Principles of toxicology

In this presentation Pharmacology III Unit V covered
Following points are included;
Various Definitions:
Acute toxicity
Subacute toxicity
Chronic toxicity
Genotoxicity,
Carcinogenicity,
Teratogenicity
Mutagenicity


General principles of treatment of poisoning

Clinical symptoms and management of various poisoning conditions.
like Barbiturate poisoning, Morphinpoisoning, Organophosphoruspoisoning, Lead poisoning, mercury poisoning, Arsenin poisoning, And its specific antidote

1. Principles of Toxicology
Miss Snehal S. Chakorkar (M.pharm)
Dept Of Pharmacology
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2. ➢Various Definitions:
Acute toxicity
Subacutetoxicity
Chronic toxicity
➢General principles of treatment of poisoning
➢Clinical symptoms and management of
various poisoning conditions.
Genotoxicity,
Carcinogenicity,
Teratogenicity
Mutagenicity
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3. Definitions:
Acute toxicity: “It is a adverse effects of a
substance that result either from a single
exposure or from multiple exposures in a short
period of time (usually less than 24hours).”
To be described asacutetoxicity, the adverse
effects should occur within 14days of the
administration of the substance.
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4. Measures of acute toxicity:
Regulatory values:Based on experimental data
American conference of governmental Industrial
Hygienists (ACGIH) and the occupational safety and
health administration(OSHA) set a standard values for
acute toxicity.
Experimental values: Various experiments are
carried out to get referenced value in the chemical
industry that is the median lethal dose, or LD50. This is
the concentration of substance which resulted in the
death of 50% of test subjects (typically mice or rats) in
the laboratory.
Which will considered as standard values.
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5. Subacutetoxicity:
Subacutetoxicity is an adverse effect occurring as a
result of repeated daily dosing of a chemical, or exposure
to the chemical, over a period of several days or weeks .
acute toxicity studies are conducted as range-finding
studies in order to choose dosage levels to be used in
subsequent subchronicand chronic toxicitystudies.
subacutetoxicity studies may support initial clinical trials
where the duration of treatment may be up to 4weeks.
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6. Chronic toxicity:
The development of adverse effects as a result of long
term exposure to a contaminant or other stressor, is an
important aspect ofaquatic toxicology.
Adverse effects associated with chronic toxicity can be
directly lethal but are more commonly sublethal,
including changes in growth, reproduction, or behavior.
Chronic toxicity is in contrast toacute toxicity, which
occurs over a shorter period of time to higher
concentrations. Various toxicity tests can be performed
to assess the chronic toxicity of different contaminants,
and usually last at least 10% of an organism’s lifespan
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7. Genotoxicity: Genotoxicitydescribes the property of
chemical agents that damages the genetic information
within a cell causing mutations, which may lead to
cancer.
Genotoxicityis a word used in genetics that describes the
possession of substance that has destructive effect on the
genetic material of the cell (DNA, RNA) thus affecting
the integrity of the cell. Genotoxinsare mutagens that
can cause genotoxicityleading to the damage of DNA or
chromosomal material thus causing mutation.
Genotoxinscan include chemical substance as well as
radiation. Genetic toxicology is the branch of science that
deals with the study of agents or substances that can
damage the cell’s DNA and chromosomes. It is noted that
often genotoxicityis confused with mutagenicity
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8. Genotoxinscan be of the following
category depending on its effects for ;
Carcinogens or cancer causing agents
Mutagens or mutation causing agents
Teratogensor birth defect causing
agents
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9. Carcinogenicity:
Carcinogenicityis the ability or tendency of a chemical
to induce tumors(benign or malignant), increase their
incidence or malignancy, or shorten the time of tumor
occurrence when it is inhaled, ingested, dermally
applied, or injected.
A few well-knowncarcinogensare asbestos, nickel,
cadmium, radon, vinyl chloride, benzidene, and
benzene. Thesecarcinogensmay act alone or with
anothercarcinogento increase your risk. Forexample,
asbestos workers who also smoke have a higher risk of
lung cancer.
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10. Teratogenicity:
A teratogenis an agent that can disturb the development
of the embryo or fetus. Teratogenshalt thepregnancyor
produce a congenital malformation (a birth defect).
Classes of teratogensincluderadiation, maternal
infections, chemicals, anddrugs.
Examples:
Fetalalcohol spectrum disorder (FASD):
A baby born to a mother who drinks alcohol during pregnancy can
have many problems. This is called fetalalcohol spectrum disorder
(FASD).
Fetalhydantoinsyndrome:
baby born to a mother who took phenytoinhas a 5 in 100 to a 1 in
10 chance of having a birth defect. This birth defect is a
combination of problems called fetalhydantoinsyndrome.
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11. Mutagenicity:
Mutagenicityrefers to a chemical or physical agent's
capacity to cause mutations (genetic alterations). Agents
that damage DNA causing lesions that result in cell
death or mutations are genotoxins.
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12. General principles of treatment
of poisoning
Poisoning is commonly due to ingestion but can result
from injection, inhalation, or exposure of body surfaces
(eg, skin, eye, mucous membranes).
Many commonly ingested nonfood substances are
generally nontoxic ; however, almost any substance can
be toxic if ingested in excessive amounts Causes toxicity
and poin.
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13. General measures for poisoning Treatment:
Drugs along with 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 supportive and symptomatic treatment is all that
can be done for others, and this is also important for
poisons which have a selective antagonist.
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14. The general detoxification and supportive
measures are:
1. Resuscitation and maintenance of vital
Functions.
2.Termination of exposure (decontamination) &
Ensure patent airway, adequate ventilation.
3. Prevention of absorption of ingested poisons
4. Hastening elimination (Fast removal)
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15. 1. Resuscitation and maintenance of vital functions
a. Ensure patent airway, adequate ventilation, give
artificial respiration/100% oxygen inhalation as
needed.
b. Maintain blood pressure and heart beat by fluid and
crystalloid infusion, pressoragents, 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
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16. 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
haemodynamicallyunstable patient, as well as for kerosene
poisoning due to risk of aspiration into lungs.
contraindicated in corrosive and CNS stimulant poisoning.
Emesis/gastric lavageis 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.
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17. 3. Prevention of absorption of ingested poisons
A suspension of 20–40 g (1g/kg) of activated charcoal,
which has large surface area and can adsorb many
chemicals, should be administered in 200 ml of water.
However, strong acids and alkalies, 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 ileusor intestinal obstruction or when
the patient reports > 2 hours after ingesting the
poison.
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18. 4. Hastening elimination of the poison by inducing
diuresisor altering urinary pH :
Inducing diuresis(furosemide, mannitol) or altering
urinary pH (alkalinizationfor acidic drugs, e.g.
barbiturates, aspirin).
However, excretion of many poisons is not enhanced
by forced diuresisand this procedure is generally not
employed now.
Haemodialysis and haemoperfusion(passage of blood
through a column of charcoal or adsorbantresin) are
more efficacious procedures.
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19. 1.Barbiturates poisoning
Causes: Mostly suicidal, sometimes accidental. It is infrequently
encountered now due to inavailabilityof barbiturates.
Sign and symptoms: Due to excessive CNS depression—
patient is flabby and comatose with shallow and failing
respiration, fall in BP and cardiovascular collapse, renal shut
down, pulmonary complications, bullouseruptions.
Lethal dose depends on lipid solubility. It is 2–3 g for
the more lipid-soluble agents (short-acting barbiturates) and
5–10 g for less lipid-soluble phenobarbitone.
Treatment
1. Gastric lavage; leave a suspension of activated charcoal
in the stomach to prevent absorption of the drug from
intestines.
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20. 2. Supportive measures: such as, patent airway, assisted
respiration, oxygen, maintenance of blood volume by fluid
infusion and use of vasopressors—dopamine may be
preferred for its renal vasodilatingaction.
3. Alkaline diuresis: with sodium bicarbonate 1 mEq/kg i.v.
with or without mannitolis helpful only in the case of longacting
barbiturates which are eliminated primarily by renal
excretion.
4. Haemodialysis and haemoperfusion(through a column
of activated charcoal or other adsorbants) is highly effective
in removing long-acting as well as short-acting barbiturates.
There is no specific antidote for barbiturates. In the past,
analeptics like metrazol, bemegride, etc. have been used in
an attempt to awaken the patient. This is dangerous, may
precipitate convulsions while the patient is still comatose—
mortality is increased. The emphasis now is on keeping the
patient alive till the poison has been eliminated.
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21. 2.Morphine poisoning
Causes:Accidental, suicidal or seen in drug abusers. In
the nontolerantadult, 50 mg of morphine i.m.
produces serious toxicity. The human lethal dose
is estimated to be about 250 mg.
Sign and symptoms:
are extensions of the pharmacological action. Stupor or coma,
flaccidity, shallow and occasional breathing, cyanosis, pinpoint
pupil, fall in BP and shock; convulsions may be seen
pulmonary edemaoccurs at terminal stages, death is due to
respiratory failure.
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22. Treatment:
pressure respiration also opposes pulmonary edemaformation)
and maintenance of BP (i.v. fluids, vasoconstrictors). Gastric
lavageshould be done with pot.
Permanganate to remove unabsorbed drug.
Lavageis indicated even when morphine has been injected.
Being a basic drug it is partitioned to the acid gastric juice,
ionizes there and does not diffuse back into blood.
Specific antidote: Naloxone0.4–0.8 mg i.v. repeated
every 2–3 min till respiration picks up, is the specific
antagonist of choice because it acts rapidly, does not have any
agonistic action and does not per se depress respiration (see
p. 483).
Due to short duration of action, naloxoneshould be repeated
every 1–4 hours, according to the response.
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23. 3.Organophosphosphorus compound poisoning
Causes:Chronic organophosphate poisoning repeated
exposure to certain fluorine containing and triaryl
organophosphates results in polyneuritis and demyelination
after a latent period of days to weeks.
Sign and symptoms:
Sensory disturbances occur like muscle weakness, tenderness
and depressed tendon reflexes—lower motor neurone
paralysis.
In the second phase, spasticity and upper motor neurone
paralysis gradually supervenes. Recovery may take years.
The mechanism of this toxicity is not known, but it is not due
to inhibition of ChE; there is no specific treatment.
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24. Lead/Mercury/Arsenic poisoning
Causes:Chronic , repeated exposure to certain ions like lead,
mercury and arsenic containing compounds in indusrtyor by
accidental.
Sign and symptoms:
Common like poisoning condition.
Treatment :
CaNa2EDTA; 1 gm is diluted to 200–300 ml in saline or glucose
solution and infused i.v. over 1 hour twice daily for 3–5 days.
The urinary excretion of Pbis promptly increased, but declines
quickly as the metal is removed from accessible sites (primarily
bone).
A second course of CaNa2EDTA may be repeated after 5–7 days,
allowing time for Pbto redistribute to extracellular sites.
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25. Typeof poisoning Antidote
1.Barbiturates poisoningBZD antagonistflumazenil
2.Morphine poisoningNaloxone
3.Organophosphosphorus
compound poisoning
Atropine, Cholinesterase reactivators
Oximes
4.Lead poisoning EDTA chelationtherapy
5.Mercury poisoningDMPS is an analogof British Anti-
Lewisite (BAL)
6.Arsenic poisoningDimercaproland dimercaptosuccinic
acidare chelating agents,Supplemental
potassium
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26. Reference:
Rang H.P. and Dale M.M.: Pharmacology, Churchill
Livingstone, Edinbergh.
KatzungB.G.: Basic and Clinical Pharmacology, Lange
Medical Publications, California.
Craig C.R. and StitzelR.E.: Modern Pharmacology, Little
Brown and Co., Boston.
Bowman W.C. and Rand M.J.: Textbook of Pharmacology,
Blackwell Scientific Publications, Oxford.
P.N Bennett & M J Brown: Clinical Pharmacology,
Churchill Livingstone, Edinburgh.
TripathiK.D.: Essentials of Medical Pharmacology, Jaypee
Brothers, Medical Publishers, New Delhi.
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