“the study of poisons” - medilam.ac.ir
TRANSCRIPT
“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