General Principles Of Toxicology Flashcards
What is toxicology?
The study of poisons
What is a toxicologist?
One who studies poisons
What is a poison?
Any chemical substance that can cause harm
Differentiate hazard and risk.
Hazard: likelihood an event will occur based on how the product is packaged, formulated, or its accessibility
Risk: the probability that an event will occur based on patient vulnerability
Define drug overdose.
Taking a harmful amount of a drug
What is a co-ingestant?
Xenobiotic (foreign substance) in circulation at the time of toxicity
Why is toxicology important?
Among Canadians of all ages, poisoning is the 4th leading cause of injury deaths and 5th leading cause of hospitalization
Most common cause of poisoning is Rx medication
10,000 people overdose on acetaminophen annually in Canada
88% of opioid hospitalizations were non-pharmaceutical
Provide a more detailed definition of toxicology.
Study of adverse effects of chemicals on living systems, including:
-MOA 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 AEs of chemicals
Differentiate ED, TD, and LD.
ED: effective dose (therapeutic dose of a drug)
TD: toxic dose (dose at which toxicity occurs)
LD: lethal dose (dose at which death occurs)
Differentiate ED50, TD50, and LD50.
ED50: dose at which 50% of the population therapeutically responds
TD50: dose at which 50% of the population experiences toxicity
LD50: dose at which 50% of the population dies
What is the TI?
Therapeutic index
-ratio of the doses of the toxic and desired response
-used as an index of comparative toxicity of two different materials
-approximate statement of the relative safety of a drug
What does a larger TI signify?
The larger the ratio, the greater the relative safety
How do you calculate the TI?
TI = TD50/ED50
What are the different branches of toxicology?
Mechanistic: cellular, biochemical, and molecular mechanisms by which chemicals cause toxic response
Forensic: cause of death, legal aspects
Clinical: treatment for poisonings and injuries caused by xenobiotics
Environmental: environmental pollutants, effects on flora and fauna
Food: adverse effects of processed or natural food components
Regulatory: assigns risk to substances of commercial importance
What are the factors affecting toxicity?
Route and site of exposure
-GI (77%)
-lungs
-skin
-parenteral routes (most toxic and rapid response due to bypassing 1st pass)
-ocular
-GU and other routes
Duration of exposure
-acute: within previous 24h
-subacute: repeated exposure x 14d
-subchronic: repeated exposure x 3m
-chronic: repeated exposure > 6m
Elimination and frequency of exposure
What are some examples of drugs that undergo enterohepatic circulation?
NSAIDs
Antibiotics
Warfarin
Opioids
Digoxin
What is toxicokinetics?
PK of toxic substance
-these characteristics may be different with respect to doses within therapeutic doses
-pharmacologic effects of the toxicant itself may affect the TK
Why is absorption important in toxicokinetics?
Rate and extent of absorption are important because they determine concentration and ultimately, the likelihood of toxic effect
Differentiate Cmax and Tmax for oral, IV, and inhaled routes of admin.
oral: Cmax is low and Tmax is large
IV: Cmax is larger and Tmax is smaller even though conc of drug administered is same (skips 1st pass metabolism)
inhalation: Cmax is even larger and Tmax is further smaller
Does AUC differ between routes of administration?
no
different routes may cause different Cmax and Tmax at same conc of drug but AUC is the same
Why does the curve of inhaled route of admin fall faster than oral route?
rate of excretion is proportional to the current conc of the drug as the drug follows 1st order kinetics
What happens with half-life as route of admin changes?
half-life of the drug is same regardless of the route of admin
What are pharmacobezoars?
mass trapped in GI system
-can cause lack of blood flow to colon which may cause secondary adverse effects
-if they are dissolve, they can cause a whole lot of other toxicant effects
What are the 4 compartments that drug can distribute into?
fat
blood
extracellular fluid
intracellular fluid
What is Kc?
equilibrium constant
-number that tells if the balance is in forward or backward direction
What is Kc dependent on?
permeability of barriers
pH of compartments
binding capacity
drug characteristics (such as fat solubility)
What is volume of distribution?
how much of the drug needs to be in the body to get a certain conc in the plasma
What is the equation for Vd?
amount of drug in the body (mg) / plasma concentration of the drug (mg/L)
Differentiate a high and low Vd drug.
a drug with a high Vd has a propensity to leave the plasma and enter the extravascular compartments of the body
-higher dose required to achieve a given plasma concentration
a drug with low Vd likes to remain the plasma
-lower dose of a drug required to achieve a given plasma concentration
What are the factors impacting distribution?
blood flow
plasma protein binding
volume of distribution
transporters (genetic polymorphisms)
pH of the blood (affects how the toxicant is moving through the body)
What are the three things CYP enzymes can do to a drug?
oxidation
hydroxylation
hydrolysis
What is the purpose of phase II metabolism?
adding another group to the drug to make it more soluble for excretion
What are the factors affecting metabolism?
saturation
-shifts kinetics from 1st order to zero order
-cofactors/enzymes
genetic polymorphisms
variation - rate of blood flow, protein binding, and the intrinsic ability
What are examples of high and low extraction ratio drugs?
low extraction: CBZ, warfarin
high extraction: propranolol
What is drug clearance?
volume of plasma cleared of a drug over a specified period of time
What are the four mechanisms of renal excretion?
glomerular filtration
passive back diffusion
tubular secretion
tubular reabsorption
reabsorption and secretion are active methods and occur through transporters, prone to polymorphisms
Who do you report toxic ingestions to?
PADIS
What is the approach to a poisoned patient?
- resuscitation and stabilization
- history and physical exam
- symptomatic & supportive care
- diagnostic testing
- decontamination
- elimination
- antidote
What is involved in resuscitation and stabilization?
ABCs
airways
breathing
circulation (BP and HR)
What kind of info should be gathered for a poison patient?
who? (age, sex, weight)
what? (all meds and substances)
when?
where?
why? (intentional or accidental?)
Differentiate hyperthermia and fever.
hyperthermia:
-increased heat production or decreased heat loss
-caused by drugs
fever:
-thermal set point in the hypothalamus is increased
-caused by microorganism, drugs, etc
Differentiate bradycardia, tachycardia, tachypnea, and bradypnea.
bradycardia: decreased HR
tachycardia: increased HR
bradypnea: decreased RR
tachypnea: increased RR
What is the first thing to do when a person is exhibiting an altered mental status or seizures?
check blood glucose
What is methemoglobinemia?
hemoglobin can carry oxygen but cant release it
-can be caused by benzocaine, dapsone, nitrites
-consider if cardiac and pulmonary diseases ruled out for cyanosis
What is diaphoresis?
excessive sweating
-can be caused by sympathomimetics
List different breath odours and their likely cause.
fruity or “nail-polish remover”: acetone
garlic: organophosphates
mothballs: napthalene
wintergreen: methylsalicylate
What are the three things that can lead to vomiting/hematemesis?
direct GI mucosal irritation
chemoreceptor trigger zone (CTZ) stimulation
intracranial hemorrhage (pressure)
What can lead to diarrhea?
intestinal irritation
increased autonomic bowel activity
What are toxidromes?
comprise a constellation of clinical signs and symptoms which, taken together, are likely associated with exposure from certain classes of toxicological agents
What are the ways to distinguish if a person is experiencing toxicity due to an anticholinergic or a sympathomimetic?
anticholinergic: dry skin, no bowel sounds, urinary retention
sympathomimetic: wet skin, hyperactive bowel sounds, no retention
What is the treatment of metabolic acidosis?
sodium bicarbonate
What are the pros and cons of toxicity screens?
pros
-identify most drugs present in overdose patients
cons
-may not add information to whats already gathered
-rarely affect treatment course or how to manage
-misinterpretation of a positive drug of abuse
