Toxicology General Principles Flashcards
Why is toxicology important?
- Among Canadians of all ages, poisoning is the fourth-leading cause of injury deaths and the fifth-leading cause of hospitalizations.
- Overall, the most common cause of poisoning is prescription medication
Define toxicology
The study of poisons
Toxicology is the study of adverse effects of chemicals on living systems, including: (5)
- Mechanisms of action and exposure to chemicals as a cause of acute and chronic illness.
- Understanding physiology and pharmacology by using toxic agents as chemical probes.
- Recognition, identification, quantification of hazards from occupational exposure to chemicals.
- Discovery of new drugs and pesticides.
- Development of standards and regulations to protect humans and the environment from adverse effects of chemicals
Define ED50
Dose at which 50% of the population therapeutically responds
Define TD50
Dose at which 50% of the population experiences toxicity
Define LD50
Dose at which 50% of the population dies
What is NOAEL?
Highest dose at which - No Observed Adverse Effect Level
What is LOAEL?
Lowest dose at which - Observed Adverse Effect Level
How is therapeutic index (TI) calculated?
TI = LD50/ED50
TI = TD50/ED50
What is therapeutic index?
TI is the ratio of the doses of the toxic and the desired responses
What do you need to know about TI and ratio?
The larger the ratio, the greater the relative safety
Who is the father of toxicology?
Paracelsus
What are the branches of toxicology? (6)
- Mechanistic
- Forensic
- Clinical
- Environmental
- Food
- Regulatory
What are 3 major factors affecting toxicity?
- Route and site of exposure
- Duration of exposure
- Elimination rate and frequency of exposure
Major poisons access the body via: (6)
- GI (77%)
- Lungs
- Skin
- Parenteral routes - most toxic and rapid response (BYPASS FIRST PASS METABOLISM)
- Ocular
- GU and other routes
Should know the timeframes for the following exposure classes:
Acute
Subacute
Subchronic
Chronic
Acute - within previous 24 hours
Subacute - repeated exposure x 14 days
Subchronic - repeated exposure x 3 months
Chronic - repeated exposure > 6 months
Pharmacologic effects of the toxicant itself may affect the toxicokinetics. Such as? (2)
- Gastric hypomobility or delayed gastric emptying from anticholinergic effect
- Pathophysiologic consequences: hypotension, hypothermia –> hypoperfusion
Why is absorption important to know about in toxicology?
Rate and extent (bioavailability) of absorption are important because they determine concentration and ultimately, the likelihood of toxic effect
Should know whether Cmax and Tmax is high or low in the following routes of drug absorption:
GI
IV
Inhalation (lungs)
GI - Cmax is low and Tmax is large
IV - Drug does not undergo first pass metabolism. Cmax is larger and Tmax is smaller. Even though the conc of the drug administered is the same
Inhalation - Cmax is even large and Tmax is further smaller e.g., anaesthetics
True or False? Different routes may cause different Cmax and Tmax at same conc of the drug
True - AUC is same (body is exposed to same amount of drug - bioavailability) but some routes spread the exposure to the drug over greater time
Thinking back to the chart with the 3 curves, why does the fast and high peak curve fall faster than the other curves?
Rate of excretion is proportional to the current conc of the drug as the drug follows first order kinetics
True or False? Half-life of the drug depends on route of administration
False - t1/2 is same regardless of route of administration. T1/2 is drug characteristics and not route based
What are pharmacobezoars and why are they bad?
- Clumps of medications that build up in the GI that have not dissolved properly, resulting in a mega tablet.
- If that bezoar were to dissolve it would cause a whole lot of other toxicant effects.
- It can also cause obstruction in the GI, causing secondary adverse effects due to lack of blood flow and oxygen to the tissues
How do high Vd drugs act? How does that affect dosing?
Have a propensity to leave the plasma and enter the extravascular compartments of the body, meaning that a higher dose of a drug is required to achieve a given plasma conc. (High Vd –> more distribution to other tissues)
How do low Vd drugs act? How does that affect dosing?
Low Vd drugs like to remain in the plasma, meaning a lower dose of a drug is required to achieve a given plasma conc (Low Vd –> less distribution to other tissues)
What are factors that affect distribution of a drug? (5)
- Blood flow
- Plasma protein binding
- Vd - how much of a drug needs to be in the body to reach a certain plasma conc
- Transporters
- pH of the blood (affects how the toxicant is moving through the body)
What does onset of toxcity depend on?
The rate of distribution to the toxic effect compartment
What are 3 factors that affect metabolism?
- Saturation
- Genetic polymorphism
- Variation - Rate of blood flow, protein binding, and the intrinsic ability (organ clearance)