative effect

Mercury toxicity• a result of protein binding, which results in a change of

structure and function. • The most significant result of this interaction is the

inhibition of many enzymes. Acute gastrointestinal disturbances

− binding to intestinal proteins after ingestion of inorganic mercury

Severe bloody diarrhea− Ingestion of moderate amount− Ulceration and necrosis of the GI tract

Shock / Death− Severe cases

Clinical Significance• Tachycardia• Tremors• Thyroiditis• Disruption of renal function – most significant

– Glomerular proteinemia– Loss of tubular fxn

• Neurologic symptoms– Primary toxic effect of organic Hg.

Low levels of exposure causes

Higher levels of exposure result in

Tremors Hyporeflexia

Behavioral changes Hypotension

Mumbling speech Bradycardia

Loss of balance Renal dysfunction

Death

Atomic Absorption• Analysis of mercury• Uses whole blood or an aliquot of a 24-hr

urine specimen or anodal stripping volametry.• Requires special techniques as a result of the

volatility of elemental Hg.

Pesticides• are substances that have been intentionally

added in the environment to kill or harm undesirable life form

• Classified into several categories – insecticides, herbicides, etc.

• Purpose:been applied to the control of vector-

borne disease and urban peststo improve agricultural productivity

• Can be found in occupational settings and in the home frequent opportunities for exposure

• Contamination of food– major route of exposure to the general

public• Inhalation common occupational

• Transdermal adsorption and accidental routes

• Ingestion of exposure

Pesticides

• Action: target specific but (most) nonselective

toxic effects to many nontarget species (inc. human)

• Health effects:1. Short-term, low-level exposure

– Not yet ellucidated2. Extended low-level exposure

– may result to chronic disease states3. High-level exposure

– may result in acute disease states or death

Pesticides

• People applying the pesticide– most common victims of acute

poisoning • Ingestion by children – also common• Pesticide ingestion

– A common suicide vehicle

Pesticides

• Wide variation in the chemical configuration– from simple salts of heavy metals to complex

HMW-organic compounds• INSECTICIDES are the most prevalent of pesticides

– most common insecticides based on chem configuration

1. Organophosphate– most abundant pesticides– reponsible fo about 1/3 of all pesticide

poisoning2. Carbamates3. Halogenated hydocarbons

Pesticides

• Acetylcholinesterase inhibitor– action of organophosphates and

carbamates• in mammals

– acetylcholine is responsible for stimulation of muscle cells and several endocrine and exocrine glands

• action is terminated by postsynaptic acetylcholinesterase

inhibition of acetylcholinesterase

prolonged presence of acetylcholine on its receptor

Pesticides

Pesticides • Low-level of exposure

Salivation Lacrimation Involuntary urination and defecation

• Higher-level of exposure– Bradycardia -Slurred speech– Muscular twitching -Behavioral changes– Cramps -Death may occur– Apathy

Pesticides • Absorbed organoPO4 bind with high affinity to

proteins (acetylcholinesterase)• Protein binding

– prevents direct analysis = indirect measurement of acetylcholinesterase inhibition

sensitive and specific for organoPO4 exposure

• acetylcholinesterase – membrane-bound enzyme = low serum

activity1. Erythrocytic enzyme

– RBC that have high surface activity are commonly used to increase analytic sensitivity of the assay

– Not commonly performed

Pesticides: Lab Diagnosis

2. Serum pseudocholinesterase(SCHe)– alternative test– inhibited by organoPO4 in a similar

manner to the RBC enzyme – changes in the serum activity of SCHe

lack sensitivity and specificity for organoPO4 exposure

Pesticides: Lab Diagnosis

Pseudocholinesterase (SCHe)– found in liver, pancreas, brain, and serum– biologic fxn: not well defined– decrease level

• Acute infxn• Pulmonary embolism• Hepatitis • Cirrhosis

– several variants demo diminished activity

– not specific for organoPO4 poisoning

– normal ref range: 4000-12000 U/L– intraindividual variation

• degree of variance within an average individual• 700 U/L

• SCHe test is considered as screening test• Immediate antidotal therapy

– initiated in cases of suspected organoPO4 poisoning with decreased SCHe activity

Pseudocholinesterase (SCHe)

Toxicology of Therapeutic Drugs

Salicylates• Aspirin, Acetylsalicyclic acid• Analgesic, Antipyretic, Anti-inflammatory• Functions by decreasing thromboxane and

prostaglabin by inhibiting cyclooxygenase• Drawback: interferes with platelet aggregation

and GI function• Acidic in nature therefore excessive ingestion

is associated with metabolic acidosis

• Treatment: neutralization and elimination of excess acid

• GC or liquid chromatography have the highest analytic sensitivity and specificity

• Trinder reaction- most common chromogenic assay; reacts with salicyclate with ferric nitrate to form a colored complex

Acetaminophen (Tylenol)

• analgesic drugs• overdose is associated with a severe

hepatotoxicity2 forms:• Solely• In combination with other compound

Process of elimination:• Hepatic uptake• Biotransformation• Conjugation• ExcretionPathway of major concern: Hepatic mixed-function

oxidase system• Transformed into reactive intermediates• Conjugated with reduced glutathione

• In overdose situation- glutathione becomes depleted, reactive intermediate increases

• Nomograms are available that predict hepatotoxicity based on serum concentration

Toxicology of Drug Abuse• Drug Abuse

1.Drug Overdose- it is essential to identify the responsible agent to ensure appropriate treatment.

2. Drug Abuse in non overdose situation-provide rationale for treatment for addiction.

Testing for Drug Abuse• Involves screening of a single urine specimen

for many substances by qualitative screening procedures.

• This procedure detects only recent drug use.

• With abstinence of relatively short duration-abusing patient may not be identified

Testing for Drug Abuse• Evaluation of chronic abuse usually involves

several positive test results.

• A positive drug screen cannot discriminate between a single casual use and a chronic abuse.

Drug Abuse or Overdose• Prescription• Over-the-counter• Illicit drugs• Recreational or Performance enhancement

Purposes-most common

Testing for Drug Abuse• Testing for drug abuse has become

commonplace in: – Professional– Industrial – Athletic setting.

• The potential punitive measures associated with the testing may involve or result in criminal litigation .

Testing for Drug Abuse• Laboratories must ensure that data are legally

admissible and defendable.

• Analytic methods are used(accurate and precise)

• Documentation of specimen security.

• Protocols and procedures must be established to prevent and detect specimen adulteration.

Testing for Drug Abuse• Measurement of the ff.:

– Urinary temperature– PH– Specific Gravity – Creatinine

*to ensure that specimen has not been diluted or treated with substances that may interfere with testing.

Drug Abuse Testing1. Screening Test

– Simple– Rapid– Inexpensive– Capable of being automated

2.Confirmatory Test

Screening Test• Often referred to as “SPOT TESTS”

• Have good analytical sensitivity with marginal specificity.

• Detect classes of drugs based on similarities in chemical configuration.

• Allow detection of parent compounds and congeners which have similar effects.

Screening Test• Drawback

– May also detect chemically related substances that have no or low abuse potential .

*Interpretation of positive test results requires integration of clinical context and further testing.

Confirmatory test• Uses methods with high specificity and

sensitivity.

• Provide quantitative and qualitative information.

• GC-mass spectrophotometry (GC/MS)-Reference method for confirmation of most analytes.

General Analytic Procedures commonly used for Analysis of

Drug Abuse1. Chromogenic Reactions- used as screening

procedures.2. Immunoassay-based procedures-screening

and confirmatory assay. Offer a high degree of sensitivity and are easily automated.

Chromatography Technique1.Thin-layer Chromatography

• Inexpensive method for the screening of many drugs.

• No instrumentation is required. • Qualitative identification and

quantitation of drugs.

AMPHETAMINES

a stimulant used for narcolepsy and attention-deficit disorder

Initial effect: Increased mental and physical capacity along with a perception of well-being.

Followed by: Restlessness, irritability, possibly psychosis

AMPHETAMINES

Overdose (rare in experienced users): hypertension, cardiac arrhythmias,

convulsions, possibly death

OTC amphetamines: ephedrine, pseudoephedrine, and phenylpropanolamine

amphetamine-like compounds are common in allergy and cold medications

AMPHETAMINES

Screening: Immunoassay systems (urine)

Confirmatory: Liquid or Gas Chromatography

Usually administered orally in tablets (50-150 mg)

circulating half-life: 8-9 hours

eliminated by: hepatic metabolism (20% unchanged in urine)

onset if effect: 30-60 minutes (up to 3.5 hours)

MDMA“ECSTASY”

METHYLENEDIOXYMETHYLAMPHETAMINE

METHYLENEDIOXYMETHYLAMPHETAMINE

Desired effects: hallucinations, euphoria,

emphatic and emotional responses, and increased visual and tactile sensitivity

A screening test would usually not test positive, thus a confirmatory test must be

performed.

ANABOLIC STEROIDS

Chemically related to testosterone

used as therapy for male hypogonadism

increases muscle mass and improves athletic performance

ANABOLIC STEROIDSANABOLIC STEROIDSANDROGENIC

ANABOLIC ANDROGENIC STEROIDS

Chronic use of steroids: toxic hepatitis

accelerated arthrosclerosis abnormal aggregation of platelets (MI/stroke)

enlargement of the heart (death)

Malestesticular atrophy, sterility,

and impotence

Femalesmasculine traits, breast reduction

sterility

Screening Test:

Testosterone to Epitestosterone Ratio(T/E)

high ratios associated with exogenous testosterone testosterone

ANABOLIC ANDROGENIC STEROIDS

Cannabinoids• Group of psychoactive compounds found in

marijuana.• THC (tetrahydrocannabinol)- most potent and

abundant• Marijuana or Hashish (processed product) can

be smoked or ingested.

Cannabinoids• Subjected effect of exposure:

– Sense of well-being– Euphoria

• Associated with:– Impairment of short-term memory– Intellectual function

• Overdose has not been associated• With chronic use, Tolerance and mild

dependence may develop

Cannabinoids• THC – a lipophilic substance, rapidly removed from

the circulation by passive distribution into hydrophobic compartments, such as brain and fat.

• Results in slow elimination as a result of redistribution of back into circulation and subsequent hepatic metabolism

• Half life: – 1 day after a single use – 3-5 days in chronic, heavy consumers

• Hepatic metabolism products are eliminated in urine.

Cannabinoids• Major urinary metabolite

– 11-nor- - tetrahydrocannabinol-9-carboxylic acid(THC-COOH)

• Can be detected in urine:– 3-5 days after single use– 4 weeks in chronic

• Immunoassay for THC-COOH – screening test• GC/MC – confirmatory• Passive and Direct inhalation

Cocaine • An effective local anesthetic with a few

adverse effects at therapeutic concentrations• A potent CNS stimulator that elicits a sense of

excitement and euphoria• Administered directly

– Insufflation or intravenous injection– Inhaled as a vapor when smoked in the

free-base form (crack)

Cocaine • It has high abuse potential• Half life: 0.5-1 hr• Due to its short half life, it requires repeated

dosages of increasing quantity • Acute cocaine toxicity is associated:

– Hypertension– Arrhythmia– Seizure– MI

Cocaine • Primary factor that determines toxicity:

– Dose– Route of administration

• Intravenous administration-greatest hazard followed by smoking

• Cocaine’s short half-life is a result of rapid hepatic hydrolysis to inactivate metabolites. Major route of elimination.

Cocaine • Benzoylecgonine

– Primary product of hepatic metablism – Eliminated in the urine– Half life: 4-7 hours– Sensitive and specific indicator of

cocaine use– Detected in urine for up to 3 days after

single use and up to 20 days after the last dose for chronic heavy abusers

– Immunoassay (screening)– GC/MC (confirmatory)

Opiates• Class of substances capable of:

– Analgesia– Sedation– Anesthesia

• ALL derived from or chemically related to substances derived from the opium poppy

• Naturally occurring substances– Opium– Morphine– Codein

• Chemically modified forms of naturally occuring opiates– Heroin– hydromorphone

(Dilaudid)– oxycodone

(Percodan)• Common synthetic

opiates– Meperidine

(Demerol)– methadone

(Dolophine)– propoxyphene

(Darvon)– pentazocine

(Talwin)– fentanyl

(Sublimaze)

Opiates

• Have high level of overdose• Chronic use tolerance (physical and psychological dependence)• Acute overdose

– presents with respiratory acidosis– possibly an increase in serum indicators of

cardiac damage• High-level opiate overdose

– may lead to death• Tx: use of naloxone (opiate antagonist)

Opiates

• Laboratory test:1. Immunoassay

– initial screening– most are primarilly designed to detect morphine

and codeine– Cross-reactivity

2. GC/MS– confirmatory method of choice

Opiates

Phencyclidine (PCP)• an illicit drug• properties

– Stimulant– Depressant– Anesthetic– Hallucinogenic

• has high-abuse potential

• Adverse effects are commonly noted at doses that produce the desired subjective effects

• Overdose - assoc with coma and stupor• PCP can be

– ingested– inhaled (by smoking PCP-laced tobacco

or marijuana)

Phencyclidine (PCP)

• a lipophilic dug that rapidly distributes into fat and brain

• Elimination is slow• about 10-15%

– administered dose that is eliminated unchanged in the urine

• Hepatic metabolism forms various products

Phencyclidine (PCP)

• Detection of the parent drug in the urine– ID of PCP

• In chronic heavy users – PCP can be detected 7-30 days after

abstinence• Laboratory test:1. Immunoassay – screening procedure2. GC/MS – confirmatory method

Phencyclidine (PCP)

Sedative-Hypnotics• ALL members of this class are CNS depressants

• High to low abuse potential• Most common type of sedative hypnotics

abusedBarbiturates - have higher abuse

potentialBenzodiazipines -more commonly

found in abuse and overdose situations

• Commonly abused barbiturates:– Secobarbital– Pentobarbital– Phenobarbital

• Commonly abused benzodiazepines:– Diazepam

(Valium)– Lorazepam

(Ativan)– Chlordiazepoxide

(Librium)

Sedative-Hypnotics

• Initial overdose lethargy progress slurred speech

coma

• Respiratory depression– most serious toxic effect

• Hypotension – can occur with barbiturates• Toxicity of these agents is potentiated by ethanol

Sedative-Hypnotics

• Laboratory tests:1. Immunoassay

– most common screening for both barbiturates and benzodiazepines

– Broad cross-reactivity2. GC or Liquid chromatography

– Confirmatory test

Sedative-Hypnotics