FARMAKO

TOKSIKOLOGI

Noor Wijayahadi
 Definitions
Toxicology
 Ilmu  pelajari bahan toksik: detection,
properties, effects and regulation of
toxic substances, including poisons.

Racun (Poison)
 Semua bahan yang menimbulkan efek merugikan
(harmful effect)  digunakan sengaja ataupun
tidak sengaja

 Poisoning is quantitative concept

Poisonous substances are produced
by plants, animals, or bacteria.

Phytotoxins
Zootoxins
Bacteriotoxins
 Toksikan
Absorbsi

Sirkulasi sistemik

disposisi

distribusi eliminasi

Tempat Aksi ekskresi

metabolisme
Reseptor
Sel sasaran metabolit
(antaraksi)

toksik Tak toksik

EFEK TOKSIK
Dose Response Curve related to
Toxicity
Blood Plasma Level Toxicity
 Toxicological Terms
1. LD50 – dose at which 50% die
Only animals
TD50 – dose at which 50% have toxicity
Measure of harmfulness

2. T.I. – Therapeutic Index

TD50 / ED50
The larger the number, the safer the drug
Measure of safety

3. Acute Toxicity
Single dose within 24 hrs
Defines intrinsic toxicity
 Toxicological Terms (con’t)
4. Chronic Toxicity
Daily exposure for up to a lifetime

5. TLV – Threshold Limit Value

Concentration below which there is no expected untoward

effect over a period of 8hrs/day 5 days/week

NOEL – no observable effect level

ADI – allowable daily intake

ADI = (NOEL) / x
 Toxicological Terms (con’t)
6. STEL – Short term exposure level
4x a day, with the average being equal to the TLV

7. ALD – Average Lethal Dose

Estimated from accidental deaths in humans

8. Toxicon
Toxic principle of a given chemical entity
 Tylenol – quinone imine
 CCl4 – free radicals

9. Primary Determinant of Toxicology

Dose, Dose and Dose
Selective vs. Nonselective Toxicity

Nonselective
Nearly all chemical are nonselective in their
actions
Few chemicals are sufficiently selective to harm
certain cells

Selective
One man’s poison is another man’s pill.
What may be harmful to one specimen may be
relatively harmless to another.
Garden spray
 Toxidromes
Not every drug fits into a broad based
category
 Lots of meds have unique effects not easily
grouped
5 Basic Toxidromes
 Sympathomimetic
 Opiate
 Anticholinergic
 Cholinergic
 Seditive Hypnotic
 Dose/Time Principle
Toksisitas dipengaruhi oleh:
Besar Dosis Paparan
Akut
Lama Paparan
Keccepatan Paparan Kronis

HOST

ENVIRONMENT AGENT
Common Causes of Death in the
Acutely Poisoned Patient
Comatose patient:
 Loss of protective reflexes
 Airway obstruction by flaccid tongue
 Aspiration of gastric contents into
tracheobronchial tree
 Loss of respiratory drive
 Respiratory arrest
Hypotension – due to depression of
cardiac contractility
Common Causes of Death in the
Acutely Poisoned Patient
Shock – due to hemorrhage or internal bleeding
Hypovolemia – due to vomiting, diarrhea or
vascular collapse
Hypothermia – worsened by i.v. fluids
administered rapidly at room temperature
Cellular hypoxia – in spite of adequate
ventilation and O2 admin. – due to CN, CO or
H2S poisoning
Common Causes of Death in the
Acutely Poisoned Patient
Seizures – may result in pulmonary
aspiration;asphyxia
Muscular hyperactivity resulting in
hyperthermia, muscle breakdown,
myoglobinemia, renal failure, lactic
acidosis and hyperkalemia
Behavioral effects –traumatic injury
ferom fights, accidents, fall from high
places. Suicides, etc
Common Causes of Death in the
Acutely Poisoned Patient
Massive damage to a specific organ
system:
 Liver (acetaminophen; amanita phylloides
[poison mushroom]
 Lungs (paraquat)
 Brain (demoic acid)
 Kidney (ethylene glycol)
 Heart (cobalt salts)
Note: death may occur in 48 – 72 hrs
 II. Management of a Poisoning

Segera Lakukan:

1. Support Vital Functions

2. Identifikasi racun
3. Upaya pengeluaran racun dari tubuh
 CEGAH ABSORBSI
PERCEPAT ELIMINASI
Support vital life functions (ABC’s)
Airway – endotracheal tube if needed, watch for fluid
accumulation in airway (i.e.. Aspiration of vomit)

Breathing – Supplemental Oxygen, bag valve mask

(BVM) and respirator.

Circulation – Monitor ECG, watch for arrhythmias, cardiac

arrest and shock

 Vasogenic Shock – faulty vasomotor tone, increase capillary

permeability.

 Cardiogenic Shock – inadequate cardiac output can be due to

cardiac dilation (barbituate, Ca channel blocker)
 Supportive Drug Therapy
Use drugs to treat emergent
conditions, ie:
Seizures – anticonvulsants (valium)
Cardiac Dysrhythmias – anti-
arrhythmias (lidocaine, digoxin)
Severe Agitation – anxiolytics
(benzo)
 Identifikasi Racun?
1. Patient history

2. Laboratory testing

3. Comparison of drugs or chemicals

with known toxicology standards
 TOXIDROME
 Identification of the Poison
(Sample Types)
Urine - 1st choice – easier to detect presence of
the drug due to the accumulation of drug in the
urine.

Blood/Serum – 2nd choice – get exact serum

levels to better identify the health effects of the
drug (coma/stimulant panels)

Gastric Contents – 3rd choice –less helpful, but

can tell if you should perform a gastric lavage.
 Identify Poison (Tests)
Urine tests
Immunoassay (EMIT, ELISA) – semiquantitative tests
usually with automated instrumentation. Can detect
cannabinoids, amphetamines, cocaine, barbs etc.

Thin Layer Chromatography (TLC) – ToxiLab, 4

stage solvents, qualitative test

Urine/Blood tests
High Performance Liquid Chromatography (HPLC),
gas chromatography and Gas
Chromatography/Mass Spectroscopy (GCMS) are
quantitative tests that can detect many compounds.
Coma and Stimulant panels
Removal of the Drug (Emesis)
Utilize syrup of Ipecac to Induce
emesis to remove unabsorbed
drug.

Emesis inducers
 Mechanical
 Apomorphine
 Syrup of ipecac
 Contraindications?
 Contraindications of Emesis
Emesis is contraindicated in cases of:
Petroleum hydrocarbon solvent – chemical
pneumonitis
Caustic acid or alkali agent (rupture)
Seizing Patient
Comatose Patient
Removal of the Drug
(Gastric Lavage)
Gastric Lavage – washing of
the stomach. (early tx.)

A tube is inserted through the

nose or mouth, down the
esophagus, and into the
stomach. Sometimes a topical
anesthetic may be applied to
minimize irritation and gagging
as the tube is being placed.

Stomach contents can be

removed using suction
immediately or after irrigating w/
fluids through the tube.
Activated Charcoal/Cathartics
Activated Charcoal (AC)
Used to bind compounds and to prevent absorption in the
GI tracts. (many drugs)
Contraindicated with caustic agents and petroleum
distillates due to the lack of absorption of these agents by
the charcoal and risk of vomiting associated with the
charcoal

Order of use of charcoal and ipecac

Cathartics
Promotes rapid passage of poison through the GI tract
Counteracts the constipative effects of AC
I.E. sorbitol, Mg Citrate, Mg Sulfate
 Removal of the Drug (Other)
Alteration of pH of urine – to enhance excretion of the
drug, useful for salicylates, chlorpropamide, etc (tx)

Diuresis – often used in conjunction with urine pH

alteration

Dilution with water – useful in the treatment of skin or

eye exposure to harmful agents. ( no neutralizers)

Demulcents – soothes mucous membranes and coats

the stomach, i.e. milk of magnesia

Hemodialysis – blood transverses a semipermeable

membrane that is bathed in dialysis solution or
dialysate. Drugs or toxins diffuse across this
membrane. (protein binding)
B. Antidotal Treatments (1. Complexation)
A. Heavy Metals
Chelators (BAL, EDTA) complexes with the metals
making them inert

B. Heparin
Protamine (base) binds to acidic heparin to terminate its
action and is excreted by glomerular filtration.

C. Toxins-
Botulinum Toxin ALD- < 0.5mcg LD50=10ng/kg
Most potent poison known, rapidly absorbed and
prevents ACH release from nerve terminals
Tx: ABCs, lavage, emesis, charcoal,Trivalent anti-toxin
Mortality of 70% to 10% with treatment
 Complexation (con’t)
D. Organophosphates
Pralidoxime is a nucleophillic reagent that ties up
the organophosphates and permits its excretion.

E. Cyanide
Binds to cytochrome oxidase, LD50= 2mg/kg
Causes death in 1 to 15 minutes at high doses.
Chelator is made in the body, methemoglobin
(Fe3+)

Give Amyl Nitrites and Na Nitrite with O2 and

whole blood to convert hemoglobin to
methemoglobin (LD50 increases 5 fold) .
 Antidotal Treatments (con’t)
2. Enhancement of metabolic conversion to a
safer form
Example: Cyanide Poisoning and thiosulfate
treatment (LD50 increases 3 fold)

CN- SCN
Rhodanese

Treatment: Give
Sulfur Thiosulfate
(Sulfur source)
 Antidotal Treatments (con’t)
3. Inhibition of metabolic conversion to
toxic forms.

A. Ethylene glycol / Methanol – ethanol

administration prevents Alcohol dehydrogenase
(ADH) from converting these substances into toxic
forms. (Km – Mechanism of Toxicity)

4. Accelerating rate of excretion

Compete with reabsorption (Renal Tubules).
I.e. For Sr2+ or Ra2+ radiation give Ca2+; For Br1-
poisoning give Cl1- to aid in excretion.
5. Competition for Essential receptors
A. Carbon Monoxide
CO is found in cigarette smoke (5%) and auto
exhaust (9%). Not in natural gas itself.

Commonly used as a means of suicide; over 5000

fatalities a year from CO poisoning.

Carboxyhemoglobin is found in very small amounts

in non-smokers ~2.5% of the body’s hemoglobin and
7-10% for smoker

TLV – 35ppm STEL – 200ppm (15min)

ALD - 0.1%
 Carbon Monoxide Poisoning
Carboxyhemoblobin Symptoms
Concentration
0-10% None
20-30% Slight headache, exertional dyspnea
30-40% Throbbing headache, fatigue, dizziness,
SOB
40-60% Severe headache, weakness, dizziness,
confusion, dimness of vision (some have a
cherry red appearance)
>60% Convulsions, coma, Respiratory collapse
leading to death

Treatment: Artificial Respiration with pure O2 to promote

displacement of CO
Competition for Essential receptors
(con’t)
B. Turbocurare/pancuronium
Cause a competition between the poison and Ach at the
skeletal muscle endplate.
Treatment: Cholinesterase Inhibitors (i.e. Neostigmine
and physostigmine)
Administration of ACH alone ineffective

C. Coumarin
Anticoagulant that interferes with synthesis of
coagulation factors II, VII, IX and X.
Treatment: Vitamin K

D. Opiates
Competition at opiate receptors with antagonists like
naloxone and naltrexone.
 6. Repair or Bypass effect of poison
A. Nitrites/sulfa drugs
Converts hemoglobin into methemoglobin, which reduces
the ability of the blood to carry O2.
Methylene blue causes a direct reduction of
methhemoglobin back to hemoglobin.

B. Digitalis
Toxic effects include GI disturbances, neurologic, disorders
and cardiac arrhythmias.
Give antidote of Digibind

C. 5-Fluorouracil and 5-fluodeoxyuridine

Antitumor agents used to decrease DNA synthesis.
Thymidine is a specific and effective antidote.
 7. Blockade of receptors
responsible for Toxic Effects

The toxic action and the therapeutic action

are mediate by different receptors.

A. Anticholinesterases
Found in pesticides and chemical warfare agents.
increases level of acetylcholine resulting in
Cholinomimetic effects
Atropine blocks muscarinic receptors to block the
effect of the ACHe inhibitors. (anticholinesterases)
 SPECIFIC ANTIDOTES
Poison Antidote
Acetaminophen Acetylcysteine
Acetylcholinesterases, Atropine
OP’s, physostigmine
Iron salts Deferoxime
Methanol, Ethylene glycol Ethanol
Mercury, lead Metal Chelators
Narcotic drugs Naloxone
Anti/muscarinics-
cholinergics Physostigmine
OP anticholinergics Praladoxime (2-PAM)
 Toxidromes
Toxidromes are clinical syndromes that are
essential for the successful recognition of
poisoning patterns  sindroma toksik.

The most important toxidromes, clinically,

are:
Sympathomimetics Cholinergics
Sedative Hypnotics Tricyclics (TCAs)
Opiates Salicylates
Anticholinergics
 Sympathomimetic Toxidrome
CNS Agitation, hallucinations, paranoia

Respiration --
Pupils Mydriasis

Other Seizure, hypertension, tremor,

hyperreflexia, hyperthermia

Drugs Cocaine, amphetamines, PCP

 Sedative/Hypnotic Toxidrome
CNS Coma

Respiration Decreased
Pupils Mydriasis

Other Hypothermia, decrease reflexes,

hypotension

Drugs Alcohol, barbiturates,

benzodiazepines
 Opioid/Opiate
CNS Coma
Respiration Depression
Pupils Pinpoint

Other Hypothermia, hypotension, triad,

histamine release

Drugs Opiates, morphine, codeine,

propoxyphene, oxycodone,
hydrocodone
 Anticholinergic Toxidrome
CNS Agitation

Respiration ---
Pupils Mydriasis

Other Fever, dry skin, flushing, urinary

retention (ACS) [Hot, dry, mad, red,
blind]
Drugs Anticholinergics, antidepressants
 Cholinergic Toxidrome
CNS Coma (not quaternary)

Respiration ---
Pupils PPP

Other Fasciculation, incontinence,

salivation, wheezing, lacrimation,
bradycardia (SLUDE)
Drugs Organophosphates, carbamates,
nicotine
Tricyclic Antidepressant Toxidrome
CNS Coma agitation

Respiration ----
Pupils Mydriasis

Other Arrythmias, convulsions,

hypotension, mycoclonus,
hyperthermias
Drugs TCA’s, amipramine, imipramine,
desipramine
 Salicylate Toxidrome
CNS Variable up or down

Respiration Can increase or normal

Pupils -----

Other Diaphoresis, tinnitis, agitation,

alkalosis (early), acidosis (late),
fever
Drugs ASA, aspirin, (salicylates)
 Specific Poisons Frequently
Encountered
2. Base
Source Lye, liquid plumber, oven cleaner
Signs Swallowing is painful and difficult,
vomitus thick and slimy and may
contain blood, shock, esophageal
strictures, causes progressive
damage…25% mortality
Treatment ABC’s, demulcents, lots of water,
analgesics, steroids, antibiotics, no
lavage or emetics
Differences between acids and Bases

Acids Bases

1. Primary cause of
1. Immediate pain chemical burns
in buccal cavity and
2. Rapidly penetrating
esophagus liquefactive necrosis.

2. Less often 3. Primary effects on

esophagus and only 20%
swallowed than on stomach.
bases
4. Esophageal damage
severe including
 Specific Poisons Frequently
Encountered
3. Opiates
Source Heroin, morphine, oxycodone,
hydrocodone

Signs Bilateral miosis (PPP), CNS

depression, apnea, decrease in body
temperature, heart rate and
respiratory depression/arrest.
Treatment ABC’s, Naloxone, gastric lavage and
supportive care.
 Specific Poisons Frequently
Encountered
4. Meperidine
Source Demerol
Signs Dilated pupils due to antimuscarinic
effects, increase in HR, convulsions
due to metabolite (nor-meperidine),
respiratory depression/arrest, coma.
Few fatalities with meperidine
(tolerance).
Treatment ABC’s, Gastric lavage (if oral),
diazepam for seizures and naloxone
for depressive effects (not for tremors)
 Specific Poisons Frequently
5. Atropine Encountered
Source Atropine, Deadly Nightshade plant
Signs Dry mucous membranes, burning in
throat, intense thirst, dilation of pupils,
hot dry skin, hyperpyrexia, tachycardia,
mania and delirium; death from
respiratory failure
Hot, dry, mad, red and blind.
Treatment ABC’s, Lavage with 4% tannic acid,
pilocarpine or physostigmine, aspirin
(antipyretic) and alcohol sponges.
 Specific Poisons Frequently
Encountered
6. Barbiturates
Source Suicide, automatism (forget you
already took your dose)
Signs CNS depression (progressive),
drowsiness, shallow rapid respiration,
CV collapse, low body temp and death
due to respiratory depression
Treatment ABC’s, Lavage with KmNO4, charcoal,
alkaline diuresis (NaHCO3),
hemodialysis (long acting barbs)
 Specific Poisons Frequently
Encountered
7. Benzodiazepines
Source Diazepam (long acting), alprazolam
(short acting), triazolam (ultra short)
Signs Same as barbiturates, rarely fatal
unless taken with ETOH or other CNS
depressant due to synergistic CNS
depression
Treatment ABC’s, emesis, gastric lavage,
antidote: flumazenil short T1/2 may
require multiple doses.
 Specific Poisons Frequently
Encountered
8. Ethanol
Source Whisky, wine, beer etc.
Signs Odor on breath, impaired motor
coordination, slurred speech,
dehydration, gastritis, hypothermia,
coma and death due to respiratory
depression

Treatment ABC’s, gastric lavage with bicarb,

caffeine, hemodialysis (if >500mg%)
 Specific Poisons Frequently
Encountered
9. Neuroleptics
Source Major tranquilizers, antipsychotic agents
(phenothiazines, thioxanthenes)
Signs Extrapyramidal signs (EPS),
hyperactive, tardive dyskinesia, CNS
depression, seizures, hypotension,
poikilothermia
Treatment ABC’s, lavage (even hours hours later
due to lower gastric motility), Treat
arrhythmias as needed and
diphenhydramine for EPS.
 Specific Poisons Frequently
Encountered
10. Kerosene
Source Illuminating fuels, paint thinners
Signs Euphoria, burning in the chest,
headache, weakness, drowsiness,
convulsions, death due to respiratory
arrest or ventricular fibrillation

Treatment ABC’s, large amounts of water, olive

oil and saline cathartic, antibiotics,
corticosteroids to reduce kerosene
pneumonitis, no emetics or lavage.
 Specific Poisons Frequently
Encountered
11. Parathion
Source Organophosphate insecticide
Signs SLUDE, fixed pin point pupils, loss of
muscle coordination, muscle twitching,
mental confusion, death due to
respiratory arrest.
Treatment ABC’s, atropine, pralidoxine, lavage
with 5% NaHCO3, wash affected
areas, avoid morphine, barbituates
and phenothiazines.
 Specific Poisons Frequently
Encountered
12. Salicylates
Source Aspirin, percodan
Signs Deep and rapid breathing, tinnitis,
hallucinations, convulsions, resp.
alkalosis (adult), metabolic acidosis
(child), respiratory and CV collapse
Serum level > 400mcg/ml
Treatment ABC’s, emetics, gastric lavage 5%
NaHCO3, monitor pH, barbituates or
benzo’s for seizures, hemodialysis if
needed.
 Specific Poisons Frequently
Encountered
13. Acetaminophen
Source Tylenol, Vicodin, Percocet
Signs After depletion of glutathione, nausea,
vomiting, elevated liver enzymes
(SGOT, SGPT, bilirubin), hepatic
necrosis and death due to hepatic
failure.

Treatment ABCs, emetics, lavage, charcoal, N-

acetylcysteine to restore glutathione
earlier the better (grapefruit juice),
monitor liver enzymes.
 Acetaminophen Blood level
Effects
Plasma levels of > 250mcg/ml at 3-5
hours post ingestion.

Rumack Matthew nomogram – Probable

toxicity

Children (9-10yrs) are less susceptible to

the toxic effect of acetaminophen.
 Specific Poisons Frequently
Encountered
14. Cocaine
Source Coca plant, cocaine, crack
Signs CNS stimulation, euphoria, “cocaine
bugs”,halo lights, seizures, hallucinations,
cardiac arrhythmias lead to cardiac
arrest
Treatment ABC’s, charcoal, diazepam (seizures),
lidocaine (arrhythmias), no dialysis or
lavage.
 Forms of cocaine
Crack (type of free base)
Baking soda, hard rock, volatile

Cocaine HCL (salt)

Non-volatile, white crystalline powder
 Specific Poisons Frequently
Encountered
15. Phencyclidine (PCP)
Source Angel dust, Sernyl (old veterinary
general anesthetic)
Signs Psychosis, sensory analgesia, rotary
nystagmus, hypertension, hyperactive
reflexes, seizures.

Treatment Lock in padded room, diazepam,

antipsychotic agent (Haloperidol),
cranberry juice (100x increase in
excretion)
 Specific Poisons Frequently
Encountered
16. Tricyclic Antidepressants
Source Amitryptyline, imipramine, doxepin
Signs Anticholinergic Syndrome (ACS) [dry
mouth, mydriasis, hyperpyrexia, increase
HR, decreased GI motility] hallucinations,
seizures, respiratory depression, cardiac
arrhythmias (quinidine-like effect)

Treatment ABC’s, emesis, lavage, physostigmine

(till ACS stops), treat arrhythmias
(phenytoin, bicarb)
 Specific Poisons Frequently
Encountered
17. Methaqualone
Source Quaalude, ludes (sedative/hypnotic)
Signs Depersonalization, tongue
discoloration, dizziness, nausea,
hemorrhage, abstinence syndrome

Treatment ABC’s, emesis, lavage, hemodialysis

 Specific Poisons Frequently
18. Digoxin Encountered
Source Digitalis, digoxin
Signs Headache, nausea, vomiting, blurred
vision, delirium, slowed pulse, cardiac
irregularities, hypokalemia,
arrhythmias, ventricular fibrillation…
low TI
Treatment ABC’s Dose adjustment, drug
withdrawal, lavage, charcoal, emesis,
Digibind, K+ supplement, treat
arrhythmias (lidocaine, phenytoin,
propranolol)
 Specific Poisons Frequently
Encountered
19. Phenytoin
Source Dilantin
Signs Nystagmus, ataxia, drowsiness,
seizures…death is rare but is usually
due to ventricular fibrillation and
cardiac arrest. Toxicity >25mcg/ml
Treatment ABC’s, emesis (if conscious), lavage,
charcoal, cathartics, discontinue
phenytoin
 Specific Poisons Frequently
Encountered
20. Theophylline
Source Aminophylline
Signs CNS stimulation, hyperreflexia,
cardiac arrhythmia, convulsions, death
is due to respiratory failure. Toxic
plasma level >20mcg/ml.

Treatment ABC’s, discontinue drug, charcoal,

emesis, fluids and anticonvulsants
(diazepam) as needed.
 21. Dioxin (2,3,7,8 TCDD)
Source Herbicides, cigarette smoke, smoke
from burning trash and debris

Signs Chloracne (small yellow comedones)

mainly on the face can last 30 years,
hepatomegaly, fatigue, irritability,
blurred vision, porphyria cutanea tarda
(slate gray skin pigmentation), limited
systemic effects, Death??

Treatment ABC’s, alkaline diuresis, If recent

ingestion: [emesis, lavage, charcoal,
cathartic], mainly supportive care
 Dioxin Poisoning

Viktor Yushchenko: Ukraine President