Exam 1 Flashcards
Study of Movement of drugs in the body across biological membranes from the time of absorption until Elimination
Drug Disposition
Which one of the Following Procedures is Incorrect in Diagnostic Toxicology:
- Specimens should be taken free of Chemical Contamination or Debris
- Specimens shoud be Washed
- Animal and Tissue Specimens should be Frozen
2
*Specimens should NOT be Washed- Washing is a Dilution Step- It will Dilute the amount of Toxin in the Specimen
True/False: Most Toxicity Pathologies are Pathoneumonic for Specific Toxins/Poisons
False
*Most Clinical Signs/Pathologies are General to all Poisoning and not Specific to any Poison Agent
Which Rodenticide are Guinea Pigs Resistant to?
Bromethalin
*Guinea Pigs lack the Metabolic Enzymes
Six Factors that Affect Distribution of Drugs
Physiochemical Properties of the Drug (ex. Lipid Solubility)
Concentration Gradient
Plasma Protein Binding
Blood Flow
Tissue Barriers
Affinity of Drugs to Certain Tissues
The Acute LD50 of Cyanide is 2.3 mg/kg Body Weight. What Category of Toxicity does Cyanide Fall into?
Highly Toxic
*Toxicity is between 1-50 mg/kg
2-PAM is Contraindicated with ____ Toxicity as it can Potentially Increase the Carbamylation Process
Carbaryl (Sevin)
For a Drug to be Actively Secreted at the Renal Tubules, it has to be Water Soluble (Hydrophilic), Polar and ____
Ionized
*This is achieved by Biotransformation for Lipid Soluble, Non polar, Non Ionized Drugs
*Drugs that are Lipid Soluble, Non Polar and Non Ionized in the Renal Tubules, will be Passively Reabsorbed back to the Plasma, and NOT excreted
The Highest Dose that Does not cause any death
LD0
When Diluting a Solution from a Concentrated Stock Solution, the mL needed = _______ X The Volume Required in mL from the Stock
(% Required Diluted/ % in the Stock)
*mL Needed = (% Required Dilution/ % in the Stock) X Volume required in mL
1600g (1.6kg)
All of these are Correct about Drug Absorption, Except:
A. The Smaller Molecular Size the Faster the Absorption
B. The Greater the Lipid Solubility, the Greater the Absorption
C. The Lower the Ratio between N/I, The Greater the Absorption
D. Oral Absorption of Liquid Drugs is Faster than Solid Drugs
E. The Higher the Drug Concentration at Absorption Site, the Faster the Absorption
C. The lower the Ratio between N/I, The Greater the Absorption
*The HIGHER the Ratio between N/I, The Greater the Absorption
All of these are Correct about Drug Absorption, Except:
A. Increased Blood Flow, Increases Drug Absorption
B. Heat or Massage of intramuscular Injection site Increases Blood Flow and Absorption
C. Sympathetic Stimulation Decreases Blood Flow to Skeletal Muscles
D. Sympathetic Stimulation Decreases Blood Flow to the GI Tract and Skin
C.
*Sympathetic Stimulation Increases Blood Flow to Skeletal Muscle
True/False: Blood Flow, Species, and the Presence of Food and Chemicals in the GI Tract affects Drug Absorption from the GI Tract
True
Main Organ of Biotransformation (Drug Metabolism)
Liver
*Smooth Endoplastic Reticulum
High ____ Soluble Drugs are usually Metabolized First in the Liver
Lipid
Some Drugs are Eliminated Solely through Secretion, However most Drugs are Lipophilic and therefore Must go through the Two Step Process of Secretion and _______ before being Eliminated
Biotransformation
Drugs used in Vomitting Animals such as Dogs and Cats within 1-2 Hours from Ingestion of the Poison
Emetics
*Contraindicated in Unconscousness, Corrosives, Dehydration, Severely ill animals and Unknown Toxicants
True/False: There is No Specific Anidote for Pyrethrin/Pyrethroid Toxicity
True
*Treatment = Decontamination (Wash Skin) and Avoid Exacerbating the Toxicity
Cholecalciferol is a _____ Toxicosis
Vitamin D
Toxicity that is the Effect of Exposure from 30 days to 90 days
Subchronic Toxicity
True/False: In Amitraz Toxicity, if Flea and Tick Collar was Ingested the Treatment is to Induce Emesis and/or remove via Endoscopy
True
*Need to get the collar out of the patient
True/False: Cats are More Sensitive to Naphthalene Toxicity, but Dogs are more likely to Ingest
True
*Cats are more Sensitive but Dogs are more Susceptible- Dogs are far more likely to eat Mothballs
Water Soluble Alkaloid from Dried Leaves of Nicotiana Tabacum. Feeds can be contaminated with _____ Sulfate, which is used as a plant Insecticide. Animals gain Toxicity through Ingestion of Tobacco Products (Leaves, Cigarettes, Cigars)
Nicotine
Which Pathway is ACT and PTT Measuring?
ACT- Intrinsic
PTT- Intrinsic
PT- Extrinsic (Factor VII)
Three Factors affecting Simple Diffusion
Concentration Gradient
Lipid Solubility
Degree of Ionization
*Concentration Gradient- Drugs move across membranes from High Concentration to Low Concentration
*Ionization- Drugs cross Biological membranes in the NON- Ionized form
True/False: Certain Individuals may be Deficient or Lack certain Enzymes due to Genetic Differences
True
Organophosphates cause Irreversible Inhibition of Cholinesterases. What Three Pathologies Follow at Receptors?
First: Muscarinic Receptor Stimulation
Second: Nicotinic Receptor Stimulation
Last: Nicotinic Blockade
*Normally Patients will be Hyperstimulated, but as things progress you may see Nicotinic Blockade, if you are stimulating the Nerve continuously eventually it is going to Depolarize to the point that it can’t repolarize
C. Chlorinated Hydrocarbons
If Toxicity is Greater than ____, it is considered Relatively Harmless
15 g/kg
There are several Types of Organophosphates, Some have direct Acetylcholinesterase Activity while others have none and must be _____ before they become Active
Desulfurated
*Need to undergo Liver Metabolism, before they have Acethylchlinesterase Activity
Cholecalciferol is Mainly excreted in Bile/Feces, however can also be Excreted in ____ at Toxic Levels and can undergo Enterohepatic Recirculation
Milk
C. Cholinesterase Activity can be Tested for Either
*Carbamates do not Undergo Storage Activation or Lethal Synthesis
* Pralidoxime (2-PAM) is not an effective Treatment for Carbamates
Six Factors Related to the Drug that Affect Absorption
Molecular Size
Lipid Solubility
Degree of Ionization
Dissolution of Drug in Water
Concentration of Drug at Absorptive Site
Route of Administration
Organophosphates are Fairly _____, they are readily Absorbed from the GIT, Skin and Mucous Membranes and Well distributed throughout the Body, including the CNS
Lipophilic
Lab Findings for Which Rodenticide Toxicity:
Hypercalcemia
Hyperphosphatemia
Decreased PTH
Elevated serum Calcidiol (25-dihydroxyvitamin D)
Cholecalciferol
Any Substance when applied or introduced into the body may interfere with Life Processes or Biological Functions of the cells of the Animal
Poison (Toxicant)
True/False: Every Toxin is a Toxicant (Poison), but not every Toxicant (Poison) is a Toxin
True
*A Toxin is a Toxicant (Poison) from a Biological Source- Ex. Snake Venom. However Lead is a Toxicant, but not a Toxin
A Chronicity Factor greater than ____ indicates a Relatively Cumulative Toxicant
2.0
True/False: Most Toxicosis DO NOT have Pathognomonic Signs
True
*Most Poisonings have very similar Clinical Signs
Accuracy of Chemical Results depends on _____. Interpretation of Results should be done Carefully Considering other Evidence
Sampling
True/False: Cats are more Sensitive to Pyrethrins than Dogs
True
*Very Common in Small Animal Practice- Use of Canine “Spot On” Pyrethrin Products on Felines is a common Presenting Issue
True/False: Decontamination with Soap/Water and Symptomatic Treatment are the Only Treatments for DEET Toxicity
True
*DEET Generally has low Toxicity and Mild Signs
Anticoagulant Rodenticides are Odorless and Tasteless and Formulations are Resistant in the Environment for Weeks to Months. Anticoagulant Rodenticides have a ____ Onset of Action
Slow
*Will not see Clinical Signs for at least 24 Hours or Longer after Ingestion
*Onset of Clinical Signs takes 1-5 Days
Term used to Describe the Deleterious or Undesirable Effects of Poisons
Toxic
Four Treatment Principles of Toxicosis
Symptomatic (Supportive) Treatment- Respiratory and Cardiovascular
Removal of Poison
Specific (Antidotal) Treatment
Observation of the Acutely Poisoned Animal
Chlorinated Hydrocarbon Insecticides are HIGHLY _____, that leads to Bioaccumulation in the Food Chain
Lipophilic
*Toxin is Sequestered in Body Fat. If Herbivore has Toxin within its fat and it is Eaten by a Carnivore, the Toxin will now Sequester into the Carnivores Fat- Bioaccumulation
Rotenone is Considered an _____ and will cause Conjuctivitis, Congestion, Dermatitis, and GI Upset if Ingested
Irritant
Disease Caused by Exposure to a Poison
Toxicosis
Criteria of Diagnosis defined by Clinical Pathology and Chemical Analysis, where Positive Chemical Results Consistent with other Criteria my confirm a Diagnosis
Laboratory Diagnosis
*Chemical Analysis- Best way to Confirm a Diagnosis
*Should be done by qualified Toxicology Laboratory
*Negative Lab Results does not Eliminate the Possiblity of Toxicosis
Which Color Corresponds to the Intrinsic and Extrinsic Pathways?
Intrinsic- Yellow
Extrinsic- Blue
*Common Pathway is Green
True/False: If a Drug is Hydrophilic (Water Soluble), Polar, and Ionized it is entirely Excreted by Secretion without undergoing Biotransformation
True
*Biotransformation only occurs to Lipophilic, Non-Polar or Non-Ionized Drugs in order to Make the Drugs Hydrophilic, Polar and Ionized so that they can be Excreted
*In order to be excreted from the Body, a Drug must be Hydrophilic, Polar and Ionized- must be achieved by Drug Metabolism (Biotransformation)
When Sampling Feeds or Forage for Analysis, Green Forage or Silage should be _____ or Green Forage Dried. The Sample Size should be about a Quart or Kilogram
Frozen
*Samples should be Taken from different Bales and from different Parts of the Bale
The Biological ______ is composed of a Lipid Bilayer, where the Membrane Contains Membrane Proteins and Carbohydrates and the Cells are Seperated by Aqueous Pores and Junctions
Cell Membrane
Tachycardia
Toxicity due to a Single Dose or Multiple Doses during a 24-hour Period
Acute Toxicity
*One day Exposure
Fluid Therapy and Diuretics ____ Renal Excretion of drugs by Reducing the Time needed for Tubular Reabsorption
Enhance
*Decreasing the Transit Time of the drug through the Tubules, Enhances Drug Excretion
True/False: Specimens Submitted for Chemical Analysis in Diagnostic Toxicology should be accompanied with a Complete HIstory, Clinical Signs, Postmortem findings ect.
True
Of these Four Coagulation Parameters, which will Become Abnormal First with Anticoagulant Rodenticide Toxicity:
Activated Clotting Time (ACT)
Prothrombin Time (PT)
Activated Partial Thromboplastin Time (APTT)
Proteins Induced by Vitamin K Antagoists (PIVKA)
PIVKA
*In Anticoagulant Rodenticide Toxicity, PIVKA will Increase First
PIVKA, PT, PTT, ACT- Order in Which they begin to Increase
Second Most important Organ for Excretion of Drugs where Drugs may be Transported from the Cells to Bile or Blood by Passive Diffusion or Active Transport
Liver
*Hepatic Excretion
1 ppm = ______%
* 1 ppm = 0.0001%
*If you want to convert from ppm to percent, move the decimal 4 places to the Left. If you want to Convert from percent to ppm, move the decimal 4 places to the Right
90% of Steady-State Concentration is achieved in ____ Half Lives
3.3
*After 4 Half Lives, the Plasma Concentration is 93.75% of the eventual steady-state plasma concentration
*Steady State- Is the Plasma Concentration of Drug when the Maintenance Rate of Drug Administration is Equal to the Rate of Elimination
Anticoagulant Rodenticides are Most Commonly ingested by Pets, mainly Canines, as ______
Baits
*Most common Exposure is via Ingestion of Baits
Specimens from different Organs should be Packaged _____ in Clean Glass or Plastic Containers that can be tightly Sealed. Waterproof Ink should be used to ____ Specimens and should include the Owners Name, Animals Name and tissue of Specimens
Separately
Label
*Waterproof Labeling is Very Important!
The Volume of Fluid which would be Required to Contain the amount of drug in the body if it were uniformly Distributed, and the concentration in that fluid was equal to the concentration in the plasma
Apparent Volume of Distribution (Vd)
*Extent of Distribution is Measured by the Apparent Volume of Distribution (Vd)
Which of the Following is Correct about Sampling Forage:
A. Forage should be cut to a Length of 3 Inches
B. Sample Size should be a Quart or Kilogram
C. Forage or Silage should be Frozen or Dried
D. Samples should be Taken from Different Bales
E. Samples should be packaged Tightly and Sealed Airtight
D. All Letters should be Sealed in First Class Mail Envelope
All of the Above are Correct
The Rate of Tissue Perfusion relative to the Tissue Mass, that affects Distribution of Drugs
Blood Flow
*Higher Blood Flow = Higher Drug Distribution
*Lower Blood Flow = Lower Drug Distribution
*Highly Perfused Tissues- Brain, Liver, Kidneys and Endocrine Glands- will Recieve Higher Distribution of Drugs
If the Toxicity is ____ or Less it is considered Extremely Toxic
1 mg/kg
Plasma Protein Binding ______ Glomerular Filtration and Renal Drug Excretion
Decreases
*Only Unbound Drugs can be Filtered and are Eliminated at a Rate Equal to their Creatinine Clearance Rate
*If the Drug is Bound to Plasm Proteins, it cannot be Filtered
Equation to Calculate the Half Life of a Drug
*You need to Volume of Distribution and the Clearance in order to Calculate the Half Life
*Increasing the Volume of Distribution, prolongs the Half Life
*Increasing the Clearance, Decreases the Half Life
All Animals are Susceptible to Chlorinated Hydrocarbon Toxicity, but ____ are the Most Sensitive
Cats
With Chlorinated Hydrocarbon Toxicity, Brain Concentrations are Better Correlated with Toxicosis than _____ Concentrations, which do not Correlate with Severity of Clinical Signs
Fat
*Brain Concentrations will give a Better Indication of Toxicity than Fat
More than One Correct Answer!
Fresh, Whole Blood
Fresh Frozen Plasma
Cryoprecipitate (Concentrated Coagulation Factors)
*You need the Clotting Factors- Frozen Plasma, Stored Whole Blood, and Platelet Rich Plasma Do NOT have Clotting Factors
True/False: Ivermectin is Well Distributed in the Body, but Does NOT cross the BBB
True
*Kept out of CNS by Glycoprotein Efflux Pump
Weak Acidic or Weak Basic Drugs cross Biological Membranes in the _____ Form, while Charged Drugs can not Cross Biological Membranes
Nonionized
Insecticides that Work by Reversible Inhibition of Acetylcholinesterase
Carbamates
Type ___ Pyrethroids have a Greater Effect on Sodium Channels leading to More Potent Effects
2 (Alpha-Cyano Group)
Drug Molecular Charge affects Glomerular Filtration at the Kidney. Largely ____ Charged Molecules are Inhibited by the Proteins in the Capillary Wall leading to less Renal Drug Excretion
Negatively
Technique for Removal of Poison where the Link Between the Animal and the Sourse of Poisoning is Cut
Removal of Suspected Source of Poisoning
*Examples of Sources- Feed, Water, Pasture, Pesticides, Chemicals ect.
True/False: Alkalinization of Urine will Enhance Excretion of Nicotine
False
*ACIDIFICATION of Urine will Enhance Excretion of Nicotine
Overall, Pyrethrins and Pyrethroids have Low Toxicity to Mammals, However they are Very Toxic to ____ and some Birds
Fish
* Caution when Using around Fish Tanks/ Koi Ponds. A Dog Treated with Topical Pyrethrin that goes Swimming in your fish pond is a Source of Exposure
Drugs with a Molecular Weight less than ____ Dalton charged or uncharged are freely filtered through the glomerular membrane and Excreted Readily by the Kidney
7000 Dalton
Three Types of Metabolic Reactions that are Part of Phase I Reactions of Biotransformation
Oxidation
Reduction
Hydrolysis
*Most Common Type of Biotransformation Reaction- Oxidation- Most Drugs are Metabolized by Oxidation
500 ppm = ____%
0.05%
*Move decimal 4 places to the Left
Eliminiation of Most Drugs follows ____ order Kinetics, where the Rate of Removal of Drug from plasma is Proportional to the Concentration present at a given Time
First
*A Constant Percent of Drug is Eliminated per unit Time
Two Synergistic Compounds that are Added to Pyrethrins that will slow down the Metabolism and Increase the Toxicity of Pyrethrin in the Insect
Piperonyl Butoxide
MGK-264
*These Synergists Make the Insecticide Last Longer and Increases Toxicity to the Insect
*There appears to be a Greater Risk of Moderate/ Major Symptoms among those Exposed to Products Containing Pyrethrins and Piperonyl Butoxide than those exposed to Pyrethrins Alone
Insecticide that is Readily Absorbed via Inhalation or through Skin that reaches Peak Plasma concentrations within 5 Hours with a Elimination Half-life of Around 24 Hours
Amitraz
*Hangs around in the Body longer
Two Assumptions associated with Exposure of 7 mg/kg body weight of Chemically Sprayed Forage:
- Good Quality Pasture will produce app. __ gram green forage per square foot
- Grazing animals consume __% of their body weight green Forage
45 grams
3%
Specific type of Endocytosis where the cell Engulfs the drug molecules dissolved in Water
Pinocytosis
*Ex. Sequestration of Aminoglycoside Antibiotics by Renal tubular Cells
Active Tubular Secretion occurs in the Proximal Convoluted Tubule of the Kidney. The Convoluted Tubule has an Organic Anion System for Secretion of Organic Acids and an organic Cation System for Secretion of Organic Bases. Both Systems require energy which is provided by the _____ in the Basolateral Membrane
Sodium Pump
Insecticide that is very commonly used as an Endoparasiticide in Large Animals (Cattle, Swine, Sheep, and Horses) and is Labeled for Prevention of Heartworm in Dogs and Cats
Ivermectin
Insecticides that are Synthetic Analogs of Pyrethrins
Pyrethroid
*Pyrethroid = Synthetic
Pyrethrin = Natural
*Not a Big Distinction Clinically between the Two and are Often used Interchangably
A Poison (Toxicant) from a Biological Source, such as Plant or Bacterial Toxins
Toxin
*Poisons are also known as Toxicants. All Toxins are Poisons (Toxicant), but Not all Toxicants are Toxins
Insecticide that works by Blocking Oxidative Phosphorylation in the TCA Cycle preventing NADH From being Oxidized to NAD and thus Interfering with Production of ATP
Rotenone
*Strong Inhibitor of Electron Transport and Cell Respiration will be Inhibited
Main Clinical Sign of Ivermectin Toxicity
CNS Depression
*Stupor, Ataxia, Disorientation
B. No
*This is Hyperparathyroidism. PTH should be Decreased with Cholecalciferol Toxicity
True/False: Drugs can be Poisons and Poisons can be Drugs
True
*The Dose is the Difference- Treatment versus Toxicity
True/False: Charcoal is most effective when Given as soon as Ingestion of a Toxicant is suspected and can be Used as Multiple Doses in Toxicants that undergo Enterohepatic Circulation
True
Bromethalin is Metabolized by N-demethylation in the Liver to the More Toxic Metabolite, ______
Desmethylbromethalin
A _____ Test can be Run on Mothballs to See if they Contain Napththalene
Salt Solution
*Put Mothballs in Concentrated Salt Solution and the Naphthalene should Float
A. Weak Base
*Drugs are better absorbed in the NONIONIZED State. They will be Ionized in the Opposite Environment (Ex. Weak Acid in Alkalinized Enviornment) and NONIONIZED in the Same Enviornment (Ex. Weak Base in Alkalinized Enviornment)
*In an Alkalinized Enviornment, a Weak Base will be nonionized and therefore better absorbed
*A Weak Acid will be very Ionized in an Alkaline Enviornment
If a Canine Ingests a Preventative Flea and Tick Collar, which Toxicity will they most likely Develop?
Amitraz Toxicity
Emetic of Choice in Dogs that works by Activating Central Dopamine Receptors that can be Given IV, IM, SC, or instilled into the Conjunctival Sac
Apomorphine
*Commonly Administered into the Conjunctival Sac
*Antidote to Apomorphine = Naloxone
Most Common cause of Death in High Exposure cases of Organophosphate Toxicity
Respiratory Failure (Paralysis)
Which is Correct about Telephone Instructions to Clients for Treatment of Toxicosis:
A. Animal should be Isolated in a quiet Place to avoid Further Stress
B. In case of Topical Exposure, the skin and eyes should be Cleansed with Copious Amounts of Water or Shampoo
C. If Oral Toxicosis, Induce Emesis with 3% or Less Hydrogen Peroxide
All of the Above are Correct
*Hydrogen Peroxide must be 3% or Less Concentration
In Active Tubular Secretion, Drugs move ____ their Electrochemical Gradient
Against
Drug Eliminiation is Measured by _____ or Total Body Clearance
Half Life (T1/2)
*Half Life- Time Required for the Body to Eliminate one-Half of the Drug it contains
Specimens Submitted for Diagnostic Toxicology will be evaluated for Toxicants Qualitatively and ______. Specimens should be Representing, Avoiding Dilution, Contamination and Putrefaction
Quantitatevely
*If the Specimen undergoes Contamination or Putrefaction, that will affect the level of Toxin
True/False: The Source of Cholecalciferol Toxicosis is commonly by Ingestion of Pesticides for Control of Rats/Mice
True
True/False: Pyrethrins are Most Commonly used as Insecticidal “Spot On” Treatments for Cats
False
*Most Commonly Used as Insecticidal “Spot On” Treatments for Dogs
Pigs are Deficient in _____ Conjugating Enzymes
Sulfate
Main Clinical Sign of Chlorinated Hydrocarbon Toxicity is _____
CNS Stimulation
*Ex. Salivation, Vomiting, Tremors, Spastic Gait, Tonic-Clonic Seizures, Ect
1 ppm = ____mg/kg
* 1 ppm (Part per Million) = 1 mg/kg
1 kg = 1000 g
1 g = 1000 mg
1 ppb ( part per billion) = 1 ug/ kg
1 ppt ( part per trillion) = 1 ng/ kg
1 ppm = 1 ug/ g
*ug = Microgram
The Dose that causes death in any animal during the period of Observation
Lethal Dose
Anything that Increases Glomerular Filtration or Active Tubular Secretion will _____ Excretion of the Drug, while Anything that Increases Passive Tubular Reabsorption will _____ Excretion of the Drug
Increases
Decrease
*Excretion = (Glomerular Filtration + Active Tubular Secretion) - Tubular Reabsorption
_*_Reabsorption- the Drug is going back into the Body
Newborn and Geriatric Patients may have ____ Biotransformation than Adults
Less
*Not Producing as many Metabolic Enzymes
Four Factors affecting Glomerular Filtration of a Drug
Glomerular Filtration Rate (Blood Flow)
Molecular Size
Molecular Charge
Plasma Protein Binding
D. 4 Weeks (28 Days)
* If unknown Rodenticide, always treat at least 3-4 Weeks
True/False: D-Limonene is Treated by Decontamination (Shampoo with Mild Dish Soap) and Monitoring for Iatrogenic Hyperthermia
False
*Monitor for Iatrogenic Hypothermia
*I_n D-Limonene and Pyrethrins- Watch for Hypothermia- These Patients will be Hypotensive and Hypothermia will Prolong Metabolism of the Toxin_
Which Species is more Susceptible to Poisoning? (Dogs or Cats)
Dogs
*Cats are Sensitive about what they eat. Because of their Sensitivity, they are not very Susceptible to Toxicants
*Dogs are More Susceptible because they Have Low Sensitivity and will eat Anything
True/False: In Diagnostic Toxicology, Positive Results DO NOT always mean Intoxication
True!!!
*Positive Lab Results do NOT Gaurantee Toxicosis
*Negative Results do not always mean that Poisoning did not occur
Carrier-mediated Transport that Does Not Need Energy, where a drug moves across the membrane from High Concentration to Low Concentration at a Faster Rate
Facilitated Diffusion
*Transporters can Move Drugs from Outside the cell into the Cell or from Inside the Cell outside the Cell
Which Rodenticides Inhibit Vitamin K Epoxide Reductase , which Reduces Carboxylation and Activation of Precursors of Clotting Factors II, VII, IX, and X
Anticoagulant Rodenticides
Most common Type of Biotransformation Reaction in Phase II Drug Metabolism
Glucuronidation
*Conjugation to Glucuronic Acid
Technique for Removal of Poison using Precipitation, Adsorption, and Ion Trapping
Decreasing the Rate of Absorption
*Adsorption by use of Activated Charcoal is Very Commonly done
The Rate of Drug Elimination from the Body, by all Routes, Relative to the Concentration of Drug in Plasma
Total Body Clearance (ClB)
Examples of ______ Include:
- Active Drug (Aspirin) to Active Metabolite (Salicylic Acid)
- Inactive Drug to Active Metabolite
- Nontoxic Drug to Toxic Metabolite
Biotransformation
For Estimating Dosages when Exposure is based on Consumption of Green Forage that has been sprayed, Every Animal Ingests green Forage that has been sprayed by a chemical at a rate of 1 lb/ acre, will be approximately exposed to ___mg per Body Weight
7
* 1 lb of Chemical / acre = 7 mg/kg body weight Exposed
Criteria of Diagnosis that Includes both Gross and Microscopic Examinations, where Negative Results are as Good as Positive Results
Postmortem Findings
*The Presence or Absense of Postmortem Lesions are Important
True/False: Cholecalciferol can be excreted through Milk from the Mother to the Neonate
True
Which Drug is Given as a Treatment for Organophosphate Poisoning
Atropine
*Atropine will Antagonize the Muscarinic Signs
C. Hypothermia may Further Alter Sodium Channel Kinetics
*Hypothermia will Alter Sodium Channel Kinetics and can Prolong Clinical Signs. Hypothermia may also decrease Hepatic Bioactivation of the Drug.
*Patients are normally Hyperthermic due to Muscle Tremors
Three Categories of Chlorinated Hydrocarbons
Diphenyl Aliphatics- DDT
Aryl Hydrocarbons- Lindane
Cyclodienes- Aldrine/Toxaphene
A Large amount of Which Insecticide is Excreted in Feces of Horses and is a potential Source of Toxicity for Canines
Ivermectin
Carrier-Mediated Transport that Requires Energy, where a Drug moves across the Membrane from Low Concentration to High Concentration
Active Transport
*Low concentration to High concentration (Uphill)
Chlorinated Hydrocarbons are HIGHLY Lipophilic and are able to Persist in the Enviornment within Soil with a Half-Life between ______ Years
2-15 Years
*Chlorinated Hydrocarbons- Can Stay in Soil for VERY Long time and can Bioaccumulate in the Food Chain
True/False: There is No Specific Antidote for Chlorinated Hydrocarbons. Treatment is a Combination of Decontamination and Symptomatic Treatment
True
*Decontamination- Induce Emesis, Wash with Soap and Water
Symptomatic Treatment- Diazepam to Control Seizures/ Oxygenation
In Diagnostic Toxicology, Blood Samples should be _____ while other Body Fluids should be Frozen
Refrigerated
*We never Freeze Whole Blood- Whole Blood needs to be Refridgerated. All other Body Fluids can be Frozen
*Whole Blood needs to Be Refrigerated, while Serum, Plasma and Tissue have to be Frozen Immediately
True/False: Cats are more Sensitive to DEET Toxicity than Dogs
True
*Young Animals may be more Sensitive as well
Which of the Following is Incorrect about Transporting Specimen:
A. Liquids (Blood ect.) should be Shipped in Glass or Heavy Plastic Containers that can be Tightly Sealed
B. Tissue Specimen can be Transported in Ziplock Plastic Bags, Glass or Plastic Containers
C. Samples should be Wrapped Together for Mailing
C.
*Samples should be Wrapped Individually for Mailing
Insecticide that has Low and Incomplete Absorption from the GI Tract, and is Far More Toxic when Inhaled than when Ingested
Rotenone
*Well Absorbed via Gills in Fish- Inhalation- More toxic to Fish
An Acutely Poisoned Animal must be considered as an _____, where Control of Life Threatening Conditions should be the First Approach in this case
Emergency
*Most poisoning Cases are Acute
Match these Rodenticides to their Side Effects:
- Anticoagulant Rodenticides A. Hypercalcemia
- Cholecalciferol B. Bleeding
- Bromethalin C. Neurotoxicant
Anticoagulant Rodenticides- Bleeding
Cholecalciferol- Hypercalcemia
Bromethalin- Neurotoxicant
Insecticides that are Extracts of Pyrethrum Flowers and sometimes advertised as “Natural”
Pyrethrins
Insecticide that is Commonly Found in Flea and Tick Collars and as a Topical Therapy for Generalized Demodicosis. It is Particularly useful for Certain Mites and Ticks because it Paralyzes the Mouth Parts
Amitraz
*Not labelled for Cats or Horses
Factors Altering ______ include:
Species
Individual
Route of Administration
Enzyme Inducers/Inhibitors
Liver Disease
Hepatic Blood Flow
Biotransformation
Four Stages of Drug Disposition
Absorption
Distribution
Biotransformation
Excretion
Need a Diluted Solution of 500 ppm from a Stock Solution that is 1000 ppm and we need to make 500mL. How many mL of Stock Solution is needed?
250mL
*mL of Stock = (500ppm/1000ppm) x 500 mL
*Diluted Solution = 250 mL of Stock Solution and 250 mL of Water
Which Insecticide is commonly Combined with Other Insecticides in Pet Products and can Increase the Dermal Absorption of other Products, such as Pyrethrins, leading to a Higher Chance of Toxicity
DEET
*DEET is commonly Combined with other Insecticides, such as Pyrethroid, in Pet Products and will Increase the Absorption of the Other Product leading to a higher risk of Pyrethrin Toxicity
Calculation for Apparent Volume of Distribution (Vd)
*The Amount of Drug in the Body = the Dose IV
*For IV the Vd = Dose (mg/kg) / Plasma Drug Concentration (mg/L)
DEET Toxicity can lead to CNS _____, and Clinical Signs such as Hypersalivation, Vomiting, Tremors and Seizures
Excitation
Factors that _____ Anticoagulant Rodenticide Toxicity:
Vitamin K Deficiency
Liver Disease
Enzyme Inhibitors
Trauma/Surgery
Renal Insufficiency
Enhance
*Enzyme Inhibitors will Prevent Metabolism
Standard Measurement of Toxicity in Mammals
LD50
*Lethal Dose in 50% of the Population. AKA Median Lethal Dose (MLD)
*LD50 is a measure of Toxicity and therefore measured in mg/kg Body Weight
Which Two Diuretics are most commonly used to Enhance Drug Excretion in Poisoning
Mannitol
Furosemide
*Only use Diuretics if the Patient is Well Hydrated
True/False: Liver Disease, Kidney Disease, Age, Urine pH Modifiers, Fluid Therapy, Diuretics, and Plasma Protein Binding all Affect Renal Excretion
True
*Neonates don’t have a fully functional mechanisms of Excretion- Secretion is less in Neonates
*Diuretics can be used only if the animal is well Hydrated
Fat acts as a “Sink” for Chlorinated Hydrocarbons, where Redistribution occurs when Equilibrium is Reached. _____ can Disrupt Equilibrium and lead to Re-emerging Clinical Signs of Toxicity
Weight Loss
*If the Animal starts Loosing Weight/Fat, then suddenly there will be a Lot of Chemical in the Blood stream, leading to Re-emergence of Clinical Signs
Lesion Associated with Bromethalin Toxicity
Cerebral Edema
True/False: Hepatic Blood Flow, Plasma Protein Binding, Age, Sex, Diet and Nutrition all affect Biotransformation
True
273 g/ton
*100 g / ton = 110 ppm
Transport of Drugs from the Plasma to the Tissues (Site of Action, Site of Storage or Site of Biotransformation)
Distribution
Test where we Administer Atropine at 0.02mg/kg, where a Strong Response to a Low Dose of Atropine ( Mydriasis, Significant Increase in HR, and Dry Mouth within 15 MInutes) means is it LESS Likely to be Organophosphate Poisoning
Atropine Response Test
*Strong Response = Not Organophosphate Poisoning
True/False: The Higher the Lipid Solubility of the Drugs, the Faster the Drug crosses cell Membranes
True
*Simple Diffusion- Lipid Solubility is a Factor
______ of Toxicosis depends Mainly on History of Exposure, Clinical Signs and the Presence or Absence of Lesions
Diagnosis
Between Dogs and Cats, who is most Sensitive to Poisoning?
Cats
*Cats are More Sensitive to Poisoning because they are Deficient in many Oxidative Enzymes and Conjugation enzymes to Glucoronic Acid
*Large Animals are more Tolerant than Small Animals to Poisoning, and Dogs are More Tolerant than Cats to Poisoning
Insecticide that is Highly Toxic to Canines with Oral LD50 of 9.2 mg/kg and Clinical Signs Reported at 1mg/kg
Nicotine
*Very Toxic to Dogs- Ingestion of Cigarette, Cigar, Nicotine Patches ect.
The Chemical Alteration of the Drug Molecule by the Cells of the Animal
Drug Metabolism (Biotransformation)
Warfarin has an Acute LD50 of 1.6 and a 90-day LD50 of 0.077. Warfarin’s Chronicity Factor is 21.0. Is Warfarin a Cumulative Toxicant?
Yes
*Chronicity Factor is Greater than 2. Warfarin is Cumulative and therefore is Not Rapidly Excreted
*Warfarin is more likely to become Toxic if given More than Once. If only given once, it is not likely to be Toxic
Insecticide that at Low Doses Simulates Post Synaptic Nicotinic Receptors. At High Doses, Stimulation will be Followed by Nicotinic Blockage
Nicotine
True/False: Toxicity Values are influenced by Several Factors including Species, Breed, Age, Sex, Dosage and Duration of Exposure
True
B. It Delays Metabolism of the Drug in Insects
*Prolongs the presence of the Insecticide in the Insect
Naphthalene is Derived from Petrolium Hydrocarbons and will ____ at Room Temperature
Sublimate
*Sublimate- Go Directly from Solid to Gas Form- At Room temperature Naphthalene will turn into a Gas
True/False: Nutrition plays an important role in the Regulation of Drug Conjugations and Malnutrition and Undernutrition may Decrease Biotransformation
True
4.2 grams
*4200mg = 4.2 grams
True/False: Activated Charcoal is Considered a Universal Antedote for Toxocosis because it Adsorbs almost 99% of Chemicals
True
Renal Excretion of Nicotine is Decreased in ____ pH, and will Increase Re-absorption of the Nicotine back into the Body. Therefore, ____ Urine pH Enhances Excretion
Alkaline
Acidic
*Acidify the Urine to Enhance Urinary Excretion
Transfer of the Drug from the Site of Administration to the Circulation
Absorption
The LD50 of Urea is 0.45 g/kg Body Weight. What is the Toxicity of Urea?
Moderately Toxic
*0.45 g/kg Falls between 50-500 mg/kg
*(can also be written as 450 mg/kg)
1g = 1000 mg
*Side Note- In class Shokry said the Answer was Slightly Toxic, but In reality it is Borderline Slightly Toxic and Moderately Toxic
True/False: The Metabolites of Phase II Biotransformation (Conjugation) are usually Inactive, Water Soluble (Hydrophilic),
Polar and Ionized
True
*After Conjugation (Phase II), drugs will be Inactive, Hydrophilic, Polar and Ionized and therefore ready for Excretion
_____ Diagnosis may be Reached by using all Criteria of Diagnosis including Laboratory Work
Confirmed
D. Cats
Insecticides that Work by Delaying the Closure of Sodium Ion Channels in the Axonal Membrane of the Insect leading to a “Knockdown Effect” of Rapid Paralysis where the Insect is Immobile but not Dead
Pyrethrins/Pyrethroids
If we have a 5% Concentrated Stock Solution and we need to make
1 L 1%. How much mL is needed from the 5%?
200 mL
* (1%/5%) X 1000 mL
*1 L = 1000 mL
(Take 200 mL from the 5% Stock Solution and add 800 mL (to Equal 1000mL) and now we have 1000 mL of 1% Solution
True/False: D-Limonene is Lipid Soluble, Readily absorbed through GI and Skin Contanct and is Widely Distributed throughout the Body
True
____ Generation Anticoagulant Rodenticides are Less Potent and become Most Toxic when Ingested Daily for about a Week
First
*Ex. Warfarin
The needed Solution Dilution is 1:1000 and the Stock Solution is 1% and we Want to make 1 Quart, how many mL of Solution do we Need?
100mL
*To Change 1:1000 to a Percent:
(1/1000) x (X/100) = 0.1%
mL From Stock = (0.1% / 1%) x 1000mL
mL from Stock = 100 mL
Diluted Solution will be 100mL Stock and 900mL Water
*Side Note: 1 Quart = 1 L = 1000 mL
If Toxicity is Greater Than _____, it is considered Moderately Toxic
50-500 mg/kg
List the Four Vitamin K Dependant Factors
II (Prothrombin), VII, IX, X
True/False: Conjugation (Glucuronidation) is Deficient in Neonates
True
Five Criteria of Diagnosis
Case History
Clinical Signs
Postmortem Findings
Laboratory Diagnosis
Laboratory Animal Tests
Which Insecticides work by Slowing Sodium Influx and Inhibiting Potassium Efflux in Peripheral Nerves and Brain Leading to Partial Depolarization causing Repetitive Firing of Neurons (Stimulation)
Chlorinated Hydrocarbons
*Leads to Nervous System (CNS) Excitation
The Ratio Between Acute LD50 and Chronic LD50
Chronocity Factor
*When the Chronic Toxicity (90-day LD50) value is close to the Acute Toxicity (Acute LD50) Value, the Chemical is not Cumulative
*If the Acute Toxicity (Acute LD50) is much greater than the Chronic Toxicity (90-day LD50), then the chemical is Cumulative
B. Pituitary Dependent Hyperadrenocorticism
*o,p-DDD is the same as Mitotaine
Physiological Antidote for Treatment of Amitraz Toxicity
Yohimibine or Atipamezole
(Alpha 2 Antagonists)
Insecticide that Works as a GABA Agonist leading to CNS Depression
Ivermectin
*GABA- Inhibitory Neurotransmitter in CNS
Of the Vitamin K Factors (II, VII, IX, and X), which has the SHORTEST Half-Life?
VII
*PT measures Factor VII- PT will be Prolonged First (after PIVKA)!
PIVKA , PT, PTT, ACT
*You can Check PT in Clinic, but PIVKA must be sent out. Therefore PT is usually chosen for Testing first
C. Neurogenic Vasodilation
*KNOW FOR TEST
Which Two Organophosphates are More Lipophilic leading to More Sequestration in Fat and can stay in the Body Longer?
Dichlorvos
Chlorpyrifos
*Only two Organophosphates where you get Tissue Accumulation
Name the Two Types of Passive Diffusion. Which one is Hydrophilic and Which is Lipophilic?
Simple Diffusion (Lipophilic)
Transmembrane and Paracellular Movement (Aqueous Pores)
*If a Drug with Water Soluble (Hydrophilic) it will pass through the Aqueous Pores
*If a Drug is Lipophilic it will travel via Simple Diffusion
True/False: Sublingual and Inhalation have Very Rapid Drug Absorption Rates
True
Less Common Bromethalin Toxicity that is seen with a Supralethal Dose that leads to Muscle Tremors, Hyperexcitability, and Seizures
Acute
*Less Common- Poor Prognosis- Most likely Patient will Die
No
* 5% = 5g/100mL = 50mg/mL
5% (add a Zero to make it Mg/mL)
5mg% = 5mg/100mL = 5mg/dL = 5000 mcg/ dL
*We recommend it at a level of 5000 mcg/dL and we have a level of 900 mcg/dL, which is not High enough
Need a Diluted Solution of 500 ppm from a Stock Solution that is 1% and we need to make 1 Pint. How many mL of Stock Solution is needed?
25mL
*500 ppm = 0.05%
mL from Stock = (0.05% / 1%) x 500 mL
*Side Note: 1 Pint = 500 mL
In Diagnostic Toxicology, Positive Results may be helpful in Aiding Diagnosis, but ____ Results do not Eliminate the Possibility of Intoxication
Negative
With Carbamates, Laboratory Diagnosis of Cholinesterase Levels can produce _____ Results because Binding is Reversible and “Reactivation” of ACh can Occur during Transit
False Negative
*Need to Analyze the Sample VERY Fast before the Sample begins to Re-activate
Which of the Following is Correct for Obtaining a Serum Sample:
A. Use Clean, Dry Syringes, Needles or Tubes
B. Avoid Hemolysis of Sample by Avoiding Pressure/Shaking
C. Allow enough Time for Blood to Clot (1-2 hours)
D. Put Tubes with Blood in Oblique Position to Obtain more Serum
E. Obtain Serum by Centrifugation
F. All of the Above are Correct
F. All of the Above
Continued Exposure of Organosphosphates can lead to _____ due to Enzyme Induction, Functional Adaptation to Decrease Esterases and Adaptation of ACh Receptors to Excessive Amounts of ACh (Receptor Down Regulation)
Tolerance
Toxicity that is the effect produced by daily exposure for a period of 3 months or more
Chronic Toxicity
*Greater than 90 days
True/False: Physiological Factors (Ex. Exercise), Drugs and Disease can Alter Blood Flow and Drug Distribution
True
Results of ____ include Changes in Physiochemical Properties of the Drug where the Metabolite is more Water Soluble, Polar and Ionized
Biotransformation
100 g / ton = ____ ppm
110
C. Enterohepatic Recirculation
*Lipophilic Drugs in the Bile are Reabsorbed back into Circulation
Main Clinical Signs of Anticoagulant Rodenticides is _____
Hemorrhage
*If Rodenticide was the Cause of Death, then Hemorrhage should be found Somewhere
Organophosphates cause Muscarinic, Nicotinic, and CNS stimulation. What are some Clinical Signs you would Expect the Patient to Present with?
Muscarinic- DUMBELS
Nicotinic- Tremors, Twitching, Spasms
CNS- Anxiety, Hyperactivity, Tonic-clonic Seizures
*These are the Most common Clinical Signs to see in Patients with Organophosphate Toxicity- Mainly Tremors!!!
Tetracyclines to the Calcium in Skeletal Tissues, Aminoglycosides to Kidney Tissue and Trapping of Iodine by the Thyroid Gland are examples of ____ of Drugs to Certain Tissues
Affinity
The Movement of the Drug from the Tissues to the Blood
Redistribution
Common Clinical Signs of Which Rodenticide:
PU/PD
GI Bleeding (Hematomesis/Melena)
Depression/ Muscle Twitching
Cholecalciferol
*PU/PD- VERY Common due to Hypercalcemia and Renal Damage (Soft Tissue Mineralization)
Which Toxicity is characterized by these Clinical Signs:
Ataxia/Weakness
Paralysis
CNS Depression
Hypotension
Patient Smells like Lemons
D-Limonene
*Hypotension caused by Vasodilation
True/False: Bromethalin creates Bait Shyness
False
*No Bait Shyness with Bromethalin. Ingestion of the Bait is the main source of Bromethalin Toxicosis
True/False: Metabolites of Phase I Biotransformation are More or Less Water Soluble, Inactive, less Active, or More Active
True
Nicotine is Absorbed Well by Inhalation and from Intact Skin, but poorly via Ingestion. However, _____ of the Stomach will Increase Absorption
Alkalinization
*Nicotine is a Weak Base and will be Nonionized in Alkaline enviornments
Irritating Insecticide whose Oxidation Products causes Methemoglobinemia and Hemolysis leading to Tissue Hypoxia
Naphthalene
*Blood will be a Brown Color
Hepatic Enzymes responsible for Drug Metabolism Lack _____. These Microsomal Enzymes cause Oxidation, Reduction, Hydrolysis, and Conjugation to Glucoronic Acid
Specificity
4 mg/kg
Main Treatment for Cholecalciferol Toxicity
Decontamination
*Emesis, Activated Charcoal- Repeated Doses
Technique for Removal of Poison that uses Fluid Therapy, Diuretics, Urine pH Modifiers, Peritoneal Dialysis, and Hemodialysis
Enhancing Elimination
Drugs may be Transported from the Hepatic Cells to ____ or Blood by Passive diffusion or Active Transport
Bile
*Lipophilic Drugs in Bile will Undergo Enterohepatic Recycling and Pro-long the Half Life of the Drug
*Drugs are excreted in Bile either Unchanged or as Glucuronides. Acidic, Basic and Neutral Drugs can be excreted in bile by Active Transport
Two Specific Treatments for Naphthalene Toxicity used to Treat Methemoglobinuria
Ascorbic Acid
Methylene Blue 1%
*Neither of these Work very Well
Henderson and Hasselbalch Equations for an Acid and Base
*Drugs cross Biological Membranes in the Non-Ionized Form. The Rate of Diffusion depends on the Ratio between the Non-Ionized form of the Drug to the Ionized Form (N/I)
*The Higher the pka of a weak Acid, the Higher the N/I
*The Lower the pka of a weak Base, the Higher the N/I
*The Higher the N/I = more Drug crossing Membrane
Second Generation Anticoagulant Rodenticides have ____ Half-Lives, compared to First Generation.
Long
*Warfarin is a First Generation with a Half Life of only 19 Hours. Diphenadione and Brodifacoum are Second Generation with Half Lives of 4.5 and 6 Days
Syndrome that is Associated with Cats and the More Lipophilic Agents due to Chronic Exposure to Organophosphates. This Syndrome is Characterized by No Muscarinic Signs but a Wide Range of Muscle Fasciculations and CNS Signs
Intermediate Syndrome
One of the Oldest Botanical Insecticides that is used in Home/Garden, Lice/Tick Treament for Pets and Horses as well as Mites on Chickens
Rotenone
*Used in Fish Research- Restricted Substance
The _____ the pka of a Weak Acid, the Greater the N/I, and the _____ the pka of a Weak Base, the Greater the N/I
Higher
Lower
Name the Treatments for Each Anticoagulant Rodenticide Toxicity:
A. Exposure/Normal Coagulation Panel
B. Exposure/ Prolonged Coagulation Factors
C. Bleeding/ PCV > 15-20%
D. Bleeding/PCV
A. Exposure/Normal Coagulation Panel - Decontamination/ Start Vitamin K
B. Exposure/ Prolonged Coagulation- Vitamin K/ Consider Giving Clotting Factors
C. Bleeding/ PCV > 15-20% - Vitamin K/ Give Clotting Factors/ Consider giving RBCs (Fresh Whole Blood)
D. Bleeding/PCV - Vitamin K/ Give Clotting Factors and Fresh Whole Blood
Level in Feed (ppm) = (_____) / (% of Feed consumed Daily)
Toxicity (mg/kg)
True/False: Microsomal Enzyme Inducers Increase Toxicity of Drugs that are Bioactivated into Toxic Metabolites
False
*Microsomal Enzyme Inducers Decrease Toxicity of Drugs whose Metabolites are Toxic
Organophospohates that Require Desulfuration in the Liver will be Activated by Liver Metabolism, known as _____
Lethal Synthesis
*Less Toxic Substance being Metabolized into a More Toxic Substance
Phase II Biotransformation Reaction where a Combination of a Drug or its Metabolite is Mixed with an Endogenous Substance most commonly Resulting in Glucuronic Acid
Conjugation
*Conjugation to Glucuronic Acid is the most Common Conjugation Reaction
Which of the Following about Anticoagulant Rodenticides is Incorrect:
A. Largely Bound to Plasma Proteins
B. Slow Onset of Action ( >24 Hours before Clinical Signs)
C. Achieves High Concentrations in the Liver
D. Crosses the Placenta and Excreted in Milk
E. All the Above are Correct
E. All the Above are Correct
0.03mL
*1% = 10mg/mL
300mcg = 0.03mg
Most common Type of Biotransformation Reaction in Phase I Drug Metabolism
Oxidation
The Movement of Glucose across a muscle cell membrane by Insulin-Sensitive Glucose Transporter is an Example of ____ Diffusion
Facilitated
The Extent of Absorption is Measured by Systemic Bioavailability (F%). What is the Equation to Calculate Systemic Bioavailability?
*Systemic Bioavailability- the Fraction of the Dose which reaches the Systemic Circulation Intact
*AUC- Area under the plasma concentration-time curve
If Toxicity is is Greater than ____, it is considered Practically Nontoxic
5-15 g/kg
Insecticide that is Very Toxic to Fish and Cold Blooded Animals, with a Generally Low Toxicity for Mammals
Rotenone
*In Fish/Insects it is converted to Highly Toxic Metabolites, while in Mammals it is generally Converted to Non-Toxic Metabolites
The amount of a Poison in mg/kg Body Weight that under certain circumstances will cause Toxic Effects
Toxicity (Expressed in mg/kg Body Weight)
*Toxicity = Amount. Must be a Numerical Number
The Danger from the Possibility of Exposure
Hazard (Risk)
*A Poison may be Highly Toxic but not Hazardous. Hazard has to do with the Exposure Rate. Ex. A Fish Toxin is Highly Toxic but has a Low Hazard. Ex. Aspirin has a Lower Toxicity but is Very Hazardous
*Risk (aka Hazard) is defined by a Comparison of Toxicity and use Level
The Lowest Dose which Produces Toxic Alterations and Administering Twice this Dose will not Cause Death
Toxic Dose Low (TDL)
Orally Administered Non Absorbed Drugs and Drugs excreted in Bile that are Not Reabsorbed are excreted in _____
Feces
A. Alteration of Neuronal Sodium Channels
Drug _____ depends on the Ratio between the Uncharged (Nonionized) and Charged (Ionized) Drug
Diffusion
Rodenticide that Produces Changes Mainly in the Spinal Cord and Brain, leading to Alterations in Fluid Movement and Cerebral Edema
Bromethalin
Passive tubular Reabsorption occurs in the Proximal and Distal Convoluted Tubules for _____ Forms of Weak Acids and Weak Bases
Nonionized
D. Irreversible Inhibition of Acetylcholinesterase
*Acetylcholine gets released and is normally Broken Down by Acetylcholinesterase. Acetylcholine Increases because it is not being Broken Down
A. GI Bleeding
If Organophosphate Toxicity eventually leads to Nicotinic Blockade, what are some Clinical Signs you will see?
Nicotinic Blockade- Paralysis, CNS Depression, Coma, Dsypnea
*Usually leads to Death causd by Respiratory Failure
Volatile Compounds, such as Inhalation Anesthetics are mainly Excreted via _____
Expired Air
Symptomatic (Supportive) Treatment of Toxicosis can be Cardiovascular, where Adequate Circulatory Volume is Provided by Blood Transfusion or ____ Therapy depending on Hypovolemia
Fluid Therapy
*Fluid Therapy is very commonly Given in Patients with Toxicosis
_______ is Microsomal, but all other Conjugations are Nonmicrosomal
Glucuronidation
Chlorinated Hydrocarbon Metabolites are Lipophilic in Bile, and can be Reabsorbed via ______
Enterohepatic Recycling
The Blood-Brain Barrier Functions by Tight ____ endothelial Junctions, Glial Cells, and Active Transport Mechanisms for Extrustion of Organic Acids and Bases
Capillary
Water Soluble, Ionized and ____ Drugs are Excreted in Urine
Polar
True/False: Anticoagulant Rodenticides can lead to Relay (Secondary) Toxicosis in Swine, Dogs and Cats who eat Rats/Mice that have Ingested the Toxin
True
Bromethalin is Highly Lipophilic and Widely Distributed in the Body, with Highest Concentrations in the Fat and ____
Brain
*Bromethalin will get into the Brain
Insecticide that works as an Alpha-2 Adrenergic Agonist in the CNS
Amitraz
Muscle Relaxant Drug that is used to Treat the Fine Muscle Tremors assocaited with Pyrethrins Toxicity
Methocarbamol
90 ppm is High Enough to Cause Toxicity
Hepatic Blood Flow may be Decreased due to Liver Disease or Drugs resulting in ___ Biotransformation
Decreased
With Amitraz Toxicity, the most common Clinical Sign is _____ and may Last for 24-72 Hours
Transient Sedation
*Massive Exposure to Amitraz can Cause Cardiovascular Collapse and Respiratory Failure. However, Most Patients Only experience Transient Sedation for a Short period of Time and then are Fine
Emetic Drug of Choice in Cats that is an Alpha 2 Agonist which is Administered IV but causes CNS Depression for Several Hours
Xylazine
Cholecalciferol Causes ____ and Hyperphosphatemia due to:
Increased Calcium GI Absorption
Decreased Calcium Renal Excretion
Hypercalcemia
*Massive Overdose of Vitamin D
*When Calcium Levels Rise enough it will cause Mineralization of Soft Tissues leading to Tissue Damage and Renal Ischemia
True/False: Ruminants and Horses have High Levels of Oxidative enzymes and are Less Likely to get Drug Toxicity
True
*The More Oxidative Enzymes the Animal Has, the Less Likely to become Poisoned/Toxic
*Side Note- Birds, Fish, and Reptiles are very Deficient in Oxidative Enzymes and therefore are more likely to get Drug Toxicity. Birds Lack Oxidative Enzymes
Technique for Reducing the Amount of Toxicant Absorbed where Activated Charcoal physically Binds to the Toxicant
Adsorption
*Charcoal is not very effective against Ammonia, Cyanide, Heavy Metal Salts ect.
Insecticides that are Subject to “Storage Activation” where if they are Sealed and Stored for 1-2 Years they can become More Toxic
Organophosphates
Later Synthesized Carbamate that Mimics the structure of Acetylcholine and is the most Toxic of the Carbamates
Aldicarb
B. PT
*PIVKA will not be available in the clinic, therefore, PT is the Best
Insecticide that is a Common Insect Repellant used for Control of Mosquitoes, Flies and Ticks that is found in Products such as “Off”
DEET
*Concentration of DEET can range from 5% to 100%, but generally less than 10% in those marketed for pets
____ Generation Synthetic Pyrethrins do Not Contain an Alpha-Cyano Moiety, while _____ Generation Synthetic Pyrethrins Do contain the Alpha-Cyano Moeity which Increases their Insecticidal Potency
First Generation (Type I)- Do NOT
Second Generation (Type 2)- Does
Most Common Source of Naphthalene Toxicity is Ingestion of _____
Mothballs
*Old Fashon Mothballs contain Naphthalene
Increasing Renal _____, Increases GFR and Leads to More Renal Drug Excretion
Blood Flow
Increasing Renal Blood Flow = Increasing Drug Excretion
Decreasing Renal Blood Flow = Decreasing Drug Excretion
*In Renal Failure and Heart Failure Patients, you get Decreased Renal Blood Flow, and Decreased Renal Drug Excretion
The ____ of a drug is the pH at which a weak electrolyte is 50% Ionized and 50% Non Ionized
pKa
*Acidic Drugs Ionize in Alkaline Mediums and Basic Drugs Ionize in Acidic Mediums
Treatment for Nicotine Toxicosis Includes Inducing Emesis and Activated Charcoal. However ____ should be Avoided because it would Increase Absorption and Reduce Excretion of Nicotine
Antacids
*Avoid Antacids in Nicotine Treatment
Clinical Signs associated with the Initial Signs of Muscarinic Stimulation from Organophosphate Poisoning
(DUMBELS)
D- Diarrhea
U- Urination
M- Myosis
B- Bronchoconstriction and Bradycardia
E- Emesis
L- Lacrimation
S- Salivation
Alkanization of the Urine pH by IV Sodium Bicarbonate Enhances Renal Excretion of Weak ____ drugs such as Aspirin or Phenobarbital
Acidic
*Use IV Sodium Bicarbonate
Syndrome that occurs after Surviving Acute Organophosphate Poisoning characterized by signs of Muscle Weakness, Ataxia and Rear Limb Paralysis
Delayed Polyneuropathy
*Occurs 10-14 Days after Exposure. Chickens are the Most sensitive to this effect!!!
Mainstay of Treatment for Anticoagulant Rodenticide Toxicity
Vitamin K1
*Oral Route Recommended- Do not give IV
*Vitamin K1 Does NOT stop Bleeding, it just Enhances Coagulation Factors
C. Known Enterohepatic Recirculation
True/False: While Drugs and Poisons have the same Principles for Pharmacokinetics, they are different because Poisons are always reversible, while Drugs can be Reversible or Irreversible
False
*Drugs should always be Reversible, while Poisons can be Reversible or Irreversible
True/False: If Mammals are Exposed to a High enough Dose of Pyrethrins to Show Clinical Sings, the Signs Include Generalized Muscle Tremors, Depression, Blindess, and Progressive Seizures
True
*Predominant Sign- Fine Muscle Tremors
Organophosphates that Undergo Lethal Synthesis in the Liver will be _____ Toxic to Young Patients and ____ Toxic if Enzyme Inducers are Present
Less
More
*Young Animals- Liver Metabolism isn’t completely Developed
Standard Measurement of Drug Efficiency/ Therapeutic Dose in Mammals
ED50
*Effective Dose in 50% of the Population. AKA Median Effective Dose (MED)
Which of the Following Are used as Treatments for Cardiovascular Issues with Toxicosis:
A. Cardiac Stimulants - Atropine/ 10% Calcium Gluconate
B. Hypotension- Fluid Therapy
C. Acidosis- IV Sodium Bicarbonate/ Lactated Ringers
D. Alkalosis- IV Normal Saline/ Ammonium Chloride
E. Pain- Opioids
All of the Above are Correct
*All of these are used as Cardiovascular Treatments for Patients with Toxicosis
B. Alkalinize the Urine (Bicarbonate)
True/False: Most Toxic Diagnosis are Generally made based on History of Exposure, Appropriate Clinical Signs and Ruling out other Causes
True
*Most Poisons don’t have Pathonumonic Lesions or Clinical Signs
Significant _____ Recycling prolongs the Half-Life of the Drug
Enterohepatic
*Conjugates of Lipophilic Compounds excreted in Bile can be Hydrolized in the Intestine to Lipid Soluble Free Drugs that can be Reabsorbed via Enterohepatic Circulation
Once Nicotine is Absorbed, it is well Distributed, Metabolized in the Liver and Excreted in ____ and Urine
Bile
*Half Life of 2 Hours
Which Breed of Dog classically gets Ivermectin Toxicity?
Collies
*MDR1 Gene Mutation
_____ Gene Mutation encodes the P-Glycoprotein which is a Component of the Blood Brain Barrier. Deletion Mutation of this Gene Results in 50x’s the concentration of Certain Drugs (Ivermectin) in the CNS
MDR1
(aka ABCB1)
*Collies lack the MDR1 Gene- Never use Ivermectin
Criteria of Diagnosis characterized by:
Looking for Evidence
Relying on Information Provided by the Owner
Making Sure the Animal has Ingested/Been Exposed to the Poison
Case History
*Most Important Criteria in Diagnosing Toxicosis
If Toxicity is Greater Than _____, it is considered Highly Toxic
1-50 mg/kg
Removal or Clearance of the Drug from the Body
Excretion
_____ Diagnosis can be Reached when the History and Clinical Signs are Supported by Circumstantial Evidence and Identification of the Source of Poisoning
Presumptive
The Highest or Largest Dose which does not Result in Undesirable or Toxic Alterations
Maximum Tolerated Dose (MTD)
*AKA Minimal Toxic Dose
*This Dose is between the Effective Dose Range and the Toxic Dose Range
______ Generation Anticoagulant Rodenticides are More Potent and are Toxic after One Dose
Second
*Ex. Brodifacoum and Diphacinone
727 g
_____ Diagnosis of Toxicosis can be Obtained by detailed Case History and through Clinical and Postmortem Examinations
Tentative
Symptomatic (Supportive) Treatment of Toxicosis where Patients recieve a Tracheostomay under Anesthesia or Cuffed Endotracheal Tube in Unconscious Animals where Artificial Respiration is Provided using Respirators or even an Anesthetic Machine
Respiration Treatment
*AKA Life Support
The Vd of Penicillin is 0.2-0.3 L/kg. How is Penicillin Distributed in the Body?
Limited Distribution
*Tends to Stay in the Plasma
Insecticide that is used in OTC Products, usually Shampoos, for Control of Lice, Fleas, Ticks and more Recently is becoming available as Essential Oils
D-Limonene
*Toxic to the Flea at all life stages- Dries them out and Kills them
True/False: Plasma Protein Binding Increases Drug Biotransformation
False
*Decreases- not as much Drug getting to the Liver
Which of the Following is NOT a Treatment for Organophosphate Toxicity:
A. Induce Emesis if Recent, NOT if Depressed or Seizuring
B. Wash Gently with Soapy Water if Dermal Exposure
C. Activated Charcoal
D. Oxygen and Fluids
E. All the Above are Acceptable Treatments
E. All the Above
When Testing for Anticoagulant Rodenticides we are going to be Testing for _____ of Coagulation Parameters, Including:
Activated Clotting Time (ACT)
Prothrombin Time (PT)
Activated Partial Thromboplastin Time (APTT)
Proteins Induced by Vitamin K Antagoists (PIVKA)
Prolongation
Drugs, such as Chloramphenicol, that Inhibit the Liver to Produce Metabolic Enzymes that may lead to Drug-Drug Interactions
Microsomal Enzyme Inhibitors
Accurate and Confirmed _____ is the most important Aspect in dealing with Toxicosis
Diagnosis
*Specific Treatment and Prevention is based on Accurate Diagnosis
Specific Antedote for Organophosphates that is a Cholinesterase Reactivating Oxime
2-PAM (Pralidoxime, Protopam)
*2-PAM binds to the Organophosphate and causes a molecular Change which releases it from the Acetylcholinesterase, so that it can go back to breaking down Acetylcholine
*Aging- if the Organophosphate has been bound to Acetylcholinesterase for a long time (>24 Hours), it will undergo aging and now the Bond is so Strong that even the 2-PAM cannot pull it off
What is the Difference between Plasma and Serum
Plasma Contains Proteins
Serum DOES NOT contain Proteins
*Don’t use Anti-coagulant to get Serum. You use Anti-coagulant (Heparin) to Collect Plasma
Metabolic Reaction that is considered a Phase II Reaction of Biotransformation
Conjugation
Criteria of Diagnosis characterized as Administration of Susptected Material (Food or Water) to a Susceptible Animal and Observing its effects that is usually done by the Toxicology Laboratory
Laboratory Animal Tests
*Normally Food or Water Testing
True/False: Carbamates Undergo “Storage Activation” and Require Hepatic Bioactivation
False
* C_arbamates DO NOT undergo Storage Activation and DO NOT Require Hepatic Bioactivation_
_*_No Hepatic Bioactivation- Thus Carbamates are more Toxic than some Organophosphates in very young patients
Which Rodencitide works by Uncoupling of Oxidative Phosphorylation that Reduces ATP Production leading to Insufficient Energy for Na+/K+ Ion Pumps
Bromethalin
Weak Acids are more Ionized in an ____ Medium, and Weak Bases are more Ionized in an_____ Medium
Weak Acids- Alkaline Medium
Weak Bases- Acidic Medium
Predominant way that Drugs cross Cell Membranes
Simple Diffusion
*Most Drugs are Lipophilic
Two Main Clinical Signs associated with Nicotine Toxicity
Tremors and Convulsions
*Within 1 Hour of Exposure
*May also see Ataxia, Hypersalivation, and Vomiting
*Later (At Higher Doses) you may see CNS Depression, Paralysis
True/False: Activated Charcoal is a Common Treatment for Pyrethrin/Pyrethroid Toxicity
False
*Activated Charcoal is Generally Not used- Pyrethroid/Pyrethins are so Rapidly absorbed and Metabolized, the Activated Charcoal does not make a Difference
If Toxicity is Greater Than _____, it is considered Slightly Toxic
0.5-5 g/kg
Clinical Signs associated with What Insecticide Poisoning:
Mothball Breath
Salivation/Vomiting
Hemolysis
Heinz Bodies
Methemoglobinemia
Naphthalene
Caffine has an Acute LD50 of 192.0 and a 90-day LD50 of 150. The Chronicity Factor is 1.3. Is Caffine a Cumulative Toxicant?
No
*Chronicity Factor is Less than 2. Caffine is Non-Cumulative and therefore is Rapidly Excreted
The Dose which Produces Toxic Alterations and Administering Twice this Dose will result in Death
Toxic Dose High (TDH)
True/False: Chlorinated Hydrocarbons are Highly Lipophilic therefore Readily Absorbed and Distributed to all Body Tissues, including Brain, Liver, Kidney and ADIPOSE Tissue
True
Drugs that Stimulate the Liver to Produce more Metabolic Enzymes that may lead to Tolerance or Drug-Drug Interactions
Microsomal Enzyme Inducers
*May Decrease Risk of Toxicity with some Drugs
*Ex. Phenobarbital
Two Predominant Clinical Signs associated with Rotenone Toxicity
General Depression
Convulsions
Technique for Removal of Poison from the Skin, Mucous Membranes, and GI Tract via Emetics, Gastric Lavage, Rumenotomy and Purgatives
Removal of Poison from the Site of Absorption
*AKA Decontamination
1 ppm = 1 mg/kg
1 ppm = 1 mg/L
- 8 mg/ L = 0.8 mg/ 1000mL
(0. 8 mg / 1000 mL ) / 10 = 0.08 mg/100mL = 0.08mg%
*1 mg/100mL = mg% = mg/dL- KNOW
(0.08 mg/ 100 mL) / 100 = 0.0008 mg/ mL
1 mg = 1000 micrograms
(0.0008 mg/mL ) x 1000 = 0.8 mcg / mL
*KNOW HOW TO DO THIS FOR THE EXAM
Toxicology is the Science of _____
Poisons (Toxicants)
______ (mg/kg) = ppm in Feed X % of Feed consumed Daily
Toxicity
Five Factors of Drug Absorption related to the Animal
Blood Flow
Absorbing Surface Area
Connective Tissue
Species
Individual
______ (Activated Vitamin D) is Metabolized in the Liver to _____(25-hydroxycholecalciferol), which is transportred to the Kidney and Metabolized to ____ (1,25-dihydroxycholecalciferol), which is VERY Potent
Cholecalciferol- Activated Vitamin D
Calcidiol- Liver (Form in Circulation)
Calcitriol- Kidney (Very Potent)
*Calcitriol Massively Increases Calcium by working on Bone, Kidney, and GI Tract
True/False: Diagnostic Testing for Nicotine Toxicity includes Testing Urine, Stomach Contents, Kidney, Liver and Blood for Nicotine
True
Atropine can be used as a Treatment for Both Organophosphate and Carbamate Toxicity, however ______ is not Reliably Effective against Carbamates
2-PAM
*Reversible Binding of Carbamates reduces the Benefit of 2-PAM
Common Lesion of Cholecalciferol Toxicity
Hemorrhagic Gastroenteritis
*Also Mineralization of Affected Tissues
The Mechanism of Action for D-Limonene is Unknown, however it may work through Central and peripheral _____ due to an Undetermined Neuronal Mechanism
Vasodilation
Laboratory Test that Correlates well to Brain Cholinesterase activity that can be used to Detect Organophosphate Toxicity
Acetylcholinesterase Activity Level
*Refrigerate and Asses ASAP to Preserve Activity
*If Acetylcholinesterase Activity Level is Normal, that is Diagnostic for Organophosphate Poisoning
The Upper Part of the Small Intestine, _____, is the main site of Absorption for all drugs given orally because of the Extensive Surface Area and Rich Blood Supply. The Rate of Absorption depends on the Rate of _____
Duodenum
Gastric Emptying
Biotransformation most Commonly Results in _______ and Detoxification of Drugs
Bioinactivation
*Rarely Biotransformation Results in Bioactivation or Lethal Synthesis
True/False: Pyrethrins/ Pyrethroids are Lipid Soluble, Very Well Absorbed, and Rapidly Metabolized in GIT, Plasma and Liver
True
*Rapidly Metabolized- Pyrethrins don’t last Long in the Environment or Animal- Usually Metabolized and Excreted within 24 Hours
Urea has a Toxicity of 300 mg/kg and a Use Level of 100mg/kg. Urea’s Risk Ratio is 3:1. Monensin has a Toxicity of 20 mg/kg and a Use Level of 1mg/kg. Monensin has a Risk Ratio of 20:1. Which Toxicosis has a Much Higher Risk (Hazard)?
Urea
*The Risk of Urea Toxicosis would be higher than the Risk of Monensin Toxicosis, even though Monensin is much more Toxic than Urea.
Weak Basic Drugs are Excreted in _____ because of Ion Trapping that can lead to Drug Residues, Treatment of Mastitis Systemically, and Possible Adverse Effect on the Newborn
Milk
*Weak Basic Drugs are Excreted in Milk
*High pKa Drugs will have High Levels in Milk
If the Milk : Plasma Ratio is < 1, then Drug is mainly found in ______
Plasma
*If the Milk:Plasma Ratio = 1, then the amount of Drug in Milk is equal to the amount of Drug in Plasma
Plasma Protein Binding Acidic Drugs mainly bind to ____, while Basic drugs bind mainly to acid alpha1-glycoprotein. Plasma Protein binding is Reversible and Prolongs the half life of the Drug. The Bound Form is inactive and cannot be Distributed, Metabolized or Excreted by glomerular Filtration
Albumin
*Ex. Warfarin binds 90% to Plasma Proteins
*The Rate of Binding depends mainly on the amount of Drug
What does it mean if the Vd for a Drug is 2 Liters / Kg Body Weight?
The Cutoff Point is 1. If the Vd is > than 1 L/kg Body Weight, then the Drug is Widely Distributed
*If a Dog is 10kg, then the Vd is 20L
5 Main Routes of Drug Excretion
Renal (Main Route of Excretion)
Hepatic - Main Organ of Biotransformation
Feces
Milk
Semen
*Saliva, Eggs, Hair, Feathers, Sweat Glands and Expired Air are Minor Routes of Drug Excretion
Toxicity that is the Effect Produced by daily exposure from One day to 30 Days
Subacute Toxicity
Three Physiological Processes of Renal Excretion
Glomerular Filtration
Active Tubular Secretion
Passive Tubular Reabsorption
Factors that _____ Biotransformation
Hypothermia
Shock
Anesthesia
Animals in the Tropics
Decrease
*Animals in the Tropics may have Less Biotransformation
True/False: Dogs are deficient in most Oxidative Enzymes and Glucuronidation leading to Higher Chances of Drug Toxicity
False
*CATS
*Cats are Deficient in Glucuronyl Transferases
*Aspirin is only given to cats every 48 hours because it is not Metabolized as fast as in Dogs
C. Amitraz
*The Other three are primarily CNS Stimulants
Pyrethrins bind more Strongly at ____ Temperatures. Insect Sodium Channels are ____x’s More Sensitive to Pyrethrins than Mammalian Sodium Channels
Lower
1000Xs
*Insect Body Temperature = 25 Degrees Celsius
Mammalian Body Temperature = 38 Degrees Celsius
*Pyrethrins have Low Toxicity in Mammals, because their Temperature is Higher and Pyrethrins cannot Bind as Well
*Insect Metabolism of Pyrethrins is much Slower than Mammals
All of these Factors make Pyrethrins Effective Against Insects with Low Toxicity to Mammalian Species
Which Insecticide works by Irreversible Inhibition of Cholinesterases, that Increases ACh at all Cholinergic Sites
Organophosphates
*Acytelcholine Cannot be Broken Down
Organophosphates Degrade quickly in the Environment, most Persist ____ Weeks and can Penetrate Intact Skin and Waxy coatings of Leaves and Fruits
2-4 Weeks
______, aka Activated Vitamin D3, is Absorbed from the GI Tract and Binds to the Vitamin D binding Protein in Plamsa for Transportation to the Liver
Cholecalciferol
*Cholecalciferol is Metabolized in the Liver to Calcidiol (25-Hydroxycholecalciferol)
*Calcidiol (25-Hydrocholecalciferol) is Trasported to the Kidney and Metabolized to Calcitriol (1,25-Dihydroxycholecalciferol)
True/False: Biotransformation is the first phase of Drug Elimination
True
True/False: Laboratory Animal Testing is Important for Bacterial, Fungal and Plant Toxins and Feed Additives in Animal Feeds
True
True/False: Age, Inflammation, Trauma, Allergic Reactions, Severe Hypotension, and Hypoxia Do Not Influence the Blood Brain Barrier
False
*All these factors influence the Blood Brain Barrier
*Animal must be older to have an Effective Blood Brain Barrier
Acidification of the Urine pH by Oral Ammonium chloride or Methionine Enhances renal Excretion of Weak ____ Drugs such as Amphetamine
Basic
*Use ORAL Ammonium Chloride or Methionine
More Common Bromethalin Toxicity that develop within 2-3 Days Post Exposure that progresses into Hind-Limb Ataxia, Paresis, Paralysis, CNS Depression ect.
Subacute
* 2-3 days to Onset
*Higher chance for Survival
