Chapter 4

Toxic agents of pharmaceutical importance

 Chapter outlines
 Pesticides :
 Insecticides
 Herbicides
 Fungicides
 Fumigants
 Rodenticides

 Toxic effects of solvents and vapors

 aliphatic hydrocarbons – mainly chlorinated
 aromatic hydrocarbons
 alcohols
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Pesticide
 Any substance or mixture of substances intended for preventing,

destroying, repelling, or mitigating any pest

 May also be described as any physical, chemical, or biological

agent that will kill an undesirable plant or animal pest

 The term pest includes harmful, destructive, or troublesome

animals, plants, or MOs

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 Pesticides are grouped based on their targets of action as:

• Insecticides

• Herbicides

• Fungicides

• Fumigants

• Rodenticides …

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Uses of pesticides

 Control of vector-borne diseases like malaria

 Promotion of agricultural production

 For the control of domestic pests (e.g. household & garden pests)

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Individual may be exposed to pesticides

Occupationally (manufacturing, mixing/loading, application,

harvesting, and handling of crops)

Environmentally e.g. from food products such as fruits &

vegetables treated for pests

At their residence e.g. from use as home or garden insecticides

Accidental/suicidal

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 INSECTICIDES
 They are substances that destroy / repel / prevent harmful insects

 All of the chemical insecticides in use today are neurotoxicants and act
by poisoning the NS of the target organisms

 They are not selective and affect non target species

 A chemical that acts on the insect’s NS will elicit similar effects in higher
forms of life

 The target sites and/or mechanism of action may be similar in all

species
 Only the dosage (level of exposure and duration) will dictate the intensity
of biological effects

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Mechanism of action of insecticides
 Interference with the membrane transport of sodium, potassium,
calcium, or chloride ions

 Inhibition of selective enzymatic activities; or

 Contribution to the release and/or the persistence of chemical

transmitters at nerve endings

Classes of insecticides
 Organochlorine insecticides

 Organophosphate and carbamate insecticides (anticholinesterase

agents)

 Insecticides of biological origin

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 Organochlorine (chlorinated HCs) insecticides
 The properties (low volatility, chemical stability, lipid solubility,
slow rate of biotransformation and degradation)

made these chemicals such effective insecticides

Also contribute to their demise because of their persistence in

the environment, bioconcentration and biomagnification in
food chains

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 The organochlorine insecticides belongs to three distinct
chemical classes:

 Dichlorodiphenylethane e.g. DDT

 Chlorinated cyclodiene and benzene e.g. aldrin, dieldrin

 Cyclohexane-related structures e.g. lindane

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DDT (Dichlorodiphenyltrichloroethane)

 Highly potent against insect NS but is relatively nontoxic to man

 High oral doses of DDT results in

 paresthesia of the tongue, lips, and face; apprehension

 hypersusceptibilty to external (light, touch, sound) stimuli

 irritability, dizziness, and vertigo

 tremor and tonic and clonic convulsions which generally

appear several hours (6 to 24 h) after exposure to large doses

 Little toxicity is for dermal exposure to DDT

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 There have been a number of fatalities however following
poisoning by the cyclodiene- and hexachlorocyclohexane-type
insecticides

 These pesticides are efficiently absorbed through the skin

and

 therefore pose an appreciable hazard to occupationally

exposed individuals

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 Mechanism of action
mechanisms for DDT – type insecticides at the neuronal membrane

• DDT affects the permeability to K+ ions, reducing K+ transport

across the membrane

• DDT alters the porous channels through which Na+ ions pass

• DDT inhibits neuronal ATPase, particularly the Na+/K+ -ATPase

and Ca2+ATPase, which play vital roles in neuronal repolarization

• DDT also inhibits the ability of calmodulin to transport calcium ions

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 The chlorinated cyclodiene-, benzene-, and cyclohexane-type
insecticides are different from DDT in many respects

 localized more in the CNS than in the sensory division of the

PNS

 Unlike DDT, convulsions are a prominent aspect of poisoning

 The lindane and cyclodiene compounds antagonize the action of

the neurotransmitter GABA

 Bind to a specific site on the chloride channel and effectively

decrease Cl- permeability of neurons

 thus antagonizing the inhibitory action of GABA

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 Toxicokinetics of organochlorine insecticides
Once absorbed, biotransformation/degradation proceeds at an
exceptionally slow rate, in part due to:
 The complex aromatic ring structures
 The number of the chlorine substituent;
o the latter being exceedingly difficult to remove by the
enzymatic processes available in tissues
 the highly lipophilic nature of the compounds
 Bioaccumulation: If the intake exceeds the ability to
metabolize or excrete the substance
 Biomagnification: magnified hundreds or thousands of time
as the contaminant passes up the food chain
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 Treatment of Poisoning
• Mainstays of therapy: supportive care & ttm of symptoms

• No specific therapy

• Gastric decontamination

• Convulsions – diazepam (0.3 mg/kg IV; maximum dose of 10 mg)

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 Organophosphate and carbamate
(anticholinesterase agents) insecticides

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 OP have become widely used insecticides as replacements for
the most persistent organochlorine insecticides

 OP are not considered to be persistent pesticides because

Relatively unstable and break down in the environment –have a

small impact on the environment

 OP don’t bioaccumulate in tissue or organisms or accumulate

in the environment

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 However, because of the acute toxicity of some of the OP
compounds, another class of pesticide – pyrethrins – are
becoming more widely used

Examples:

 OP

 Malathion, parathion, diazinon, chlorpyrifos, sarin,

metamidophos, azinphosmethyl, dichlorvos …

 Carbamate insecticides:

 Aldicarb, carbaryl, carbofuran, propoxure …

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 Mechanism of Action
OP

 MOA: inhibiting cholinesterases, which are responsible for

removing Ach

 Malathion itself is not a substrate for cholinesterases (requires

metabolism to malaoxon)
 Those containing =S must undergo metabolic bio-activation to become
biologically active (with =O)

 (Parathion →paraoxon, Malathion → malaoxon, Diazinon → diazoxon)

 This takes place readily in insects but in mammals hydrolysis is

the preferred route & this leads to a readily excreted
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• With many OP ester insecticides, an irreversibly inhibited
enzyme is formed, and the signs and symptoms of
intoxication are prolonged and persistent

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• After the initial binding-hydrolysis step, the phosphorylated

enzyme complex may undergo a process called aging

breaking of one of the oxygen-phosphorus bonds of the

inhibitor (dealkylation)

• If given before aging has occurred, pralidoxime is able to break

the phosphorus-enzyme bond and can be used as

"cholinesterase regenerator" drugs for OP insecticide poisoning

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Carbamates

 Carbamates also inhibit AChE enzyme in an identical fashion by

carbamylation but not phosphorylation.

 However, the carbamate– AChE bond is weaker than that formed

by OPs.

 Thus, carbamate-AChE bonds spontaneously hydrolyze more

rapidly and AChE function returns typically within 24 to 48
hours.

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 Signs and Symptoms of Poisoning
• Muscarinic stimulation causes:

 defecation ,urination, miosis

 bradycardia, bronchorrhea, bronchospasm

 emesis, lacrimation, salivation

• Stimulation of the nicotinic receptors in the sympathetic ganglia and NJ

will cause:

 mydriasis, tachycardia, weakness

 hypertension, fasciculations

• CNS effects are varied and can be both nonspecific and severe , and includes:

 headache, dizziness, insomnia, anxiety, restlessness

 confusion, ataxia, tremors, seizures

 coma, central respiratory depression

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• Some OP compounds: triorthocresyl phosphate (TOCP)
cause delayed neurotoxicity where the nerves in the arms &
legs die, known as organophosphorus-induced delayed
neuropathy (OPIDN) or peripheral neuropathy & the result is
paralysis

• Most clinical manifestations of acute poisoning are resolved

within days to weeks, however, those of neuropsychological
symptoms, appear to persist for months or longer

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 Treatment of Poisoning
General supportive measures
 Decontamination, or gastric lavage

 Maintenance of a patent airway, including endobronchial

aspiration

 Artificial respiration

 Treatment of convulsions with diazepam (5 to 10 mg, IV)

To relieve anxiety in mild cases, and to reduce muscle

fasciculations and prevent convulsions in serious cases

 Treatment of shock

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Treat with antidotes: atropine and pralidoxime (2-PAM)

• Atropine to antagonize the actions at muscarinic receptor sites

• 2 – PAM reactivates the OP inhibited enzyme

 not effective in aged enzyme

• The oximes are not effective in antagonizing the toxicity of the

carbamoyl ester inhibitors –

 even aggravate the toxicity (pralidoxime itself has weak anti-ChE

activity)

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 Insecticides of biological origin

Extracts from the chrysanthemum flower (e.g. pyrethrum) and

leguminacaea genera (e.g. rotenone) have insecticidal activity

Used in household insecticide and pet products (e.g. flea &

tick dips & sprays)

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 Pyrethrins
 Pyrethroids – are synthetic derivatives of pyrethrin
MOA
 Open voltage-gated sodium (↑ [Na]i)
 They keep Na channel open for long time, causing flow of
Na which results in persistence depolarization
 Pyrethroids elicit little toxicity in either in animals or
humans due to
 may be little storage or accumulation and an efficient
detoxification of the chemicals
 and also differences in Na channel – more toxic to insects

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 Ingestion (poisoning/ suicide) cause

 epigastric pain, nausea and vomiting

 headache, dizziness, anorexia, fatigue, chest tightness

 blurred vision, paresthesia, palpitations

 coarse muscular fasciculations in the large muscles of the

extremities, convulsive attacks (sever cases)

 Recovered completely within 2 to 3 weeks

 No chronic toxicity has been reported

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 Treatment of Poisoning
• Limited experience

• Removal from exposure

• Lavage with vegetable and/or vitamin E cream will alleviate

dermal paresthesia

• Symptomatic: topical steroids for contact dermatitis,

antihistaminics, decongestants

• Systemic poisoning is more difficult to treat, symptomatic and

supportive measures

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 Rotenone
• Rotenone has been used topically for treatment of head
lice, scabies, and other ectoparasites

• Acute poisoning in animals is characterized by an initial

respiratory stimulation followed by respiratory
depression, ataxia, convulsions, and death by respiratory
arrest – respiratory toxicant

• Human intoxications are rare

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 HERBICIDES
• A herbicide is any compound that is capable of either killing
or severely injuring plants

• It may be used for the elimination of plant growth or the killing

of plant parts

• With the exception of a few chemicals, the herbicides have

demonstrated low toxicity in mammals

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• Concerns over demonstrated or suspected mutagenicity,
teratogenicity, carcinogenicity associated with the agent or with
contaminants

• General toxicity: because the major route of exposure to

herbicides is dermal, dermal irritants, can cause skin rashes and
contact dermatitis

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 Chlorophenoxy compounds

• 2,4-Dichlorophenoxyacetic acid (2,4-D), 2,4,5-

trichlorophenoxyacetic acid (2,4,5-T), and their salts and
esters are the major herbicides used for the destruction of
broad leaf weeds

 2,4 -D + 2,4,5-T used in combination called Agent Orange

• In plants, these chemicals mimic the action of auxins,

hormones that stimulates growth (produce uncontrolled and
lethal growth in target plants ): less effect in non target organ

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• Ingestion of 2,4-D has caused several cases of acute poisoning
in humans, usually at doses above 300 mg/kg, though lower
doses have been reported to elicit symptoms

 Clinical signs include: vomiting, burning of the mouth,

abdominal pain, hypotension, myotonia and CNS
involvement with coma

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 Bipyridyl Derivatives

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Toxicity
• Cell membrane is extensively damaged & photosynthesis is
reduced
• Both compounds are not active in soils
• Paraquat is a nonselective contact herbicide, which is one of
the most specific pulmonary toxicants; poorly absorbed
through the skin
• Upon absorption, it accumulates in the lung (primarily
affected acutely) and then kidney
• Its toxicity is not due to paraquat or its metabolites but rather
to release of ROS
3/23/2025 40
 Bipyridyl Derivatives ……
• Diquat is slightly less toxic than paraquat

Treatment of paraquat poisoning

 Gastric lavage, administration of mineral adsorbents [Fuller’s

earth (kaolin), bentonite clay, or activated charcoal]

 hemodialysis

 Oxygen to maintain acceptable arterial oxygen tension (40 to

50 mmHg)

 No antidote

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 FUMIGANTS
Are gents used to kill insects, nematodes, weed seeds, and
fungi in soil and to prevent stored food staffs e.g. HCN, CS2,
phosphine (PH3)…

Are gaseous formulation (could be insecticide, fungicide, herbicide)

 May be liquids e.g. formaldehyde that readily vaporize at

ambient tO;

 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)

 These chemicals are nonselective, highly reactive, and cytotoxic

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 Cyanides (hydrocyanic acid, HCN- prussic acid)
 Cyanide has very high affinity to Fe in ferric state.

 When absorbed, it reacts readily with Fe3+ of cytchrome

oxidase – inhibiting cellular respiration(oxidative
phosphorylation) resulting in lactic acidosis and cytotoxic
hypoxia – death due to respiratory arrest

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 Treatment of cyanide poisoning
 Diagnosis aided by the toxic odor of cyanide

 Treatment is aimed at prevention or reversal of binding of

cyanide to cytochrome oxidase by providing a large pool
of ferric iron to compete for cyanide

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A. Nitrite that oxidize hemoglobin (Fe2+) to methemoglobin
(Fe3+)

 Methemoglobin (Fe3+) competes with cytochrome oxidase

for cyanide ion;

 the reaction favours metHgb whereby cyanometHgb is

formed and cytochrome oxidase is restored

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B. 4- dimethylaminophenol – MetHgb former

C. Hydroxycobalamin

 Combines with CN- to form cyanocobalamin (vitamin B12)

which is non toxic

D. Rhodanese (transulfurase) 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

Na2S2O3 + CN- Rhodanese SCN- + Na2SO3

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 Rodenticides
 Used to control rodents

 Warfarin, bromadiolone, difenacoum, chlorophacinone

 Act through inhibition of blood clotting & animals bleed to

death in about a week

 Ttm

 Vit. K

 Blood transfusions (severe)

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 ANTU (α-naphthylthiourea)

 Strychnine

 Red squill (glycosides scillaren-A &-B)

 Similar to digitalis, have cardiotonic & central emetic
effects

 Fluoroacetate
 Block Krebs (tricarboxylic acid) cycle

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Solvents and vapours
 TOXIC EFFECTS OF SOLVENTS AND VAPORS

 Solvent refers to a class of liquid organic chemicals of variable

lipophilicity and volatility

 Solvents are frequently used to dissolve, dilute, or degrease

materials that are insoluble in water

 They are widely employed

 as degreasers and as constituents of paints, varnishes, inks,

aerosol spray products, dyes, and adhesives

 as intermediates in chemical synthesis, and as fuels and fuel

additives
50
Classes of solvents (based on molecular structure or functional
group)

 Aliphatic hydrocarbons – mainly chlorinated

 Aromatic hydrocarbons

 Alcohols

 Others: (ethers, esters, amides, amines, aldehydes, ketones …)

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CHLORINATED HYDROCARBONS

Carbon Tetrachloride (CCl4)

 Uses as a solvent, cleaning agent, fire extinguisher, grain fumigant

 Its use has declined due to its hepatorenal toxicity, carcinogenicity,

and contribution to ozone depletion in the atmosphere

Toxicokinetics and Toxicodynamics

 Ingested CCl4 reaches the liver, undergoes metabolic activation,

produces lipoperoxidation,

 covalently binds and inhibits microsomal ATPase activity

52
 Binds covalently to lipids and proteins
and inhibition of a variety of enzymes
causing structural damage of membrane

CCl4 CCl3•
CYP2E1 (low doses of CCl4)
CYP3A4 (high doses)

Reacts with oxygen

Cl3COO• (trichloromethylperoxy radical)

53
Chloroform (CHCl3)
CHCl3 was among the first inhalation anesthetics

Nowadays, it is used in the production of the refrigerant

chlorodifluoromethane

CHCl3 is hepatotoxic and nephrotoxic

It was suggested that a metabolite, mainly phosgene, is

responsible for hepatorenal toxicity of CHCl3

54
 HCl

CHCl3 HOCCl3 Cl2C=O (phosgene) CO2

CYP2E1 (low doses)
CYP2B1/2 (high does) detoxification (GSH)

 Initially detoxified by covalently binding cytosolic GSH

Once GSH is depleted, phosgene is free to covalently bind hepatic
and renal proteins and lipids.
 Such binding damages membranes and other intracellular
structures, leading to necrosis

55
AROMATIC HYDROCARBONS

Benzene
Widely used for its solvent properties and as an
intermediate in the synthesis of other chemicals

Plays an important role in unleaded gasoline

Inhalation is the primary route of exposure in industrial

and in everyday settings

Gasoline vapor emissions is the other key contributor to

exposures of the general public
56
 The most important toxic effect of benzene is hematopoietic
toxicity

Chronic exposure to benzene can lead to bone marrow

damage, which may be manifest initially as anemia, leukopenia,
and thrombocytopenia

Continued exposure may result in marrow aplasia and

pancytopenia, an often fatal outcome

 The acute toxic effect of benzene is depression of the CNS

 Euphoria, locomotor problems, coma, drowsiness, headache, fatigue,

nausea, & loss of appetite
57
Toluene (methyl benzene)
Toluene is present in paints, thinners, cleaning agents,
glues, etc.

Gasoline is the largest source of atmospheric emissions

and exposure of the general population

Inhalation is the primary route of exposure

Toluene is well absorbed from the lungs and GI tract.

It rapidly accumulates in and affects the brain

58
 The CNS is the primary target organ of toluene

 range from slight dizziness and headache to unconsciousness,

respiratory depression, and death

 Mechanism not well understood

but enhancing GABAA receptor function

 It may have carcinogenic effect

Management

 Remove the patient from the source of exposure

 Provide supportive therapies

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ALCOHOLS

Ethanol
Ethyl alcohol used as a solvent in industry and in many household
products and pharmaceuticals, and in intoxicating beverages

Ethanol is metabolized to acetaldehyde by three enzymes:

Alcohol dehydrogenase (ADH) – major pathway

Catalyzed oxidation to acetaldehyde; the acetaldehyde that is

formed is rapidly oxidized by acetaldehyde dehydrogenase (ALDH)
to acetate

60
Catalase, utilizes H2O2

Catalase will normally account for < 10% of ethyl alcohol

metabolism –

o little H2O2 available in hepatocytes to support the reaction

CYP2E1

 Uses NADPH as a cofactor - is the principal component of the

hepatic microsomal ethanol oxidizing system

61
62
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, thereby enhancing the metabolic activation
and potentiating the toxicity of ethanol

Modulation of ALDH activity can influence adverse effects

experienced by drinkers

63
 Acetaldehyde is acutely toxic

 It is reactive and binds covalently to proteins and other

macromolecules

 Caucasians, blacks, and Asians have varying percentages of

different ALDH isozymes, which impact the efficiency of
acetaldehyde metabolism

 50 percent of Asians have inactive ALDH, due to a single base

change in the gene that encodes for the enzyme

 These persons may experience flushing, headache, tachycardia,

nausea, vomiting, and hyperventilation upon ingestion of ethanol

64
 Disulfiram, an ALDH inhibitor, is used to treat alcoholism

Gender differences in responses to ethanol are well recognized

Females exhibit slightly higher blood ethanol levels than men

following ingestion of equivalent doses of ethanol

 More extensive ADH-catalyzed metabolism of ethanol by the

gastric mucosa of males (deficient in females)

 Women’s smaller volume of distribution for relatively polar

solvents such as alcohols

65
• Ethanol can be an effective antidote for poisoning by methanol,
ethylene glycol, and diethylene glycol.

• As ethyl alcohol has a relatively high affinity for ADH, it

competitively inhibits the metabolic activation of the other alcohols

66
 Clinical description /symptoms Blood alcohol conc. Part of brain affected
(W/V)
Mild 50 -100mg/dL Frontal lobe
Slight visual impairment
Table: Range of toxicity of ethanol

Slowing reaction time

Increased confidence

Moderate 150- 300 mg/dL Parietal lobe

Ataxia, slurred speech,
↓motor skills, ↓attention
Dilopia, altered perception Occipital lobe
Altered equilibrium Cerebellum
Severe 300-500mg/dL
Visual impairment Occipital lobe
Total loss of equilibrium Cerebellum
Stupor Diencephalon
Coma > 500mg/dL Medulla
Respiratory failure

Chronic
• liver disease (8-20% cirrhosis) most common, esophageal varices, pancreatitis, CHF
67
as cause of death
Management of poisoning
 Supportive symptomatic care

 Protect airway from aspiration

 Administer glucose solution for hypoglycemia, ketoacidosis,

volume depletion

 In alcoholic correct nutritional deficiencies (Mg, thiamine,

pyridoxine, Vit K, Vit C)

 Hemodialysis if BAC > 450mg/dL or decreased hepatic function

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Methanol
 Used in the manufacture of formaldehyde and methyl tert-butyl
ether; as a gasoline additive and alternative automotive fuel

Metabolism

Methanol ADH Formaldehyde ALDH Formate

THF formyl-THF synthetase

10-formyl-THF

formyl-THF dehydrogenase

CO2 + H2O
69
• The conversion of formate to CO2 occurs via a two-step,
tetrahydrofolate (THF)-dependent pathway

• First, formate is converted to 10-formyl-THF by formyl-THF

synthetase, then 10-formyl-THF is oxidized to CO2 by formyl-THF
dehydrogenase

• Dietary and chemical depletion of endogenous folate cofactors tend to

increase formate accumulation following methanol,

 resulting in the development of metabolic acidosis and ocular

toxicity

70
Management of poisoning of MeOH

 Prevent further absorption by emesis or lavage

 IV sodium bicarbonate – to correct severe acidosis

 Metabolic blockade with ethanol and fomepizole/4-

methylpyrazole (ADH inhibitor)

 both acting as effective competitive inhibitors of ADH

 Folate therapy is also indicated to increase the efficiency of

formate oxidation

 Hemodialysis for blood MeOH > 25mg/dl

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Ethylene Glycol
 It is a major constituent of antifreeze, deicers, hydraulic fluids,
drying agents, and inks, and is used to make plastics and
polyester fibers

 The most important routes of exposure are dermal and

accidental or intentional ingestion

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Acute poisoning of EG has three clinical stages

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

degree depending upon dose

II. The cardiopulmonary stage 12 to 24 h after exposure,

characterized by tachycardia and tachypnea, which may
progress to cardiac failure and pulmonary edema

III. The renal toxicity stage 24 to 72 h post exposure

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 Metabolic acidosis can become progressively more
severe during stages II and III

 Metabolic acidosis largely due to accumulation of glycolic

acid

Hypocalcemia can result from calcium chelation by oxalic acid to

form calcium oxalate crystals

Deposition of these crystals in tubules of the kidney and small

blood vessels in the brain is associated with damage of these
organs

74
Management of poisoning of EG

 Correct acidosis with bicarbonate

 Enhance elimination with hemodialysis (if renal failure)

 Inhibit metabolism with ethanol or 4-methylpyrazole

 Calcium salts

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