Definitions:
Toxicology: It is the study of the poisonous effect of drugs and other chemicals with emphasis on
detection, prevention and treatment of poisonings. It also includes the study of adverse effects of drugs,
since the same substance can be a drug or a poison, depending on the dose.
Toxicity tests
The aim is to determine safety of the compound in at least 2 animal species, mostly mouse/rat and dog by
oral and parenteral routes.
Acute toxicity: Single escalating doses are given to small groups of animals that are observed for overt
effects and mortality for 1–3 days. The dose which kills 50% animals (LD50) is calculated. Organ toxicity
is examined by histopathology on all animals.
Subacute toxicity: Repeated doses are given for 2–12 weeks depending on the duration of intended
treatment in man. Doses are selected on the basis of ED50 and LD50. Animals are examined for overt
effects, food intake, body weight, haematology, etc. and organ toxicity.
Chronic toxicity: The drug is given for 6–12 months and effects are studied as in subacute toxicity. This
is generally undertaken concurrently with early clinical trials.
Reproduction and teratogenicity: Effects on spermatogenesis, ovulation, fertility and developing foetus
are studied.
Mutagenicity: Ability of the drug to induce genetic damage is assessed in bacteria (Ames test),
mammalian cell cultures and in intact rodents.
Carcinogenicity: Drug is given for long-term, even the whole life of the animal and they are watched for
development of tumours.
Poisoning: In a broad sense, poisoning implies harmful effects of a chemical on a biological system. It
may result from large doses of drugs because ‘it is the dose which distinguishes a drug from a poison’.
Poison is a ‘substance which endangers life by severely affecting one or more vital functions’. Not
only drugs but other household and industrial chemicals, insecticides, etc. are frequently involved
in poisonings. Specific antidotes such as receptor antagonists, chelating agents or specific antibodies
are available for few poisons.
General principles in the treatment of poisoning:
1. Resuscitation and maintenance of vital functions AirwayBreathingCirculationDepression of cns
a. Ensure patient airway, adequate ventilation, give artificial respiration/100% oxygen inhalation as
needed.
b. Maintain blood pressure and heart beat by fluid and crystalloid infusion, pressor agents, cardiac
stimulants, pacing, defibrillation, etc, as needed.
c. Maintain body temperature.
d. Maintain blood sugar level by dextrose infusion, especially in patients with altered sensorium.
e. If convulsions then give diazepam
f. Fluid and electrolyte therapy for restoration of cardiac output and for blood volume expansion
2. Termination of exposure (decontamination) by removing the patient to fresh air (for inhaled poisons),
washing the skin and eyes (for poisons entering from the surface), induction of emesis with syrup ipecac
or gastric lavage (for ingested poisons).
Emesis should not be attempted in comatose or hemodynamically unstable patients, as well as for
kerosene poisoning due to risk of aspiration into lungs. These procedures are also contraindicated in
corrosive and CNS stimulant poisoning.
Emesis/gastric lavage is not recommended if the patient presents > 2 hours after ingesting the poison; if
the poison/its dose ingested are known to be non life-threatening, or if the patient has vomited after
consuming the poison.
3. Prevention of absorption of ingested poisons: A suspension of activated charcoal, which has large
surface area and can adsorb many chemicals, should be administered in water. However, strong acids
and alkalis, metallic salts, iodine, cyanide, caustics, alcohol, hydrocarbons and other organic solvents are
not adsorbed by charcoal. Charcoal should not be administered if there is paralytic ileus or intestinal
obstruction or when the patient reports > 2 hours after ingesting the poison.
4. Hastening elimination of the poison by inducing diuresis (furosemide, mannitol) or altering urinary pH
(alkalinization for acidic drugs, e.g. barbiturates, aspirin). However, excretion of many poisons is not
enhanced by forced diuresis and this procedure is generally not employed now. Haemodialysis and
hemoperfusion (passage of blood through a column of charcoal or adsorbent resin) are more efficacious
procedures.
Gastric lavage, Emetics(NaCl soln) and Cathartics(Purgatives) are other ways to empty the G.I.T.
Barbiturate Poisoning:
Barbiturate: sedative-hypnotic, anti epileptic drug category
Mechanism of toxicity: Bind to GABA receptors, prolong the opening of chloride channels, hence inhibit
cells from getting excited. They cause direct CNS depression, and can cause depression of respiratory
and cardiovascular centres too.
Symptoms: Weak and rapid pulse, peripheral circulatory collapse, slow and shallow breathing, stupor and
coma
Management:
1. Resuscitation and maintenance of vital functions/ Cardiorespiratory support:
Clear airway is ensured by suctioning and insertion of oral airway. Barbiturates can cross BBB,
cause hyperventilation and worsening of respiratory failure, hence immediate intubation is done.
Dehydration is corrected using fluid and electrolyte therapy. If hypotension persists, volume
expanders and vasopressors are started.
2. Prevention of absorption:
Gastric lavage is done, if no more than 2-4 hours have passed since ingestion. Activated
Charcoal(non toxic adsorbent) can be used, which binds to high molecular weight compounds
and prevents their absorption. Emesis can also be done using NaCl solution, etc.
3. Removal/ Elimination from the body:
Forced diuresis is done, with high urine flow rate, clearance of the poison is increased. This
shortens duration of coma and decreases plasma concentration. Alkalinization of urine causes
barbiturates to precipitate and hence prevents them from getting reabsorbed from tubules.
Haemodialysis and hemoperfusion (passage of blood through a column of charcoal or adsorbent
resin) are more efficacious procedures.
Morphine/Opioid Poisoning:
Morphine: analgesic from Papaver somniferum; most common drug of abuse
Mechanism of poisoning: Binds to Mu (opioid) receptors in cerebral cortex and hypothalamus and causes
analgesics, sedative and euphoric effects. Overactivation can cause neurotoxicity, respiratory depression
and death.
Symptoms: Respiratory depression, hypoxia, stupor, coma, miosis, renal failure, hypothermia
Management:
1. Resuscitation and maintenance of vital functions/ Cardiorespiratory support:
2. Naloxone: Antidote; Competitive Mu receptor antagonist that reverses all effects of
opioids. Can be given intranasal, intravenously and via orotracheal intubation. Dose
should be increased every two minutes till maximum dose, if no response is seen.
3. Clonidine: Helps patients with withdrawal; centrally acting alpha-2 adrenergic agonist.
Limited use due to hypotensive and sedative effects.
4. Naltrexone: Mu receptor antagonist; also antagonises Kappa and delta receptors. Used in
combination with Clonidine.
Organophosphate poisoning:
Organophosphates: popular and widely used insecticide in agriculture
Mechanism of poisoning: Acetylcholine esterase inhibitor; AChE is responsible for degrading ACh after it
has propagated action potential. Inhibition causes accumulation of ACh and overstimulation, eventually
causing nerve or muscle paralysis.
Symptoms:
1. Acute poisoning: Muscarinic effects like Salivation Lacrimation Urination Diarrhoea GI distress Emesis
and Nicotinic effects muscle fatigue, paralysis, fasciculations.
2. Chronic poisoning: Polyneuropathy (muscle cramps, fatigue), CNS effects (drowsiness, confusion,
anxiety) and Sheep Farmer’s Disease.
Management:
1. Decontamination: If spillage has occurred on the body, the patient should be stripped out
of the clothing and washed with soap and water, and hair too should be rinsed. First wash
is with cold water and the second is with warm water.
2. Antidotes:
a. Atropine: Competitive antagonist of ACh, blocks muscarinic effects of ACh
poisoning. Given every 15 mins till there is drying up of tracheobronchial
secretions.
b. Pralidoxime: Has high affinity for the phosphate group of organophosphates;
binds to it and frees AChE enzymes, reactivating them.
c. Diazepam: Addition to above drugs improves survival and reduces risk. Phenytoin
and phenobarbitone can also be used.
3. Supportive measures: Fluid therapy, maintenance of airway and oxygenation, monitoring of pulse
and oximetry, etc.
Lead poisoning:
Symptoms:
1. Acute poisoning: typical neurological signs are pain, muscle weakness, paraesthesia,
abdominal pain, nausea, vomiting, diarrhoea, and constipation. Hemolysis (the rupture of red
blood cells) due to acute poisoning can cause anaemia and haemoglobin in the urine is also
seen.
2. Chronic poisoning usually presents with symptoms affecting multiple systems, but is associated
with three main types of symptoms: Gastrointestinal (nausea, abdominal pain), Neuromuscular
(loss of coordination, and numbness and tingling in the extremities), Neurological (short-term
memory or concentration, depression).
Mechanism of poisoning:
1. The primary cause of lead's toxicity is because it binds to sulfhydryl groups found on many
enzymes. It interferes with the activity of an essential enzyme, delta-aminolevulinic acid
dehydratase, or ALAD, which is important in the biosynthesis of heme.
2. Lead also inhibits the enzyme ferrochelatase, another enzyme involved in the formation of
heme. Ferrochelatase catalyses the joining of protoporphyrin and Fe2+ to form heme.
3. Interferes with the release of glutamate by blocking NMDA receptors (main causes for lead's
toxicity to neurons)
Management:
1. Initial treatment of the acute phase of lead intoxication involves supportive measures. Prevention
of further exposure is important.
2. Seizures are treated with diazepam or phenytoin, fluid and electrolyte balances must be
maintained, and cerebral edema is treated with mannitol and dexamethasone or controlled
hyperventilation.
3. The concentration of lead in blood should be determined or at least a blood sample obtained for
analysis prior to initiation of chelation therapy.Chelation therapy is indicated in symptomatic
patients or in patients with a blood lead concentration in excess of 50–60 μg/dL
4. Four chelators are employed: edetate calcium disodium (CaNa2EDTA), dimercaprol,
D-penicillamine, and succimer (2,3–dimercaptosuccinic acid [DMSA]). CaNa2EDTA and
dimercaprol are usually used in combination for lead encephalopathy because the
chelator–lead complex is believed to be nephrotoxic.
Mercury poisoning:
Symptoms: peripheral neuropathy (presenting as paresthesia or itching, burning or pain), skin
discoloration (pink cheeks, fingertips and toes), swelling, and shedding or peeling of skin.
Mechanism of toxicity:
1. Mercury readily forms covalent bonds with sulphur; When the sulphur is in the form of sulfhydryl
groups, divalent mercury replaces the hydrogen atom to form mercaptides. Even in low
concentrations, mercurials are capable of inactivating -SH groups of enzymes, thus interfering
with cellular metabolism and function.
2. Mercury also combines with phosphoryl, carboxyl, amide, and amine groups.
Management:
1. Identifying and removing the source of the mercury is crucial. Decontamination requires
removal of clothes, washing skin with soap and water, and flushing the eyes with saline
solution as needed. Inorganic ingestion such as mercuric chloride should be approached as the
ingestion of any other serious caustic.
2. Immediate chelation therapy is the standard of care for a patient showing symptoms of severe
mercury poisoning or the laboratory evidence of a large total mercury load.
3. Chelation therapy for acute inorganic mercury poisoning can be done with DMSA,
Dimercaptopropane sulfonic acid (DMPS), D-penicillamine (DPCN), or dimercaprol (BAL).
4. DMSA is the most frequently used for severe methylmercury poisoning, as it is given orally, has
fewer side-effects, and has been found to be superior to BAL, DPCN, and DMPS.
5. α-Lipoic acid (ALA) has been shown to be protective against acute mercury poisoning in
several mammalian species when it is given soon after exposure; correct dosage is required, as
inappropriate dosages increase toxicity.
Arsenic poisoning:
Symptoms: headaches, confusion, severe diarrhea, and drowsiness. As the poisoning develops,
convulsions and changes in fingernail pigmentation called leukonychia striata. The final result of arsenic
poisoning is coma and death.
Arsenic is related to heart disease (hypertension related cardiovascular), cancer, stroke (cerebrovascular
diseases), chronic lower respiratory diseases, and diabetes.
Mechanism of toxicity:
1. Arsenic interferes with cellular longevity by allosteric inhibition of an essential metabolic enzyme
pyruvate dehydrogenase (PDH) complex, which catalyzes the oxidation of pyruvate to acetyl-CoA
by NAD+. With the enzyme inhibited, the energy system of the cell is disrupted resulting in a
cellular apoptosis episode
2. Inorganic arsenic trioxide found in ground water particularly affects voltage-gated potassium
channels, disrupting cellular electrolytic function resulting in neurological disturbances,
cardiovascular episodes such as prolonged QT interval, neutropenia, high blood pressure, central
nervous system dysfunction, anemia, and death.
Management:
1. Supplemental potassium decreases the risk of experiencing a life-threatening heart
rhythm problem from arsenic trioxide.
2. Dimercaprol and dimercaptosuccinic acid are chelating agents that sequester the arsenic
away from blood proteins and are used in treating acute arsenic poisoning.
3. Dimercaprol is considerably more toxic than succimer. Calcium sodium edetate is also used.
