Toxicology

TOXICOLOGY (PART I)

Mrs. Ma. Indira P. Bio, RMT

TOXICOLOGY

l The basic science of poisons

l The study of the adverse effects of chemicals on living organisms

Different Areas of Toxicology:

• Mechanistic

• Descriptive

• Regulatory

The Importance of Dose

Poison - any agent capable of deleterious response in a biological system, seriously injuring function or producing death

“What is there that is not poison? All things are poison and nothing is without poison. Solely the dose determines that a thing is not a poison”

-Paracelsus

DOSE - the total amount of a toxicant administered to an organism at a specific time intervals.

- quantity per unit body weight or per body surface area

“There are no harmless substances, only harmless ways of using substances”

Emil Mrak

Major factors that influence toxicity:

1. Route & Site of Exposure

Major routes by which toxic agents gain access to the body:

GI Tract

Lungs

Skin

Bloodstream

Other parenteral routes

2. Duration & Frequency of Exposure

Acute - exposure to a chemical for less than 24 hours

Subacute - repeated exposure to a chemical for 1 month or less

Subchronic - 1-3 months

Chronic – more than 3 months

Drugs of Abuse

COCAINE

History of Cocaine Use

• Cocaine was first extracted from coca in the 19th century and was at first hailed as a miracle drug, being the first ever discovered local anaesthetic.

• In 1880s, it was freely prescribed for exhaustion, depression and morphine addiction

• Cocaine was originally a vital ingredient in "Coca cola", hence the name, and until its addictive characteristics were discovered, it remained in the drink.

Source

• Derived from the plants of Erythroxylon coca indigenous to Peru and Bolivia

Chemistry

• Cocaine is benzoylmethylecgonine

• An ester of benzoic acid and a nitrogen base

Route of administration

• Inhalation

Effects

• Induces a euphoric state, hallucinatory states and violent behavior

• Has dopaminergic effects that induce increased calcium influxes in dopaminergic neurons which activates phospholipases.

Treatment

• Antidepressants, including tricyclics and fluoxetine (Prozac)

Half-life of cocaine: 0.5-1 hour

Benzoylecgonine - the primary product of hepatic metabolism which is eliminated in the urine

- the presence of this metabolite in the urine is a sensitive and specific indicator of cocaine use.

- can be detected in the urine for up to 3 days after a single use

- in chronic heavy users it can be detected for up to 20 days after the last dose.

Screening test: immunoassay

Confirmatory Test: GC with mass spectrometry

OPIATES

• Morphine

• Codeine

• Heroin

“Poppies will make you sleep”

- Wizard of Oz

Source: Papaver somniferum or poppy plant

Morphine

Morphine is a narcotic analgesic. Morphine was first isolated from opium in 1805 by a German pharmacist, Wilhelm Sertürner. Sertürner described it as the Principium Somniferum. He named it morphium - after Morpheus, the Greek god of dreams.

Route of Administration:

• Morphine can be taken orally in tablet form, and can also injected subcutaneously, intramuscularly, or intravenously

Opiates share the same brain receptors and have analgesic properties similar to the naturally occurring painkillers in the body known as endorphins or enkephalins. Their sensory and motor CNS depressant effects make them valuable clinically as analgesics, sedatives and antispasmodics

Codeine

Also known as methylmorphine or morphine monomethyl ether

Heroin

• Derived from the dried sap of the opium poppy.

• Heroin is in the same category of painkillers as morphine, its derivatives and codeine.

• The effects of heroin include significant pain relief, but as dose is increased, euphoria is produced.

• At very high doses, sedation, respiratory depression and coma may occur.

Route of Administration

• Intravenous

Addiction to the drug is readily recognized by the presence of needle tracks on the user’s arm and hands and by extensive thrombosis of the peripheral veins.

Major metabolite of heroin: N-acetyl morphine and morphine

Treatment: Naloxone given intravenously

Methadone for chronic cases

Confirmatory test: GC with spectrometry

Methadone

• Introduced into the United States in 1947 as an analgesic (Dolophine),

• A non-bicyclic drug that binds competitively with morphine to m- receptors in the brain.

• Addictive effects are less than those of equivalent concentrations of heroin

• Methadone is primarily used today for the treatment of narcotic addiction

Amphetamines

• Amphetamines belong to a group of drugs called psychostimulants that stimulate the central nervous system.

• Street terms for methamphetamine: Meth, poor man's cocaine, crystal meth, ice, glass, speed

• Typically meth is a white powder that easily dissolves in water

Amphetamine-like substances that causes cross-reactions with amphetamine assays:

Effects:

• Exerts symphathometic effects due to its uncanny resemblance to epinephrine and norepineprine

• They have effects on the dopaminergic pathways causing psychic stimulation and excitability leading to euphoric states and increase mental and physical activity.

Route of Administration:

• Most commonly swallowed, injected (methamphetamine) or smoked. They are also snorted , or sniffed , through the nose.

MDMA(Methylendioxymethylamphetamine)

• Another designer drug related to amphetamines. It is usually swallowed in the form of small tablets, but is also sometimes injected.

Similar (in nature) to other amphetamines and hallucinogens

It speeds up the nervous system and acts as a mood enhancer.

Benzodiazepines

• Also referred to as minor tranquillisers.

• They work by slowing down the activity of the CNS.

• They slow the messages going to and from the brain to the body, including physical, mental and emotional responses.

• family of drugs used to treat insomnia, anxiety, panic attacks, muscle spasms, and seizure disorders.

• Diazepam (Valium) is the most prominent drug among these.

• The benzodiazepines act mainly through the GABA-A receptor subtype by potentiating GABA transmission. GABA is a ubiquitous neurotransmitter, involved in the majority of inhibitory synapses in the brain. Thus, GABA suppresses neural firing, inhibiting or regulating other neurotransmitters including serotonin, norepinephrine, and dopamine

Rohypnol

• Also known as "the date-rape drug".

• A tablet can be dropped into a victims drink causing them to become drowsy and to lose their memory of any subsequent events.

Phencyclidine

Angel Dust or “PCP”

PCP (phencyclidine) was originally developed in the 1950's by Parke, Davis & Company.

Parke Davis marketed it for a short amount of time as a surgical anesthetic for humans under the trade name Sernyl, but it caused agitation, delusions, and terrifying hallucinations in patients after surgery.

Because of these side effects, it was removed from the human market and sold to veterinarians for surgery on animals under the trade name Sernylan.

The commercial product Sernylan(R) was withdrawn from the market in 1978.

Street Names:

• PCP is classified as a dissociative anesthetic

• It can act as a stimulant, a depressant, an analgesic (decreasing pain) or a hallucinogen depending on the dose and route of administration.

• In its pure form, PCP is a white crystalline powder that readily dissolves in water

• . It is available as a liquid (PCP base dissolved most often in ether), but typically it is sprayed onto leafy material such as marijuana, mint, oregano, or parsley, and smoked.

Effects

• PCP affects multiple neurotransmitter systems in the brain. For example, PCP inhibits the reuptake of dopamine, norepinephrine and serotonin and also inhibits the action of glutamate by blocking receptors. Some types of opioid receptors in the brain are also affected by PCP.

Marijuana

• Cannabis sativa

• One of the oldest and widely used of the mind altering drugs

• It is a mixture of cut, dried and ground portions of the hemp plant Cannabis sativa

Hashish refers to a more potent product produced by extraction of the resin from the plant

Route of administration:

• Smoked

• Oral ingestion

The principal psychoactive agent in marijuana is delta-9 tetrahydrocannabinol (THC)

THC Molecule

• THC is a very potent cannabinoid chemical.

• THC mimics the actions of anandamide.

• When THC binds with cannabinoid receptors inside the hippocampus, it interfered with the recollection of recent events.

• An IV dose of only one mg can produce serious mental and psychological effects.

Lysergic Acid Diethylamide (LSD)

• A semisynthetic indolakylamine and a hallucinogen

• Can be found in several others forms -- powder or crystal, liquid, gelatin squares, laced on a sugar cube and capsules, or as a small pill.

• Most commonly sold in the form of blotter paper, which is small paper squares that has been dipped in LSD.

TOXICOLOGY (PART II)

Route and Site of Exposure:

• Ingestion (Gastrointestinal)

• Inhalation (Lungs)

• Dermal or Percutaneous (Skin)

• Parenteral

Duration and Frequency of Exposure:

• Acute exposure – exposure to a chemical for less than 24 hours

• Subacute – repeated daily exposure for less than 1 month by a specific route

• Subchronic – extends the daily exposure to 90 days or 3 months

• Chronic – lifetime exposure

Dose-Response Relationship

• characterizes the correlation between exposure concentration and the spectrum of effects.

Toxicity Rating System

Toxicity Rating Lethal Oral Dose in Ave. Adult

Super Toxic <5 mg/kg

Extremely Toxic 5-50 mg/kg

Very Toxic 50-500 mg/kg

Moderately Toxic 0.5-5 g/kg

Slightly Toxic 5-15 g/kg

Practically Non-toxic >15 g/kg

Alcohol

The most commonly abused substance

• The effects of alcohol may appear within 10 minutes after consumption; proportional to its concentration in the blood.

• Alcohol intoxication is defined by blood alcohol concentration. BAC is defined as grams of alcohol per deciliter of blood.

• Alcohol acts as a CNS depressant.

Effects:

0.05 produces inhibition and facilitates social interaction

0.10 results in slurred speech

0.20 euphoria and motor impairment

0.30 confusion

0.40 stupor

0.50 coma

0.60 respiratory paralysis and death

Major Metabolic Pathway

alcohol O acetaldehyde O

dehydrogenase II dehydrogenase II

CH3-CH2-OH ® CH3-CH ® CH3-C (acetate)

(ethanol) (acetaldehyde) I

• The oxidation occurs chiefly in the liver

• Between 90-98% of the ethanol that enters the body is completely oxidized

• Oxidation is relatively constant with time, and it is little increased by the raising the concentration in the blood

• In the adult, the average rate at which ethanol can be metabolized is 120mg/kg per hour, or about 30 ml (1oz.) in 3 hours.

Common Indicators of Ethanol Abuse

Test Comments

GGT Increases can be seen before the onset of pathologic consequences

AST Increases occur in conjunction with ethanol- related diseases

AST/ALT ratio A ratio of greater than 2.0 is highly specific for ethanol related diseases

HDL High serum HDL is very specific for ethanol consumption

MCV Increased erythrocyte MCV is commonly seen with excessive ethanol consumption

Reference:

• Clinical Chemistry

Bishop, Duben Engelkirk, Fody

• Widmann’s Clinical Interpretation of Laboratory Tests

Sacher, McPherson

• The Pharmacological Basis of Therapeutics (8th ed, Vol. 2)

Gilman, Rall

TOXICOLOGY (PART III)

Note from editor: This one seems unfinished to me… But I’ll be including this anyway. ^_^

Heavy Metals

Mercury

Classification:

Inorganic mercury: elemental mercury

mercury salts

Organic mercury: ethylmercury/methylmercury/phenylmercury

Physical/Chemical Properties:

® Odorless, shiny, silvery liquid; non-flammable; produces poisonous gas in fire

® Combines readily with S, Cl, or O2 to form inorganic mercury.

® Binds with C to form organic mercury

Hazards:

® Vapor pressure is high

® Passes into the brain and interferes with brain development

® Rapidly crosses the placenta

Toxic Dose: 10-42 mg/kg

Toxidromes: