Poisoning of plant origin

1. Toxicty of castor seed

Peter Hermann Stillmark (1860 1923) succeeded in isolating a poisonous protein component from castor beans which he named ricin Ricin is part of the waste "mash" produced when castor oil is made. Ricin is 6,000 X more powerful than cyanide Ricin is a stable substance.

For example, it is not affected much by extreme conditions

such as very hot or very cold temperatures
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 Ricin is a glycoprotein lectin composed of 2 chains, linked by a disulfide bond B chain: binds to galactose-containing glycoproteins and glycolipids expressed on the surface of cells
facilitates the entry of A chain into cytosol.

A chain: inhibits protein synthesis by irreversibly inactivating eukaryotic ribosomes through removal of a single adenin residue from the 28S ribosomal RNA loopprevents chain elongation of polypeptides and leads to cell death

CDC categorizes ricin as a Category B agent

Moderately easy to disseminate, resulting in low mortality but

moderate to high morbidity
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Ingestion
No literature reports of poisoning from ingesting of purified ricin All reports refer to castor bean ingestion Median lethal dose (LD50) in mice is 30mg/kg, or approximately

1000-fold higher than by injection

Lethal oral dose in humans ~1-20mg of ricin/kg of body weight (~8 beans!)

Animal studies: ricin is absorbed within 2 hours by both

lymphatic and blood vessels, accumulates mainly in the liver and spleen and ~20% - 45% is excreted unchanged in the feces up to 72 hours after ingestion
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Symptoms
Symptom onset within 4 6 hours but may be as late as 10 hours Initial symptoms nonspecific: colicky abdominal pain, vomiting, diarrhea, heartburn, and oropharyngeal pain Fluid losses lead to electrolyte imbalances, dehydration, hypotension and circulatory collapse

Leukocytosis, elevated transaminases and creatinine kinase,

hyperbilirubinemia, renal insufficiency and anemia

Unless treated, death can be expected to occur within 35 days, however in most cases a full recovery can be made.
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History of Opium
Opioids have been the mainstay of pain treatment for thousand of years, and they remain so today The search for a safe, orally active, and non-addictive analgesic based on the opiate structure is one of the oldest fields in medicinal chemistry The opiates are perhaps the oldest drugs known to humanity The first undisputed reference to opium is found in the writings

of Theophrastus in the third century B.C.

The use of opium was recorded in China over 2000 years ago, and was known in Mesopotamia before that
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 Its use in medicine is quoted in a twelfth-century

prescription: Take opium ,mandragora, and henbane in equal parts and mix with water. When you want to saw or cut a man, dip a rag in this and put it to his nostrils. He will sleep so deep

that you may do what you wish.

Morphine Opium contains a complex mixture of 20 alkaloids, principle one being morphine Responsible for analgesic activity
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 Because of morphines poor oral bioavailability, it was little used in medicine until the hypodermic syringe was invented in 1853 Morphine was used during the American Civil War and the Franco-Prussian war. Due to poor understanding about:
Safe dose levels Effects of long-term use And increased risks of addiction, tolerance and respiratory

depression

Many casualties were either killed by overdoses or became addicted to the drug
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Toxicities of morphine
Dangerous side effects are those of tolerance and dependence

Respiratory depression Most common cause of death from morphine overdose is suffocation Addiction Clinical observation and experimental studies have indicated that a single exposure to morphine could induce tolerance and dependence

 Recent study shows that prolonged ventral tegmental area (VTA) dopamine neuron activities (DA) and opiate receptor desensitization followed single morphine exposure This may underlie the development of dependence and tolerance that may associate with the acute analgesic tolerance and acute addiction of morphine Withdrawal symptoms associated with morphine
Anorexia, Weight loss, Pupil dilation, Chills, Excessive sweating,

Abdominal cramps, Muscle spasms, Hyperirritability, Lacrimation,

Tremor, Increased heart rate, Increased blood pressure

Strychnine
The Strychnine tree (Strychnos nux-vomica L.) also known as Nux vomica, is an evergreen tree native to Southeast Asia, a member of family Loganiaceae. It is a major source of the highly poisonous alkaloids strychnine and brucine, derived from the seeds inside the

tree's round, green to orange fruit

The seeds contain approximately 1.5% strychnine, and the dried blossoms contain 1.023%.

the tree's bark also contains poisonous compounds, including

brucine.
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 Acts on spinal cord, brain, motor and sensory nerve centres, causing a condition of excessive irritation & excitability, which inturn causes muscular inco-ordination and paralysis.

Irritates mucous membrane of the alimentary tract, producing

dyspepsia like symptoms and stimulate constipation, diarrhoea, dysentery etc.

Stimulates Vasomotor centre and thus gives rise to blood

pressure, heart symptoms etc.

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Toxicty of paracetamol

First synthesized and used in the late 1800s

Widely available Potential toxicity underestimated Toxicity unlikely to result from a single dose of less than 150 mg/kg in child or 7.5 to 10 g for adult

Toxicity is likely with single ingestions greater than 250

mg/kg or those greater than 12 g over a 24-hour period Virtually all patients who ingest doses in excess of 350

mg/kg develop severe liver toxicity unless appropriately

treated
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Factors influencing toxicity

Dose ingested Excessive cytochrome P450 activity due to induction by chronic alcohol or other drug use eg carbamazepine, phenytoin, isoniazid, rifampin Decreased capacity for glucuronidation or sulfation Depletion of glutathione stores due to malnutrition or chronic

alcohol ingestion
Acute alcohol ingestion is not a risk factor for hepatotoxicity and may even be protective by competing with acetaminophen for

CYP2E1
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N-acetyl para quinone imine (NAPQI)Toxicity

The quantity of paracetamol ingested exceeds the capacity of the high affinity glucuronidation and sulphation pathways The flow through the P450 route uses up the livers stock of

glutathione.
NAPQI is thus free to react with the next most convenient substances, like protein and lipid. This process may be prevented, interrupted, and reversed NAPQI-derived organ damage

Liver, Renal,Heart, kidney

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Management
Administration of N-acetylcysteine : a glutathione precursor Limits the formation and accumulation of NAPQI

Powerful anti-inflammatory and antioxidant effects

Activated charcoal

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Salicylate overdose
Fatal intoxication can occur after the ingestion of 10 to 30 g by
adults and as little as 3 g by children Most patients show signs of intoxication when the plasma level exceeds 40 to 50 mg/dL (2.9 to 3.6 mmol/L) Inhibition of cyclooxygenase results in decreased synthesis of prostaglandins, prostacyclin, and thromboxanes Stimulation of the chemoreceptor trigger zone in the medulla causes nausea and vomiting Direct toxicity of salicylate species in the CNS

cerebral edema, and neuroglycopenia

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Salicylate overdose
Activation of the respiratory center of the medulla results in tachypnea, hyperventilation, respiratory alkalosis

Interference with cellular metabolism leads to metabolic

acidosis. Salicylate toxicity

The fatal dose varies with the preparation of salicylate. Death

has followed use of 10 to 30 g of sodium salicylate or aspirin in adults.

The lethal dose of methyl salicylate (oil of wintergreen, sweet

birch oil, gaultheria oil, betula oil) is considerably less than that of sodium salicylate (4 ml/4.7 g).
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Salicylate toxicity
Prominent features of poisoning by methyl salicylate include central excitation, intense hyperpnoea, and hyperpyrexia. The odor of the drug can be detected easily on the breath and in the urine and vomitus.

Poisoning by salicylic acid differs only in the increased

prominence of GI symptoms due to the marked local irritation. Mild chronic salicylate intoxication is called salicylism.

When fully developed, the syndrome includes

headache, dizziness, tinnitus, difficulty hearing, dimness of vision, mental confusion, lassitude, drowsiness, sweating, thirst, hyperventilation, nausea, vomiting, and occasionally diarrhea.
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Salicylate toxicity
In high doses, toxic effects on the CNS, consisting of stimulation followed by depression.

Confusion, dizziness, tinnitus, high-tone deafness, delirium,

psychosis, stupor, and coma may occur. Tinnitus generally resolves within 2 or 3 days after withdrawal of the drug. Salicylates induce nausea and vomiting, which result from stimulation of sites that are accessible from the CSF, probably in the medullary chemoreceptor trigger zone. It may also occur at much lower plasma levels as a result of local gastric irritation. The respiratory stimulatory effects of salicylates contribute to the

serious acid-base balance disturbances and hyperthermia.

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Salicylate toxicity
Metabolic acidosis is caused by accumulation of acids as a result of three processes.

Toxic concentrations of salicylates displace plasma HCO3 vasomotor depression caused by toxic doses of salicylates impairs renal function, with consequent accumulation of

sulfuric and phosphoric acids.

salicylates in toxic doses may decrease aerobic metabolism as a result of inhibition of various enzymes. This disturbance of carbohydrate metabolism leads to the accumulation of organic acids, especially pyruvic, lactic,

and acetoacetic acids.

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Salicylate toxicity
The same series of events also causes alterations of water and electrolyte balance

due to renal tubular reabsorption of bicarbonate and

increased renal excretion of Na+, K+, and water. Water also is lost by salicylate-induced sweating (especially in

the presence of hyperthermia) and hyperventilation;

dehydration, which can be profound, particularly in children, rapidly occurs.

Because more water than electrolyte is lost through the lungs

and by sweating, the dehydration is associated with hypernatremia. large doses (more than 5 g per day) induce uricosuria and lower 22

Clinical features
Early symptoms of aspirin toxicity include tinnitus, fever, vertigo, nausea, hyperventilation,

vomiting, diarrhoea More severe intoxication can cause altered mental status,

coma, pulmonary edema and death.

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Management
Activated Charcoal
IV fluids Supplemental glucose Hemodialysis Alkalinizing the serum ionizes the salicylate, which

keeps it from entering the tissues.

Serum pH should be in the 7.5-7.6 range (not > 7.6) Alkalinizing the urine to pH=7.5 to 8

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Barbiturates
Include phenobarbitone (long acting), pentobarbitone (intermediate) , thiopental (ultra-short acting). Potentiate GABA-induced activities by prolonging the duration of Cl- channel opening Reduce glutamate-induced depolarization

Toxicty
Severe poisoning is likely to occur when more than 10 times the full hypnotic dose is ingested at once.

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Symptoms

Neurologic:
lethargy & impairment in thinking coma hypothermia decreased pupillary light reflex nystagmus respiratory depression - the most common cause of death Cardiovascular:

tachycardia or bradycardia
hypotension
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 ABCs.

Treatment

Check for hypothermia & if present, warm the patient to avoid precipitating a fall in blood pressure. Perform GI decontamination once the airway is protected and

hemodynamic stabilization addressed.

Activated charcoal orally or by nasogastric tube is recommended for all patients with potential barbiturate toxicity.

Induction of emesis with ipecac syrup is contraindicated in these

patients
because the depressed neurologic response increases risk of aspiration.
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 Alkalinization of the urine with sodium bicarbonate to enhance the elimination of phenobarbital and, likely, other longacting barbiturates by ion trapping. Urinary alkalinization is not recommended for short-acting barbiturate toxicity. Aggressively initiate fluid therapy if the patient is hypotensive

or appears to be in hypovolemic shock.

Hemodialysis and hemoperfusion enhance elimination of barbiturates.

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Benzodiazepines
Increase the frequency of Cl- channel opening by promoting the binding of GABA to the GABAA receptors.

Benzodiazepines and their active metabolites bind to plasma

proteins. The Vd of the benzodiazepines are large, cross the placental

barrier and are secreted into breast milk.

Metabolized extensively by cytochrome P450 enzymes, particularly CYP3A4 and CYP2C19 and have many active metabolites.
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Biotransformation of Benzodiazepines

* Active metabolite
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Symptoms
Drowsiness, nystagmus
confusion, slurred sppech Ataxia, Coma, weakness, amnesia, hypotension respiratory depression

Respiratory arrest is less likely than with barbiturates, but

has been reported with newer short-acting

benzodiazepines such as triazolam

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Treatment
Flumazenil is the drug of choice to reverse effects of bzd
It is an antagonist for the benzodiazepine binding site. ABCs Single-dose activated charcoal is recommended for GI decontamination
in patients who present within 4 hours of ingestion or in symptomatic patients when the time of ingestion is unknown.

Ipecac syrup is contraindicated for pre hospital or hospital use

because of the risk for CNS depression and subsequent aspiration

with emesis. Respiratory depression may be treated with assisted ventilation.
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Digoxin
Sources positive intropic (prescription) drug for CHF

various plants (foxglove, lily of the valley, oleander, wallflower)

Mechanism of toxicity Digitalis inhibits Na/K+ ATPase enzyme by competition with potassium at its site on the enzyme Reduction of energy for sodium pump leads to increase of the intracellular sodium This increased intracellular sodium intern
increases calcium which result in their interaction producing contraction of the myocardial cell
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Manifestations of toxicity: CV toxic effects: Heart block and arrhythmias GIT effects: Anorexia, nausea, vomiting, diarrhea and abdominal

cramps, (due to local irritant effect and central effect on

chemoreceptor trigger zone). Neurological effect: Headache, fatigue, drowsiness, muscle

weakness, disorientation, confusion, hallucination and convulsions.

Visual disturbances: Blurred vision and disturbed color vision.

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Treatment
Digoxin Fab fragments (Digibind ) are generally indicated for

potentially fatal overdose

Lidocaine for ventricular arrhythmias Activated charcoal or cholestyramine can be used for acutely ingested digoxin/digitoxin Note: gastric lavage may intensify vagal tone & may worsen arrhythmias Treat any hyperkalemia >5.5 mM with Na bicarb, glucose & insulin. Note: diuretics that are commonly taken in patients with CHF can

cause hypokalemia which will increase digitalis toxicity (potassium

supplements should be used to correct hypokalemia).
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Thalidomide
Synthesized by W. Kunz and others in 1956 Distributed in Europe, Australia, and Canada Marketed as safe, potent, non-barbiturate sedative and antiemetic Not approved by the FDA for use in the US

Withdrawn in December of 1961

Exposure from day 21 through day 40 of gestation 10,000 cases of birth defects worldwide Only 17 infants in the USA 10 from investigative use

7 from exposure to sources outside US

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Birth Defects
Amelia
phocomelia hypoplasticity of the bones absence of bones external ear abnormalities facial palsy Eye abnormalities (anophthalmos, microphthalmos) Congenital heart defects Alimentary, urinary, and genital malformations

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Phenytoin
Effective against all types of partial and tonic-clonic seizures, but not absence seizures. Exerts anti-seizure activity without causing general

depression of the CNS. Toxic effects Depression of the CNS occurs particularly in the cerebellum

and vestibular system,

lethargy, fatigue, in-coordination, blurred vision, higher

cortical dysfunction, and drowsiness.

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 Inhibition of insulin secretion so that hyperglycemia and glucosuria results Behavioral changes, such as confusion, hallucination Phenytoin causes teratogenic during pregnancy.

Fetal hydantoin syndrum

Include cleft lip, congenital heart disease, as well as

slowed growth and mental deficiency.

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Tricyclic antidepressants
Mechanism of action:
They block the uptake of catecholamine leading to their accumulation at the receptor sites and potentiating of their activity. Inhibition of reuptake in synapse of NA and 5-HT They possess anticholinergic, antihistaminic, 1-receptor blocking

activity
Toxic Effects Dry mouth, blurring of vision, retention of urine, glaucoma, constipation, postural hypotension, arrhythmias, tremors, mild parkinsonian syndrome and hypersensitivity reactions.
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Food poisoning
Any illness resulting from the consumption of food There are two types of food poisoning: food infection and

food intoxication.
Food infection refers to the presence of bacteria or other microbes which infect the body after consumption. Food intoxication refers to the ingestion of toxins contained within the food, including bacterially produced exotoxins.
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Causes
Improper handling, preparation, or food storage. large variety of toxins that affect the environment chemicals

pesticides or medicines in food and naturally toxic

substances like poisonous mushrooms. Food that has been exposed to environment with temperature greater than 30 degree Celcius

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Examples of toxic food additives and contaminants

Agent Nitrate, Nitrite Type Preservative Source and effect Present in vegetables form carcinogenic amines Sulfites Preservative Antioxidant used to reduce spoilage can produce allergic reaction specially in asthmatic Tartrazine Boutlinum toxin Colourant Contaminant Can cause urticaria in sensitive individuals Produced by Chlostridium boutlinum in improperly canned vegetables Toxic effect: nausea, vomiting, diarrhea, paralysis Aflatoxin Contaminant Produced by Aspargilus flavus specially in grains, corn and peanut; Toxic effect: carcinogenic and hepatotoxic Ochratoxin, citrinin contaminant Produced by penicillium strains; Toxic effect: nephropathy
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