Clinical toxicology lecture 1 Flashcards
Hemlock
Drink it as a Greek capital punishment
Aconite
Soldiers dipping arrows
What did King Mithridates do?
Sampled poisons to build resistance
Paracelsus
Father of modern toxicology
Said that all substances are poisons, the dose determines if a remedy or poison
Threshold dose
Highest dose that doesn’t cause obvious adverse effects
ED1
Effective Dose, dosage affective in 1% of the population
NOEL
Highest dose where no significant effect occurs
LOEL
Lowest dose where a significan effect occurs
NOAEL
No observable adverse effect level
Dosage
Amount of toxin/ drug per body wt (mg/kg/day)
Dose
Total amount the animal receives
Acute responses/ effects
Redness, swelling, pain
Chronic responses/ effects
Contraction, organization, loss of pain
Timely effect of toxins
(Fastest) peracute –> acute –> subacute –> subchronic –> chronic –> accumulation –> delayed
Which gov organization approved drugs?
FDA
Acute toxicity
Single and short term exposure
Effects observed <24 hours
Subacute toxicity
Repeat exposure to small doses
30 days or less, two week studies
Effects cellular functions and tissues
Subchronic toxicity
Repeated exposure
Study of toxic effects for 1-3 months
Chronic toxicity
Long term exposure
Used to demonstrate general toxicity and carcinogensis
Period usually > one year
Chronicity factor (CR)
Ratio of acute chronic LD50
CR= acute LD50/ chronic LD50
Chemical accumulates if CR >2
Inhereited sensitivities of MDR1 gene mutation
Ivermectin
Butorphenol
Anticancer drugs (doxrubricin, vincristine)
Acepromazine
Immodium
Mibemycin
Erythomycin
Rifampin
Routes of administration
Oral*
IV, IM, SC
Dermal*
Inhalation*
Intrathecal
Sublingual
Intraocular
Transdermal
Factors influencing toxic responses
- Composition of sample (purity & solubility)
- Physiological features (species, age, gender)
- Route of administration
- Pathological conditions (liver & kidney)
- Diet (ingredients, quality & quantity)
Exposure
Poison/ drugs gain entry —> drugs transported to site of action —> drugs bind to receptors (DR complex) —> initiates rx (effect/ response) —> drug removed from receptor —> drug excreted from body
Dose response relationship
Biological response is related to the dose
Different in different species as well as the same species
How is dose response used?
To determine margin of safety
Optimize dosage schedule (efficacy)
Predict toxicity poisoning
Biological variation
Dose can produce a variety of responses in a population
Determines repulse of a large # of individuals
Predicts the response of an individual within a certain range of probability
How is Dose-response plotted?
Log dose v. Percent response
Methods to predict dose response relationships
- Graded DR (overall effect)
- Frequency/ Quantal DR (% responding/ population)
Therapeutic index
TI= LD50/ ED50
Ratio between lethal dose (50%) and effective dose (50%)- no units
Margin of safety (MS/MoS/ SSM)
MS= LD1/ ED99
Ratio between lethal dose (1%) and effective dose (99%)- no units
BETTER SAFETY ASSESSMENT THAN TI
Toxicokinetics abbreviated
Concentration: Cp
Volume of distribution (Vdss)
Clearance (Cl)
Bioavailability (F)
Half life
t1/2
Time required to decrease concentration to one half
Parts per _____ conversions
1 ppm = mg/kg= ug/g
1 ppb = ug/kg= ng/g
1 ppt = ng/kg= pg/g
Expression of chemical concentrations
Kg= 1000 g
1g =1000 mg
1 mg= 1000 ug
1 ug = 1000 ng
1 ng= 1000 pg
To convert PPM to %…
Move decimal 4 points to the left
1 ppm: 0.0001%
10 ppm: 0.001%
to convert % to PPM move to right
Additive effects
When 2 or more chemicals combine and produce a chemical with a total effect equal to the sum of the effects of each inidival chemical in the rx
Ex: 1+1=2
Synergistic effects
The combined effect of 2 compounds are drastically greater than the sum of 2 effects
Ex: 1+1=10
Antagonism
Toxic effect of chemical A (agonist) can be reduced when give with chemical B (antagonist)
Ex; 1+1=0
Antagonist are used as_________
Antidotes (because they reduce toxicity)
Potentiation
A chemical doesn’t have a specific toxic effect, makes another chemical more toxic
Ex: 1+0= 2
Routes of exposure/ administration
- Oral/ GI (water or fat soluble)
- Dermal- percutaneous (environmental contaminants)
- Inhalation, respiratory, pulmonary (gas, liquid, solid, size of particles)
Oral/ GI
Generally toxicants in food or water
Some unstable in acidic stomach
Some taken up by liver and partially destroyed
Some removed in stomach, duodenum, large bowel and feces
Dermal/ Percutaneous
Toxicants must be in a soluble vehicle, capable to penetrating keratin, and enter a BV
What other factors contribute to dermal administration?
Duration fo exposure
PPE/ skin protectants
Integrity of the skin
What does distribution depend on?
Blood flow
Ability to cross the cell wall
Lipid solubility/ physiochemical properties
Central compartment
High perfused (blood flow to tissues)
Blood, kidney, liver
Peripheral compartment
Less blood flow tissues
Fat, bone, muscle
Biotransformation/ Metabolism organ capabilities
Greatest: liver
Major potential: kidney, GIT, skin
Great fetus potential: brain, heart, placenta
Objective of biotransformation
Make chemical more soluble
Enhance urinary and binary excretion
Decrease toxicity fo chemicals
Storage of xenobiotics
Storage can be a protective mechanism and potentiate toxicosis
Storage sites in the body
Depending on the drug:
Fat, plasma proteins, bone, liver, kidneys, BBB
FARAD: Residue Avoidance Database
Computer based program designed to provide practical info on how to avoid drug , pesticide, and environmental contaminant residue problems
Target: livestock producers, extension specialists and vets
