Tox- Intro

pbhati17's version from 2018-01-10 18:48

Intro to Tox

Question Answer
Defintion of Toxicology is?the study of the effects of poisons on the function of living systems (including ecotoxicity) (environment is a living system)... You need Knowledge about natural and man-made chemicals that are harmful for humans, animals and the environment
we need to understand _________ and _________ chemicals are toxicWhy and when
example of environmental toxivermectin- 70% admin oral will be in feces- ends up in environment-- caused near extinction of dung beetles (it is elim as active or not active <--depending on how much metabolism I assume) (another example is mercury in fish)
how diff doses can be toxic or not (graph pic)
What is clinical toxicology?toxicology dealing with patients. It is a Toxicological effect of a substance in the direct environment of the animal
(relating to clinical toxicology) 3 examples of Toxicological effects of substances in the direct environment of the animal(1) Medication (including accidental ingestion of (human) drugs) (2) Feed and feed contaminants (3) Contact materials and accidental exposure
In clinical veterinary practice, ___ are an important differential diagnosis intoxications
If you are just given a bunch of toxins, how do you know which one is most toxic? what is the measurement by which you can compare toxicities?need to know LD50s -- this is the basis of tox and pharm across the world. based on experiment in rats. However, you also need to keep in mind the exposure factor
What is LD50?INTERNET DEFINITION: The name LD50 is an abbreviation for "Lethal Dose, 50%" or median lethal dose. It is the amount of the substance required (usually per body weight) to kill 50% of the test population. WERNERS IN CLASS SAID: LD 50 is a SINGLE VALUE- given X to rats today. watched them die from X. acute toxic response to a certain compound, and LD50 is not a nice measure to look at tox (as in we are killing mice), so we doing less and less of LD50 tests. might look at inc in BP or renal tubule, sthing else to define toxic margin that isnt just LD50. also all about the shape of the it a steep or shallow response curve?
It's not only about which LD50 is higher, but another factor to consider steep the curve is (if it's super steep, it gets more toxic faster)
What is the #1 thing that causes toxicity in COMPANION animals? FOOD animals? What does this tell us?Tells us exposure varies between different types of groups. COMPANION: Parasite control (usually incorrect parasite control dose-- such as pyrethrins in cats). FOOD: Feed contamination
compare the kinds of things which are common toxicity problems in companion animals versus food animals?COMPANION: Parasite control, Accidental exposure, Household products, Drugs (human and veterinary), (human) Food material. FOOD ANIMAL: Feed contamination, Natural toxins (plant, mycotoxins, bacterial toxins, environmental pollutants), water contamination, Inhalation of gasses and vapors


Question Answer
Toxic effects can differ with what 4 major factors?(1) DOSE (2) ROUTE OF EXPOSURE (3) BETWEEN SPECIES (gender and age also a factor) (4) ACUTE VS CHRONIC exposure
what is the equation for intoxication?concentration (mg/kg b.w.) x duration of exposure (major parameters= concentration of dose and duration of exposure)
what are the 2 major parameters to determine intoxication?the conc of the dose and the duration of the exposure are the major parameters. [ Equation is: concentration (mg/kg b.w.) x duration of exposure]
there was a popular train of thought that the higher the dose, the more toxic something is, but that isn't always the case- what is an example where this isnt true?aminoglycosides- lower doses are more toxic. (high dose SID < low dose BID is more toxic)
What is the abbreviation for a therapeutic dose? Toxic effect dose? A lethal effect dose?Therapeutic EFFECTIVE DOSE (its effective as a useful drug)= ED50. Toxic= TD50. Lethal dose= LD50.
So you have substances X, Y, and Z. X has a LD50 of 1mg/kg. Y has a LD50 of 2mg/kg, and Z has a LD50 of 3mg/kg. Which is the most toxic substance?The one with the LOWEST DOSE to kill 50% of the test mice means it is the MOST toxic. So X is the most toxic substance.
explain how route of exposure affects the toxic effects of a drug?diff route of exposure, such as inhalation,SQ, IM, IV- determines conc in blood which distributes to tissues-determines conc in tissues
Garlic and onions are toxic in carnivores. explain the major toxic components and some of their effects.(1) Flavanoids- antioxidants and/or janus carcinogens (depending on tissue can be carniogenic or anticarcinogenic). (2) Alkenyl cysteine sulfoxides aka allicines, allyl sulfides, disulfides, trisulfides, tetrasulfides (3) N-propyl sulfoxides- inhibits glucose-6-phosphate dehydrogenase---> (a) Depletes glutathione(antioxidant) in erythrocytes --> hemolytic anemia and heinz body formation(oxidative damage) (b) (K's notes say:) Carnivores have less activity of glucose-6-phosphate dehydrogenase- butt can have effects on rumen microflora
Garlic and onions are toxic in carnivores. What is the exposure dose for Dogs? Cats? and what are the clinical signs of exposure?DOGS: 15-30 gram. CATS: 5 gr/kg b.w. (cats). CSs: gastroenteritis, abdominal pain, loss of appetite, depression, hemolysis, methemoglobinemia, brown discoloration of urine
Undesired effects or adverse side effects: depends on the primary objective of therapy. Can have desirable OR undesirable effects. two examples of this?(1) Diphenhydramine- histamine receptor antagonist. Was supposed to be allergy med, but since it crosses the BBB it has depressant effects on CNS-extrapyramidal system and would cause drowsiness. But that means it can be used as over the counter sleep remedy. (2) Aspirin can be used for its anti- inflammatory properties, but it also inhibits platelet function (and "thins" the blood) may be undesirable effect depending on therapy (did you want to just stop a headache? or are you trying to make the dog less hypercoagulable? Bad for sx but good for cardiac patients)


Question Answer
*What are Adverse Drug Reactions (ADRs)?ADRs are noxious or unintended responses occurring at therapeutic doses*****
What is a "type A" ADR (adverse drug reaction) and what are some examples of this?effects which are related to known pharmacology but are undesirable. These are common, dose-related effects and are predictable. Examples of this would be: Drowsiness from taking diphenhydramine for allergies, Hemmorrhage w/ anticoags, respiratory depression with opioids, sedation with anxiolytics
what is a "Type B" ADR (adverse drug reaction) and what are some examples of this?these are effects which are UNrelated to the known pharmacology of the drug and are rare, often unpredictable, and often idiosyncratic (idiosyncratic meaning it depends on individual sensitivity). Examples include: anaphylaxis with penicillins, allergic liver damage with halothane, bone marrow depression with chloramphenicol
how is penicillin G toxic?neurotoxic
how is enrofloxacin toxic?cartilage damage in young dogs and blindness in cats
how is moxidectin toxic?PGP or MRD-1 gene transports moxidectin out of the BBB. With some breeds (collies/collie-like breeds) a point mutation in this gene makes transporter inactive. Moxidectin effects gaba receptors--> coma
how is gentamycin toxic?damages inner ear, damages kidney (ototoxic, neurotoxic)
explain the precipitating events which lead to Hypersensitivity reactions with drugsMost chemicals and their metabolic products are too small to be recognised by the immune system. But the hapten (small chemical) COMBINED with an endogenous protein causes it to become a recognizable antigen. (MHC= surface proteins which recognize foreign molecules.)
what are different ways hypersensitivity reactions can manifest?can be involvement of many organ systems.. range from minor skin reactions to fatal anaphylactic reactions. The way there is a reaction often differs in different animal species.
what are some drugs which can cause CUTANEOUS hypersensitivity reactions?carbamazepine, hydralazine, lidocaine, penicillin, phenobarbital, phenytoin, procainamide, sulfamethoxazole, trimethoprim
what are some drugs which can cause HEPATIC hypersensitivity reactions?carbamazepine, co-trimazole, diclofenac, dihydralazine, halothane, phenytoin, reserpine, streptomycin
what are some drugs which can cause HEMATOLOGICAL hypersensitivity reactions?captopril, chlorpromazine, gentamycin, haloperidol, penicillin, rifampicin, sulphamethoxazole, sulphasalazine, valproic acid
what are some drugs which can cause SYSTEMIC ANAPHYLAXIS as a hypersensitivity reaction?Aspirin, cephalosporin, nitrofurantoin, penicillin, quinolone antibiotics, sulphametoxazole, suxamethonium, tetracycline, thiopental, trimethoprim, tubocurarine, vancomycin, vincristin
what is a type 1 hypersensitivity reaction?Mast cells w/ IgE Fc receptor bind hapten(on the endogenous protein)- release histamine (serotonin, leukotrienes) (classic allergic reaction)
What is a type 2 hypersensitivity reaction?Neutrophils, Macs, NK cells w/ IgG receptors- attack/bind hapten on HOST cell (cytotoxic hypersensitivity)
what is a type 3 hypersensitivity reaction?Neutrophils, Macs, NK cells w/ IgG receptors bind hapten on protein- mediate immune complex dz
what is a type 4 hypersensitivity reaction?T killer cells- bind hapten on host cell- delayed type hypersensitivity (cell mediated not Ab mediated for this type)
summary pic of all the hypersensitivity types


Question Answer
explain what a Idiosyncratic reaction is? What are two ways it can present? When does this usually occur? (example?)*****Genetically determined abnormal reactivity to a chemical. The response is qualitatively similar, but may take the form of: (1) extreme sensitivity to low doses. (2) extreme INsensitivity to high doses. These reactions Typically occur in the first 1-2 months of drug therapy. A good example is: carprofen in dogs --> idiosyncratic hepatotoxicity
explain the MECHANISM of Idiosyncratic reactions (pic included)Drug gets metabolized via liver- creates reactive metabolite- causes oxidative stress leading to necrosis and apoptosis- binds to protein- creates drug hapten- causes immune system response- humoral and t-cell mediated. FMO (enzyme) in liver-->fish odor dz. MPO (enzyme) in neutrophils.
idiosyncratic- Phenylbutazone- what is the resulting tox, what is the mechanism? who should you not use this in?Aplastic anemia due to Oxidation by peroxidases-- DO NOT USE IN CATS/DOGS
idiosyncratic- Fenbendazole- what is the resulting tox, when would you see a reaction? how common is this?Pancytopenia, bone marrow necrosis. RARE.
idiosyncratic- Flucytosine- what is the resulting tox, when would you see onset, what is the area seen? How do you help with this reaction?Skin eruptions, depigmentation and ulcerations. Onset after 2-6 weeks, affecting the mucocutaneous junctions. Discontinuation, supportive care.
idiosyncratic- Mitotane- what is the resulting tox, when do you see signs? how common?Hepatopathy, bone marrow necrosis. Seen after 1 month-- lesions are rare.
(these examples skipped in class) idiosyncratic- Griseofulvine- what is the resulting tox, what will you see and in who specifically? how can you help with this prob?Pancytopenia (or neutropenia in cats), Neutropenia in FIV cats, Use alternatives (not griseo)
idiosyncratic- Albendazole- what is the resulting tox, what is the mechanism? What can you do to help this?Bone marrow suppression in one cat (lol what). Mechanism unknown. Reversible with drug withdrawal
idiosyncratic- Meloxicam- what is the resulting tox, When would you see a reaction?Vasculitis with ulcers, vesicles and erosions within 2 days. Rare.
(these examples skipped in class) idiosyncratic- Sulphonamides- what is the resulting tox, what is the mechanism? What should you do?Hepatopathy, blood dyscrasia, skin eruptions. Oxidised hydroxyl amine metabolite (CYP450, MPO). Discontinue sulphonamide
(these examples skipped in class) idiosyncratic- Methimazole- what is the resulting tox, what is the mechanism? what should you do?Hepatopathy, blood dyscrasia, skin eruptions. N-methylthiourea metabolite (FMO) --> antibodies. Counsel owners, discontinue drug therapy
where is most of the FMO enzymes?liver
where are the MPO enzymes?neutrophils (leukocytes)
Tox can be immediate or delayed- it can be Rapid development of toxic effects after single administration, or occurrence after the lapse of some time. 3 examples?Asbestos toxicosis (delayed), Diethylstilbestrol- both delayed and acute?, Organophosphorus- delayed polyneuropathy
Reversible versus irreversible toxic effects- what does this often depend on?Depends on affected body system and it's ability to regenerate (liver versus CNS regeneration). Carcinogenic and teratogenic effects are usually considered irreversible
Local versus systemic toxicity--> How do local effects happen? What needs to happen for systemic effects to happen?Local effects: at the site of first contact (ingestion of caustic substances; inhalation of irritant material). Systemic effects: requires absorption and distribution from its entry point
things you should do for your tox diagnostic workup (3) What if you can't dx what is wrong?(1) History (do not believe everything!) (2) Exclusion of causes that may induce the same range of symptoms (differential diagnosis). (3) Analysis of feed, other materials, the environment, stomach content, body excretions (we can only measure what we know to look for though, and we can only measure what is present (so if it has been biotransformed we won't find it) ).... if you can't figure it out, Treat the patient first before you worry about the diagnostic uncertainties!!

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