INTRODUCTION TO

CLINICAL TOXICOLOGY
19/5/20
INTRODUCTION TO CLINICAL TOXICOLOGY
Clinical toxicology involves the study and treatment of poisonings due to a
variety of chemicals, including household and industrial products, plants,
poisonous and venomous animals, environmental agents, pharmaceuticals
products and illegal drugs.
Indications for toxicology screening
1. Determination of prognosis
2. Collection of research data
3. Response to order of court, medical examiner or law enforcement official.
4. Monitoring treatment
5. Identification of a substance to establish a diagnosis
6. Assessment of severity of poisoning
7. Exclusion or confirmation of toxic exposure
Toxicological tests
1. Selective testing – directed towards identification, confirmation and
measurement of drugs
2. Specimen – gastric aspirate, saliva, blood (plasma, serum), urine, hair, nails,
bone etc.
3. Type of test – can be qualitative or quantitative
Qualitative – determination of drugs whose serum concentration does not
correlate with severity of toxicity. Example is urine drug screening for common
drugs of abuse like cocaine, cannabis, opioids etc.
Quantitative – determination of poisonings in which serum concentration and
severity of toxicity correlate e.g acetaminophen, salicylates, ethanol, methanol,
ethylene glycol, anticonvulsants (phenytoin, vaproic acid), digoxin, iron, lithium
Everything is a poison. The dose differentiates a poison
Definitions
Poison is defined as a substance which when administered, inhaled or swallowed
is capable of acting deleteriously on the body. They are substances when
absorbed in a sufficient quantity cause harmful effects in organisms.
Poisoning refers to the development of dose related adverse effects following
exposure to chemicals, drugs or xenobiotics.
Acute poisoning refers to effects produced from a single or short exposure (24 to
96 hours) to poisons resulting in severe harm or death
Chronic poisoning is a long term repeated or continuous exposure to a poison
where symptoms do not occur immediately. Patient becomes gradually ill.
Chronic poisoning most commonly occurs following exposure to poisons that
bioaccumulate e.g mercury, lead, gandolinium
Reasons for acute poisoning:
Suicidal – potassium cyanide, opium, organophosphates, barbiturates
Homicidal – arsenic, antimony, aconite, thallium
Stupefying – belladonnas, recreational drugs (cocaine, opium)
Accidental – methanol
Epidemiology – over 5 million are treated for drugs every year. Overall mortality
is low. 1 – 3% of cases are suicidal. High incidence between 18 – 25 years. M: F =
1: 1.2
Classification of poisons
1. Corrosive poisons – these are highly active irritants which produce both
inflammation and ulceration of tissues e.g strong acids and alkalis
2. Irritant poisons – these produce symptoms of pain in the abdomen, vomiting
and diarrhea
a. Inorganic poisons – Metallic – arsenic, mercury, lead, copper
Nonmetallic – phosphorus, chlorine
b. Organic poisons – Vegetable – castor oil, asparagus
Animals – snakes, scorpions, spiders
c. Mechanical – diamond dust
3. Neurotic poisons – these acts on central nervous system. Symptoms usually
consist of headache, drowsiness, delirium, convulsion, coma
b. Cerebral poisons – opium, alcohol, sedatives, hypnotics
c. Spinal – strychnine
d. Peripheral – curare
e. Cardiac poisons – digoxin,
f. Asphyxiants – coal gas, carbonmonoxide, war gases
f. Others – analgesics, antidepressants, tranquilizers

Mechanism of action of poisons

1. Local action – acts directly on the tissues and cause corrosion, irritation and
inflammation
2. Remote action – as the poison gets absorbed systematically, it produces both
specific central nervous system and cardiac symptoms
Factors that modifies the actions of poisons
• Dosage
• Form of poison – gases and vapors acts faster than liquid, liquid acts faster
than solid
• Method of administration – oral, intramuscular, intravenous
Fate of poisons
Greater part is lost by vomiting and diarrhea
After absorption, poisons undergoes biotransformation in the liver. They are
excreted through the kidney. Other routes – bile ducts, sweat gland, saliva,
mucus, lungs.
Epidermis, hair and nails retains inorganic poisons like arsenic
Bone skeleton holds substances like lead
Diagnosis of acute poisoning
• History – most important
• Physical examination – evaluate airway, respiration, circulation and mental
status. Assess muscle tone and reflexes
Laboratory evaluation – General/ routine tests
Clinical toxicology tests
General tests –
Blood – glucose, electrolytes (Na, K, HC03, Cl), urea, creatinine, liver function
test, arterial blood gases (PH, PCo2, PO2).
Urinalysis – urine glucose, ketones, nitrites, blood, protein, specific gravity
Clinical toxicology tests –
Alcohol breath tests – ethanol, methanol
Urine drug test – for commonly abused drugs
Quantification tests e.g paracetamol poisoning
Clinical considerations
The team managing the patient should work closely with the laboratory. The
following clinical information should be provided
1. The time and date of the suspected exposure with time and date of sample
collection
2. History from the patient or witness that might aid in identification of the
toxin
3. Assessment of the physical state of the patient at the time of presentation.
This information will guide test selection and interpretation of results.
 Toxic syndrome
These are clinical syndromes that are essential for successful recognition of
poisoning patterns
Anticholinergic
Cholinergic
Opioid
Sedative
Sympathomimetic
Anticholinergic – anhidrosis, myadriasis, flushing, fever, delirium,
restlessness, apprehension, abnormal speech confusion, tremor, ataxia,
stupor, hallucination, tachycardia, nausea, vomiting and coma. Common
agents that gives this syndrome include antihistamines, atropine, tricyclic
antidepressants, phenothiazines, scopolamine
Cholinergic – acetylcholine is a neurotransmitter found throughout the central
nervous system. It binds to and activate muscarinic and nicotinic receptors. The
enzyme acetylcholinesterase regulates the activity of acetylcholine. The enzyme
breaks acetylcholine into choline and acetic acid. Respiratory effect of cholinergic
poisoning is the major cause of death in this patients. Patient presents with
respiratory failure, sinus tachycardia or bradycardia, arrhythmias, prolonged PR
intervals, profuse sweating, abdominal pain, urination and diarrhea
Agents include – organophosphate and carbamate insecticides, certain species of
mushroom that contains muscarine and nicotine
Opioids – can induce coma, respiratory depression, bradycardia, hypotension,
hypothermia, pulmonary oedema
Agents – morphine, codeine, methadone
Sympathomimetic – norepinephrine is the neurotransmitter for postganglionic
sympathetic fibers. Stimulation of sympathetic nervous system produces central
nervous system excitation (agitation, anxiety, tremors, delusions) tachycardia,
seizures, hypertension, hyperpyrexia and diaphoresis. In severe cases cardiac
arrhythmias and coma may occur.
Agents – amphetamines, cocaine, ephedrine, pseudoephedrine
Hyperthermic syndrome – these are devastating and requires rapid
management. Fever in a poisoned patient can be associated with
• Sympathomimetic toxicity
• Uncoupling of oxidative phosphorylation
• Serotonin syndrome
• Neuroleptic malignant syndrome
• Malignant hyperthermia
• Anticholinergic poisoning
• Withdrawal syndromes
Sympathomimetics such as amphetamines and cocaine, may produce
hyperthermia as a result of excess serotonin and dopamine
Uncoupling of oxidative phosphorylation as seen in salicylate poisoning
Withdrawal syndromes can produce excessive adrenergic responses and
subsequent heat generation
CYANIDE POISONING
Cyanides are used in numerous industries such as metallurgy, photography,
plastic manufacturing, fumigation and mining. Many plants such as cassava,
apple, sorghum, and lotus contain cyanogenic glycosides. Iatrogenic cyanide
poisoning may occur during use of nitroprusside a vasodilator given to reduce
blood pressure. Cyanide binds to hemoglobin and cause cellular hypoxia.
Patients present with flushing, headache, tachypnea, dizziness, respiratory
depression which progress to coma, seizures, complete heart block and death
Antidote – hydroxycobalamin a vitamin B12 precursor. It forms complexes with
cyanide to for cyanocobalamin which is excreted in the urine
METHEMOGLOBIN FORMING AGENTS
The heme iron in hemoglobin is present in ferrous state. When oxidized to the
ferric state methemoglobin is formed and this form cannot bind to oxygen.
Methemohlobinemia may be caused by drugs like chloroquine, dapsone,
nitroglycerine, primaquine and sulfonamides
Presentation – seizures, dyspnea, exercise intolerance, weakness, coma,
metabolic acidosis. All these are due to hypoxia.
Treatment – administration of methylene blue

ETHANOL POISONING
Most widely used and often abused. The principal pharmacologic action is
central nervous system (CNS) depression. Symptoms vary from euphoria and
decreased inhibition to disorientation and then coma and death due to many
factors not all individuals experience the same degree of CNS dysfunction at
similar blood alcohol concentration. When alcohol is consumed with other
CNS depressant drugs, ethanol exerts a potentiating depressant effect. Ethanol
enhance major inhibitory neurons and impairs excitatory neurons. The
principal inhibitory neuron is mediated by neurotransmitter gamma-
aminobutyric acid (GABA)
Ethanol is metabolized by liver alcohol dehydrogenase to acetaldehyde which
is subsequently oxidized to acetic acid by aldehyde dehydrogenase. This rate
varies among individuals. Elimination rate is also influenced by drinking
practices e.g alcoholics have increase elimination rates. Ethanol is teratogenic,
its consumption during pregnancy can result in birth defect.
METHANOL
Used as a solvent in commercial products, as a constituent of antifreeze and
window cleaning fluids. It may be consumed intentionally by alcoholics as
an ethanol substitute or accidentally when present as a contaminant in
illegal whiskey. CNS effect are less severe than ethanol. Methanol is oxidized
by liver alcohol dehydrogenase to form formaldehyde. Formaldehyde is
rapidly oxidized by aldehyde dehydrogenase to formic acid, which may
cause acidosis and optic neuropathy resulting in blindness or death.
Treatment – administration of ethanol or fomepizole as a competitive
alcohol dehydrogenase inhibitor, either folate or folinic acid and dialysis
ETHYLENE GLYCOL
Present in antifreeze products. Ethylene glycol itself is nontoxic. Its metabolism
by alcohol dehydrogenase results in formation of lactic acid, oxalic acid and
glycolic acid. These acids are responsible for ethylene glycol toxicity.
Treatment – administration of ethanol or fomepizole as a competitive alcohol
dehydrogenase inhibitor and dialysis.
ACETAMINOPHEN
Its actions are related to overwhelming of the gluthathione (an antioxidant)
pathway. Its toxicity may cause severe hepatic toxicity or death. Less frequently
nephrotoxicity.
Initial findings – nausea and vomiting, abdominal pains begins 24 to 36hrs after
ingestion and becomes more severe by 72 to 96hrs.
Patient can present with coma, features suggestive of metabolic acidosis and
hepatic necrosis.
Treatment – N-acetylcysteine before hepatic injury begins as evidenced by
elevated AST and ALT.
SALICYLATE
Aspirin has analgesic, antipyretic and anti-inflammatory properties. It inhibits
biosynthesis of prostaglandins by irreversible inhibition of COX-1 and COX-2
isoenzymes. Salicylate is a metabolite of aspirin. Aspirin also interferes with
platelet aggregation and thus prolongs bleeding time (it inhibit platelet COX
and reduce formation of thromboxane A2, a potent mediator of platelet
aggregation.
Salicylates directly stimulates the respiratory center to cause hyperventilation
and respiratory alkalosis.
oxygen consumption and metabolic rate may be increased. Following acute
salicylate overdose patient may be asymptomatic initially and later develop,
nausea and vomiting, abdominal pains, tinnitus, tachypnea, oliguria and altered
mental status ranging from lethargy to coma.
Mortality is associated with acidemia. CNS depression is more pronounced
when acidemia is severe
ANTIMUSCARINIC AGENTS
Several plants and mushroom species contain antimuscarinic compounds that
mimic anticholinergic symptoms when ingested. Commonly centrally acting
antimuscarinic agents are atropine and scopolamine. These compounds have
been isolated from plants like Atropa belladonna (deadly nightshade) and
Datura stramonium (jimson weed) and are abused for their hallucinogenic
potentials.
Scopolamine is used clinically for motion sickness, atropine is an antidote for
cholinesterase inhibitors such as insecticides and chemical warfare nerve
agents
Clinical presentation – tachycardia, hypertension, hyperthermia, dry skin, skin
flushing, reduced bowel sounds, urinary retention, agitation, disorientation
and hallucination.
Patients are managed based on clinical presentation
ORGANOPHOSPHATE COMPOUNDS
Organophosphate insecticides are toxic because they inactivate
acetylcholinesterase an enzyme that degrades acetylcholine into choline and
acetic acid. Once acetylcholinesterase is inactivated, acetylcholine
accumulates and results in overstimulation of muscarinic and nicotinic
receptors
Activation of muscarinic receptors causes restlessness, agitation, lethargy,
confusion, slurred speech, seizures, cardiorespiratory depression, diaphoresis,
salivation, lacrimation, urination, diarrhea, bronchospasm, coma and death
Stimulation of nicotinic receptors at the neuromuscular junction causes
fasciculations, cramping, weakness, respiratory muscle paralysis
Stimulation of nicotinic receptors at sympathetic ganglia results in hypertension,
tachycardia, pallor, mydriasis.
Organophosphates can be absorbed cutaneously, ingested, inhaled or injected.
The onset and severity of symptoms depend on the specific compound, amount,
route of exposure and rate of metabolic degradation
Lab diagnosis – it is a clinical diagnosis. Confirmation is based on the
measurement of cholinesterase activity.
Other findings – leukocytosis, hemoconcentration, metabolic and respiratory
acidosis, hyperglycemia, hypokalemia, elevated troponins, elevated amylase,
elevated LFTs
Treatment – airway control
Adequate oxygenation
Intubation in cases of respiratory distress
Use of atropine and benzodiazepins (diazepam)