Introduction Material Flashcards
Toxicology is defined as
The science of toxicants, their physical properties, sources, toxicity, toxicokinetics, MOA, clinical signs, lesions (post-mortem), lab diagnosis, diagnosis, DDx, and treatment (or prevention) of diseases caused by toxicants
Most common poisoning in dogs?
Human food and drugs (legal and illegal).
Diagnosis and Treatment
Main aspects of clinical Tox
Drugs can be poisons and poisons can be drugs…. The difference is
The dose (Dose or amount of exposure)
Drugs and Poisons are….
Xenobiotics (foreign chemicals that the body does not produce)
Any substance (gas, liquid, solid) when applied or introduced into the body that may interfere with life processes or biological functions of the cells of the animals
Poison (Toxicant) - can be used interchangeably
Natural Poisons
Plant Animals (venom, insect sting, fish toxin) Minerals (lead, zinc) Fungi or bacteria (mycotoxin)
Organophosphate and chlorinated hydrocarbon insecticides, organic herbicides are…
Synthetic Poisons
Toxin
BIOTOXIN!! Poison from a biologic process (zootoxins or animal toxins, phytotoxins or plant toxins, bacterial toxins and mycotoxins)
Toxicant
Can be living or non-living
Deleterious or undesirable effects of poisons
Toxic
Disease caused by exposure to a poison
Toxicosis (Poisoning or intoxication)
Toxicity
Amount of a poison that under certain circumstances will cause toxic effects
Toxicity in mammals is
LD50 Mg/kg body weight
Toxicity in Birds….
LC50 (lethal concentration) Mg/kg FEED
Toxicity in Fish….
LC50 Mg/liter WATER
Effect of a single dose or multiple doses during a 24 hour period
Acute Toxicity
Effect produced by daily exposure from one day to 30 days
Subacute Toxicity
Effect of exposure from 30 days to 90 days
Subchronic Toxicity
Effect produced by daily exposure for a period of 3 months or more
Chronic Toxicity
Chronocity Factor
Ratio between acute LD50 and chronic LD50
Toxicity values are influenced by several factors…
Species, breed, age, individual, sex, dosage of a poison, duration of exposure and other factors
Extremely Toxic
= 1mg/kg or less
Highly Toxic
> 1-50 mg/kg
Moderately Toxic
> 50 - 500 mg/kg
Slightly Toxic
> 0.5 - 5 g/kg
Practically Nontoxic
> 5-15 g/kg
Relatively Harmless
>15g/kg
Highest NonToxic Dose (HNTD)
The highest or largest dose which does not result in undesirable or toxic alterations (clinical, hematologic, biochemical, or pathologic alterations)
This is similar to the highest nontoxic dose
Maximum Tolerated Dose Or Minimal Toxic Dose (MTD)
Toxic Dose Low (TDL)
The lowest dose which produces toxic alterations and administering twice the dose will not cause death
Toxic Dose High (TDH)
The dose which produces toxic alterations and administering twice the dose WILL result in death
No Effect Level (Maximum Nontoxic Level)
The amount of a chemical that can be ingested without causing any deaths, illness or toxic alterations in any of the animals for the stated period (usually 90 days to 2 years or more depending on the species)
The dose that causes death in any animal during the period of observation
Lethal Dose
LD 0 (zero)
the highest dose that dose not cause any death
LD 50
The dose that kills 50% of the animals in the group
LD 100
The lowest dose that kills ALL the animals in a group
Hazard
Is the danger from the possibility of exposure
A poison may be _____ ________ but not _________
Highly Toxic , Hazardous
The risk factor can be calculated as the _______ between _______ and _____ ______
Ratio , toxicity , and use level
Toxicology is
The study of poisons (toxicants)
Parts per million (ppm) on weight/weight basis
Is the most common method of expressing concentrations in toxicology 1ppm = 1mg / kg
Converting from PPM to percent %
Move the decimal point 4 places to the left Ex: 1 ppm - 0.0001%
Convert from Percent % to PPM
Move the decimal point 4 places to the right Ex: 0.0001% –> 1 ppm
Diluted Solution from Stock
The mL needed = (% required dilution / % stock ) x required in mL Ex: (2.5% diluted / 50% stock) x 500 mL =
Feed to PPM
100g/ton = 110ppm
The study of movement of drugs in the body across biological membranes from the time of absorption until elimination
Drug Disposition
What are the Stages of Drug Disposition
Absorption Distribution Biotransformation Excretion
Biological Cell Membrane
Composed of lipid by layer Contain membrane proteins and carbohydrates There are aqueous pores or junctions between cells
Transmembrane movement of water is either by _________________ through aqueous channels or by flow resulting from_________ or ____________ difference across the membrane
Passive diffusion, osmotic, hydrostatic
Paracellular transport of water is through…
Intracellular aqueous pores
Tissues that have a barrier mechanism have..
“Tight” intracellular junctions
Bulk flow of water can carry…
Small water soluble substances
Concentration Gradient
Drugs move across membranes from high concentration to low concentration
Lipid Solubility is measured by
Lipid partition coefficient ( the ratio between solubility of drug in lipid to its solubility in water)
The higher the lipid solubility the….
Faster the drug crosses the membranes
Drugs cross membranes in the
Non-ionized form (Lipid soluble and do not carry electric charge)
The rate of diffusion depends on the ratio between the ____________ of the drug to the ____________ form.
(N/I) Non-ionized, ionized
Ionization of a drug depends on…
PH of the drug Pka of the drug PH of the medium (environment)
The pKa of a drug is the pH at which a weak electrolyte is
50% ionized and 50% non-ionized
Most drugs are
Weak electrolytes (weak acids or weak bases)
Acidic drugs ionized in __________ medium and basic drugs ionized in ___________medium
Alkaline, acidic
The higher the pKa of a weak acid the _______ is N/I and the lower the pKa of a weak base the ________ is N/I
Higher, higher
Quaternary ammonium compounds like d-tubocurarine are
Mostly ionized
Phenylbutazone
A weak acid mostly ionized in the stomach
Facilitated Diffusion
A carrier mediated transport that DOES NOT NEED ENERGY
In facilitated diffusion a drug moves across the membrane from high to low concentration…
At a faster rate (downhill movement)
In facilitated diffusion, transporters can move
Drugs from outside the cell to inside or from inside to outside
Facilitated diffusion Transporters may act as a _______________ to protect cells from toxic substances by ….
Barrier system Moving them from inside to outside of the cell
Movement of glucose across a muscle cell membrane by insulin sensitive glucose transporters is an example of
Facilitated Diffusion
In active transport, a drug moves across the membrane from
Low concentration to High concentration (uphill movement)
Active transport is a carrier mediated transport
That requires energy
Primary active transport uses energy directly from
ATP such as Na/K ATPase
Secondary Active Transport
Uses stored energy in the Na electrochemical gradient
Active transport is characterized by
Saturability, selectivity, and competitive inhibition by cotransported compounds
Specific type of endocytosis where the cell engulfs the drug molecules dissolved in water
Pinocytosis
The transport of drugs from the plasma to the tissues
Distribution
Factors that affect distribution of drugs
Physiochemical properties Concentration gradient Plasma protein binding Blood Flow Tissue barrier Drug affinity to tissues
Acidic drugs bind mainly to
Albumin
Basic drugs bind mainly to
Alpha 1 - glycoproteins and lipoproteins
What drugs bind to globulin
Steroids
Plasma protein binding
Prolongs the half life of the drug
Plasma protein binding is generally
Reversible
The bound form of the drug is
Inactive, so it cannot be distributed, metabolized or excreted
The rate of binding depends
On the amount of the drug
Plasma protein binding can be modified by
Disease
Highly perfused tissues
brain, liver, kidney, endocrine glands
Moderately perfused tissues
Muscle, skin
Poorly perfused tissues
Bone, adipose tissue
The Blood Brain Barrier (BBB)
- Tight capillary endothelial junctions
- Presence of glial cells
- Flow of the CSF into venous drainage
- Active transport mechanisms for extrusion of organic acids or bases
Factors that limit the BBB…
Age Inflammation Trauma Allergic Rxn Severe hypotension Hypoxia High doses of organic solvents (alcohol) Heavy metals
Name some Tissue Barriers
Brain Eye Testicles Placenta Mammary glands
Tetracycline has an affinity to
Calcium in skeletal tissues
Aminoglycosides have an affinity to
Kidney tissue
The thyroid gland traps
Iodine
The movement of the drug from the tissue to the blood
Redistribution
The chemical alteration of the drug molecule by the cells of the animal
Metabolism (biotransformation)
Parts per million (ppm) on weight/weight basis
Is the most common method of expressing concentrations in toxicology 1ppm = 1mg / kg
Converting from PPM to percent %
Move the decimal point 4 places to the left Ex: 1 ppm - 0.0001%
Convert from Percent % to PPM
Move the decimal point 4 places to the right Ex: 0.0001% –> 1 ppm
Diluted Solution from Stock
The mL needed = (% required dilution / % stock ) x required in mL Ex: (2.5% diluted / 50% stock) x 500 mL =
Feed to PPM
100g/ton = 110ppm
The study of movement of drugs in the body across biological membranes from the time of absorption until elimination
Drug Disposition
What are the Stages of Drug Disposition
Absorption Distribution Biotransformation Excretion
Biological Cell Membrane
Composed of lipid by layer Contain membrane proteins and carbohydrates There are aqueous pores or junctions between cells
Transmembrane movement of water is either by _________________ through aqueous channels or by flow resulting from_________ or ____________ difference across the membrane
Passive diffusion, osmotic, hydrostatic
Paracellular transport of water is through…
Intracellular aqueous pores
Tissues that have a barrier mechanism have..
“Tight” intracellular junctions
Bulk flow of water can carry…
Small water soluble substances
Concentration Gradient
Drugs move across membranes from high concentration to low concentration
Lipid Solubility is measured by
Lipid partition coefficient ( the ratio between solubility of drug in lipid to its solubility in water)
The higher the lipid solubility the….
Faster the drug crosses the membranes
Drugs cross membranes in the
Non-ionized form (Lipid soluble and do not carry electric charge)
The rate of diffusion depends on the ratio between the ____________ of the drug to the ____________ form.
(N/I) Non-ionized, ionized
Ionization of a drug depends on…
PH of the drug Pka of the drug PH of the medium (environment)
The pKa of a drug is the pH at which a weak electrolyte is
50% ionized and 50% non-ionized
Most drugs are
Weak electrolytes (weak acids or weak bases)
Acidic drugs ionized in __________ medium and basic drugs ionized in ___________medium
Alkaline, acidic
The higher the pKa of a weak acid the _______ is N/I and the lower the pKa of a weak base the ________ is N/I
Higher, higher
Quaternary ammonium compounds like d-tubocurarine are
Mostly ionized
Phenylbutazone
A weak acid mostly ionized in the stomach
Facilitated Diffusion
A carrier mediated transport that DOES NOT NEED ENERGY
In facilitated diffusion a drug moves across the membrane from high to low concentration…
At a faster rate (downhill movement)
In facilitated diffusion, transporters can move
Drugs from outside the cell to inside or from inside to outside
Facilitated diffusion Transporters may act as a _______________ to protect cells from toxic substances by ….
Barrier system Moving them from inside to outside of the cell
Movement of glucose across a muscle cell membrane by insulin sensitive glucose transporters is an example of
Facilitated Diffusion
In active transport, a drug moves across the membrane from
Low concentration to High concentration (uphill movement)
Active transport is a carrier mediated transport
That requires energy
Primary active transport uses energy directly from
ATP such as Na/K ATPase
Secondary Active Transport
Uses stored energy in the Na electrochemical gradient
Active transport is characterized by
Saturability, selectivity, and competitive inhibition by cotransported compounds
Specific type of endocytosis where the cell engulfs the drug molecules dissolved in water
Pinocytosis
The transport of drugs from the plasma to the tissues
Distribution
Factors that affect distribution of drugs
Physiochemical properties Concentration gradient Plasma protein binding Blood Flow Tissue barrier Drug affinity to tissues
Acidic drugs bind mainly to
Albumin
Basic drugs bind mainly to
Alpha 1 - glycoproteins and lipoproteins
What drugs bind to globulin
Steroids
Plasma protein binding
Prolongs the half life of the drug
Plasma protein binding is generally
Reversible
The bound form of the drug is
Inactive, so it cannot be distributed, metabolized or excreted
The rate of binding depends
On the amount of the drug
Plasma protein binding can be modified by
Disease
Highly perfused tissues
brain, liver, kidney, endocrine glands
Moderately perfused tissues
Muscle, skin
Poorly perfused tissues
Bone, adipose tissue
The Blood Brain Barrier (BBB)
Tight capillary endothelial junctions Presence of glial cells Flow of the CSF into venous drainage Active transport mechanisms for extrusion of organic acids or bases
Factors that limit the BBB…
Age Inflammation Trauma Allergic Rxn Severe hypotension Hypoxia High doses of organic solvents (alcohol) Heavy metals
Name some Tissue Barriers
Brain Eye Testicles Placenta Mammary glands
Tetracycline has an affinity to
Calcium in skeletal tissues
Aminoglycosides have an affinity to
Kidney tissue
The thyroid gland traps
Iodine
The movement of the drug from the tissue to the blood
Redistribution
The chemical alteration of the drug molecule by the cells of the animal
Metabolism (biotransformation)
What are the changes in physiological properties of a drug as a result of biotransformation
The metabolite is more water soluble, polar and ionized
Changes in pharmacological activity as a result of biotransformation
Bioinactivation or detoxification (most drugs)
Bioactivation or lethal synthesis (few drugs)
Sites of Biotransformation
*LIVER
Smooth endoplasmic reticulum (microsomes)
Hepatocyte cytoplasm, mitochondria, lysosomes, nuclear envelope, plasma membrane
*OTHER TISSUES
nervous tissue, kidney, GI tract, lungs and skin
*PLASMA
Phase I reactions
Oxidation
Reduction
Hydrolysis
Phase II Reactions
Conjugation
Factors Altering Biotransformation
Species
Individual
Route of Administration
Enzyme Inducers
Distribution and Storage
Age
Sex
Diet and Nutrition
Liver Disease
Hepatic Blood Flow
Plasma Protein Binding
Body Temperature
Environmental Factors
Cats are deficient in…
glucuronyl transferases
hydroxylation
dealkylation
Dogs lack….
acetylating enzymes
Ruminants have _________________ than horses, dogs, and cats
less plasma pseudochoinesterases
What species have high levels of oxidative enzymes
Ruminants and horses
Species deficient in sulfate conjugating enzymes
pigs
Lacks oxidative enzymes
Birds
low levels of metabolizing enzymes
Fish
Enzyme inducers
Drugs that stimulate the liver to produce more metabolic enzymes
Ex: phenobarb, phenylbutazone, griseofulvin, rifampin
Enzyme inhibitors
Drugs that inhibit the liver to produce metabolic enzymes
Ex: chloramphenicol, cimetidine, ketoconazole
-may lead to drug drug interactions
Have less biotransformation then adults
newborns and geriatrics
T/F:
Charcoal broiled foods are enzyme inducers
TRUE
CYP1A
Grapefruit juice
Enzyme inhibitor (CYP3A)
Malnutrition and undernutrition
may decrease biotransformation
