Toxicology
- branch of pharmacology that deals with the study of poison, the mechanism of toxicity, and
treatment
- Gk. “toxicon” (arrow poison), “logia” (to speak of)
Goals of Toxicological Research
- Examine the mechanism of toxicity
- Examine the functional effects
- Assess the probability of occurrence of poisoning
Risk Assessment – estimate of potential effects to human health and environmental significance of
various types of exposure
Special Areas of Toxicology
1. Mechanistic Toxicology – mechanisms of toxicity of poisons
2. Descriptive Toxicology – involves toxicity testing which provides information for safety
evaluation and regulatory requirements
3. Regulatory Toxicology – involves policymaking based on data gathered from mechanistic and
descriptive toxicology
4. Clinical Toxicology – effects in patients caused by accidental poisoning or intentional overdoses
5. Forensic Toxicology – involves the medico-legal aspect of poisons
6. Industrial / Occupational Toxicology – estimation of toxic effects of chemicals found in the
workplace
7. Environmental Toxicology – impact of chemical pollutants to water and wild life
Mechanisms of Toxicity (MOT)
1. Effects
a. Local effect – same route of administration and site of action (e.g. phenol, caustics,
corrosives causing skin burn)
b. Remote effect – different route of administration and site of action (e.g. Paraquat ingestion
→ Pulmonary Edema)
c. Systemic effect – widespread derangement (e.g. metabolic acidosis)
[MUDPILES] – causes metabolic acidosis
Methanol
Uremia
Diabetic ketoacidosis
Paraldehyde
Iron and isoniazid
Lactic acidosis
Ethylene glycol
Salicylates
2. Common Major Pathophysiological Mechanisms
a. Interfere with O2 utilization
o e.g. Carbon monoxide (CO) → carboxy hemoglobin
o e.g. Cyanide – inhibits cytochrome oxidase
b. Stimulation of CNS
o Stimulant (e.g. Strychnine)
o Inhibition of glycine receptors
o Excitation of CNS → seizures
c. Depression of CNS
o Depressants (e.g. Barbiturates, BZDs)
o Cause lethargy → coma, respiratory depression
d. Affect the ANS
o Parasympathomimetic: e.g. Organophosphates
o [DUMBELS]
▪ Diarrhea
▪ Urination
▪ Miosis / Muscle fasciculation
▪ Bronchoconstriction / Bradycardia
▪ Emesis
▪ Lacrimation
▪ Salivation
o Sympathomimetic: e.g. Amphetamine
o [MATHS]
▪ Mydriasis
▪ Agitation
▪ Tolerance
▪ Hypertension
▪ Seizure / Sweating
e. Affect the heart and vasculature
o Heart: Antiarrhythmics
o Blood vessels: Nitric Oxide
▪ MOA: First activated by glutathione in endothelial cells → nitric oxide synthase
activation
f. Affect the lungs
o e.g. Hydrocarbon and petroleum distillates → aspiration → airway irritation
g. Affect the liver and kidney
o Liver: Paracetamol
o Kidney: Heavy metals
Factors that affect the effects of poisons
A. Poison Related
1. Concentration
o ↑concentration, ↑poison effects
2. Solubility
o ↑lipid solubility, ↑absorption, ↑poison effects
o ↑water solubility, ↑excretion – decontamination
3. Route of administration
a. Oral – most important route
b. Dermal – ↑lipid solubility, better dermal absorption
c. Inhalational – substances <0.5 microns (µm) are absorbed through the lungs
d. Intravenous (IV) – provides the fastest clinical route
e. Intramuscular (IM) – variable absorption
f. Rectal – variable absorption
[Insert Rectal vein image]
B. Patient Related Factors
1. Tolerance – continuous activation of receptors/enzymes → depletion of essential
substances (e.g. Nitrates – Monday sickness)
2. Idiosyncrasy / Pharmacogenetics – genetic polymorphism
o variability of expression/ production of enzymes based on genetic characteristics
o Extensive metabolizers: normal amount of enzymes (EM)
o Ultra-metabolizers: excessive (EM)
o Poor metabolizers: inadequate (PM)
o e.g. N-acetyltransferase-2 (NAT-2)
▪ acetylation reaction
▪ [HIPPS] – SJS-TEN
• Hydralazine
• Isoniazid
• Procainamide
• Phenytoin
• Sulfonamides
o Fast Acetylators (EM): Asians, Eskimos
o Slow Acetylators (PM): Caucasians, Egyptians, African, Americans, Mediterranean Jews
o G6PD Deficiency
▪ HMP shunt
• NADPH
• Ribose-5-Phosphate
▪ May cause hemolytic anemia
▪ Resistant to malaria
[Insert mechanism]
3. Pregnancy – US FDA Pregnancy Risk Classification
Category Human Studies Animal Studies
A Safe Safe
B No information Safe
C No information Not safe
No information No information
D Not safe: Benefits > Risk
X Completely contraindicated: Teratogenic Effects
o Timing
▪ Conception to implantation (0-3 weeks AOG)
• Spontaneous abortion
▪ 3-8 weeks AOG (Embryogenesis)
• Teratogenic effects
• E.g.
o Thalidomide – phocomelia / Amelia
o Warfarin – hypoplastic nose
o Tetracycline – tooth discoloration
o Lithium – Ebstein Anomaly (cardiac)
o ACE Inhibitor – renal dysgenesis
o Diethylstilbestrol – clear cell carcinoma of vagina / cervix
o Methimazole – aplasia cutis
o Carbamazepine, Valproic acid – neural tube defect (spina bifida)
o Phenytoin – Fetal hydantoin syndrome (midline structure)
o Alcohol – Fetal alcohol syndrome
▪ Facial anomalies
▪ Growth retardation
▪ Neurodevelopmental delay
▪ >8 weeks AOG – minor abnormalities
o Signs of exposure
1. Acute: <24 hours (large amount of poison in short amount of time)
2. Subacute: >24 hours but <1 month
3. Subchronic: >1 month but <3 months
4. Chronic: >3 months
General Management of a Poisoned Patient
1. Initial assessment / Primary Survey
o [ABCDE]
▪ Airways – chin elevation
▪ Breathing – pulse oximeter
▪ Circulation – carotid pulse
▪ Degree of disability – quick neurologic exam: GCS (Glasgow Coma Scale)
▪ Exposure – identification of the patient and poison (SATS)
o [GCS]
▪ Eye opening
▪ Verbal response
▪ Motor response
▪ GCS 15:
o [SATS]
▪ Substance
▪ Amount
▪ Time
▪ Symptoms (Toxidromes)
2. Secondary survey
o [AMPLE]
▪ Allergy
▪ Medication
▪ Past medical history and Pregnancy
▪ Last meal
▪ Events / Environment related to injury
3. Decontamination
a. Oral Route
1. Emesis
2. Dilution
3. Gastrointestinal Dialysis
4. Lavage
5. Whole Bowel Irrigation
6. Cathartics
7. Forced Diuresis
b. Dermal
c. Inhalational
d. Ocular
4. Antidotal Therapy
5. Extracorporeal Methods
