Tox Definations

Question 1

Toxicology

Answer 1

Toxicology is the science of poisons (toxicants)- their physical and chemical properties, sources, toxicity, toxicokinetics, mechanisms of action, clinical signs, lesions, laboratory diagnosis, diagnosis, differential diagnosis and treatment (or prevention) of diseases caused by toxicants

Question 2

Poison/Toxicant

Answer 2

Poison/Toxicant; can be natural or synthetic

Question 3

Toxin (biotoxin):

Answer 3

Toxin (biotoxin): poison from a biologic process (e.g., zootoxins or animal toxins, phytotoxins or plant toxins, bacterial toxins and mycotoxins)

Question 4

Toxic:

Answer 4

Toxic: deleterious or undesirable effects of poisons

Question 5

Toxic: deleterious or undesirable effects of poisons

Answer 5

Toxic: deleterious or undesirable effects of poisons

Question 6

Toxicity:

Answer 6

Toxicity: amount of a poison that under certain circumstances will cause toxic effects –“heart and sole”

Question 7

LD50

Answer 7

• In mammals is usually expressed as LD50 (lethal dose fifty) in mg/kg body weight

Question 8

LC50

Answer 8

• In birds is expressed as LC50 (lethal concentration fifty) in mg/kg feed and in fish as LC50 in mg/liter water

Question 9

Acute toxicity -

Answer 9

Acute toxicity - effect of a single dose or multiple dose during a 24‐hour period

Question 10

Subacute toxicity -

Answer 10

Subacute toxicity - effect produced by daily exposure from one day to 30 days

Question 11

Subchronic toxicity

Answer 11

Subchronic toxicity- effect of exposure from 30 days to 90 days

Question 12

Chronic toxicity

Answer 12

Chronic toxicity - effect produced by daily exposure for a period of 3 months or more

Question 13

Chronocity factor

Answer 13

Chronocity factor- ratio between acute LD50 and chronic LD50
• the higher it is (>2), the toxicant is more toxic/cummulative with repeated exposure and a single exposure may not toxic
• if low (

Question 14

toxic dose low (TDL):

Answer 14

• toxic dose low (TDL): lowest dose which produces toxic alterations and administering twice this dose will not cause death

Question 15

toxic dose high (TDH):

Answer 15

• toxic dose high (TDH): toxic alterations and administering twice this dose will result in death

Question 16

No‐effect level (maximum non toxic level):

Answer 16

• No‐effect level (maximum non toxic level): 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 two years or more depending on the species), used for feed additi

Question 17

highest non toxic dose (HNTD)

Answer 17

Maximum tolerated dose or minimal toxic dose (MTD)

Question 18

LD0

Answer 18

highest dose that does not cause any death

Question 19

LD50

Answer 19

dose that kills 50% of animals in a group

Question 20

LD100

Answer 20

lowest dose that kills all the animals in a group

Question 21

TOXICOKINETICS-

Answer 21

TOXICOKINETICS- the study of absorption, distribution, biotransformation and excretion of toxic agents

Question 22

Importance of studying toxicokinetics

Answer 22

• Importance of studying toxicokinetics
o Knowing the routes of exposure
o Knowing distribution of the poison to target organs (sites of action) which will be manifested as clinical signs and lesion
♣ Ex. Lead is the only toxic metal that causes major issues..
o Knowing absorption (if local or systemic effects)
o Selection of proper specimens for chemical analysis
o Knowing the sites of storage
♣ Ex paraquat (sp?) gets stored in lungs, thus is in higher concentrations
o Elimination and the half‐life can be of some use in knowing withdrawal or quarantine periods due to excessive chemical residues in food‐producing animals

Question 23

xenobiotics

Answer 23

• Drugs and toxicants are xenobiotics (foreign chemicals)

Question 24

Drug Disposition

Answer 24

Drug Disposition – study of movement of drugs in the body across bio-membranes from the site of absorption until elimination

Question 25

Stages of Drug Disposition:

Answer 25

Stages of Drug Disposition: (1) Absorption (2) Distribution (3) Biotransformation (4) Excretion

Question 26

Absorption-

Answer 26

1. Absorption- transfer of the drug from the site of administration (ingestion > inhalation > mucous membranes>injection) to circulation a. Factors related to the drug i. Molecular size ii. Lipid solubility iii. Ionization- higher the ration b/w N/I, the greater the absorption iv. Dissolution in water v. Concentration vi. Route of Administration/Exposure 1. Sublinqual & inhalation= vary rapid > IM > SQ> Oral b. Factors related to the animal i. Blood Flow** 1. Heat or massage of the IM injection site increases blood flow and absorption 2. Sympathetic stim increases blood flow to skeletal muscles(β2) and decreases blood flow to GI tract and skin (α1) 3. Shock and edema decrease blood flow ii. Absorption Surface Area iii. Connective tissue iv. Species v. Individual c. Absorption from the GI tract i. The upper small intestines in the main site of absorption due to extensive surface area and blood flow ii. Rate of absorption depends on the rate of gastric emptying – can be changed by disease and drugs (atropine, morphine etc) iii. Oral absorption of solid drugs depends on the rate of dissolution (“slow release”, ”fast release” ) iv. Can be altered by activity, other substances (food decreases absorption, except if it is related to acidity- food increases acidity - ex. Ketoconazole) , blood flow, and species/individual differences

Question 27

Distribution-

Answer 27

1. Distribution- transport of drugs from the plasma to the tissues (site of action/storage/biotransformation) Factors Affecting Distribution: • Drug properties – lipid solubulity • Concentration gradient • Plasma protein binding- generally reversible, prolongs half-life, inactivates it, rate of binding depends on the amount of drug o Acid= albumin o Basic= glycoproteins & lipoproteins o Steroids= globulin • Blood flow – brain, liver, kidney, endocrine >> muscle , skin >> bone, adipose tissue • Tissue barriers o Brain (BBB)- tight endothelial junctions (prevent hydrophilic, not lipophilic), glial cells, CSF flushing, active transport of organic acids/bases ♣ Influenced by age, inflammation, trauma, allergies, hypotension, hypoxia, organic solvents (alcohol), heavy metals o Eye, Testicles, Placenta, Mammary glands • Affinity to certain tissues (Sequestation) o Tetracycline – to calcium in skeletam tissues o Iodine – thyroid o Aminoglycosides – kidney Redistribution- movement of drug from the tissue to the blood Ex. Thiopental vs. phenobarbital

Question 28

Passive Diffusion

Answer 28

1. Passive Diffusion- simple (if lipid soluable/hydrophobic- majority of drugs), transmembrane and paracellular a. Factors affecting simple diffusion i. Concentration Gradient – “dose” ii. Lipid solubility – measured by lipid partition coefficient (the ratio b/w solubility of drug in lipid to solubility in water) 1. The higher the lipid solubility, the faster the drug crosses cell membranes iii. Degree of ionization- drugs cross membranes in the NON-ionized form (=lipid soluble & no electrical charge) 1. Rate of diffusion depends on the ratio of non-ionized form of the drug to the ionized form (N/I) 2. Depends on pH & pK of the drug and the pH of the environment a. Acidic drugs ionize in alkaline medium & vice-versa b. Hendersan Hasselbalch = i. pK Acid= pH + log (N/I) (ANI) ii. pK Base = pH + log (I/N) (BIN) 3. Ex. Quaternary ammonia compounds such as d-tubocurarine are mostly ionized

Question 29

Facilitated Diffusion

Answer 29

1. Facilitated Diffusion- carrier mediated, no energy, downhill a. Ex. Glucose (insulin lowers K and glucose levels)

Question 30

Active Transport

Answer 30

1. Active Transport- requires energy, uphill, primary & secondary a. Characterized by saturability, selectivity and competitive inhibition by cotransporter compounds b. Ex. Active tubular secretion

Question 31

Pinocytosis-

Answer 31

1. Pinocytosis- engulf drug molecules dissolved in water | a. Ex. Aminoglycoside sequestration by the renal tubular cells – do not use with amphotericin

Question 32

Drug Metabolism

Answer 32

``` Drug Metabolism (Biotransformation) Chemical alteration of the drug molecule by the cells of the animals ```

Question 33

Results of Biotransformation

Answer 33

• Change in physiochemical properties of the drug o The metabolism is more water soluable, polar and ionized • Changes in pharmacological activity o Bioinactivation or detoxification (most drugs) o Bioactivation of lethal synthesis (few drugs) o Pro-drug (inactive) active

Question 34

Sites of Biotransformation

Answer 34

Sites of Biotransformation • Liver o Smooth ER (microsomes)= MAIN SITE o Hepatocyte cytoplasm, mitochondria, lysosomes, nuclear envelope, plasma membrane • Other tissues (the nervous tissue, kidney, GI, lungs, skin) • Plasma

Question 35

Hepatic Metabolism

Answer 35

Hepatic Metabolism • Enzymes lack specificity (ex. Cytochrome-P450, CYP P450, MFO) • Enzymatic reactions are saturable reactions • Drugs can compete on the same enzyme • Enzymes can be induced or inhibited by drugs • Microsomal enzymes cause oxidation, reduction, hydrolysis and conjugation to glucuronic acid

Question 36

Phase 1

Answer 36

• Oxidation o Microsomal – hydroxylation, deamination, dealkylation, desulfuration, sulfoxide formation o Non-microsomal – cytosol or mitochondria ♣ Alcohol and aldehyde dehydrogenase (ex. Ethanol to acetaldehyde) ♣ Xanthine oxidase (ex. Xanthine to uric acid) ♣ Tyrosine hydroxylase (ex. Tyrosine to dopa) ♣ Monoamine oxidase (ex. Metabolism of catecholamines and serotonin) o MOST COMMON biotransformation reaction **important!! ♣ High oxidative =insensitive (ruminants and horses) ♣ Low oxidative enzymes= sensitive (cats, birds) • Reduction o Microsomal (ex. Nitro reduction of chloramphenicol) o Non-microsomal (ex. Aldehyde reduction of chloral hydrate) ``` • Hydrolysis o Microsomal hydrolases o Non-microsomal hydrolases ♣ Esterases (ex. Acetylcholine, succinylcholine, procaine) ♣ Amidases (eg. Procainamide) ♣ Peptidases (eg. Proinsulin) ```

Question 37

Phase II Reaction (synthetic)

Answer 37

Phase II Reaction (synthetic) • Conjugation- combination of a drug or its metabolite with an endogenous substance o Occurs with foreign compounds and endogenous chemicals o Conjugation is to glucuronic acid, sulfuric acid, acetyl group, methyl group, glycine, methionine and glutathione o Conjugation to glucuronic acid is the most common conjugation reaction ♣ Glucuronidation is microsomal but all other conjugationare non-microsomal o Deficient in the neonates o Metabolite conjugates are usually inactive and water-soluble o Certain conjugation reactions may lead to formation of metabolites (acyl glucuronidation of NSAID) that are hepatotoxic ♣ NSAID approved in cats= Meloxicam