Definitions Of Toxicology

• The word toxicology is derived from toxicon – a poisonous substance into which arrow heads were dipped and toxikos a bow.

• Toxicology originally developed as the study of poisons.

• Toxicology is now described as the study of the adverse effects of chemical or physical agents on living organisms.

• A toxicologist is a scientist that determines the harmful effects

of agents and the cellular, biochemical, and molecular mechanisms responsible for the effects.

Adverse effects can range from obvious ones like death, cancer, an injury or the undesired effects.

It is often necessary to evaluate exposure and effect in a large group or population of people to assess subtle changes.

Knowledge of how toxic agents damage the body has

progressed along with medical knowledge.

Historical aspects of Toxicology

• The historical development of toxicology began with early cave dwellers who recognized poisonous plants and animals and used their extracts for hunting or in warfare.

• 1500 BC Elbers apyrus did the earliest collection of medical records and describe several poisons known at that time. (Hemlock)

• 400 BC Hippocrates showed that the ancient Greeks had professional awareness of poisons and of principle of Toxicology.

History of Toxicology

• Socrates (470-399 BC) poisoning by drinking hemlock is one of the best known cases of execution by poisoning.

• Notable poisoning victims include Socrates, Cleopatra, and Claudius.

HISTORICAL DEVELOPMENT OF TOXICOLOGY

• The scientific foundations of toxicology were laid by Paracelsus.

• He stated the principle of dose- response as All substances are poisons, there is none that is not a

poison. The right dose differentiates a poison and

a remedy .

HISTORICAL DEVELOPMENT OF TOXICOLOGY

• Orfila , a Spanish physician (1787–1853) who is known as the modern Father of Toxicology:

• He was the first one that treat toxicology as a separate scientific subject and introduced chemical analysis as an essential component.

Developed toxicology into a science.

Compiled chemical and biological information on most known poisons.

Proposed the necessity of chemical analysis to prove cause-and-effect.

HISTORICAL DEVELOPMENT OF TOXICOLOGY

• The 20th century is marked by an advanced level of understanding of toxicology.

• An event that impacted the discipline very deeply was the advent of World War II due to the significant development of chemical used for warfare like pesticides, ammunitions and drugs.

• DNA (the molecule of life) and various biochemicals that maintain body functions were discovered.

• Our level of knowledge of toxic effects on organs and cells is now being revealed at the molecular level.

Areas of scientific study relevant to toxicology

BASIC DEFINITIONS AND TERMINOLOGY

• A poison, toxicant, or toxin is a substance capable of causing harm when administered to an organism.

- Toxic—having the characteristic of producing an undesirable or adverse health effect.

• Toxicity—any toxic (adverse) effect that a chemical or physical agent might produce within a living organism.

• A poison can be defined as any agent capable of producing a deleterious response in a biological system.

BASIC DEFINITIONS AND TERMINOLOGY

• Toxin is toxic substances that are produced by biological systems such as plants, animals, fungi, and bacteria.

• Toxicant is toxic substances that are produced by or are by-products of anthropogenic (human) activities.

• Risk is the probability of injury, disease, loss of function, or death for an individual or population exposed to a hazardous substance.

• Hazard is an agent or situation that can produce or cause a harmful or adverse effect.

Xenobiotics

• Xenobiotic is derived from Greek term Xeno which means foreign and bios means 'life' .

• Humans are exposed daily to a wide variety of foreign compounds .

• Xenobiotics are substances absorbed across the lungs or skin or, more commonly, ingested either accidently as compounds present in food and drink or deliberately as drugs for therapeutic purposes.

• Some xenobiotics produce beneficial or stimulatory effects at low doses but have adverse effects at higher doses.

• Many xenobiotics distribute in the body and often affect only specific target organs.

• Others, can damage any cell or tissue that they contact.

Introduction to Toxicology

Ms. Sara Faroug

School of pharmacy

College of pharmacy & Nursing

University of Nizwa

Fate and effect of Toxicants in the body

Duration and Frequency of Exposure

• Toxicologists usually divide the exposure of experimental animals to chemicals into four categories:

1- Acute is defined as exposure to a chemical for less than 24 h.

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

3-Subchronic refers to repeated exposure to chemical for 1 to 3 months.

4- chronic for more than 3 months.

• In human exposure situations, the frequency and duration of exposure usually are not defined as clearly as they are in animal studies, but many of the same terms are used to describe general exposure .

• For example, acute exposure applies to a single episode.

Action of poisons 1. Local effect:

• Occur at the site of first contact between the biological system and the toxicants. Examples corrosives (include an acid’s ability to cause burning of the eyes, upper respiratory tract irritation and skin burns.

2. Systemic effect:

• Require absorption and distribution of a toxicant from its entry point to a distant site at which deleterious effects are produced.

• Some poisons exert their effects on one or more organ system.

• Examples, adverse effects on the kidney or central nervous system resulting from the chronic ingestion of mercury.

Action of poisons

3. Combined effect :

• Some poisons have both local and systemic effects, e.g Carbolic and Oxalic acids.

• In some cases, the effect may occur at only one site, this site is referred to as the specific target organ.

• Benzene is a specific organ toxin in that it is primarily toxic to the blood-forming tissues.

Types of toxicity

I. Direct toxic action ( tissue lesions):

- Direct toxicity to tissues, results in tissue damage often manifested as necrosis.

II. Biochemical lesions:

- Biochemical lesions may lead to the development of pathological change such as cell degeneration.

- They may also simply cause death of the whole organism.

- Some biochemical effects are reversible, such as the binding of carbon monoxide to hemoglobin which may not be at a sufficiently high level to cause death of the organism.

VII. Teratogenesis • Is the specific interference with the development of the

embryo and fetus in the uterus resulting in a structural or functional abnormality.

• Teratogens are selective, specific for the embryo/foetus.

VIII. Genetic toxicity

• Is the specific interference with the genetic material of the cell to cause a heritable change in the cell genotype.

• Mutagens are agents that cause changes (mutations) in the genetic code, altering DNA.

VIIII. Carcinogenesis: • Is the production of a malignant tumor, resulting from the

uncontrolled proliferation of cells, as a response to chemical exposure.

• Two types of carcinogenic mechanisms have been identified:

- Epigenetic

- Genotoxic

Factors Influencing Toxicity • There are many factors which can enhance, increase or

decrease toxicity.

• The toxicity of a substance depends on the following:

I. The species

- Species are differ in response to toxic substance.

- A dose which is lethal for one species may have no effect on another.

II. Age

- Some chemicals are more toxic to infants or the elderly than to young adults.

- Elderly persons have diminished physiological capabilities

- for the body to deal with toxic insult.

III. Gender and Hormonal Status: • Gender characteristics may affect the toxicity of some

substances.

• Certain chemicals can affect the reproductive system of either the male or female.

• Women have a larger percent of fat in their total body weight than men, and women also have different susceptibilities to reproduction system disorders and teratogenic effects.

IV. Genetic Makeup • Genetic factors influence individual responses to toxic

Substances.

• For example, people lacking in the G6PDenzyme are more likely to suffer red blood cell damage when given aspirin or certain antibiotics.

V. Routes of exposure

• Toxicity can be different for the same dose, depending on whether the chemical is inhaled, ingested, applied to the skin, or injected.

• Natural barriers impede the intake and distribution of material once in the body.

VI. Dose of poison:

- It is the amount of a substance administered at one time.

- There are numerous types of doses

- The units used in toxicology are basically the same as those used in medicine. The gram is the standard unit. However, most exposures will be smaller quantities and thus the milligram (mg) is commonly used.

• A common dose measurement is mg/kg which stands for mg of substance per kg of body weight.

• Since some xenobiotics are toxic in much smaller quantities than the milligram, smaller fractions of the gram are used, such as microgram (µg).

• In the environmental sciences Environmental exposure units are expressed as the amount of a xenobiotic in a unit of the media.

- mg/liter (mg/l) for liquids

- mg/gram (mg/g) for solids

- mg/cubic meter (mg/m3) for air

- Other commonly used dose units for substances in media are parts per million (ppm), parts per billion (ppb) and parts per trillion (ppt).

VII. Form and innate chemical activity of Substance

• The form of a substance may have a profound impact on its toxicity especially for metallic elements.

• Some toxicants can quickly damage cells causing immediate cell death. Others slowly interfere only with a cell's function. E.g. Nicotine and hydrogen cyanide .

• Cr3+ is relatively nontoxic whereas Cr6+ causes skin or nasal corrosion and lung cancer.

VIII. The presence of other chemicals may decrease toxicity (antagonism), add to toxicity (additivity), or increase toxicity (synergism or potentiation) of some xenobiotics.

VII. Health factors:

• Persons with poor health are generally more susceptible to toxic damage due to the body's decreased capability to deal with chemical harms.

VIII. Toxicokinetic factors:

• Toxicokinetics is the study of "how a toxic substance gets into the body and what happens to it in the body".

• Four processes are involved in toxicokinetics:

1. Absorption

2. Distribution

3. Biotranformation

4. Excretion

DOSE-RESPONSE RELATIONSHIPS

Ms. Sara Faroug

School of pharmacy

College of pharmacy & Nursing

University of Nizwa

Measures of Toxicity

• Toxicity of chemicals is determined in the laboratory.

• The normal procedure is to expose test animals.

• Toxicity is measured in numerous ways. The classic measure is LD50: Lethal Dose that kills 50% of the population.

• Dose-Response Curves characterize the response to different concentrations of a drug or toxin.

Dose Response Curve

• The dose-response relationship is a fundamental and essential concept in toxicology.

• Paracelsus who is first person recognized the relationship between the dose of a compound and the response elicited .

• It correlates exposures and the spectrum of induced effects.

• The relationship of dose to response can be illustrated as a graph called a dose-response curve.

Dose- response relationship

• -The dose-response curve normally takes the form of a sigmoid(S-shape) curve.

• Lethal dose 50 (LD50)is defined as the dose of substance that required to kill 50% of a population.

Dose- Response Curve for Drinking Wine.

THRESHOLD DOSE AND NOAEL

- For some compounds and types of toxic effects ,there will clearly be a dose below which no effect or response is observed. This called threshold dose.

- The concept of a threshold dose for the toxic effect is an important one in toxicology because it implies that there is a‘no observed adverse

effect level (NOAEL).

THRESHOLD DOSE AND NOAEL

• NOAEL is highest data point at which there was not observed toxic or adverse effect.

• The acceptable daily intake(ADI) is based on the NOAEL.

• This is a factor used to determine the safe intake for food additives and contaminants such as pesticides and residues of veterinary drugs.

• NOAEL is generally accepted for most types of chemicals and toxic effects.

• The shape of the curve is controversial(no-threshold phenomenon) for chemical carcinogens acting by a genotoxic mechanism.

Dose- Response Curve

The different segments of the curve are represented as follow:

- Segment I:Those doses

of the toxicant that elicited no response to the treated population.

- Segment II:Those doses of the toxicant that affected only the most susceptible members of the exposed population.

Five Segments of sigmoidal Dose -response curve.

Dose- Response Curve

- Segment III: those doses at which most of

the groups of organisms elicit some response to the toxicant.

- Segment IV: Those dosages of the toxicant that

are toxic to even the most tolerant organisms in the populations.

- Segment V: those dosages at which 100%

of the organisms exposed to the toxicant have been affected.

Spectrum of undesired effects

• Each drug produces a number of effects, but only one is associated with the primary objective of the therapy; all other effects are considered undesirable or side effects.

• Some of side effects may be desired for another therapeutic indication.

-Atropine is used in parkinson̓s.

- Postoperatively atropine used to dry up secretion.

• The effects that are always undesirable are referred to as adverse, deleterious or toxic effects of the drug.

Spectrum of undesired effects

• Overdose :Adverse effects of a drug when taken in doses which are in excess of therapeutic range.

• Allergic reactions is an immunologically mediated adverse reaction to a chemical.

• Idiosyncratic reactions refers to genetically determined abnormal reactivity to a chemical.

Therapeutic Index (TI)

- TI is the ratio of the dose producing toxicity (TD50 or LD50)to the dose needed to produce the desired therapeutic response(ED50).

- IT= TD50/ED50 or LD50/ED50

- The TI is used as a measure of the relative safety of the drug. -Toxic Dose(TD) is the dose that causes adverse toxic effects.

- Effective Dose (ED) is the dose that produces beneficial effects

Toxicology I

Ms. Sara Faroug

School of pharmacy

College of pharmacy & Nursing

University of Nizwa

Classification of Toxic Agents (poisons)

• Toxic substances are classified into the following:

1- Heavy metals:Most metals occur in nature in rocks, ores, soil, water, and air.

- Lead (Pb)

- Mercury (Hg)

- Chromium

- Cadmium

- Arsenic

- Iron

- Aluminum

2- Pesticides: can be defined as any substance or mixture of substances used to control, destroy or repel pests.

• The primary classes of pesticides in use today are :

- Fungicides

- Herbicides

- Insecticides

- Rodenticides

3- Toxins: are substances produced by animals, plants, insects, or microbes.

A- Animals:

• These toxins can result from venomous or poisonous animal releases .

- Arachnids (scorpions, spiders)

- Insects (water bugs)

- Reptiles (Snake venoms)

- Fish (Tetrodotoxin)

- Amphibians (Batrachotoxin)

B- plants:

• Plants contain chemicals that may exert toxic effects on the body systems.

- Atropa belladonna (Atropine)

- Nicotiana glauca (tree tobacco)

- Ricinus communis (castor bean)

- Aconitum plants (Aconitine)

C- Microbial Toxins:

• Toxic substances produce by microorganisms.

- Botulism toxins (Bacteria: Clostridium botulinum)

D- Mycotoxins(Fungal Toxins):

- Aflatoxin (Aspergillus sp.)

- Ergot alkaloids (Claviceps sp.)

E- Algal Toxins:

- Algal toxins are broadly defined to represent the chemicals derived from many species of cyanobacteria (blue-green bacteria), dinoflagellates, and diatoms.

4- Solvents & vapours :

• Solvents are liquid organic chemicals with variable lipophilicity and volatility, small molecular size, and lack of charge.

- Alcohols,Benzene,Propylene glycols and Chloroform.

5- Therapeutic Drugs

• All therapeutic drugs can be toxic, producing deleterious effects at some dose.

- Thalidomide

- Paracetamol

- Digoxin

- Phenytoin

6- Drugs of abuse:

• Drug of abuse either have no medicinal

function or are taken at dose levels higher than would be required for therapy.

• Examples:

- Opioids

- Nicotine

- Methamphetamine (speed)

- Hallucinogens

7- Radiation and Radioactive Chemicals

• Ionizing Radiation

• Non-ionizing Radiation

GENERAL MANAGEMENT OF POISONING

Ms. Sara Faroug

School of pharmacy

College of pharmacy & Nursing

University of Nizwa

Management of the poisoned patient

• Poisoning is a clinical or physiologic status induced by exposure to a xenobiotic.

• A Poisoning case is usually a mystery in clinical medicine.

• The presence and severity of poisoning after exposure to a particular agent is dependent on number of factors.

• Poisoning is rarely fatal if victims received prompt medical attentions and good supportive care.

• Patients should be identified as stable or unstable.

• Unstable patients with one or abnormal vital signs, dyspnea and altered mental status.

• General approach for management of poisoned patient:

o A- Initial Patient Assessment and Supportive Care

- A specific toxicologic diagnosis only delays the “ABCDs" of poisoning treatment:

Airway should be cleared of vomitus or any other obstruction and an oral airway or endotracheal tube inserted if needed.

A- Initial Patient Assessment and Supportive Care

Breathing should be assessed by observation and by

measuring arterial blood gases.

Circulation should be assessed by continuous monitoring of pulse rate, blood pressure, urinary output and evaluation of peripheral perfusion.

Disability : every patient with altered mental status should receive a challenge with concentrated dextrose unless a rapid blood glucose test demonstrates that the patient is not hypoglycemic.

Have patient removed from the hazardous environment.

Establish an open airway.

Maintain airway and administer oxygen.

Remove any contaminated clothing.

B- History & Physical Examination

I- History:

- An accurate history should include identification of the poison, amount and time of ingestion or length of contact and the patient psychological profile.

- Patient or family members should be asked to describe the story.

- If the patient is unable or unwilling to cooperate, family members or friends should be contacted for additional information.

- Some poisoning may diagnosed if patients present with a toxidromes that is associated with exposure to a particular agents.

II- Physical examination - A brief examination should be performed on those areas

which are most likely to give evidence to the toxicologic diagnosis.

- These include vital signs(Bp , HR respirations, Temp), eyes, mouth, skin abdomen and nervous system.

- Cardiac status is assessed by recording and monitoring the pulse, blood pressure and urinary out.

- Hypothermia and hyperthermia are common complications in

many poisoned patient.

History

Personal

history

History of present

illness

Past history Family

history

The 5W’s of toxicology

• Who – pt’s age, weight, relation to others • What – name and dose of medication, coingestants

and amount ingested,pre-consultation treatment. • When – time of ingestion, single vs. multiple

ingestions • Where – route of ingestion, geographical location • Why – intentional vs. unintentional

C- Laboratory & Imaging procedures:

I- Essential clinical laboratory tests

- Provide important information to the diagnosis of poisoning and may guide the investigation toward specific toxicology testing.

- Routine tests include electrolytes, serum glucose, blood urea and creatinine , complete blood count , liver function test , arterial and venous blood gas and electrocardiogram(ECG).

- Laboratory tests are more likely to be of greater benefit than toxicology screening except in the case of commonly used drugs such phenytoin and digoxin.

• II- Toxicology screening - Toxicology laboratories use several methods to screen for

poisons .

- In many cases of poisoning, it may be sufficient to know the nature of poison ( qualitative analysis) or there may be a need for estimation of its concentration in the body ( quantitative analysis) .

- Color tests: example Ferric chloride test ( Add 1 ml of 5% of ferric chloride solution to 2ml urine. A persistent purple colour indicates the presence of phenol , phenothiazines or salicylate.

D. Decontamination - Decontamination involves removing toxins from the skin or

gastrointestinal tract.

I- Skin:

- Contaminated clothing should be completely removed.

- Wash contaminated skin with soap and water.

II- Gastrointestinal tract

- The severity of poisoning is related directly to the amount of compound absorbed by the patient.

- In some cases, removing a fraction of available drug from gastrointestinal tract may convert a fatal to a severe but nonfatal one.

• Some arguments regarding the roles of emesis, gastric lavage, activated charcoal, whole bowel irrigation and cathartics to decontaminate the gastrointestinal tract, especially when treatment is initiated more than 1 hour after ingestion.

• Orogastric lavage is refers to the use of tube inserted through the mouth to evacuate the contents of the stomach.

• Induction of emesis must be attempted only in the conscious and alert patient.

- The drug of choice to induce vomiting is syrup of ipecac.

• Whole bowel irrigation is a medical process involving the rapid administration of large volumes of an osmotically balanced polyethylene glycol solution either orally or via a nasogastric tube, to flush out the entire gastrointestinal tract.

- The goal of WBI is to prevent absorption by flushing any unabsorbed toxin rapidly through the intestinal tract.

• Activated charcoal decrease the systemic absorption of many drugs .

Remove contaminated clothing and other articles.

Irrigate with clear water for at least 20 minutes.

Administer activated charcoal as directed.

Position patient for vomiting. Save all vomitus. Have suction equipment ready.

E. Enhancement of Elimination

- Methods of Enhancing Elimination of Toxins are the following:

I- Forced Diuresis and Urinary PH Manipulation:

- The may be used to enhance the elimination of substances, whose elimination is primarily.

II- Dialysis :

- Hemodialysis is used for substances that are water soluble and have a low molecular weight.

F. Use of specific antidotes: - Antidote is substance which counteract or antagonize the

effect of poison.

- Examples of specific antidotes

- In some cases where the identity of poison was not known, the following three antidotes (coma Cocktail) must be administered.

- Coma Cocktail includes Dextrose , Thiamine and Naloxone.

Poison (s) Antidote

Paracetamol

(acetaminophen)

Acetyl cysteine

Morphine , Heroin (opioids) Naloxone

ALCOHOL

• Many members of the general public probably do not consider alcohol to be a drug but it has both pharmacological and toxic effects.

• Ethanol, methanol, and Ethylene glycol are the important alcohols due to their wide availability.

• Commercial beer, wine and liquors contain various amount of ethanol.

• Ethanol also found in perfumes, mouthwashes, many food flavoring and pharmaceutical preparation (Elixir).

• Methanol is common ingredient in many solvents, windshield-washing solutions and paint removers.

• Ethylene glycol commonly is used in antifreeze solutions.

Ethanol

• Ethanol is frequently ingested recreationally and is the most common co-ingested with other drugs in suicide attempts.

• Alcohol dehydrogenase converts ethanol to acetaldehyde which is then converted to acetic acid.

• Ethanol block the metabolism of methanol to its toxic metabolites, so it can be used in emergency treatment of methanol and ethylene glycol poisonings.

• People who continue to drink alcohol in spite of adverse medical or social consequences related directly to their alcohol consumption suffer from alcoholism.

Mechanism of ethanol toxicity • The central nervous system (CNS) is markedly affected by

acute alcohol consumption.

- Ethanol causes CNS depression and sedation .

- Ethanol has additives effect with other CNS depressant such as barbiturates, benzodiazepines, opioids and antidepressants.

• Cardiovascular System

- Significant depression of myocardial contractility has been observed in individuals.

• Lowering body temperature is greater and more dangerous when the environmental temperature is low.

• Hypoglycemia: A level of 100mg/dL of blood ethanol may be enough to inhibit the gluconeogenesis.

•

Toxic dose of Ethanol:

• 0.7 g/kg pure ethanol ----------- 100mg/dL (BEC).

• The level of ethanol that causes deep coma or respiratory depression depend on individuals degree of tolerance to ethanol.

• levels greater than 300 mg/dL usually cause deep coma, but regular users are often tolerant to the effects of ethanol.

Clinical Symptoms:

• A- Acute intoxication with ethanol

1- Mild to moderate intoxication, euphoria, incoordination, ataxia and nystagmus may occur.

Clinical Symptoms

2- with deep intoxication, coma, respiratory depression and pupil constriction may occur.

- The blood pressure, heart rate and temperature are often decreased.

- Rhabdomyolysis may occur.

B- Chronic ethanol abuse

1- Hepatic toxicity:

- Liver disease is the most common medical complication of alcohol abuse.

- chronic alcohol abuse can lead to three liver diseases - Alcoholic fatty liver, hepatitis and cirrhosis.

Clinical Symptoms

2- Gastrointestinal

- Chronic alcoholics are prone to gastritis and have increased susceptibility to bleeding.

- Gastrointestinal dysfunction including abdominal pain, diarrhea, vomiting, hematemesis and pancreatitis.

3- Cardiac disorders include atrial and ventricular arrhythmias and Cardiomyopathy.

4- Neurotoxicity include cerebral atrophy, cerebellar degeneration and peripheral nerve injury.

- Other manifestations may include dementia and seizures.

5- Alcoholic ketoacidosis

6- Electrolyte imbalances ( hypokalemia, hypomagnesaemia and hypocalcaemia) are more common in chronic alcoholic.

FETAL ALCOHOL SYNDROME:

Alcohol abuse during pregnancy is associated with teratogenic effects, and alcohol appears to be a leading cause of mental retardation and congenital malformation.

Treatment of ethanol toxicity

• The most important goals in the treatment of acute alcohol intoxication are to prevent severe respiratory depression :

- Protect the airway to prevent aspiration and assist ventilation if needed.

• Give glucose and thiamine and treat coma and seizures.

• Correct hypothermia with gradual rewarming

• Metabolic alterations may require treatment of hypoglycemia and ketoacidosis by administration of glucose and thiamine.

Treatment of ethanol toxicity

• Antidotes: There is no available specific ethanol receptor antagonist despite the presence of arousal effect after administration of naloxone.

• Decontamination

- Consider aspirating gastric contents with small flexible tube if the alcohol ingestion was massive.

• Enhanced elimination

- Hemodialysis efficiently remove ethanol but rarely used.

• Chronic alcoholics are treated with disulfiram to encourage abstinence.

- Small amounts of alcohol may induce an adverse reaction in patient taking disulfiram .

- Signs and symptoms of disulfiram –ethanol reaction )DER)include flushing of face, tachycardia, nausea, vomiting and urticaria.

• Alcohol withdrawal can be treated by benzodiazepines (e.g. diazepam 2-10mg i.v initially and repeated as needed).

- Ehanol withdrawal symptoms include hypertension, tachycardia, diaphoresis, tremor, hyperthermia, agitation and insomnia.

Benzodiazepines

• Benzodiazepines (BZDs) are sedative hypnotic agents.

• BZDs are used for sedation and to treat anxiety, seizures and insomnia(sleep disorder).

• Diazepam (Valium), Lorazepam, Triazolam and Flunitrazepam are BZDs.

• Rohypnol (trade name for Flunitrazepam drug) became known as a “date-rape “ drug.

• In general, death from BZDs overdose is rare unless the drugs combined with other CNS depressant agents.

• Oral overdoses of diazepam have been reported in excess of 15-20 times the therapeutic dose without depression of consciousness.

• Mechanism of Benzodiazepines toxicity:

- They enhance the action of the inhibitory neurotransmitter GABA.

- The result is generalized depression of spinal reflexes and the reticular activating system. This can cause coma and respiratory arrest.

• Symptoms of BZDS toxicity:

- Initially CNS depression.

- Lethargy, slurred speech, ataxia, hypothermia, coma and respiratory arrest may occur.

- Triazolam can produce delirium and psychosis.

- Serious complications are more likely when newer short-acting agents are involved.

Treatment :

1- Protect the airway and assist ventilation if necessary.

2-Treat coma, hypotension and hypothermia if they occur.

3- Administration of antidote flumazenil (0.1- 0.2mg starting dose) which is a specific benzodiazepine receptor antagonist that can rapidly reverse coma.

4- Consider activated charcoal if ingestion occurred within the previous 30 minutes.

Flumazenil is not considered in routine management because:

- it may induce seizures in patients with tricyclic antidepressant overdose and may induce acute withdrawal symptoms in addicted patient.

Barbiturates

• Barbiturates are used clinically as anticonvulsant, anti-anxiety drugs or preanesthetics .

• Barbiturates are classified as ultrashort-, short-, intermediate, and long-acting, depending on how quickly they act and how long their effects last.

• The toxic dose of barbiturates varies widely and depends on the drug and route of administration and individual patient tolerance.

• Mechanism of Toxicity

- Barbiturates act partly by enhancing action of GABA, but less specific than benzodiazepines.

- All barbiturates causes generalized depression of neuronal activity in the brain.

TYPES:

• Ultra short

acting:Methohexital,Thiopental

• Short

acting:Pentobarbital,Secobarbital

• Intermediate

acting:Amobarbital,Apobarbital

• Long

acting:Mephobarbital,Phenobarbital

• Clinical presentation

- Mild to moderate intoxication: Lethargy, slurred speech, nystagmus and ataxia

- With higher doses: Hypotension, coma and respiratory arrest commonly occur.

- Hypothermia is common in patients with deep coma , also it is accompanied with hypotension and bradycardia.

• Treatment

1- protect the airway and assist ventilation.

2- Treat coma, hypothermia and hypotension if they occur.

- Administration of intravenous fluids is the initial therapy for hypotension.

3- Administer activated charcoal to bind ingested barbiturates in the gut before they can be absorbed

4- If renal and cardiac functions are satisfactory, and the patient

is hydrated, forced diuresis and alkalinization of the urine will accelerate the excretion of barbiturates.

- Intravenous sodium bicarbonate is used to alkalinize the urine.

5- Hemodialysis may be necessary for severely intoxicated patients

Toxicology I

Ms. Sara Faroug,

School of pharmacy

College of pharmacy & Nursing

University of Nizwa

Sedative And Hypnotic Agents

• The terms sedative and hypnotic are equivalent to central nervous system depressants.

• A sedative is a substance that diminishes environmental awareness and physical activity.

• A hypnotic is an agent that induces sleep.

• All of these agents depress the central nervous system and produce progressive, dose-dependent alterations in behavior which are described as being depressant in action.

The stages of behavioral Sedation

Sedative – Hypnotic Agents

• Buspirone, Chloral hydrate, Ethchlorvynol, Glutethimide, Meprobamate, Methaqualone, Methyprylon, Paraldehyde are less commonly used Sedative and Hypnotic agents.

• Barbiturates,Benzodiazepines are popularly used sedative and Hypnotic agents.

• Baclofen overdose is associated with profound CNS depression, autonomic disturbance and cardiac arrthymia.

• Chloral hydrate will lead to manifestations similar to barbiturates.

• Chloral hydrate is also gastrointestinal irritant and commonly cause nausea , vomiting and hemorrhagic gastritis and it can also hepatic injury , renal failure and cardio toxicity.

• Glutethimide has anticholinergic properties that contribute to toxicity.

• Meprobamate overdose is associated with hypotension most likely owing to depressed myocardial function.

• Mechanism of toxicity.

• The exact mechanism of action and the pharmacokinetics vary for each agent.

• The major toxic effect that causes serious poisoning or death is CNS depression resulting in coma, respiratory arrest, and pulmonary aspiration of gastric contents.

• For most of these drugs, ingestion of 3-5 times the usual hypnotic dose results in coma.

• However, co-ingestion of alcohol or other drugs may cause coma after smaller ingestions, whereas individuals who chronically use large doses of these drugs may tolerate much higher acute doses.

• So the toxic doses vary with individual.

CLINICAL PRESENTATION:

• Overdose with any of these drugs may cause drowsiness, ataxia,nystagmus, stupor, coma, and respiratory arrest.

• Deep coma may result in absent reflexes, fixed pupils, and depressed or absent EEG activity.

• Hypothermia is common.

• Most of these agents also slow gastric motility and decrease muscle tone.

• Hypotension with a large overdose is caused primarily by depression of cardiac contractility and, to a lesser extent, loss of venous tone.

Treatment • Maintain an open airway and assist ventilation if necessary

. Administer supplemental oxygen.

• Treat coma, hypothermia, hypotension,and pulmonary edema,which may lead to Hypoxia) if they occur.

• Monitor patients for at least 6 hours after ingestion, because delayed absorption may occur.

• Patients with chloral hydrate ingestion should be monitored for at least 18-24 hours because of

• the risk of cardiac arrhythmias.

• Tachyarrhythmias caused by myocardial sensitization may be treated with propranolol 1-2 mg IV,

• or esmolol , 0.025-0.1 mg/kg/min IV.

Marijuana

• Marijuana is present in the plant, Cannabis sativa, which is also known as hemp.

• Usually it is smoked in cigarettes (1-3% THC) (Joints or reefers) or pipes or added to food (cookies or brownies).

• Hashish (up to 12 % THC)is a dark resin, rich in the active ingredient, which is prepared by intense drying of the flowering tops of Cannabis.

• The psychoactive agent in marijuana is tetrahydrocannabinol (THC).

• Two synthetic forms of THC, nabilone and dronabinol (Marinol)have been marketed by the drug

industry.

• Dronabinol is available in 5- and 10-mg capsules for

the treatment of nausea and vomiting associated with cancer chemotherapy.

• Dronabinol is also used as an appetite stimulant for anorexia associated with weight loss in AIDS patients.

• Mechanism of Toxicity:

- THC, which binds to anandamide receptors in the brain, may have stimulant, sedative, or hallucinogenic actions, depending on the dose and time after consumption.

- Both catecholamine release (resulting in tachycardia)and inhibition of sympathetic reflexes (resulting in orthostatic hypotension)may be observed.

• Clinical presentation of Marijuana:

- Mild cannabis use produces euphoria, sedation, a sense of well-being, alterations in perception, and impaired memory.

- Moderate intoxication causes mood swings, significant

memory deficits, and depersonalization.

- Severe intoxication leads to slurred speech, loss of coordination, hallucinations and paranoia.

- Physical findings may include tachycardia, orthostatic hypotension and hypothermia.

- Stupor with pallor, conjunctival injection ,fine tremor and ataxia has been observed in children after they eaten marijuana cookies.

Treatment • Most psychological disturbances can be managed by Simple

reassurance ,possibly with adjunctive use of Lorazepam ,diazepam or midazolam.

• Sinus bradycardia usually does not require treatment but, if necessary ,may be controlled with beta blockers.

• Orthostatic hypotension responds to head-down position and intravenous fluids.

• Gastric lavage is not necessary if activated charcoal can be given promptly.

Toxicology I

Ms. Sara Faroug,

School of pharmacy

College of pharmacy & Nursing

University of Nizwa

Nicotine

• Nicotine is an alkaloid present in the leaves of the tobacco plant.

• The only medicinal use of nicotine as an aid in smoking cessation.

• Nicotine intoxication arises when nicotine chewing gum (Nicorette), transdermal delivery formulations (Nicoderm, Nicotrol) and nicotine nasal spray, inhaler and lozenges are widely available as adjunctive therapy for smoking cessation.

Nicotine

• Alkaloids similar to nicotine (anabasine, cystisine, coniine and lobeline) are found in several plant species.

• Accidental or suicidal ingestion of nicotine-containing pesticides (Black leaf 40) and after cutaneous exposure to nicotine such among tobacco harvesters(green tobacco sickness) may result in nicotine toxicity.

Mechanism of Nicotine Toxicity

• Nicotine first stimulates the nicotinic cholinergic receptors of autonomic ganglia and then blocks them.

• With higher doses ,parasympathetic stimulation and then ganglionic and neuromuscular blockage may occur.

• Direct effects on the brain may also result in vomiting and seizures.

Toxic dose of Nicotine • Rapid Absorption of 2-5mg can cause nausea and vomiting,

particularly in nonsmokers.

• Absorption of 40-60mg in an adult is said to be lethal, although this dose spread throughout the day is not unusual in a cigarette smoker.

• Cigarette tobacco about 1.5% nicotine or 10-15mg of nicotine per cigarette.

• Transdermal nicotine patches deliver an average 5-22mg of nicotine over 16-24hours of intended application depending on the brand and size.

• Transdermal patches may produce intoxication in light smokers or in nonsmoker, particularly children to whom a used patch accidentally.

Clinical presentation:

• Nicotine intoxication commonly causes dizziness, nausea, vomiting, pallor and diaphoresis.

• Abdominal pain, salivation, lacrimation and diarrhea may be noted.

• Confusion, agitation, lethargy and convulsion are seen with severe poisonings.

Clinical presentation

• Initial tachycardia and hypertension may be followed by bradycardia and hypotension.

• Respiratory muscle weakness with respiratory arrest is the most likely cause of death.

• Chronic nicotine intoxication:

- Smoking is potent risk factor for malignant and cardiovascular disease.

- In households where the parents smoke ,there is an increased risk of pneumonia and bronchitis in preschool and school age children

• Diagnosis: is suggested by vomiting, pallor and diaphoresis although these symptoms are non specific.

- Nicotine and its metabolite cotinine are detected in comprehensive urine toxicology screens.

Treatment of Nicotine poisoning:

• Emergency and supportive measures

-Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen.

-Treat seizures, coma, hypotension, hypertension and arrhythmias if they occur.

-Observe for at least 4-6 hours to rule out delayed toxicity, especially after skin exposure.

Treatment of Nicotine poisoning • Mecamylamine is specific antagonist of nicotine actions;

however, it is available only in tablets, a form not suitable for a patient who is vomiting, convulsion or hypotensive.

• Signs of muscarinic stimulation (bradycardia, salivation, wheezing, etc),if they occur, may respond to atropine.

• Decontamination:

- Remove all contaminated clothing and wash exposed skin with soap and water.

- Administer activated charcoal orally if conditions are appropriate.

- Gastric lavage is not necessary after tobacco ingestion if activated charcoal can be given promptly.

- Consider gastric lavage for large recent ingestion of liquid nicotine

AMPHETAMINES

• Amphetamines are a group of synthetic, indirect-acting sympathomimetic drugs that cause the release of endogenous biogenic amines, such as dopamine and noradrenaline.

• Dextroamphetamine(Dexedrine) and methylphenidate(Ritalin) are used for treatment of narcolepsy and for attention-deficit disorders in children.

• Methamphetamine( crank, speed), methylenedioxymethamphetamine (MDMA,Ecstasy), paramethoxyamphetamine (PMA) and several other amphetamine derivatives are used orally and intravenously as illicit stimulants and hallucinogens.

• Ice is a smokable form of methamphetamine.

• MDMA also began to be used recreationally under street names as ecstasy.

• In response to several reports of toxic reactions to MDMA,the FDA gave MDMA a schedule I classification (no accepted medical use and high abuse potential).

• Much MDMA use occurs at dances called raves.

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Mechanism of Toxicity

• Amphetamine and related drugs activate the sympathetic nervous system via:

- CNS stimulation

- Peripheral release of catecholamines

- Inhibition of neuronal reuptake of catecholamines

- Inhibition of monoamine oxidase.

• Toxic dose :

These drugs have a low therapeutic index.

Clinical presentation:

• Acute CNS effects of intoxication include euphoria, talkativeness, anxiety, restlessness, agitation and coma.

• Acute peripheral effects include sweating ,tremor, muscle fasciculations, rigidity, tachycardia, hypertension and acute myocardial ischemia and infarction.

• Death may be caused by ventricular arrhythmia, status epilepticus ,intracranial hemorrhage or hyperthermia.

• Chronic effects of amphetamine abuse include weight loss ,cardiomyopathy, pulmonary hypertension and dental changes and paranoia.

• Prolong use of some amphetamines has been associated with an increased risk pulmonary hypertension.

• Prolong use of some amphetamines has been associated with an increased risk pulmonary hypertension.

Treatment

• Emergency and supportive measures

• Specific drugs and antidotes: there is no specific antidote

- Hypertension is treated with sedation and if this is not effective a parenteral vasodilation such as phentolamine.

- Treat tachyarrhythmia with propranolol or esmolol.

• Decontamination: administer activated charcoal orally if conditions are appropriate.

Cocaine

• Cocaine is one of the most popular drugs of abuse.

• Cocaine is a widely available and highly addictive drug that is currently abused daily by more than 3 million people in the United States.

• Cocaine purchased on the street is usually of high purity but it occasionally may contain substitute of drugs such as lidocaine or stimulant such as caffeine and methamphetamine.

• Crack is a free base form of cocaine.

Mechanism of toxicity of cocaine • The primary actions of cocaine are local anesthetic effects,

CNS stimulation and inhibition of neuronal uptake of catecholamines.

• Cocaine has a local anesthetic action that represents the only current rationale for the therapeutic use of cocaine. cocaine is applied topically as a local anesthetic during eye, ear, nose, and throat surgery.

• Cardiovascular effects of high doses of cocaine, related to blockade of cardiac cell sodium channels, include depression of conduction and contractility.

Mechanism of action of cocaine

Clinical presentation • CNS

- Initial euphoria may be followed by anxiety, delirium, hyperactivity and seizures. High doses may cause respiratory arrest.

- Coma may be caused by hyperthermia and intracranial hemorrhage.

- With chronic use, insomnia and weight loss.

• Cardiovascular toxicity may also occur after smoking or intravenous injection and is mediated by sympathetic overactivity.

• Death is usually caused by sudden fatal arrthymia, status epilepticus, hyperthermia and intracranial hemorrhage.

Treatment 1- Emergency and supportive measures:

• Maintain an open airways and assist ventilation if necessary.

• Treat coma , agitation, seizures, hyperthermia, arrhythmias and hypotension. Benzodiazepines are good choice for initial management of hypertension and tachycardia associated with agitation.

• Angina pectoris may be treated with benzodiazepines, aspirin, nitrates or calcium channel blockers.

• Monitor vital signs and ECG for several hours.

1.11.2015 135

Angina

Treatment

2- Specific drugs and antidotes: There is no specific antidote.

• Esmolol may be also be used in combination with vasodilator such phentolaime for management of hypertension.

• QRS prolongation caused by sodium channel blockade can be treated with sodium bicarbonate.

Toxicology I

Ms. Sara Faroug,

School of pharmacy

College of pharmacy & Nursing

University of Nizwa

Pesticides • The term pesticides defined as economic poisons, regulated

by federal and state laws, that are used to control, kill, or repel pests.

• Pesticides can be divided into several groups, such as insecticides, fungicides, herbicides and rodenticides, depending on the target organism.

• The two largest classes of pesticides are insecticides, designed to kill insects, and herbicides, designed to kill plants.

• Pesticide exposure can occur through foods, drinking water, home use of pesticides in the garden, from indoor insect control, or through occupational exposure, particularly in an agricultural setting.

• Insecticides classified into four groups : -Organ chlorine Insecticides (DDT ) dichlorodiphenyltrichloroethane

-Organophosphate Insecticides (parathion, Malathion)

- Carbamates Insecticides (Carbofuran)

- Botanical insecticides ( Pyrethrins )

Organophosphorus and carbamate insecticides

• Organophosphorus (Ops) compound and carbamates also

known more generally as cholinesterase inhibitors.

• They are widely used pesticides that may cause poisoning after accidental or suicidal exposure.

• Household exposures usually don't cause a significant problem because insect spray often contain low potency cholinesterase inhibitors.

• Most Ops and carbamates can be by absorbed by any route inhalation, ingestion and absorption through the skin.

• Mechanism of toxicity: - Organophosphorus compounds & Carbamates

- Inhibit the enzyme acetylcholinestrase found in synaptic junction, red blood cells and butrylcholinestrases in the blood. Result increase the levels of acetylcholine at muscarinic and nicotinic receptor.

- CNS effects of Carbamates are often less than in OP poisoning.

- Carbamates also don't age leading to faster reactivation of AChE.

• Clinical presentation:

- Clinical manifestations may be classified into muscarinic, nicotinic and CNS effects.

- Muscarinic effects: Vomiting , diarrhea, abdominal cramping, bronchospasm, bradycardia and excessive salivation and sweating.

- Nicotinic effects :tremor , muscle weakness and respiratory muscle weakness.

- Central nervous system : agitation , seizures and coma.

Treatment

• Maintain an open airway and assist ventilation if necessary.

• Treat seizures and coma if they occur. Seizures should be treated by benzodiazepines.

• Observe asymptomatic patients for at least 8-12 hours to rule out delayed onset symptoms.

• Specific drugs and antidotes: Specific treatment include the antimuscarinic agent atropine (0.5-2mg IV initially then double the dose every 5 minutes) and the enzyme reactivator pralidoxime( is specific antidote, should be given immediately to reverse muscular weakness).

Treatment

• Decontamination

- Skin : remove all contaminated clothing and wash exposed areas with soap and water.

- Administer activated charcoal orally if conditions are appropriate.

- Gastric lavage may be appropriate soon after moderate to large ingestions.

Pyrethrins

• Direct toxicity from pyrethrins and pyrethoids is uncommon.

• Adverse effects are usually as result of allergic hypersensitivity and include bronchospasm, rhinitis ,contact dermatitis and anaphylaxis.

• After inhalation, the most common is stuffy nose with discharge and scratchy throat.

Organochlorine insecticides

• The onset of symptoms after exposure to organochlorine may vary from minutes to hours depending on the route exposure.

• Nausea, vomiting and diarrhea can occur after ingestion.

• Initial CNS effect include headache, dizziness, tremor, ataxia and disorientation.

• Stupor, coma and seizures with respiratory depression may be seen in severe cases. Chronic exposure to organochlorines can cause hepatomegaly.

Herbicides ( Paraquat and Diquat)

• Exposure to dilute solutions usually cause only local toxicity such as dermatitis, conjunctivitis, cough, throat and burning in the mouth and throat.

• Ingestion causes dysphagia, abdominal cramps , diarrhea and vomiting.

• Systemic effects occur after ingestion and include coma , seizure, pulmonary fibrosis (paraquat only), tubular necrosis, myocarditis , pancytopenia and adrenal hemorrhage.

LYSERGIC ACID DIETHYLAIME(LSD) AND OTHER

HALLUCINOGENS • Hallucination is a false perception of something that is not

really there.

• Hallucinations may be visual, auditory, tactile, gustatory(of taste) or olfactory (smell).

• Any agent which has the potential of producing intense hallucinogen is called hallucinogens and also called entactogens.

• Several hallucinogens have been used clinically to facilitate psychotherapeutic interviews.

Mechanism of Toxicity

• LSD stimulates 5-HT2 receptors and many other agents are

thought to alter the activity of serotonin and dopamine in the brain.

• MDMA are directly neurotoxic.

Clinical presentation • Mild to moderate intoxication:

- Thoughts and perceptions tend to become distorted and dreamlike, rather than being merely sharpened or dulled

- A person with dose related sympathomimetic side effects may also exhibit tachycardia , mydriasis

- sympathomimetic stimulation can cause seizures, sever hyperthermia, hypertension , intracranial hemorrhage and diaphoresis.

• Life threating toxicity:

- Intense sympathomimetic stimulation can cause seizures, severe hyperthermia, hypertension and intracranial hemorrhage and cardiac arrhythmias.

Clinical presentation • Hyperthermia patient are usually obtunded , agitated or

thrashing about diaphoretic.

• Severe hyponatremia has been reported after use of MDMA and may result from both excess water intake and inappropriate secretion of antidiuretic hormone.

Treatment

1- Treat the agitation or severe anxiety states with diazepam or

midazolam. Butyrophenones such as haloperidol are useful despite a small risk of lowering seizure threshold.

2- Treat seizures , hyperthermia, rhabdomyolysis, hypertension and cardiac arrhythmias.

• There is no specific antidote. Sedating doses of diazepam may alleviate anxiety.

• Decontamination procedures are relatively ineffective because most of these drugs are taken orally in small doses.