“The Study of Poisons”

Naser abbasi

Department of Pharmacology and Toxicology

The study of the adverse effects

of a toxicant on living organisms• Adverse effects

– any change from an organism’s normal state

– dependent upon the concentration of active

compound at the target site for a sufficient time.

• Toxicant (Poison)

– any agent capable of producing a deleterious

response in a biological system

• Living organism

– a sac of water with target sites, storage depots

and enzymes

TOXICON - LOGOS

What is Toxicology?

Toxicology is the study of how toxicants cause

adverse effects on living organisms.

STUDY OF TOXICOLOGY

Serves society in many ways :

•Protect humans and the environment from the

deleterios effects of toxicants

•Facilitate the development of more selective toxicants

such as anticancer and other clinical drugs and

pesticides.

LD50

• Quantal responses can be treated as

gradient when data from a population is

used.

• The cumulative proportion of the population

responding to a certain dose is plotted per

dose--10-30 fold variation w/in a population

• If Mortality is the response, the dose that is

lethal to 50% of the population LD50 can be

generated from the curve

• Different toxicants can be compared--

lowest dose is most potent

LD50 Comparison

Chemical LD50 (mg/kg)

Ethyl Alcohol 10,000

Sodium Chloride 4,000

Ferrous Sulfate 1,500

Morphine Sulfate 900

Strychnine Sulfate 150

Nicotine 1

Black Widow 0.55

Curare 0.50

Rattle Snake 0.24

Dioxin (TCDD) 0.001

Botulinum toxin 0.0001

Exposure: Duration

Acute < 24hr usually 1 exposure

Subacute 1 month repeated doses

Subchronic 1-3mo repeated doses

Chronic > 3mo repeated doses

Over time, the amount of chemical in the

body can build up, it can redistribute, or it

can overwhelm repair and removal

mechanisms

Toxicology• Exposure + Hazard = Risk

• All substances can be a poison

• Dose determines the response

• Pathway, Duration of Frequency of Exposure and

Chemical determine Dose

• Absorption, Distribution, Metabolism & Excretion

• The extent of the effect is dependent upon the

concentration of the active compound at its site of

action over time

• Bioactivation: compounds to reactive metabolites

• Individual variation of the organism will affect

ADME

Dose - Response

Effective dose

ED50 - the dose producing the desired (therapeutic) effect in 50% of the test animals

Toxic dose

TD50 - the dose toxic to the specified organ in 50% of the test animals administered by the stated route

Lethal dose

LD50 - the dose lethal to 50% of test animals when administered by stated route

Lethal concentration

LC50 - the concentration lethal to 50% of the test animals when administered over the stated time

From above can define ED90, LD10, ED99, LD1, etc.

Dose - Response Variables

route of entry

type of organism or species

environmental conditions

other chemicals

individual variability

Dose - Response curve

Therapeutic index = LD50

ED50

Margin of safety = LD1

ED99

Goals of treatment

Goals of treatment

Reduce absorption of the toxin (xenobiotic)

Enhance elimination

Neutralise toxin

Reduce absorption of the toxin

Removal of

Poison from the

gut

Empty the stomach

1. Emesis

A. Syrup of Ipecac

Root of cephaelis ipecacuanha (emetine cardiotoxin)

Acts on GI to stimulate chemoreceptor trigger

Takes 30 min or more to act

B. Apomorphine

Narcotic: reversed with naloxon

Acts directly on the chemoreceptor trigger

Takes less than 5 min to act

2. Exceptions

A. Ingestion of caustics or hydrocarbons

B. Seizures

C. Comatose/ severe CNS depression

D. Cardiac and pulmonary patients

E. Infants less than 6 mo, no gag

3. Gastric lavage

Out of Stomach

No : Pharyngeal stimulation -

No : Ipecacuanha

Disadvantages of Induced emesis

GL only within 2h of poisoning

Laid on the LEFT SIDE,

HEAD BELOW THE LEVEL OF REST OF THE BODY

INSERT A WIDE-BORE TUBE VIA THE MOUTH INTO

THE STOMACH (150 cm , 7 mm internal diameter)

Contraindications for Syrup of Ipecac

Children less than 6 months of age

Ingestion of a caustic agent (acid or alkali)

Depressed level of consciousness or gag reflex or

anticipation of these conditions within short period

of time

Risk of aspiration of gastric contents (e.g.

ingestion of liquid hydrocarbon with low viscosity

or low surface tension)

Gastric Lavage

Involves placing an orogastric tube into the

stomach and aspirating fluid, then cyclically

instilling fluid and aspirating until effluent is clear

As with syrup of ipecac, practice has significantly

declined in recent years due to risk of aspiration

and questionable effectiveness compared to other

methods. Gastric emptying is almost complete in

1 hour; therefore ipecac is of limited use

Lavage Fluid

300 ML via a FUNNEL

WARM WATER

WARM SALINE IN KIDS

add specific ANTIDOTES

Repeat until the fluid returning from

the stomach is clear.

Chemical analysis of initial return

DO NOT USE FORCE

Prevention of

further absorption

of drug from the

gut

Activated Charcoal

“Activated” means charcoal has been processed

with steam, carbon dioxide, oxygen, zinc chloride,

sulfuric acid, or phosphoric acid at temperatures

500-900 deg F. Small pores are created that

greatly increase surface area.

Many organic molecules are significantly bound

Low MW, polar compounds (EtOH, lithium, iron,

inorganic salts) are not well-absorbed

Popular method in emergency rooms (1-2 g/kg)

Treat with Activated charcoal

Salicylates

Barbiturates

TCAs

Dextropropoxyphene

Digitalis

Paraffin

Do not Treat with

Activated charcoal

Ferrous salts

Lithium

Methanol

Ethylene glycol

Acids & Alkalis

Petroleum distillates

Methods for Enhancing Poison Elimination

Urine alkalinization

Hemodialysis

Hemoperfusion

Hemofiltration

Plasma exchange or exchange transfusion

Serial oral activated charcoal

Reduce absorption

Removal from surface skin & eye

Emesis induction

Gastric lavage

Activated charcoal administration & cathartics

Dilution - milk/other drinks for corrosives

Whole bowel irrigation

Endoscopic or surgical removal of ingested chemical

Reduce absorption

Skin decontamination

Important aspect – not to be neglected

Remove contaminated clothing

Wash with soap and water (soaps containing 30% ethanol advocated)

However, no evidence for benefit even in OP poisoning

Decontamination

Gastric decontamination

Forced emesis if patient is awake

Gastric lavage

Activated charcoal 25 gm 2 hourly

Sorbitol as cathartic Na/Mg sulfates

do not use in renal disease or absence of peristalisis

Reduce absorption

Gastric lavage

Gastric lavage decreases absorption by 42% if done 20 min and by 16% if performed at 60 min

Performed by first aspirating the stomach and then repetitively instilling & aspirating fluid

Left lateral position better - delays spont. absorption

No evidence that larger tube better

Simplest, quickest & least expensive way - funnel

Choice of fluid is tap water - 5-10 ml/kg

Reduce absorption

Gastric lavage

Preferrably done on awake patients

Presence of an ET tube does not preclude aspiration, though preferred if GCS is low

No human studies in OP poisoning showing benefit of gastric lavage

Enhance elimination

Enhancing elimination

Diuresis in Acid or Alkaline urineMannitol: osmotic Furosemide: inhibit K+ uptake

DialysisCharcoal Haemoperfusion

Oral MDAC

Alkalinization

Requires adequate urine flow and close clinical

monitoring

Add sterile sodium bicarbonate to sterile water

with 5% dextrose for intravenous infusion

Titrate urine pH from 7.5 to 8.5

Efficacious for salicylate compounds and

phenobarbital

Diuresis in Acid or Alkaline

urine

Lipophilic Ionizable drugs

Extensive pH dependent passive re-

absorption by the renal tubules

Clearance rate close to the normal

urine flow rate (1-2 mL/min)

Diuresis in Acid or Alkaline

urine

----------------------------------------------

At physiological pH most drugs are

partiaslly ……. )

Urine pH alteration increases

the amount of ionized (polar)

form of drug in the urine

Increase the CL rate by

altering the pH of the urine

Increase urine flow rate

NOT : Forced Diuresis

(mannitol & furosemide)

Diuresis in Acid or Alkaline

urine

Salicylates pka 3.0& Lithium

Enhance Clearance in an

alkaline urine (Sodium Biocarbonate)

Amphetamines pka 9.9

Enhance Clearance in an

acid urine (Ascorbic acid or Ammonium

Chloride)

Dialysis

Peritoneal dialysis or hemodialysis

Rely on passage of toxic agent through a semi-permeable dialysis membrane and equilibration with dialysate so it can be removed

Hemodialysis incorporates a blood pump to pass blood next to a dialysis membrane, which allows permeable agents to pass through and reach equilibrium

Toxin must have:

– Low volume of distribution (meaning toxicant primarily resides in blood compartment), and in addition

• Low protein binding

• High water solubility

• Low molecular weight

Hemodialysis: Clinically Effective for these

Agents

Amphetamines Isoniazid

Antibiotics Meprobamate

Boric acid Paraldehyde

Bromide Phenobarbital

Calcium Potassium

Chloral hydrate Salicylates

Fluorides Strychnine

Iodides Thiocyanates

Dialysis

For severe cases of poisoning

with :

Salicylates

Barbiturates

Chloral Hydrate & derivatives

Iron

Li

….

Drugs & Dialysis

Factors : DrugM.Wt, Water solubility, Protein binding

V.d, Usual route of CL

PatientBody Weight

Haemodialysis EquipmentThe membrane, Rate of flow of dialysis

fluid

Drugs & Dialysis

M.Wt < 500 Daltons

Highly water soluble

Low PB

Not widely distributed to

the body tissues

Hemoperfusion Similar to hemodialysis

Patient’s blood is pumped through a perfusion cartridge, where it is in direct contact with adsorptive material (e.g. activated charcoal or Amberlite resin) , coated to prevent it from being carried back to patient’s circulation

Toxin must exhibit

– Low volume of distribution

– Adsorption by activated charcoal

Unlike hemodialysis, can be used with lipid-soluble compounds and with high MW compounds

Protein binding does not interfere with removal by hemoperfusion

Hemoperfusion (cont’d)

Medical risks can include thrombocytopenia,

hypocalcemia, leukopenia

Used for:

– Serious theophylline overdose

– Exposure to Amanita

– Paraquat and meprobamate poisoning

Haemoperfusion

Blood pumped through cartridge of

absorbent material

Removes drug from the circulation

absorbent material

Charcoal (polar compounds)

Resin (nonpolar drugs)

Haemoperfusion

Better than Dialysis if substance

to be removed is :

Large M. Wt

Lipid Soulble

High PPB

Haemoperfusion

Factors :

Affinity of the toxin for the absorbent

Rate of blood flow through the cartridge

Vd of the drug < 400 L

Haemoperfusion

Serious poisoning with :

Salicylates

Barbiturates

Theophylline

Meprobamate

Paraquat

…..

MDAC shown to be effective

Carbamazepine

Dapsone

Phenobarbital

Quinine

Theophylline

Oral MDAC

Gastrointestinal Dialysis20 g 2 - hourly

50 g 4 – hourly

Prevents absorption from the GITAbsorbs drugs that diffuse or transported

back to GIT

Absorbs drugs that are excreted into the

small intestine from the billary tract

Oral MDAC

Gastrointestinal Dialysis

Aspirin

Carbamazepine

Digoxin

Phenobarbital

Quinine

Theophylline

Oral MDAC

Gastrointestinal Dialysis

Limited PPB

Low Vd

Long t1/2

Enhance elimination

Methods

Keep a good urine output 150-200 ml/hr

Alkalinisation of urine - clinical efficacy accepted for salicylate & phenobarbital poisoning

Extracorporeal removal

Hemodialysis - Barbiturates, Salicylates, Acetaminophen, Valproate, Alcohols, Glycols

Hemoperfusion - theophylline, digitalis, lipid soluble drugs

Neutralise toxin

Antidotes

• Ethylene glycol fomepizole, HD

• Heparin protamine

• Iron deferoxamine

• Isoniazid pyridoxime

• Methanol fomepizole, HD

• Methemoglobin methylene blue

• Opioids naloxone

• Salicylate alkalinization, HD

• TCA’s sodium bicarbonate

• Warfarin FFP, vitamin K

Neutralise toxin-specific antidotes

Acetaminophen N-acetyl cysteine

Anti-cholinergics Physostigmine

Benzodiazepenes Flumazenil

Ca channel blockers Glucagon, Insulin + dextrose, Calcium

Carbamate Atropine

Cyanide Thiosulphate, nitrate

Digoxin Digoxin antibodies

INAH Pyridoxine

Methanol Ethanol, Fomepizole

Glycol Ethanol, Fomepizole

Opioid Naloxone

Oral hypoglycaemics Glucose

Organophosphate Atropine,? P2AM

Warfarin Vitamin K

Neutralise toxin-specific antidotes

Iron Desferroxamine

Copper Penicillamine, Dimercaprol, CaEDTA

Lead CaEDTA, Dimercaprol (BAL)

Mercury DMPS, DMSA, BAL

Arsenic BAL & derivatives

Antimony BAL & derivatives

Thank you