Unit four: Toxic Agents of

Pharmaceutical Importance

Aklilu Ayele (B.Pharm, MSc)

A/Minch University,
College of Medicine and Health Sciences
 Outlines
 Toxic effects of pharmaceutical agents:
Pesticides
 Insecticides
 Rodenticides
 Herbicides
 Fungicides

Solvents and vapours

animal venoms and plant toxicants
 Toxic Effects of Pesticides

What is Pesticide?
Any substance or mixture of substances intended for
preventing, destroying, repelling, or mitigating pests.
Pests can be insects, rodents, weeds, and a host of other
unwanted organisms
Highly specific for undesirable targets
Pesticides are not unitary (one/similar) class of chemicals
Classification of pesticides relies on the target species they
act on.
 Toxic Effects of Pesticides
• Classification of pesticides:
• Insecticides
• Rodenticides
• herbicides
• Fungicides
 Toxic Effects of Pesticides
• Public health benefits of Pesticides
In the uses of pesticide, the benefit must balance with risk
 control of vector-borne diseases (e.g. malaria)
 allow production of abundant, inexpensive, and attractive fruits
and vegetables
useful application in forestry, during reforestation

75% of households in the US utilize some form of pesticides

 Toxic Effects of Pesticides
• Exposure to pesticides
• Oral ingestion- for suicidal intents, or of accidental/Chronic low
doses pesticide residues in food

• Dermal routes and Inhalation

• Workers involved in the production, transport, mixing and
loading, and application of pesticides

• Human Poisoning of Pesticides

• Pesticides are not always selective for their intended target species
(use for insect protection-----can cause cancer in human)
• increased risk of cancer
• Neurodegenerative diseases such as Parkinson disease
• Reproductive and developmental toxicity

• 300,000 deaths due to pesticide self-poisoning each year

• WHO has recommended a classification of pesticides
by hazard.
Insecticides - most acutely toxic
Rodenticides
Herbicides - moderate to low acute toxicity
Fungicides - low acute toxicity
Fumigants
 1. INSECTICIDES
• Any physical or biological agent that kills an insect.
• Are neurotoxicants
• Insecticides are not selective and
• Affect non-target species as readily as target organisms.
• higher acute toxicity toward non-target species compared with
other pesticides
1. INSECTICIDES
 Chemical Classification
• Organophosphorus(OP)
• Pyrethroids
• Carbamates
• Organochlorine(OC)
1.1. Organophosphorus(OP) Compounds
• Are organic compounds containing phosphorus

The general structure of OP insecticides

• Hundreds of OP compounds have been made and

commercialized worldwide in a variety of formulations
 OP cont…..
• Route of exposure: oral, inhalation, dermal
• For all compounds that contain a sulfur bound to the
phosphorus, a metabolic bioactivation is necessary
• Reaction is oxidative de-sulfuration (replace=s by =o)
results in the formation of the ‘’oxon’’ of parent drug-
which is more toxic.
 Metabolic activation
 Parathion......paraoxon
 Malathion…..malaxon
 Diazinon……diazonon
 Chlorpyrifos.. chlorpyrifos oxon
 Parathion….paraoxon OP cont…..
• MOA: Inhibits the enzyme acetylcholinesterase (AChE)
 OP cont…..
• Higher doses cause overstimulation of both muscarinic
and nicotinic receptors(prasympathetic –NS…PSNS),
resulting in;-
• Cholinergic Toxidromes
• D – Defecation
• U – Urination
• M – Miosis
• B – BBB (Killer B’s)
• Bronchospasm, Bradycardia, Bronchorrea
• E – Emesis
• L – Lacrimation
• S – Salivation

• Nicotinic effects: Muscle weakness, Fasciculation and

respiratory failures
 OP cont…..
• Complications of OP poisoning following aspiration of the
solvent vehicle.
– Acute pancreatitis, myocardial dysrhythmias, and
hydrocarbon pneumonitis

• OP-induced delayed neuropathy (OPIDN) is a delayed

neurotoxicity that may develop 1 to 3 weeks after exposure.
– The syndrome is characterized by tingling of the hands
and feet, followed by sensory loss, progressive muscle
weakness and flaccidity of the distal skeletal muscles of
the lower and upper extremities, and ataxia.
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 OP cont…..
• Clinical management of acute poisoning
– Decontamination, airway stabilization, and activated charcoal
– Washing dermal areas with a mild soap, removal of contaminated
clothes, and rinsing the eyes is necessary for dermal or ocular
exposure.
– Atropine (until secretions dry) and pralidoxime (2-PAM) follow as
specific OP antidotes.
• Atropine 1 to 2mg repeated in twenty or thirty minutes as soon as
cyanosis has cleared + parenteral pralidoxime chloride is 1 – 2 g for
adult, or 20-40 mg/kg for children; repeat the dose in about 1hour if
muscle weakness has not been relieved (IV infusion of 500 mg of the drug
per hours)
• Diazepam (10–20 mg) is also used in the treatment of acute OP
poisoning to relieve anxiety in mild cases, and to reduce muscle
fasciculation and antagonize convulsions in the more severe cases. 18
 Gaseous form of
Organophosphorus cont.
• Gaseous form of OP… tabun, sarin, and soman
• are employed in warfare and terrorism
• military weapon…..as nerve agents
• Aging within seconds, ….pralidoxime(antidote) is less
effective.

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 1.2. Carbamates

 Carbamates: Carbofuran, Carbaryl,

Aldicarb, Propoxur
• Mechanism of toxicity : reversibly inhibit
Ach-E by carbamoylation of the esteratic site.
• Route of exposure: oral
• Signs and symptoms of acute toxicity
– Similar to OP
• It has less CNS toxicity
• Clinical management: Atropine

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 1.3. Pyrethroids
Allethrin,
Resmethrin,
Phenothrin
Deltamethrin,
Chrisanthenum cinerariaefolium Cypermethrin

• high insecticidal potency

• generally low mammalian toxicity
• relatively low tendency to induce insect resistance
• lack of environmental persistence
• Human uses medicine for the topical treatment of scabies and
head lice
• Malaria control, soaked bed nets to prevent mosquito bites 22
 Pyrethroids cont…
• MOA: disruption of the voltage-gated sodium channels
– Prolong channel opening (cause repetitive firing of action
potential)
– inhibit, GABA-gated chloride channels

• High toxicity in insects - higher sensitivity of insect

sodium channels and slower biotransformation
• Human toxicity: Increased sensitivity to external
stimuli, Whole-body tremors, choreoatetosis, skin
(paresthesia, burning)
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 1.4. Organochlorine (OC) insecticides
 These insecticides belong to three distinct chemical classes:
1. Dichlorodiphenylethanes: E.g. DDT ,diclofol, methoxychlor
,etc
2. Chlorinated cyclodiene & benzene: E.g. aldrin , dieldrin,
chlordane, etc
3. Cyclohexane-related structures: E.g. lindane

 They are
– Non-volatile, Chemical stabile, lipid soluble, and degrade
slowly

 This Properties that contribute to their

 Persistence in the environment, bioconcentration and bio-
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magnifications in food chains
 DDT
• Get accumulated for longer period in tissues(adipose tissue)
NB: doesn’t affect the adipose tissue.
• Highly absorbed-b/c its highly lipid soluble
• Affect nerve transmission (inhibit GABA)
– reduce the rate of depolarization and increase the
sensitivity of neurons to small stimuli.
• Sensitize myocardium to catecholamines (NA and A)-
increase Heart activity in its presence

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 DDT
• Signs and symptoms of acute toxicity
– Inhibition of GABA leads to motor, sensory, and
behavioral changes, typically manifested as
apprehension, irritability, confusion, sensory
disturbances, dizziness, tremors, and seizures.

– The chemicals sensitize involuntary autonomic

muscle activity to catecholamines.
• In particular, myocardial arrhythmias are
promptly precipitated.

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 DDT
• Clinical management of acute poisoning
– Decontamination, gastric lavage, and administration of
activated charcoal reduce toxicity after oral ingestion.
– Washing of the affected area may reduce absorption
after dermal exposure.
– Myocardial arrhythmias are managed with
antiarrhythmics such as lidocaine
– Benzodiazepines are indicated for preventing or
reducing development of seizures. (diazepam)

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 DDT
• Chronic exposure DDT
– increase liver weight and cause
hepatic cell hypertrophy and
necrosis
– potent inducers of
cytochromes P450
– known as human carcinogen
• breast, the endometrium, and the
prostate cancers??

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 2.Rodenticides
2.1. Anticoagulants/ warfarin,
– Grain or pellets-based baits

• Mechanism of toxicity
– Antagonizes the actions of vitamin K in the
synthesis of clotting factors II, VII, IX, and X.

• Signs and symptoms of acute toxicity

– Gingival bleeding, epistaxis, joint and muscle pain,
easy bruising, alerted PT time
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Mechanism of warfarin 30
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 Rodenticides cont…

• Human poisonings- accidental or suicidal ingestion

• Clinical management of acute poisoning
– IV Fluids
– GI decontamination (at early time)
• Activated charcoal
– Administration of vitamin K

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 rodenticides cont.
2.1. Strychnine
• Mechanism of poisoning
• Inhibits glycine/inh.NT/= excitation
• S/S
• Convulsion, Muscle spasm
• Rx
• Supportive therapy: maintain ABCD
• Symptomatic Rx: Iv diazepam for siezure,
competitive NMBs = tubocuraraine
• GI decontamination (b/c no specific antidote)
• if in circulation removal by any of
techniques--- hemodialysis
 3. Herbicides cont..
• 3.1. Paraquat (Bipyridyliums)
• Route of exposure: oral
• Mechanism of poisoning
• Gets reduced to free radicals that react with O2
to form superoxide and H2O2 which damage
tissues
• S/S
• Myocarditis
• lung, renal and liver damage, GI upset
• Rx
• Maintain ABCD
• Symptomatic Rx
• Gastric lavage, hemodialysis(b/c of no specific
antidote
 4. Fumigants
Are agents used to kill insects, weed seeds, and
fungi in soil and to prevent stored food stuffs eg.
HCN, CS2, phosphine(PH3), etc.
They are gaseous formulation (could be insecticide,
fungicide, herbicide)
May be liquid e.g. Formaldehyde that readily
vaporize at ambient temperature
Or solids that can release a toxic gas on reacting
with water (Zn2P3, AlP) or with acid [NaCN,
Ca(CN)2];or gases (methylbromide, hydrogen
cyanide, ethylene oxide)
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 Fumigants cont…

4.1) Cyanide (hydrocyanic acid, HCN-prussic acid)

 Cyanide has very high affinity to ferric state
 when absorbed, it reacts readily with Fe3+ of cytchrome
oxidase---inhibiting cellular respiration resulting in lactic
acidosis and cytotoxic hypoxia --death due to respiratory
arrest
 Diagnosis aided by the toxic odor of cyanide.
• Headache
• Nausea and vomiting
• Rapid breathing
• Rapid heart rate
• Convulsion, cessation of respiration
and heart beat
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 Fumigants cont…

Cyanide
– Sources of poisoning
• Fumigation of insects /rodents
• Cigarette smoke
• Fire combustion (plastic/silk, wood)
• Industry byproducts (petroleum refining)
• Drugs (nitropruside)--anti-HTN drug---
metabolized to CN

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 Fumigants cont…
 Treatment
1. Prevention or reversal of binding of cyanide to cytochrome
oxidase by providing a large pool of ferric iron to compete for
cyanide.
2. Nitrite that oxidize hemoglobin (Fe2+) to methemoglobin (Fe3+)
 Methemoglobin (Fe3+) competes with cytochrome oxidase
for cyanide ion; the rxn favours metHgb whereby
cyanometHgb is formed & cytochrome oxidase is restored.
3. Hydroxycobalamine ---combines with CN- to form
cyanocobalamine (vit B12) which is non toxic
4. Rhodanese (transalfurase) --converts CN- to SCN-, which is less
toxic
 To accelerate detoxification, Na thiosulfate(Na2S2O3) is given
IV and the SCN- formed is readily excreted in the urine
Transalfurase
Na2S2O3 + CN- SCN- + Na2SO3
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 Fumigants cont…

Cyanide
Msm of toxicity Goal of mgt
Inhibits cytochrome oxidase Prevention or reversal of binding
of cyanide to cytochrome oxidase

Nitrite converts Sodium thiosulfate

HbFe2+ to converts cyanide to HydroCobalamine
Large pol of ferric converts CN to
iron Fe3+ methemoglobin SCN-
HbFe3+ cyanocobalamine(Vit
B12) non toxic

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Toxic Effects of Solvents and Vapors
 Solvents
• The term solvent refers to a class of organic
chemicals of variable lipophilicity and volatility.
• Inhalation, oral, dermal – route of admin/exposure
• Used to dissolve, dilute, or disperse materials that are
insoluble in water.
– Halocarbons, aromatic hydrocarbons, alcohols, ethers,
esters/acetates, amides/amines, aldehydes, ketones
• Nearly everyone is exposed to solvents during their
normal activities.
– Toxicity - Tissue irritation, CNS depressant, organ damage,
cytotoxic/mutagenic, carcinogens

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Alcohol

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 Ethanol
• Ethyl alcohol is used as a solvent in industry, in many
household products and pharmaceuticals, and in
intoxicating beverages.
• Route of exposure: oral, inhalation, dermal

Absorption-- due to its high water miscibility, alcohol

readily passes through intestinal mucosa and enters the
blood fairly quickly.
– about 20% of the dose is absorbed empty stomach
– The remaining from small intestine

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 Ethanol cont…
Distribution
– Distributed uniformly throughout the body
– Alcohol distributes partly into the alveoli of the lungs
– Alcohol also crosses the BBB readily.
– Alcohol readily crosses the placenta in a pregnant woman

Metabolism and elimination

1. Excretion into the urine unchanged,
2. Exhalation from the lungs unchanged, and
3. Excretion without metabolism through the skin.
4. Metabolism by the liver (90% of alcohol load)

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 Ethanol cont…
 Ethanol is metabolized to acetaldehyde by three enzymes:
1. Alcohol dehydrogenase (ADH ): major pathway (rate limiting)
 Catalyzed oxidation to acetaldehyde; the acetaldehyde that is
formed is rapidly oxidized by acetaldehyde dehydrogenase
(ALDH) to acetate.
2. Catalase, utilizes H2O2
 It accounts for more than 10% of ethyl alcohol metabolism
3. CYP2E1 –is the principal component of the hepatic microsomal
ethanol oxidizing system.
 CYP2E1 plays a key role in alcoholic liver disease and
associated oxidative stress
 Pre-exposure to a single high dose or multiple doses of ethanol
can induce CYP2E1, there by enhancing the metabolic activation
and potentiating the toxicity of a considerable number of other
solvents and drugs 46
 Ethanol cont…
• Acetaldehyde oxidation by ALDH occurs much more quickly.
– Acetaldehyde is acutely toxic, --- it is reactive and binds covalently to
protein and other macromolecules
– Note: Acetaldehyde is formed slowly and metabolised rapidly.
Only small amounts are present at any one time in the blood.

• Caucasians, black and Asians have varying percentage of

different ALDH isozymes, which impact the efficiency of
acetaldehyde metabolism
 50% of Asians have active ADH and inactive ALDH

 Black populations in the United States predominantly have an

inactive ADH and active ALDH

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 Ethanol cont…

Biochemical conversion of alcohol to acetate...then to

Kreb’s cycle(Energy processing) 48
Ethanol cont…

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 Ethanol cont…

• Gender difference in responses to ethanol are well

recognized
 Females exhibit slightly higher blood ethanol levels than
men following ingestion of equivalent doses of ethanol; due
to
More extensive ADH---catalyzed metabolism of ethanol
by the gastric mucosa of males (deficiency females)
Women's smaller volume of distribution for relatively
polar solvents such as alcohols.

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 Ethanol cont…

Fetal alcohol syndrome (FAS)

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 Ethanol cont…
• Clinical manifestations of acute toxicity
• Alcohol is a central nervous system depressant.
– Sedation and relief of anxiety, reduced tension and
coordination, impaired concentration and reaction
time, tachycardia, and more severely, slurred speech,
ataxia, and altered emotions.
– Consumption of very large amounts of ethanol (>300
mg/dl) can produce metabolic and toxic coma that
presents clinically as muscular hypotonia, respiratory
depression, hypotension, and hypothermia.

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 Ethanol cont…
• Clinical manifestations of chronic toxicity

– Nervous system: damage to the frontal lobes of the brain,

brain shrinkage, paralysis of external eye muscles,
neuropathy and mental confusion
– Liver : alcoholic hepatitis, cirrhosis, or liver cancer, fatty liver
and hypoglycemia,
– GIT: gastritis and pancreatitis and causes intestine injury,
leading to vitamin deficiencies, diarrhea, and loss of weight

– Cardiovascular system: dilated cardiomyopathy with

ventricular hypertrophy, atrial and ventricular arrhythmias,
hypertension

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 Ethanol cont…
 Alcohol metabolism results in large quantity of NADH ( reduced NAD+)
• Fat synthesis is favoured in the presence of high quantities of
reduced NAD+ (NADH), as is found during alcohol metabolism.

Hypoglycemia and alcoholism.

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 Ethanol cont…
Treatment
• Disulfiram, an ALDH inhibitor, is used to treat
alcoholism, by enhancing acetaldehyde levels when
alcohol is consumed.
• Naltrexone, reduce the urge to drink and decrease ethanol
intake

• Ethanol can be an effective antidote for poisoning by

methanol ,ethylene glycol, and diethylene glycol.
– As ethyl alcohol has relatively high affinity for ADH, it
competitively inhibits the metabolic activation of the
other alcohols. 58
 Methanol
Methanol (methyl alcohol ---- CH3OH)
• Used in manufacture of formaldehyde, acetic acid, ethylene glycol,
and methyl tertiary-butyl ether (MTBE); as a gasoline additives and
alternative automotive fuel.
 Acute methanol poisoning in humans is characterized by
 Formic acidemia, ocular toxicity, comma, in extreme cases death
(12-24 hrs.).
 Visual disturbances generally develop between 18 and 48 hours
after ingestion and
 Ranges from mild photophobia and blurred vision to markedly
reduced visual acuity and complete blindness.
 The target of methanol with in the eye is the retina, optic disk and
optic nerve.
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 Methanol cont…

 Susceptibility to methanol toxicity is dependent up on the

relative rate of formate clearance.
 Dietary and chemical depletion of endogenous folate cofactor
tend to increase formate accumulation following methanol,
resulting in the development of metabolic acidosis and ocular
toxicity.
 Formate appears to act as a direct occular toxin & through the
induction of an acidotic state.

60
 Methanol cont…

Scheme for the metabolism of methanol

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 Alcohols cont…

Clinical management of toxicity

 IV sodium bicarbonates --to correct severe acidosis
 Metabolic blockade with ethanol or 4-methylpyrazole (ADH
inhibitor)
 Folate therapy is also indicated to increase the efficiency of
formate oxidation

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 Glycols
• Ethylene Glycol (1,2-dihydroxyethane)/EG
– It is a constituent of antifreeze, deicers, hydraulic fluids, drying
agents, and inks, and is used to make plastics and polyester fibers.
– Route of exposure: dermal, ingestion

 Acute poisoning of EG has three clinical stages

I. A period of inebriation (drunkenness), the duration and degree

depends up on dose
II. The cardiopulmonary stage 12 to 24h after exposure, characterized
by tachycardia and tachypnea, which may progress to cardiac
failure and pulmonary edema
III. The renal toxicity stage 24 to 72h post exposure
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 Glycols cont…

 Metabolic acidosis can become progressively more severe

during stages 2 & 3.
 Metabolic acidosis in humans appears to be due largely to
accumulation of glycolic acid
 Hypocalcaemia can result from calcium chelating by oxalic acid
to form calcium oxalet crystals.
Deposition of these crystals in the tubules of the kidney and
small blood vessel in the brain is associated with damage of
these organs.

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Glycols cont…

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 Trichloroethylene
• 1,1,2-Trichloroethylene (TCE) is a widely used solvent for metal degreasing.

• The toxicities are mediated by metabolites rather than by the parent cpd.

• TCE is rapidly absorbed in to the systemic circulation via the oral and
inhalation routes.

• Two distinct metabolic pathways exist for TCE

 The GSH pathway via glutathione s-tranferases (GSTs)-minor pathway

 The oxidative pathway via cytochrome P450s-majority of TCE

 Both metabolic pathways are implicated in the carcinogenecity of TCE

• Reactive metabolites(s) of the GSH pathway in kidney tumors

• Oxidatives metabolites in liver and lung tumors

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 Carbon Tetrachloride (CCl4 )

• Used as solvents, cleaning agent, fire extinguisher, synthetic

intermediate, grain fumigant, and anthelmintic for humans.
– Its use has declined due to its hepatorenal toxicity,
carcinogenecity, and contribution to ozone depletion in the
atmosphere.
• Ingested CCl4 reaches the liver, undergoes metabolic
activation, produces lipoperoxidation, covalently binds, &
inhibits microsomal ATPase activity.

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 Carbon Tetrachloride cont…

• Carbon tetrachloride (CCl4) is a classic hepatotoxin, but kidney

injury is often more severe in humans
• CCl4 is known to be metabolized by P450-dependent reductive
dehalogination to a trichloromethyl radical(CCl3∙)
• This radical binds covalently to lipids and proteins causing
structural damage of membrane & inhibition of a variety of
enzymes.
• CCl3∙ may also react with oxygen to produce Cl3COO∙,
trichloromrthylperoxy radical.

72
 Carbon Tetrachloride cont….

• CCl3∙ can also attack enolic fatty acids, leading to organic free
radicals, which may in turn reacts with oxygen to form peroxides
and other cytotoxic metabolites called lipid peroxidation.
• CCl4 has frequently been used as a model hepatotoxic compound with
which to examine the influence of various factors that alter CYP450s

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 Chloroform (CHCl3)

 Was among the first inhalation anesthetics

 Nowadays, it is used in the production of the refrigerant
chorodifluoromethane
 CHCl3 is hepatotoxic and nephrotoxic
 It was suggested that a metabolite, mainly phosgen (Cl2C=O), is
responsible for hepatorenal toxicity of CHCl3.
 Initially detoxified by covalently binding cytosolic GSH
 Once GSH is depleted, phosgen is free to covalently bind hepatic & renal
proteins & lipids .
 such binding damages membranes & other intracellular structures,
leading to necrosis.

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 Aromatic hydrocarbon
 Benzene
 Widely used for its solvent properties & as a intermediate in the synthesis
of other chemicals
 Plays an important role in the unleaded gasoline
 Inhalation is the primary route of exposure in industrial and in everyday
settings
 Cigarette smoke is the major source of benzene in the home
 Gasoline vapor emissions & auto exhaust are the other key contributors to
exposures of general public
 The most important toxic effect of benzene is hematopoietic toxicity.
 Chronic exposure can lead to bone marrow damage ,w/c may be manifest
initially as anemia , leukopenia, thrombocytopenia
 The acute toxic effect of benzene is depression of the CNS, cardiac
dysrhythmias, cutaneous burns, and respiratory irritation.

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 Aromatic hydrocarbons cont…

 Continued exposure may results in marrow aplasia &

pancytopenia, an often fatal outcome.
 Metabolism of benzene occurs primarily in the liver,
though metabolism in bone marrow is also believed to play
an important role in myelotoxicity

• Phenolic conjugates are formed in the liver & transported

via the blood to the bone marrow, where they are
hydrolyzed & oxidized to quinones
• The O- and P- benzoquinones are believed to be among the
ultimate toxic metabolites.

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 Aromatic hydrocarbons cont…
• There is no specific antidote for benzene.
• Treatment consists of supportive measures.
– Hemodialysis and hemoperfusion are not effective.
– Do not induce emesis Respiratory tract irritant
• Management
• ABC
• Flush exposed skin with soap and water for 2 to 5 minutes
• Gastric lavage
• Activated charcoal (at 1gm/kg, usual child dose 25–50 g).
• Do not use epinephrine due to benzene sensitization of myocardium
• Reduce cardiac sensitization and catecholamine release
• Use oxygen for patients with respiratory symptoms

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 Aromatic hydrocarbons cont…

• Consider gastric lavage with a small nasogastric tube if:

(1) A large dose has been ingested;
(2) The patient’s condition is evaluated within 30 minutes;
(3) The patient has oral lesions or persistent esophageal
discomfort; and
(4) The lavage can be administered within 1 hour of
ingestion.
• Care must be taken when placing the gastric tube because
blind gastric-tube placement may further injure the
chemically damaged esophagus or stomach.

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