Exam 2 Flashcards

Question

what are some Elapidae

Answer 1

coral snakes cobras

Answer 2

Poikilothermic- they are the same temperature as their environment Carnivorous Posteriorly curved teeth- teeth / fangs are shed and replaced throughout life Difficulty seeing stationary objects- generally poor eyesight Detect movement via ground vibration

Answer 3

Venoms are primarily composed of proteins, many with enzymatic activity.- also glycoproteins, lipids and biogenic amines Proteolytic enzymes catalyze the breakdown of tissue proteins and peptides. Esterases may mediate bradykinin-releasing and bradykinin-clotting activity. Thrombin-like enzymes have procoagulant activities.

Answer 4

Deep pit between eye and nostril Vertically elliptical pupils Fangs are hollow and retractable, located near the front of the maxilla Body is narrower than back of the head →“arrow-like” shape Can be aggressive if disturbed Most common cause of envenomation in veterinary medicine

Answer 5

Relatively common Dogs most often affected Bites tend to occur from May to September during late afternoon Head and front legs are most common sites often through aggressive or curious behavior Horses Bites are most often on the muzzle; lower limbs less so generally when grazing Cattle Bites often to the tongue and muzzle Cats More resistant to pit viper venom on mg/kg bw basis However, lesions often severe due to small size and delay before treatment Bites often occur on torso

Answer 6

Multiple, complex venoms Collagenase Hyaluronidase Phospholipases Ribonucleases Polypeptides Procoagulants and anticoagulants Toxicity Varies on species variations size of snake location of bite Amount injected is critical variable

Answer 7

Pain Rapid swelling Ecchymotic to suffusive hemorrhages in area of bite Salivation, hypernea, tachycardia, mydriasis Secondary infections Some like the Mojave rattle snakes cause neurotoxicity Bite on face ⇒ difficulty breathing

Answer 8

Observation of bite or bite wounds characterized by two puncture wounds

Answer 9

Emergency! Small Animal Shock treatment Transfusions if severe anemia or hemorrhage Antibiotics (+/-) Pain medication Diphenhydramine Antivenom: ASAP Large animals Establish and maintain airway(tube, tracheostomy) Anti-inflammatory Antibiotics (+/-) Anti-tetanus Antivenom: risk for serum sickness if equine origin antivenom is given

Answer 10

CroFab From sheep Fab fragments, affinity-purified 4 NA Crotalid species FDA approval Anaphylaxis: not reported Serum sickness: rare $$$$ Antivenin (Crotalidae) Polyvalent From horse IgG, not well purified 2 North & 2 South American snakes FDA approval Anaphylaxis: reported Serum sickness: frequent $$$$

Answer 11

Sold by Red Rock Biologics in CA Available only in CA and WA, marketed for dogs and horses USDA / VS: “conditionally licensed product” Current approach by the VMTH: Treatment protocol for vaccinated vs. non-vaccinated patient is the same (i.e. antivenom is also given to the vaccinated patient) Vaccination is not recommended due to lack of good efficacy data, cost, and low incidence rate in area.

Answer 12

Fangs are at anterior end of maxilla and are tubular or deeply grooved and fixed Coral Snakes- Red into yellow … ⇒ kill a fellow Two genera in the US: Micruroides: M. euryxanthus = Arizonan (Sonoran) Coral snake Micrurus: M. fulvius fulvius = Eastern Coral snake M. fulvius tenere = Texas Coral snake M. fulvius barbouri = South Florida Coral snake Most members of Elapidae are found in Africa, Asia, and Australia Round pupils Small pair of short fixed front fangs Venom is delivered by chewing Tend to be non-aggressive, reclusive

Answer 13

Envenomation relatively uncommon Coral snakes have small mouths making envenomation difficult

Answer 14

Proteins Curare-like effect Interferes with Acetylcholine → blocking neuromuscular junction (can’t breath) paralysis Local tissue reaction Phospholipase A Hemolytic anemia reported in dogs

Answer 15

Limb numbness, weakness, disorientation, paralysis, dyspnea Parasympathetic signs include salivation, emesis, and diarrhea. Fang marks are small.

Answer 16

Dx Difficult Rx Antivenin Respiratory support Atropine

Answer 17

Signal Transduction: A pathway of events by which each component participates in the process of transmitting a hormonal/growth factor signal to the target molecules within the cell. [L] + [R] ↔ [LR] → [LR**] →→→ Response L- ligand R- receptor LR- ligand receptor complex LR**- excitable and leads to a response alpha= 1 → full response. Fully agonist Less than one→ less than full response, not as good as an agonist Affinity = 1/KD Multiple of these pathways occur simultaneously

Answer 18

Pharmacological effects are reversible because the Ligand-receptor complex is reversible. Pharmacological effects are proportional to the number of receptors occupied. Pharmacological effects are proportional to the dose of ligand/drug. Pharmacological effects plateau because they are limited by the total number of receptors. Types of receptors Receptors coupled to G-proteins Receptors tyrosine kinases Cytosolic and Nuclear Receptors Ion Channels Signaling cascade mediators Ca2+ Ras MAP kinases Protein Kinase A Protein Kinase C

Answer 19

Relative potency- lower EC50 compared to another drug’s EC50 more left = higher potency

Answer 20

greater response than another drug higher curve = higher efficacy

Answer 21

Slope- how receptor is responding to the drug Hill coefficient- The steepness, Hill coefficient, gives information about the stoichiometry of the drug-receptor interaction (is 1 for 1:1 interaction) For nH= 1; 20% of effect is obtained at 0.25 x EC50and 80% effect at 4 x EC50 For nH< 1; suggests negative co-cooperativity. nH> 1; suggests positive co-cooperativity and a 2:1 or higher interaction between receptor and drug → makes concentration-response relationship very steep with large increases in effect at small increases in dose.

Answer 22

Graded Continuous scale (dose ® effect) Measured in a single biologic unit Relates dose to intensity of effect GRADED DOSE-RESPONSE RELATIONSHIP:indicate doses that cause 1/2 maximal response in a given INDIVIDUAL- ED50 Quantal All-or-none pharmacologic effect Ex. Cured or not Cured [ex. Parasiticides] Population studies Relates dose to frequency of effect QUANTAL Dose-Response Relationship:indicate doses that cause 1/2 of the POPULATION to respond.– mean or medium ED50

Answer 23

General experimental design Define the population to be tested Determine the number of individuals to be tested Determine time (of taking data) Define endpoint(s) level of pharmacological/toxic response Randomly assign individuals to dose groups (include placebo) Results Score % responding within each dose group Plot data as frequency distribution, cumulative frequency Gives rise to how much of population responding, how many hypersensitive, and how many resistant (%)

Answer 24

ED50 matches up with the middle of SD plot and halfway for cumulative plot Higher the ratio → higher TI → safer for population Higher TI- at higher ED90, lower TD (less overlap between the two)

Answer 25

Certain Safety Factor = LD1/ED99 Relates therapeutic effect in all animals in the absence of a risk of producing a hazardous effect. LD is the Lethal Dose of the drug. Certain safety factor is when ED99 must be increased before an LD1is reached. Standard Safety Margin= (LD1- ED99)/ ED99* 100 The Standard Safety Margin is a percent which ED99 must be increased Before an LD1is reached.

Answer 26

Concentration Response when talking about in vitro on an isolated receptor- Effective Concentration (EC). Reported as ½ Response; i. e. EC50 Dose Response when talking about in vivo where you use mg/kg body weight- Effective Dose (ED). Reported as ½ Response; i. e. ED50 Terminology used with animal use

Answer 27

A chemical structure contains information which, upon binding biological receptors, can alter their structure and function

Answer 28

Agonists enhance ongoing function Antagonist diminish ongoing function

Answer 29

An inverse agonist is a ligand that binds to the same receptor as the agonist and causes the opposite effect of the agonist ligand. Requirement: Receptor must have basal activity in the absence of any ligand for an inverse agonist to function. The efficacy of an inverse agonist is less than 0. Examples of receptors that bind to inverse agonists are GABAA, melanocortin, mu opioid, histamine and beta adrenergic receptors.

Answer 30

comp- Antagonism can be overcome by increasing [agonist] (a property limited by toxicity). Antagonists added→ right shift in the curve Schild plot- For competitive antagonists the equilibrium dissociation constant (KB) for the antagonist can be obtained. When the slope is equal -1 the antagonism is competitive. pA2is concentration of antagonist, which requires a 2-fold increase in agonist concentration non- Acts to essentially remove a fraction of the receptors from producing a response to agonist (inhibition not dependent on [agonist]). Can’t overcome inhibition with increased agonist concentration Dose response curve Addition of agonists → efficacy decreases (curve goes lower) However, EC50 value remains the same because receptors still bind Q and Qmax is lowered because receptors are not responding to binding

Answer 31

Drug selectivity- Predictable pharmacological response requires knowledge about relative potency of efficacy at all receptors with which it interacts. No drug is completely specific in biological action- can be off target effects Structure-activity relationships reveal receptor subtypes

Answer 32

The magnitude of a specific in vitro response is proportional to the fraction of receptor sites (R) complexed with a reversible ligand (L) Intrinsic efficacy- Indicate the relation between pharmacologic response and occupancy of receptor sites

Answer 33

full- 1.0> alpha > 0.8 partial- 0.8 > alpha > 0.2

Answer 34

Clinical Potency- Reflects the amount of drug needed to produce a certain level of therapeutic response Affinity for a drug for its receptor is the principle determinant of clinical potency.

Answer 35

Reflects the greatest clinical response attainable with a drug at any dose

Answer 36

Increased effects- additive or synergistic effect Increased therapeutic effect Increased toxic or adverse effects Decreased effect- antagonistic effect Decreased therapeutic effect Decreased toxic effect

Answer 37

Additive effect : Both drugs do not affect the actions of each other, but their actions together equals the sum of the actions of each drug when administered alone. Synergistic effect: Actions of both drugs administered together promote an exaggerated effect out of proportion compared to the actions of each drug administered alone. May be called super additive

Answer 38

Occurs when one drug inhibits the action of another. AKA sub additive Pharmacological antagonism: a drug antagonizes the effect of another drug by acting on the same receptor. Two types- competitive and noncompetitive Ex. Detoxify-reversal therapy- Xylazine and Yohimbine Xylazine targets the presynaptic alpha2- adrenergic receptor to reduce neural transmission Yohimbine (competitive antagonist) reverses the effects of xylazine by competing with the alpha2-adrenergic receptor

Answer 39

classical isobologram plot (predicts isoeffect curves when two drugs are together) Done in vitro EC50 value is plotted on graph (x and y interval) In this example, both are 1 Draw line to connect the two When adding the two drugs together, if it falls On the line → additive Below the line → synergistic Above the line → antagonism This depends on concentration (proportion of Drug A and B)! If you change the concentration throughout the graph, you will see synergism, antagonism, and additive features all over the graph

Answer 40

Observation: Only a fraction of the total number of receptors need be occupied to elicit a maximal response in some tissues Experimental Evidence: Titration of a known noncompetitive antagonist results in an apparent “competitive”shift in the dose-response relationship Expected: See overall drop in efficacy, but instead, they got a competitive right shift As increase non comp antagonists → less receptors available → still enough receptors to reach efficacy → only right shift → but still has less and less receptors to respond → as increased antagonist (don’t have enough receptors for response) → finally have drop in efficacy in response If EC50 is less than KD → spare receptors Seen- at 90% pharmacological response, only ~25% of receptors responding Antagonists → less receptors available → increases EC50 closer to KD

Answer 41

A tool for guiding a dosing regimen Individualize therapeutic regimens for optimal patient benefit Increasing therapeutic effects and decreasing toxic effects Assumes a relationship between: Dose, Concentration, and Response Dose-response relationship (rem. The three assumptions)

Answer 42

Animal refractory to medication Not responsive to medication (seeing if dose in therapeutic range) Animal showing toxicity PK differences in individual patients How drug is eliminated and why you are seeing toxicity Drug Interactions Steep dose response curve Small change in dose leads to massive effect Drug with a narrow therapeutic range TDM is not indicated for all drug

Answer 43

Sample Type Plasma/serum/whole blood- Vast majority of drugs are tested in plasma or serum (either or is dependent on lab and what type of test they have) Tube type- Glass vs plastic- some drugs bind to glass or plastic→ get artificially low concentrations Titer top tubes (have silicone plug) → some drugs bind to silicone plug Detailed History Any other drugs, when drugs were given, in critical condition? Assay needs to be rapid (24-48 hours) Cost Applicability to patient: Concentration – effect relationship Drug needs to have this Established “therapeutic”range Qualified individual for interpretation (vet clinical pharmacologist)

Answer 44

Drugs with a long elimination t1/2 relative to dosing interval Collect at steady state Steady state = Therapeutic range Single sample vs. peak (Cmax) and/or trough (Cmin) Single- make sure if in range peak - toxicity Trough- lack of efficacy Allow time for absorption/distribution (~1-2 hours post admin of EV drug)

Answer 45

Single sample is often sufficient for monitoring (want to know if within dosing range) Allow time for absorption/distribution

Answer 46

After loading dose- After absorption and distribution to make sure it is at therapeutic level One t1/2 after maintenance dose starts Make sure maintenance dose maintains what it achieved by LD At steady state- Make sure it is maintaining concentration Elimination half-life calculation: Peak and trough

Answer 47

Initiate drug dosing schedule Allow time to reach steady state Administer another dose Collect peak sample Collect trough sample Assay drug concentrations Calculate individual PK parameters (half life) Adjust dosing interval or dose amount

Answer 48

The “therapeutic”range is a population statistic and not a “normal.” Not based on individual 95% of the population respond somewhere within the range.

Answer 49

Drug Therapeutic index of drug (safety) Can you give a large amount of drug and pushing interval or would that cause toxicity? Need to maintain plasma drug concentrations within therapeutic range throughout dosing interval Would it fall to really small levels before giving next levels? Some drugs (like the one in lab) protect the drug concentration when it gets low → it is ok when concentrations get low because it is protected

Answer 50

proportional method new interval/old interval = existing conc/desired conc

Answer 51

proportional method old dose/existing conc = new dose/desired conc Important to check peak concentration to see if falls into therapeutic range → not toxic But therapeutic range is population value → not based on individual, so you should monitor once drug administered

Answer 52

peak - assess toxicity Trough- assess lack of efficacy

Answer 53

Having both allows to calculate rough estimate of half life Helpful when drug changes it own half life and metabolism

Answer 54

“safe concentration” Established based on safety to the person consuming the tissue. Tissue tolerances established in fat, milk, muscle, liver, kidney or skin.

Answer 55

time required for a drug to be depleted from the animal before the animal’s meat can be marketed for human consumption. FARAD- provides information to veterinarians about withdrawal times Esp if used off label

Answer 56

Closely related to elimination half life Statistical method is used to determine the time it takes for drug residues to deplete below the safe concentration. Only valid for the specified species, dose, route and frequency of administration. If used off label → Veterinarians must establish a substantially extended withdrawal period supported by scientific information with ELDU. Can be affected by physiologic condition (affects elimination half life)

Answer 57

the study of neurochemicals, including neurotransmitters and other molecules such as psychopharmaceuticals and neuropeptides, that influence the function of neurons. This field within neuroscience examines how neurochemicals influence the operation of neurons, synapses, and neural networks Endogenous molecules that are imp for determining function of nervous system

Answer 58

the study of how drugs affect cellular function in the nervous system, and the neural mechanisms through which they influence behavior. There are four main branches of neuropharmacology: molecular, cellular, systems and behavioral Drugs specifically that influence neurotransmission

Answer 59

Synapse has presynaptic that has chemical signal that triggers post synaptic signal Pre- electrical Synapse- chemical Post- electrical

Answer 60

Electrical signaling (action potential)- dramatic change in membrane potential At rest- -70 mV Less positive charge inside compared to outside Maintained by Na/K pump (can’t cross plasma membrane) Also ion channels → typically closed at rest Triggered- depolarization (increased voltage) Voltage gated Ion channels (Na)- open in response to change to depolarization Very quickly open Na channels and delays opening of K channels Na has two pressures to drive it into the cell Concentration gradient charge (electrochemical) gradient Threshold- -55mV→ all or none response Membrane potential shoots up repolarization: decrease mV Set up electrochemical gradient to drive K out K channels open up → makes cell more negative (Net loss of positive charge) Overshoot

Answer 61

Depolarization occurs first from body → positive charges (Na) going in are attracted to the adjacent lateral negative sides → depolarizes neighbor and travels down axon hillock Why only travel left to right? Because K channels open and make more negative Pump Activation gate opens with depolarization With delay, activation gate closes and inactivation gate opens → blocks Na flowing through to the left → only travels to the right

Answer 62

AP reach axon terminus → cause opening of voltage gated Ca channels → Ca flows inside → activate fusion of synaptic vesicles to presynaptic neuron → synaptic vesicles dumped in synaptic cleft → bind to receptors on postsynaptic side → allows change of ion distribution of neurotransmitter → depolarization on post side Ca always higher out of cell vs inside

Answer 63

Synthesis of neurotransmitter in the presynaptic neuron Storage of the neurotransmitter and/or its precursor in the presynaptic nerve terminal Need to be stored or else they will be degraded Release of neurotransmitter into the synaptic cleft Binding and recognition of the neurotransmitter by receptors on the target (postsynaptic) cell Termination of the action of the release neurotransmitter Always active ⇒ be no signaling

Answer 64

Binding of it to presynaptic cell receptor Can decrease how much is being released- autoinhibitory receptors Decrease synthesis on the presynaptic side Uptake proteins On presynaptic side Recycled for neurotransmission Taken up into glial cells All synapse are surrounded by glial cells Clear them out Diffuse out of synaptic cleft Inefficient Can be metabolized in synaptic cleft

Answer 65

Neurochemical phenotype of affected cell type(s) Location of molecular/cellular target(s) Physiological role of molecular/cellular target(s) Pharmacokinetics of drug/toxin/toxicant

Answer 66

A neurotransmitter used by the spinal cord neurons to control muscles, by many neurons in the brain to regulate memory and by peripheral neurons to regulate autonomic function. In most instances, it is excitatory

Answer 67

The neurotransmitter that produces feelings of pleasure when released by the brain reward system Dopamine has multiple functions depending on where in the brain it acts It can be excitatory or inhibitory

Answer 68

The major inhibitory neurotransmitter in the brain

Answer 69

The most common excitatory neurotransmitter in the brain

Answer 70

A neurotransmitter used mainly by neurons in the spinal cord It is probably always acts as an inhibitory neurotransmitter

Answer 71

NE acts as a neurotransmitter in the CNS and PNS In the PNS, it mediates the flight or fight (sympathetic) response In the brain, it acts as a neurotransmitter regulating normal brain processes NE is usually excitatory, but is inhibitory in a few brain areas

Answer 72

A neurotransmitter involved in many functions including mood, appetite, and sensory perception In the spinal cord, serotonin is inhibitory in pain pathways

Answer 73

Balance of glutamate (excitatory) and GABA (inhibitory)- EI balance Can change balance by change in excitatory vs inhibitory drive Glut neurons can inhibit another glut neuron transmission through gaba neuron Imbalance between Excitatory and Inhibitory Drive (E/I Imbalance) Contributes to Diverse Pathologies

Answer 74

Too much inhibition- death Too much excitatory- seizures and death A lot of seizure medication → targets this balance (increase GABAergic) Drugs used to control anxiety target this Anxiety- too much excitatory drive Target to decrease excitatory Critical to peripheral organ function → autonomic function From hypothalamus, balance of EI Determines rate of AP firing and strength Increase in inhibitory- decreased resp output Increased excitatory - increased resp output Many organs in periphery are dually innervated Balance between EI determines what happens in these organs

Answer 75

Somatic- single circuit Motor neuron- release acetylcholine → binds to nicotinic acetylcholine receptor → contraction of muscle Autonomic- two neuron circuit Preganglionic and postganglionic Ganglion- collection of neurons Para- send pre out very far to ganglion Can be seen in lungs and heart Post- send out acetylcholine to post and post will release acetylcholine → bind to muscarinic acetylcholine receptor sympathetic nervous- chain ganglia (lie next to spinal cord) → pre not send out far → acetylcholine to post → post release NE Pre can also release acetylcholine to nicotinic receptors → EPI released in bloodstream

Answer 76

Ligand gated ion channels Mus- activate second messaging signals in cells

Answer 77

Exocrine glands (sweat, salivary, etc) Cardiac muscle β1 receptor stimulation increases heart rate (HR), contractile force, conduction velocity Muscarinic receptor stimulation decreases HR and contractile force Smooth muscle α receptor stimulation causes smooth muscle contraction β2 receptor stimulation causes smooth muscle relaxation Muscarinic receptor stimulation causes smooth muscle contraction* except for blood vessel relaxation, which involves release of nitric oxide from endothelial cells

Answer 78

Cloven hooves No upper incisors Upper teeth is a dental pad 3 - 4 compartments that make up their digestive system before intestines Some people consider reticulum as part of other parts Rumen Omasum Abomasum- true acid stomach Pregastric fermentation Everything in rumen has first crack at everything eaten before the animal Ruminate, chew cud Ruminate comes from when they eat, they stick head in air and “think” Cattle, sheep, goats, buffalo, deer, antelope, moose, elk, giraffe

Answer 79

Rumination- brings up food from rumen to chew and then goes back in rumen Has saliva → neutralize pH, gets wet for microbes to latch onto them Ruminate 9-10 hrs / day on high forage 5 hrs on finely ground→ No tickle factor- no contractions Maybe impaired with disease Ie. vagus nerve damage, displaced abomasum (go to the L or R side, twist)

Answer 80

Food → reticulum → Esophageal hole → omasum → abomasum → duodenum → out Pillars are baffles (?) → controls sloshing of fluid, help the fluid stay where it is supposed to be, anchors for smooth muscle (since rumen contracts continuously)

Answer 81

Honeycombed Stimulation of rumination and eructation (‘Tickle factor’) Feed “tickles” reticulum → causes it to contract → causes different types of waves of contractions If fed ground feeds, no tickle factor and not many contractions Eructation = burping Fermentation occurs in rumen and need to get rid of gas If not functioning (no tickle factor), gas is not burped → bloat Sits near diaphragm Hardware disease- sharp metal objects (ie wire, screws, nails) → eat them → pierce the reticulum and can go through diaphragm Reticular groove Rumen is not functional when born so do not want milk going in there (it will rot → bloat) Directs milk from esophagus to abomasum Forms a channel away from the rumen Fold stimulated by suckling Occurs only in pre ruminant Full ruminant at 6 months of age

Answer 82

Runs 2 degrees higher than body temperature (due to fermentation) 39 C pH just below neutral (6-6.8) More hay = more alkaline More grain = more acidic Saliva production- 100-150 L/d Plays an important role Has a lot of buffers and supplies water to rumen Gas production- 30-50L Carbon dioxide and methane Top of rumen has gas → reticulum contracts → gas escapes through esophagus Todays hay below → big particles of food Grain and yesterdays hay → microbes and particles of food Need to be wet for microbes to latch on No secretions Liquid supplied by drinking and saliva which contains buffers Papillae very vascularized for absorption of volatile fatty acids to portal vein Ruminants also live off of fermentation, in addition to nutrients from food Contractions move and mix digesta If rumen acidic, papillae get damaged and decreases ability for absorption of fatty acids Can cause ulcers and get microbes into portal vein → in liver → necrosis(?) Movement coordinated by vagus nerve Blood supply by celiac artery

Answer 83

round, basketball like compartment Absorption of H2O, Volatile fatty acids (VFA) Folds act as filters to trap large particles Let small particles pass Filters out by size Large particles back into rumen for further fermentation Horses, it is oriented differently → large pieces pass Muscular action sucks digesta thru retic-omasumal orifice flushes large particles back to rumen

Answer 84

Acid or ‘true’ stomach pH ~ 2 Covered by mucus to protect from HCL and pepsin First step of digestion of proteins

Answer 85

Plant cell wall = pectin, cellulose, lignin, hemicellulose Microbes degrade pectin, cellulose, and hemicellulose Lignin- insoluble glue that holds everything together Nothing degrades it More lignin = less digestible, harder to digest Plant cytoplasm = protein, sugar, starch, lipid As plant matures, cell wall (lignin) increases, while protein and sugars (18%) decreases

Answer 86

Microbes sensitive to fat, especially non esterified fatty acids (diet must be < 3-5% fat unless it bypasses the rumen) Double bonds → introduces a kink in it → disrupts membrane → microbes can’t function as it normally would Triglycerides can also coat the material and prevent microbes from attaching to it

Answer 87

Bacteria 60% (5*109 /ml) very metabolically active Must attach, ferment locally Feed must be wet first Secrete enzymes on surface Can inhibit fungi - compete for spots on feed, but can be good because increases SA due to breaking down (both can be on there) Protozoa 30% (5*105 /ml) but 104-106 larger (half of mass) Large organisms maintain stable fermentation engulf starch Protect rumen from acidosis Fungi 10% ( 5*104 /ml) hard to quantify because they have spores as part of their cycle Have enzymes that predigest enzymes around them → Easier for bacteria to digest Have chutes that digest as well → more SA for bacteria to ferment Long life cycle, attach to feed particles Increases surface area for microbes Produce Lactate, Acetate, H+, CO2, formate, ethanol from cellulose and sugars High fiber diet = more fungi Diets where fungi is added are available as well

Answer 88

Cellulolytics- break down cellulose → Produces Acetate, H+, ethanol, may require CO2; Must attach to fiber, excrete cellulases Grows on glucose (cellulose or starch) Degrades hemicellulose but doesn’t use it Starch Digestors Cell bound and extracellular amylase Can rapidly degrade starch and grow Generation time = 12 min with unlimited substrate Don’t depend on Red-Ox (pH) to grow Can produce a lot of lactic acid Organic Acid Utilizers Utilize lactate, formate, citrate, malate, fumarate, succinate, etc. Reduces CH4 (takes the methane that would go out into environment) Convert it into things that don’t change rumen pH Megasphera elsdenii can cause milk fat depression Don’t want this for dairy cows Methanogens Works closely with cellulolytics → produces byproducts for methane How much hay in diet ⇒ how much methane is produced strict anaerobe Converts H2 and CO2 to methane Use acetate, methanol, methylamines, CO2, H2, formate Use a protein bound cytochrome as electron carrier Can produce up to 200L CH4 / day

Answer 89

Holotrichs eat soluble sugars and microbes cilia all over Entodinomorphs engulf starch prevent acidosis cilia at end Not essential: Produce VFA (volatile fatty acids) Help with grain diets Help recycle microbial N when low Cannibalize other protozoa, and microbes Tendency to lyse in rumen to feed microbes, not animal Delays acidosis

Answer 90

Substrate is limiting How much feed is given determines the rate of culture Anerobic (no mitochondria) Must maintain Oxidation / Reduction balance (need free NAD to do glycolysis) Produce ATP for microbes, leaving acetate and propionate for animal Aerobic- all ATP for microbes, no acetate or propionate made Growth rate dependent on feeding rate Microbe growth rate = rate of microbe passage Diversity dependent on feed, specialization, volatile fatty acid production Hay, Fiber Feeds = Acetate Goes towards fat production Grains, Concentrates = Propionate Glucose precursor → supply glucose to the animal Those are their energy sources

Answer 91

Microbes supply: Energy through VFA; Protein by death and passage Microbes need: Carbon and nitrogen as substrates (in the form of plants) pH range 6-6.8 Anerobic environment

Answer 92

VFA absorption Dependent on pH pH 7 => 4.7 +log Ac- / AcH : 200/1 pH 6 => Ac-/AcH : 20/1 pH 5 => Ac-/AcH : 2/1 Salivation Bicarbonate pKa~6.7 CO2 + H2O = H2CO3 = HCO3- + H+ Salivation keeps pH in 6-6.8 range Rumination and contractions; Stimulate mixing, eructation, salivation, papillae development (surface area) More water to ferment and keep pH within range Water intake- ‘flush’ problem microbes and VFAs to abomasum Protozoa Engulf starch- delays acidosis Target rapidly growing microbes

Answer 93

Overgrowth Strep gallolyticus By having a lot of highly fermentable products (starch) Low affinity for starch, but if lots, will grow rapidly At low pH, can only produce Lactic acid Other ‘good’ microbes can’t grow→ kills the cow Laminitis weeks or months later Two types Overfeeding starch S gallolyticus overgrowth Sudden switching between high / low intake Rumen pH < 5.5 for 4 / 24 hours VFA builds up in rumen Chronically low rumen pH = Sub acute ruminal acidosis (SARA)

Answer 94

Primary energy source are VFA (pro and acetate) Primary Fuels = acetate, propionate from rumen fermentation Protein supplied by microbes

Answer 95

When compared to humans Glucose is from propionate 70% and amino acids (30%) Liver needs to convert pro to glucose If something is wrong with liver, no glucose All microbes take glucose in rumen * They conserve Glucose Compartmentalization: Liver is always in gluconeogenesis Fatty acid synthesis occurs in adipose In other species, made in the liver Missing enzymes: Fatty acid synthesis is from acetate, not glucose ATP citrate lyase, Malic enzyme are missing from adipose (and liver) NADPH is from pentose phosphate path and Isocitrate dehydrogenase In adipose, glucose is used only for NADPH and a-glycerol phosphate (TCA cycle) * Lack of glucose = fat mobilization and Ketosis In starvation, ruminants mobilize adipose Cows at the beginning of lactation also have negative energy balance because DMI can drop by 30% Fat ruminants mobilize more fat But they also have low glucose → ketosis Liver picks up fatty acids from circulation Liver enzymes have huge capacity for producing ketones When starve cow Microbes die and produce toxins No more acetate and pro for the cow Mobilizing fat and ketosis

Answer 96

Ruminants (foragers) = Eat, then Ruminate Get the most nutrients from low protein and low glucose food → sit there and they digest a lot Think of them as continuous eaters (grazers, continuous process in the rumen) Even though they eat meals Nonruminants Predators = Meal eaters, high protein Switching between glycolysis and gluconeogenesis Foragers = Continuous eaters Go for quantity, not quality (low protein, low glucose)

Answer 97

Ruminants – Microbes Nonruminants – cecal fermentation Doesn’t take advantage of microbial proteins and vitamins If can’t meet protein requirements, eat their own feces Ie. pigs, horses

Answer 98

Ruminants - fat primarily from mobilization (VLDL, HDL, etc), therefore limited capacity to metabolize fat and fat interferes with microbial metabolism Nonruminants - meat, grains have higher fat content, therefore limits are relative to absorption ability (Bile) and interference with cecal fermentation

Answer 99

Browsers and Grazers: Grains Grasses (Legumes) Vegetation (leaves) Fruit, Vegetables Browers- lips are mobile Ex. giraffe Very selective about what they eat Grazers- lips aren’t mobile Not selective about what they eat Limitations: Need at least 35 - 50% hay / fiber diet

Answer 100

In the wild they are true Omnivores: Roots Acorns Berries Vegetables Grains Grasses (Legumes) Carcasses (Meat) Fecal material

Answer 101

= Animal(s) Response Intake Production (Milk, Meat, Eggs, Wool) Body Condition Scoring (BCS) Excretion (feed) , Fecal sieving

Answer 102

Obesity (fatty liver) Increase fiber (NDF, ADF) Starvation (Ketosis) Increase fiber (microbial health) Increase starch (reduce ketone formation) Probiotics? (microbial health) Disease (off feed) Increase fiber

Answer 103

Monosaccharides – carbohydrates that can not be hydrolyzed into simpler sugars Hexoses (D-glucose and D-fructose) and pentoses (D-Xylose and L-Arabinose- components of cellulose) Derivatives of these- glucosamine (glucose with amine attached), sorbitol (glucose w/o alcohol), gluconic acid, glucaric acid, and glucuronic acid (glucose with carboxylic acid attached)

Answer 104

Disaccharides (2 monosaccharides) Oligosaccharides (2-10 monosaccharides) Polysaccharides (>10 monosaccharides)

Answer 105

Sucrose (α 1,4 linked glucose and fructose), sweet substance frequently used to increase palatability sucrose may be used as a humectant to retain moisture in semi-moist foods (give texture) In diet- sugar and sorbitol helps retain moisture Lactose (β 1,4 linked galactose and glucose), digested into monosaccharides by lactase in the brush border of the small intestine Many adult animals lack sufficient lactase to digest lactose. This is the most common form of carbohydrate intolerance. Signs include diarrhea, bloat, flatulence, stomach cramps, and nausea. Lactose becomes a fiber, essentially → causes symptoms Maltose Safe upper limits for monosaccharides and disaccharides Cats- lower because they are carnivores so their ability to digest carbs are lower Cats can’t even taste sucrose due to deletions of receptor that help taste sweet

Answer 106

Short changed and soluble → used for probiotics, fermented quickly

Answer 107

Storage form of carbs Starch- can be digested by animals (amylases, maltase, isomaltases) Alpha 1,4 glucose linkages Fiber- can not be digested by animal enzymes α 1,4 and α 1,6 glucose linkages) If digested, depends on microbes Ie. cellulose- most common fiber component (insoluble fiber) β 1,4 linked glucose units Looks like starch, but instead of alpha linkages, it is beta Stacks up on top of each other → makes it hard to be soluble and hard for microbes to get to it Dogs and cats can’t digest because there is not enough time, but ruminants do a good job of breaking it down can be digested by microbial β glucosidases Hemicellulose (insoluble fiber) Not similar to cellulose common cell wall polysaccharide composed primarily of linked xylose units with side chains of glucuronic acid, glucose, galactose, arabinose, other saccharides in various linkages (grasses) low solubility and moderate fermentability Pectins (soluble fiber) consists primarily of galacturonic acid units with varying proportions of the acid groups present as methyl esters. Other monosaccharides are attached as side chains. high solubility and fermentability used commercially for gelling Gums (soluble fiber) sticky exudates of plants diverse monosaccharide subunits some gums show moderate to high fermentability Gives structure to diet Fructans (fructooligosaccharides) (Fr)n-Gu Fructose attached to glucose fructans are found in the roots, stems, leaves and seeds of a variety of plants cool season grasses (orchard grass, timothy, brome) may have high levels of fructans Energy reserve for the plant fructans have been linked with laminitis in horses Resistant starch crystallized or physically enclosed starch granules (behaves as a fiber) Once passed into large intestine, fermented by microbes Lignin not a carbohydrate (polymer of phenol derivatives) closely associated with fiber Occurs with them lignin tends to be inversely related to fiber digestibility Not digested in any animal Digestibility of Fiber Insoluble fibers are not well digested by many simple stomached animals Some fibers, like pectins and gums, show high fermentability in dogs and other simple stomached animals. Ruminants and monogastric hind gut fermenters can ferment (at least to some extent) hemicellulose, cellulose, pectins, and gums. Lignin is not well fermented by any species. The volatile fatty acids (acetate, propionate, and butyrate) and lactate are the products of fiber fermentation in the rumen and hind gut.

Answer 108

Crude Fiber measures cellulose and lignin (and some hemicellulose) Limitations- no soluble fiber measured Neutral Detergent Fiber (NDF) measures cellulose, hemicellulose, and lignin (entire plant cell wall) inversely related to food intake Give more NDF ⇒ takes longer to ferment Acid Detergent Fiber (ADF) measures cellulose and lignin inversely related to digestibility Tough part of plant cell wall because hard to ferment Acid Insoluble Lignin Lignin- tough and indigestible Total Dietary Fiber (TDF) enzymatic method that measures soluble and insoluble fiber defatted sample incubated with α-amlyase, protease, and amyloglucosidase To break down starches and protein sample is treated with ethanol to precipitate fiber and protein the residue is washed (ethanol and acetone), dried and weighed duplicated samples are analyzed for protein and ash TDF = residue (g) – protein (g) – ash (g) Gives soluble and insoluble fiber

Answer 109

Starch – major carbohydrate component in grains Water Soluble Carbohydrates (WSC) – includes monosaccharides, disaccharides, and fructans Easily digestible Ethanol Soluble Carbohydrates (ESC) – primarily monosaccharides and disaccharides Non Structural Carbohydrates – 100% - (%C. protein - % NDF - % fat - % ash) Using proximate analysis Glycemic Index – measure of the increase in blood glucose levels (AUC) caused by a particular feed relative to a reference feed Greater index ⇒ bigger increase in glucose after meal Effective NDF (eNDF) – the percentage of NDF effective at stimulating chewing, salivation, rumination and rumen motility Fiber needs to be large (bigger length) to stimulate rumen Small fibers do not stimulate rumen

Answer 110

Excess carbohydrate (not used immediately for energy) is stored as glycogen or converted to fatty acids. Carbohydrates (glucose) are required for energy by the brain and red blood cells. Carbohydrates (glucose) can be produced (gluconeogenesis) from proteins, glycerol, and propionate.

Answer 111

No standard for min amount of carbohydrate eaten due to how it is metabolized Herbivores need carbohydrates to maintain proper gastrointestinal function. Carnivores (and other animals) can synthesize carbohydrates if supplied with excess proteins

Answer 112

Increase fecal output or modulate fecal consistency. Using water soluble or insoluble fibers Modulate fecal moisture Treat constipation or diarrhea Diets for managing diabetes. Higher amounts of fiber ⇒ Slow transit time of food through the gut. Slow fat and carbohydrate absorption. Lower bile acid resorption and reduce blood cholesterol levels. Fiber binds bile and prevents reabsorption → decreases CHO improve cardiovascular health Maintain lower GI tract health. Increase production of VFAs (acetate, propionate, butyrate) Change microbial populations Prevention of colorectal cancer, inflammatory bowel disease, colitis Decrease energy density/digestibility of the Diet. Fiber used as bulking agent → dampen hunger but still low calorie Increase gut fill (short term regulation of appetite) Energy dilution Hairball prevention Bulking agent to help push hair through GI tract

Answer 113

High Fermentability: Guar Gum, Pectin, Oligosaccharides Gives structure and gel component Insoluble in Water and Moderate Fermentability: Beet Pulp, Oat Fiber, Pea Fiber, Rice Bran, xanthan gum, gum arabic Gives structure and bulk (push stuff through GI) Insoluble in Water and Low Fermentability: Cellulose, Peanut Hulls, Soy Hulls, Sunflower Hulls Gives bulk and adjust fecal consistency

Answer 114

Chemical substances used to prevent, destroy, repel or mitigate any pest Includes- Insecticides, herbicides, fungicides, rodenticides, molluscicides, bactericides

Answer 115

Worldwide estimate (2010): ~1.8 billion people engage in agriculture- most use pesticides to protect the food and commercial products. Major exposure potential. Exposure via commercial applications (golf courses, residential settings, military bases) Domestic/home uses for lawn and garden applications and in and around the home. Unintended environmental exposures due to pesticide residues & pesticide drift, leading to oral, dermal, and pulmonary exposures Possible bioaccumulation

Answer 116

National Pesticide Information Center (NPIC) Veterinary Pesticide Incident Reporting Portal CA DPR (CA Department of Pesticide Regulation)

Answer 117

Pesticides are more regulated than most industrial chemicals EPA pesticide regulations protect environmental health mandated by Federal Insecticide Fungicide and Rodenticide Act (FIFRA) Requires all pesticides sold or distributed in the U.S. (including imported pesticides) to be registered by EPA Registration is based on evaluation of scientific data and risk/benefit assessment of the product's use Label directions control how products are used Requires brand name, species it is approved for, size of animal (dose), intended use, active ingredients, warnings EPA can authorize limited use of unregistered pesticides or pesticides registered for other uses to address emergencies EPA can suspend or cancel a product's registration Training is required for workers in pesticide-treated areas and certification and training for applicators of restricted use pesticides FDA is responsible for enforcing regulations that set the limits of pesticides that are allowed in animal-derived products, and regulates the use of pesticides that act systemically *All pesticides must be approved and registered by EPA, FDA, or both Four toxic categories of pesticides I- high II-moderate III- low IV- low

Answer 118

Botanical insecticides Synthesized by particular genus or species of plant Active principle may be localized to specialized tissue of the plant and produced in extremely small quantities Not toxic to animals Active principle may have extremely high acute toxicity towards insects, or other pest sp. Chemically degrade in the environment (safe to the environment) Historically natural products have provided leads for synthetic organic pesticides pyrethrum → pyrethroids Nicotine → neonicotinoids ryanodine → ryanoids Botanicals used for home gardening are “generally considered as safe” (NOT ALWAYS TRUE, USE CAUTION!)

Answer 119

Acetylcholine Cholinesterase (AChE) Inhibitors Voltage-gated sodium channel (VGSC) modifiers (DDT, pyrethrins, pyrethroids) Nicotinic cholinergic receptor modifiers (nicotine, neonicotinoids) Gamma amino butyric acid GABA A receptor blockers (chlorinated hydrocarbon, Cyclodiene Insecticides, Polychloroterpenes)

Answer 120

Organophosphates and Carbamate Insecticides monomethyl carbamates Most widely used in agriculture (worldwide) Most direct veterinary uses discontinued in USA Banned from home use in USA and other countries

Answer 121

AChE →in cleft, allow acetylcholine clearing Inhibiting → not clearing acetylcholine out of the synaptic cleft Huge build up of acetylcholine → increased signaling → Stimulation of the sympathetic nervous system may produce sweating, hypertension and tachycardia. Nicotinic and muscarinic receptors activated SLUD- Salivation, Lacrimation, Urination, Defecation DUMBELS- Diarrhea, Urination, Miosis, Bronchospasm, Emesis, Lachrymation, Salivation

Answer 122

Both OPs and methylcarbamates have very high acute toxicity w/ OPs having somewhat higher toxicity (in general) Symptoms usually begin peripherally (eyelid twitch, tingling extremities), rapidly followed by central involvement. Since OPs and methylcarbamates have the same acute MOA, effects are additive Certain OPs (mipafox, leptophos) produce a delayed neurotoxicity known as jake-leg paralysis in humans, cattle and chickens. There is now good evidence that exposure to low levels of OPs over long periods may mediate adverse developmental outcomes that are not mediated by AChE inhibition morphogenic mechanisms

Answer 123

The first major synthetic organic insecticide Widely used in U.S. from 1942-1973 (600,000,000 lbs/year) DDT Insecticide (an Organochlorine)The first major synthetic organic insecticide Currently used in Africa, Malaysia... Directly applied to animals, including humans

Answer 124

very low mammalian toxicity at insecticidal doses high doses cause hyperactivity, tremors clonic/tonic convulsions, cardiac or respiratory arrest (Acute oral LD50~115 mg/kg) extremely effective knockdown toxicity to insects insect toxicity increases inversely with temperature (negative temperature coefficient) mechanism very similar to pyrethrins/pyrethroids delays inactivation of axonal Na+channels

Answer 125

Rapidly bioaccumulates, insect resistance leads to higher application rates, metabolized to DDE, DDD In human and animal foods, environmental exposures Hormonal effects (endocrine disruption) egg shell thinning in birds (??) xenoestrogen-estrogenic effects in mammals (??) alters thyroid hormones Breast cancer link (??) Obesogenic (??) Induces liver enzymes CytP4501A

Answer 126

equatorial regions East African highlands, Asia achenes 2-5% pyrethrins Natural Pyrethrins- Mixture of 6 esters comprised of 2 acids & 3 alcohols Pyrethrin I and Pyrethrin II most common

Answer 127

rapid knockdown of insects very low acute toxicity to mammal >1000 mg/kg (allergic dermatitis) rapidly degrades in the environment insect resistance a big problem Caution with felines!

Answer 128

Synthetic insecticides Widely used in domestic applications Widely used in large scale agriculture (millions of pounds) Widely used for veterinary applications (topicals, dips, collars) Rapid knockdown activity Extra caution for felines due to PK issues Elimination issue (liver metabolism)

Answer 129

Generally low mammalian toxicity (rat oral LD50>1000 mg/kg) Aquatic organism are especially sensitive Felines may show symptoms after dip (especially with Type II) Because elimination is not efficient Dermal and system allergies may be pronounced Type I- Aggressive behavior, Enhanced startle response, Whole body tremor Peripheral signs predominate Type II- Burrowing behavior, Tremors→ convulsions, Choreoathetosis (jerking motions), Profuse salivation CNS signs predominate

Answer 130

Interfere with axonal conductions of neurons Direct binding to voltage-operated Na+ channels → Delays inactivation of Na+ channels → Prolonged depolarization of axonal membrane → hyperexcitation Often formulated with piperonyl butoxide (inhibitor of metabolism) Insect growth inhibitor but also inhibits drug metabolism → increases likelihood of toxic effect

Answer 131

Cross-Resistance to Pyrethrums & Pyrethroids Due To Extensive Use of DDT Many Years Earlier DDT and pyrethroids target the same mechanism Insects mutate resistant sodium ion channels

Answer 132

2-14% nicotine by weight in leaves with organic solvent→ extract with sulfuric acid → ‘Black Leaf 40’ (poison) Sources- cigarettes, cigar, chewing tobacco, snuff, nicotine gum, nicotine patch, nicotine nasal spray, nicotine inhaler, e cigarettes apid dermal adsorption highly toxic to mammals dermal and oral LD50 ~50 mg/kg

Answer 133

Nicotine’s structure mimics acetylcholine at all nAChR (agonist) Does not bind to muscarinic receptors (All mAChR subtypes are insensitive to nicotine) Promote neurotransmission Very rapid progression of symptoms Activation then desensitization of nAChRs (both PNS & CNS) Chronic activation → desensitization by internalization Progression Stimulation of autonomic ganglia- salivation, nausea, diarrhea, increased respiratory rate, increased heart rate and blood pressure Depression of autonimic ganglia- decreased respiration, hypotension CNS involvement- clonic tremors, resp arrest, death

Answer 134

nicotine is a selective nAChR agonist nicotine is much more long-lived than ACh at cholinergic synapses (not metabolized by AChE) persistent activation of AChRs results in desensitization

Answer 135

Synthetic insecticides Ie. imidacloprid (advantage and related products) Kills 98-100% of the fleas on dogs within 12 hours One treatment prevents further flea infestation for at least four weeks Kills fleas before they lay eggs Convenient, easy to apply Applied as spot-on Goes into the systemic circulation Unique mode of action differentiates imidacloprid from organophosphates, pyrethrins, carbamates, insect growth regulators (IGR's) and insect development inhibitors (IDI's) Partial agonist Imidacloprid is active against adult fleas, flea larvae, eggs Imidacloprid does not protect against ticks Resistance is an increasing concern Imidacloprid is: non-teratogenic, non-hypersensitizing, non-mutagenic, non-allergenic, non-carcinogenic, non-photosensitizing Safe to use at certain doses, but there are some that are not intended for veterinary use Imidacloprid insecticide formulations not intended for veterinary use May be harmful to environment- killing honey bees

Answer 136

Applied topically formulation controls fleas topically (fleas don’t need to bite- spreads across your dog’s skin and coat) Prevents deadly heartworm Protects dog and family against worms Controls fleas, heartworms, Roundworms, Hookworms Controls Ear mites and lice Water resistant

Answer 137

Allows influx of Cl → binding negative charge in the cell → decrease membrane potential Activation leads to hyperpolarization of mature neurons Agonist and antagonists can bind Positive allosteric modulators can also bind to other sites → increase sensitivity to normal ligand → more negative membrane potential Conduction blockers (pesticide)- prevents Cl from going through pore

Answer 138

broad spectrum insecticidal activity long persistence in the environment Due to it being chlorinated tendency to bio-accumulate along food chains. Predators have the highest concentration of toxin compared to plants induce liver enzymes (CyP4501A), increase liver mass tumor promoters in cell models enhance risk of cancer Ie. Lindane resistant to metabolism and environmental degradation volatile (> 90% enters atmosphere - ultimately deposited by rain) Primarily use of exposure is inhalation and skin contact Spreads easily around the world Most uses suspende, but some uses remain Used to treat Head lice (recently banned in CA) tree borers oilseeds (rape, maize) control crop damage by soil dwelling pests fumigation of grain stores to control weevils pest control on turf areas; domestic insect control (ants primarily)

Answer 139

Synthesized after WWII Stable in soil, don’t break down in UV Used in control of termites

Answer 140

Greatest use of a single insecticide Used on cotton

Answer 141

Acute- all have potent convulsant activity Why? They inhibit GABA → increased excitatory drive → increase the risk of seizures Generally safe, but depends on dose (misuse, unexpected exposure) Nexgard, frontline, dectomax Frontline banned in france because bees are dying from it Maintain efficacy→ really smart PK/PD Insect GABA receptors differ from those expressed in mammals –take advantage of differences to design highly selective (safe) insecticides... Researchers created insecticides that only work on insects

Answer 142

Lipid- A group of chemicals insoluble in water but soluble in organic solvents (e.g., ether) Nutritional interest Fatty acids Glycerols Triglycerides (fat) Phospholipids Sterols (CHO)

Answer 143

volatile fatty acids (C2 – C4) Products of fermentation medium chain fatty acids (C6 – C12) Not as difficult to digest as long chain → go directly to portal vein and it able to be used long chain fatty acids (C14 – C18) Produced by terrestrial plants very long chain fatty acids (C20 and greater) Made by animals → short chains elongated by animals

Answer 144

saturated (no double bonds) monounsaturated (one double bond) polyunsaturated (two or more double bonds)

Answer 145

Cis (hydrogen on same side of the double bond) Trans (hydrogen on the opposite side) Does not occur naturally in animals, but occurs in microbes

Answer 146

conjugated dienes- rather than double bonds separated by a methylene structure produced by rumen microbes c9,t11-18:2 and t10,c12-18:2 are the most common (called conjugated linoleic acid)

Answer 147

Chemical Numbers System example C18:2 ∆9,12 the first number (18) equals the number of carbons the second number (2) equals the number of double bonds the numbers after the ∆ are the location of the double bonds counting from the carboxyl end Enzymes work from that end Nutrition n (or ω) series example C18:2 ω6,9 the first number (18) equals the number of carbons the second number (2) equals the number of double bonds the numbers after the ω are the location of the double bonds counting from the methyl end The double bond on the methyl end gives rise to the Omega __ fatty acid name

Answer 148

Animals can synthesize saturated fatty acids from acetyl-CoA. This fatty acid synthesis requires the enzymes acetyl CoA carboxylase and fatty acid synthase. Animals can lengthen fatty acids. This involves 2-carbon additions catalyzed by elongase enzymes. The product of fatty acid synthesis is palmitic acid (C16:0), and this can be elongated to form stearic acid (C18:0). Animals have desaturase enzymes that can add double bonds. Animals have Δ9, Δ6, Δ5, and Δ4 desaturases. The number after the Δ indicates the location of the double bond counting from the carboxyl end. Animals can not desaturate at distances greater than 9 carbons from the carboxyl end. Desaturases show the following preference for substrates: n-3 (omega 3) > n-6 > n-9 > n-7 > n-9 trans Elongases act on the fatty acids to add 2 carbons to the carboxyl end of the fatty acid. Not going to see odd length carbon chain If you do, it might be damaged

Answer 149

Trans-epidermal water loss Drink more but do not urinate more Omega 6 forms barrier along the skin, when low → it breaks down, hard to keep moisture and water in Scaly skin Course, dry hair Skin lesions Alopecia Poor reproductive capacity Red cell fragility Increased ratio of n-9 to n-6 fatty acids Also tries to compensate with omega 9→ hyperproliferation

Answer 150

Omega 3 deficiency isn’t something that could be measurable Visual acuity or brain function Therefore, recommended estimate amount

Answer 151

Linoleic Acid (C18:2 n-6) Base fatty acid α-Linolenic Acid (C18:3 n-3) Base omega 3 fatty acids Required for all animals Arachidonic Acid (C20:4 n-6) essential in cats since they have low Δ6 desaturase activity. n-3 Long Chain Polyunsaturated Fatty Acids (C20:5 n-3 and C22:6 n-3) may be beneficial for some species, even though it could be made Required by AAFCO for inclusion in dog and cat diets. Since a large amount is required for them

Answer 152

Cellular Membranes Components of phospholipids Modulate fluidity Bind to G protein-coupled receptors (n-3) Precursors of Eicosanoids Constituents of myelin (neurons), synaptosomal lipids, and the retina (n-3 fatty acids) Required for reproduction (n-6 fatty acids) Regulators of gene transcription Particularly n-3, has impact on inflammation

Answer 153

inflammation Physiologically and pharmacologically active compounds derived from n-3 and n-6 fatty acids. The eicosanoids have a wide range of actions. The eicosanoids have a short half life and generally act locally as hormones. The main eicosanoids are the prostaglandins, thromboxanes, and leukotrienes. The precursors for eicosanoids are n-6 (arachidonic acid) and n-3 (eicosapentaenoic acid) fatty acids.

Answer 154

Omega 3 and omega 6 compete with each other for fatty acids Induces symptoms * N-6 Prostaglandins (PGE2) Fever induction Increased COX-2 and IL-6 ↓ Lipoxygenase, TNF and IL-1 Thromboxanes (TXA2) Platelet aggregation Vasoconstriction Clotting Leukotrienes (LTB4) Inflammation induction Induce Reactive oxygen species Increased TNF, IL-1, and IL-6 Induce leukocyte chemotaxis * ** N-3 - prostaglandins opposite and much more weak Prostaglandins (PGE3) Weak inducer of COX-2 & IL-6 ↓ TNF-α and IL-1 Thromboxanes (TXA3) Weak platelet aggregator Weak vasoconstrictor Prostacylcin (PGI3) Vasodilation Inhibition of platelet aggregation Leukotrienes (LTB5) Weak inducer of inflammation Weak chemotactic agent **

Answer 155

Energy an energy source in commercial diets (beef tallow, fish oil, animal fat, soybean oil, corn oil, etc.) weight gain supplements Carrier of fat soluble vitamins (A,D,E,&K) Clinical Reasons Injury recovery- high fat, increased n-3 Increase energy density of diet Rebuild tissue and combat inflammation Increase palatability Decrease inflammation (n-3 fats) Digestive disorders - MCT (med chain triglycerides- not as complex digestive process), moderate fat Increase digestibility (MCT) Limit fat for improved digestibility Joint Health - increased n-3 Decrease inflammation (n-3 fats) Skin Conditions - n-6 and n-3 Insure adequate linoleic acid levels Decrease inflammation (n-3 fats) Renal Function - n-3 Decrease glomerular hypertension Weight Loss - low fat Decrease energy density Aging - n-3 Decrease inflammation (n-3 fats) Palatability Fat is palatable Coat Condition

Answer 156

Dogs- linoleic acid n-6 and n-3 EPA and DHA as well (long chain fatty acid) Imp function in brain and eye so won’t risk that they can make it easily → just give it to them Cat- linoleic acid and arachidonic acid (because issue with n-6) EP and DHA as well All other animals- linoleic acid n-3 and n-6

Answer 157

n-6 fatty acids (linoleic acid)- High in n-6 seeds and cereal grains safflower, corn, sunflower, canola & soybean oil n-6 fatty acids (arachidonic acid) animal fat Longer so need animal fat source n-3 fatty acids (α-linolenic acid)- not present in high concentrations in as many products as n-6 green material (leaves) flaxseed (linseed) oil is best source soybean and canola oil corn oil is NOT a good source of n-3 n-3 fatty acids (DHA and EPA) fish oils

Answer 158

Essential- Regulating functions of proteins by regulating oxidative state Metals are intrinsic to nature Toxins because these are naturally occurring While form (salt vs. organic vs. elemental) or valence of metals can be changed, metals themselves cannot be destroyed Many metals play essential roles in biologic processes as necessary cofactors for proteins enzymes (e.g., metalloenzymes) structural proteins (e.g., zinc finger transcription factors) transport proteins (e.g., hemoglobin) At sufficient doses, metals (both essential and non-essential) can be toxic Essential- can have issues if there is too much or too little

Answer 159

Classic U shaped → essential dose response curve Sigmoidal → nonessential dose response curve On test, seeing this graph → need to fill in the blank which metal belongs to each curve Need to know examples of essential vs nonessential metals

Answer 160

essential- Na, Mg, K, Ca, Cr, Mn, Mo, Fe, Co, Cu, Zn, Se nonessential- the rest (Li, Be, Ag, Hg, Pb, As, ...)

Answer 161

anthropogenic sources (atmospheric), natural sources (volcanoes) Exposed through environmental source or through diet and feed supplements and medicinal applications

Answer 162

Form of metal inorganic (less bioavailable) vs. organic (more bioavailable) Organic more because they are not charged → can more easily cross plasma mem Inorganic- charged → can’t cross plasma mem Elemental Hg less available (and less toxic) than methyl-Hg Exception: inorganic As (arsenic) more toxic than organic As form of salt Pb acetate (soluble in GI) vs. Pb sulfate (insoluble in GI) Pb acetate more bioavail valence state As+3 is more toxic than As+5 Cr+3 is essential trace element; Cr+6 is toxic Route of exposure inhalation vs. oral intake of elemental Hg Oral- goes through GI and is passed Inhalation- goes to the brain very quickly Age of animal Young animals more susceptible (better bioavail) WHY? Because younger animals have less developed barriers → more permeable skin and BBB Diet- very important!

Answer 163

Biologic half-lives vary according to metal as well as organ or tissue 20-30 years for Cd in kidney or Pb in bone Few hours to few days for As Metal accumulation is tissue specific Pb in bone or kidney cortex (Pb-protein complex) Lead displaces Ca in bone because they have the same valence Cu in liver (lysosomes) Some tissues serve as storage sites Storage sites are not target sites!!!

Answer 164

Metals interfere with bioavailability of essential trace elements or function of metalloproteins ADME of essential mineral nutrients Through metal metal interactions Structure/function of metalloproteins Ex. heme → Pb can displace iron → larger than iron → change shape and function of the heme Metals promote redox reactions → ↑ ROS → ↑ oxidative damage to critical macromolecules Metals bind sulfhydryl groups → deplete glutathione → promote oxidative stress Glutathione- antioxidant Enzymes in this reaction rely on selenium (essential metal) Oxidative stress can occur through directly promoting oxidative species or indirectly through this method

Answer 165

Metals compete for transport/uptake Ex. Mo and Cu Many are similarly charged → need ion channels to cross membrane → compete for ion channels Metal-metal complexes can sequester metals from site of action Hg-Se interaction sequesters metals from biological targets (can’t bind to target) Transport mechanism Albumin (through blood) ceruloplasmin (bind Cu in plasma but across mem) transferrin (iron→ in blood and mem) divalent metal transporter (DMT) (transmembrane protein that allows divalent metal to cross mem) Protective mechanism Metallothioneins (rich in thiols aka SH groups) → can be charged → binds to metals Homeostatic mechanism that controls conc of metals in the body Esp nonessential metals Can cause cell damage by interfering with fxn of proteins that need these metals to function Ligand binding is the most fundamental chemical process involved in metal toxicity and cellular defense against metals Metals influence protein function -Direct Cofactors of receptor complexes Cofactors of enzymes Zinc finger transcription factors -Indirect Body levels of metals influence transcription/translation Iron responsive elements (IRE) - Fe levels in body regulate transcription of protein involved in Fe metabolism

Answer 166

Uncommon, occurs due to ingestion or injection of Cu salts (oral dose of 25-50 mg/kg) Case report in beef calves given supplemental injections of copper (Cu disodium edetate) resulting in acute hepatotoxicity

Answer 167

Can occur in veal calves fed copper-containing hematinics in milk replacers Case reports in cattle and goats (feed-related)

Answer 168

Occurs most commonly in sheep (all sheep susceptible – Texel and Suffolk most susceptible) from exposure to excessive dietary Cu (dietary Mo concentration is a critical factor) Feed supplements, soils and plants with naturally high Cu levels, soils contaminated with poultry or swine manure with high Cu levels Can occur with normal dietary Cu levels (10-20 ppm) when: Mo is deficient (< 1 ppm) for several weeks Optimal Cu:Mo ratio is 6:1 Cu:Mo > 10.1 predisposes to Cu accumulation Facilitates excretion of Cu as Cu:Mo complex sulfate is not available Sulfur is also a factor in facilitating fecal excretion of Cu via bile (as a therapeutic approach, used in ruminants – sulfate converted to sulfide) Dietary S can influence Cu kinetics as well Underlying liver disease can predispose to Cu accumulation

Answer 169

Inherited as autosomal recessive trait Bedlington terriers, West Highland terriers, Doberman pinschers, Labrador retrievers Manifests at 2-6 years of age with no remarkable prior signs Cu accumulates in hepatocyte lysosomes until storage capacity is exceeded – released causing necrosis and inflammation

Answer 170

Llama from concentrate feeds not icteric! no hemoglobinuria enlarged liver, hepatic necrosis want 5 - 10 ppm dietary copper Goats need more copper than sheep Cu toxicity if on long term diet of swine feed, horse feed, or rabbit feed high in Cu

Answer 171

Cu salts act as direct tissue irritant to cause coagulative necrosis of GI mucosa

Answer 172

Cu accumulates in hepatocytes Lysosomal storage (rubeanic acid) Progressive organelle damage, cellular degeneration or necrosis Stressful event precipitates sudden release of Cu from liver into blood Acute hemolytic crisis free Cu forms free radicals (ROS)

Answer 173

Therapy is primarily symptomatic and supportive

Answer 174

Chelation with D-pencillamine $$$$$$ IV fluids to flush kidneys, blood transfusions if anemic Ammonium tetrathiomolybdate Subcu or IV – aids in rapid Cu binding and excretion Ammonium molybdate and sodium thiosulfate PO for 3 weeks

Answer 175

Se is an essential nutrient that has a relatively narrow window between ingested amounts that result in deficiencies and those that cause toxicosis

Answer 176

Acute intoxication from Se salts (mostly injected) Resp cyanosis, GI and neurologic symptoms Garlic odor to breath

Answer 177

Subacute intoxication from dietary supplementation (pigs) Nervous system primarily affected Focal symmetrical poliomyelolacia- spinal cord

Answer 178

Chronic intoxication from ingesting seleniferous plants or dietary supplementation Primarily affecting dermal system Infertility as well Chronic selenosis- abnormal formation in hooves, lameness in the legs Chronic intoxication of wildlife from food chain contamination Emaciation Loss of feathers on head Loss of claws on feet Coelomic effusion Hepatic lesions Teratogenic and embryotoxic in avian species abnormal beaks missing eyes, legs and wings hydroencephaly or exencephaly

Answer 179

Acute Intoxication: Oxidative damage Generates ROS (reactive oxygen species) Binds to sulfhydryl groups to deplete glutathione and other thiol containing antioxidant molecules

Answer 180

Chronic Intoxication: Replacement of S in amino acids Affects function of essential proteins Organic Se incorporated into proteins throughout the body High affinity for hair, hooves (replaces sulfur)

Answer 181

History of exposure to Se Via supplementation, seleniferous plants Clinical signs Especially with chronic selenosis Toxicological testing – Tissue and feed [Se] Acute toxicosis Blood, kidney, liver > 2ppm Chronic toxicosis Hair and hooves > 5 ppm

Answer 182

Limited, rarely successful Supportive treatment to combat gastroenteritis and shock N-acetylcysteine, a glutathione substitute may be effective

Answer 183

Similar to chronic toxicosis Death may result from complications of paralysis

Answer 184

Prevention is best approach Dietary Cu may help prevent selenosis Increasing dietary levels of sulfur containing proteins (methionine, cysteine) is beneficial

Answer 185

Pennies minted after 1982 99.2% Zn, 0.8% Cu 2.44g Zn/penny Hardware and caging materials Galvanized metal Bolts and nuts Many industrial components Zn pipes, feeders, waterers for livestock Medications and dietary supplements Zinc oxide (rarely causes toxicity) Desinex, suppositories, calamine lotion

Answer 186

Reported in dogs, ferrets, caged birds, mink, sheep, horses, cattle, ratites Young dogs Small dogs- More difficult for small objects to pass pylorus

Answer 187

Dogs and other small animals: GI→ hemolytic anemia Early: Anorexia and vomiting Intermediate: lethargy and diarrhea (within several days) Advanced: moderate anemia, hemoglobinuria and icterus Cattle Early: anorexia diarrhea, lethargy Intermediate: rate of gain milk production Advanced: Anemia and icterus, PU/PD, paresis, seizures Foals Lameness, epiphyseal swelling and stiffness Birds General depression, anorexia, weakness and weight loss PU/PD, dysphagia, diarrhea, crop stasis

Answer 188

Regenerative hemolytic anemia Pancreatic acinar cell necrosis- Relatively unique to Zn intoxication Renal and hepatic necrosis and fibrosis

Answer 189

Not well understood Competes for absorption with Cu, Fe, Ca Zn salts have direct corrosive and cytotoxic effects GI and pancreatic necrosis Oxidative damage or enzyme inhibition? Hemolysis Inhibit collagen metabolism? Osteochondrosis in horses

Answer 190

History of exposure Clinical signs especially diagnostic in acute intoxication Radiology Presence of radiodense materials in the stomach suggests the possibility of zinc toxicosis in small animals Toxicologic Testing – Tissue [Zn] Trace element-free tubes and syringes for blood sampling! Rubber-free syringes, royal blue plastic cap blood collection tubes Liver [Cu] often depressed in chronic Zn toxicosis

Answer 191

Removal of Zn objects Surgery or endoscopy Associated with rapid recovery in dogs GI protectants Supportive and symptomatic Bicarbonate for renal support Transfusion if needed for anemia Supplement Cu in large animals Chelation with calcium disodium EDTA Efficacy not established

Answer 192

Acute zinc intoxication is most common Acute onset of gastrointestinal distress along with a hemolytic anemia are common presenting problems Occasionally subacute to chronic

Answer 193

Lead, no demonstrated biological need Lead is a global environmental contaminant of significant public health concern Very low Pb levels toxic to humans Impaired neurologic development Subtle cognitive and neurobehavioral deficits Most species susceptible In vet med, clinically significant neuro-, hemato- and gastrointestinal toxicity of importance Pb toxicosis in companion animals should call attention to potential for exposure of children in household

Answer 194

Long, long list Most commonly: Cattle Old, discarded batteries Rubbish (putty, old paint tins, oil) Pets Lead-based paint, household dust Solder, foil from bottles, weighted toys, drapery weights Wildlife Lead shot, fishing sinkers, mine tailings

Answer 195

Reported in mammals, birds, reptiles Dogs, cattle, waterfowl Cats & sheep intermediate susceptibility Rare in cats Associated with paint removal/remodeling Immature animals more susceptible GI absorption Blood-brain-barrier not fully formed Trace mineral status affects absorption Greater absorption in mineral deficient animals Seasonal Increased incidence in cattle and dogs during spring and early summer Most cases of Pb poisoning are subacute; ingestion for several days or more may be necessary to reach toxic concentrations; Pb objects persisting in the GI tract provide a continuous source of exposure.

Answer 196

Absorption in duodenum and respiratory tract is variable Form of Pb Pb salts and metallic lead poorly absorbed Organic forms absorbed more readily Bioavailability as particle size Age-dependent Affected by diet Acidic diets enhance absorption by promoting dissolution of Pb Diets deficient in calcium, Zn or protein enhance Pb absorption Distribution Transported as lead proteinate on erythrocyte membrane Crosses the placenta Deposits briefly in soft tissue (kidney) Storage site is bone Excretion Low blood levels: bile High blood levels: urine Pb is excreted in milk

Answer 197

Toxic effects occur in the nervous system, gastrointestinal tract and hematopoietic systems Molecular mechanisms of lead toxicosis are not fully known Binds to –SH groups on proteins Competes with or replaces Ca and Zn Nervous System Capillary damage and neuronal necrosis in the CNS Demyelination in the PNS Neuromuscular weakness Altered neurotransmission Secondary to interference with Ca signaling Altered expression of receptors GI and hematopoietic systems GI stasis and anorexia Secondary to neurologic mechanisms(?) Hematopoietic system Inhibition of key enzymes in heme synthesis Inhibition of nucleotidase Basophilic stippling and erythrocyte fragility

Answer 198

Common to most species Encephalopathy seizures, tremors, blindness, depression, dementia, ataxia anorexia and colic proteinuria Species-specific clinical signs

Answer 199

Clinical signs Clinical pathology Radiology Tissue [Pb] Antemortem: whole blood Must use whole blood for blood Pb levels. Serum won’t work because Pb is bound to RBCs 0.4 ppm generally considered high Between 0.1 and 0.4 ppm suggest preclinical exposure Postmortem: kidney and liver Lead mobilization test using a chelator

Answer 200

Hematology Anemia Nucleated red blood cells RBC basophilic stippling Increased Zn protoporphyrin levels, esp. in dogs Increased plasma porphyrins with fluorescence under UV characteristic in cattle Radiology Pb lines in bones Histology Intranuclear inclusion bodies in renal tubular epithelial cells Neuronal necrosis in cerebral cortex, congestion, edema

Answer 201

Magnesium sulfate, PO Promotes excretion Decreases solubility Seizure control Removal of Pb material from GI tract Surgery or endoscopy Flushing of GI tract Thiamine appears to promote recovery in cattle Chelation therapy Calcium disodium EDTA Succimer D-penicillamine

Answer 202

Treatment Symptomatic and supportive treatment Reduction of metal body burdens Manipulation of dietary levels of competing metals To decrease body burden of toxic metals Surgical removal of metal objects Ingested or embedded in tissue → releases metal over time Chelation therapy- CaNa2EDTA (injected) aka calcium disodium versenate or edetate Do NOT use other salts of EDTA May chelate Ca and cause hypocalcemia Use a Ca salt to prevent this Capable of chelating many metals When combined with Pb (initially from soft tissues) a stable, soluble compound is formed that is eliminated via the kidneys Patients should be well hydrated and have an adequate urine flow prior to administration Prolonged use may damage proximal tubule cells May initially increase signs of Pb toxicosis Mobilizing Pb from bone depots, but as more is eliminated, the signs are going to decrease Chelation- Succimer (Chemet) Relatively selective, orally active, water soluble chelating agent for the treatment of lead, arsenic and mercury poisoning Does not have side effects associated with EDTA Should be used with caution in avian species because one study in cockatiels suggests narrow margin of safety Does not chelate essential minerals like zinc; not nephrotoxic NOTE: activated charcoal is NOT effective in treating metal toxicosis

Answer 203

ADE: Any harm that occurs following the use of a drug product. Can vary from mild to life threatening Can be expected or unexpected Includes: Toxicity Ineffectiveness Product defects human safety associated with handling. Reasons Drug-drug interaction Drug-Herbal (nutrient, etc.) interaction Disease alters response to drug Extra-label (off-label) use Genetic polymorphisms **Estimates are that only 5-25% of all ADEs reported in vet med Why it is hard to know how many ADE there are in vet med

Answer 204

Medication Error: Mistake of someone taking care of the animal- Wrong dose, wrong dose interval, wrong patient Adverse Drug Reaction (ADR): Toxicity of medication Type A (Type I) Type B (Type II)

Answer 205

“Augmented Response” Dose dependent = Largely predictable Manifested as: Exaggerated but expected response Lack of response Adverse events unrelated to their pharmacologic effect (cytotoxic adverse reactions) Therapeutic Drug Monitoring may be helpful In order to decrease likelihood and severity of ADE Account for 75-80% of all ADEs. Organs with the greatest blood flow are most susceptible Well perfused → more drug goes there Ie. liver

Answer 206

bizarre “Idiosyncratic” They just happen Rare Account for 6 to 12 % of all ADE’s But more serious Not dose dependent in general population Therapeutic drug monitoring NOT helpful Since not dose dependent Usually not related to desired pharmacologic response of drug May involve hypersensitivity reactions Not based on population level Usually requires drug be d/c Discontinue drug and provide supportive care Often involves metabolism to a reactive chemical (hapten) Mechanism is unknown Oxidative stress → cellular necrosis and apoptosis Hypersensitivity reactions require previous exposure/treatment (or treatment for an extended period of time Often involves binding of hapten to epitope Facilitated by inflammation

Answer 207

Actively dividing cell (metabolic cells), well perfused, high SA Liver: High blood flow CYP450s Skin: Surface area Antigen presenting cells CYP450s Bone Marrow Circulating Blood Cells High mass of rapidly dividing cells Enzymes Tissues that trap or filter immune complexes (because immune complexes can get stuck there) Glomerulus Joints

Answer 208

P-glycoprotein not working Ie. in collies ABCG2: blood retina barrier Keep substances out of the eye Not as functional in cats as other species Enrofloxacin (baytril) toxicity in cats Clinical signs: blindness MOA: generation of photoreactive compound (exposed to light → reactive metabolites) Dysfunctional transporter More drug getting into eye → exposed to light → metabolites → cats go blind

Answer 209

CYP450 Ultra rapid metabolizer → makes more metabolites → can be toxic at high levels 3 copies ⇒ low parent drug levels Extensive metabolizer- wildtype 2 copies ⇒ normal parent drug levels intermediate metabolizer 1 copies ⇒ slightly parent high drug levels Poor metabolizer 0 copies ⇒ high parent drug levels In dogs, poor metabolizers have Clearance is much lower → higher elimination half life compared to extensive metabolizer

Answer 210

Phase I: 5-20 ‘normal’ individuals Phase II: 10-200 people with disease in question Phase III: 2,000-5,000 people with disease Post Market Surveillance: Depends upon potential market; MUST FOLLOW AT LEAST 10,000 PATIENTS TO DETECT 1 IN 3300 PROBLEM WITH 95% CONFIDENCE Seen more rare events Seen in individuals with more time on drug compared to pre market

Answer 211

Target animal safety studies: 30-40 animals Efficacy studies 300-400 animals Even fewer animals exposed in veterinary drugs Mostly depends on post market surveillance BUT reporting is not required and, as a result, experts estimate that only a small fraction of ADE’s are reported. Only drug manufacturer is required to report it

Answer 212

NSAIDs –GI ulcers, idiosyncratic reactions Hormones CNS agents Anesthetics Penicillins – hypersensitivity reactions Baytril – Blindness in cats Moxidectin – Overdoses from failure of syringe- locking device

Answer 213

Complete history/definitive diagnosis- drug-drug/herbal interactions Use proper drugs Use less toxic drugs when possible Continue to evaluate/monitor patient during therapy Modify dosing regimens when appropriate D/C therapy as early as possible Educate the client as to the side effects or adverse effects Report ADEs

Answer 214

Temporal relationship-Does it make sense? Is the event consistent with reported drug side effects? Are there other possible explanations? Hx Is there improvement when the drug is discontinued? What happens if therapy is reinitiated?

Answer 215

Stop use of the drug Supportive care Contact manufacturer or FDA-CVM, fill out ADE report Set aside bottle and any packaging associated with the bottle for potential further testing

Answer 216

Detection and investigation of the effects of the use of veterinary products, mainly aimed at safety and effectiveness in animals and safety in people exposed to the products. Purpose is to assess the frequency, similarity and severity of signs so that regulators can assess the possibility of drug association. Report both when used according to label or when used extra-label.

Answer 217

Contact Manufacturer or FDA-CVM Helpful Information: Physical exam Medical history Diagnostic evaluation Veterinarian’s opinion Follow up information

Answer 218

Drug Label/Package Insert Post approval label changes Dear Doctor letters on FDA website ADE summaries webpage FDA CVM CVM Updates Journal Articles Black box warning ⇒ most important adverse drug effects on label

Answer 219

FDA Pioneer (Legend) Drug: Demonstrated safety/efficacy Manufacturing under GMP FDA approved NADA # tells us that it is an FDA approved drug Green book- has all FDA approved vet drugs and information Generic Drug: Bioequivalent to brand name drug Manufacturing under GMP FDA approved ANDA- generic approved drug Compounded Drug Mixtures of approved dosage forms or drugs formulated from bulk chemicals that are not approved by the FDA for use as drugs.

Answer 220

Medical device- an instrument, apparatus, implement, machine, contrivance, implant, in-vitro reagent, or other similar or related article, including any component, part, or accessory, which is ... intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease in man or other animals, or [which is] intended to affect the structure or any function of the body of man or other animal Ie. needles and syringes Joint lavage solutions but sometimes advertised as a drug Approval FDA does NOT require formal pre-market approval Manufacturers are not required to list their products with the FDA-CVM. NO mandatory adverse event reporting requirements. Responsibility of the manufacturer to assure safety, effectiveness and proper labeling. Write medical device

Answer 221

Established requirement of safety for human medications in 1938 Amended in 1968 to include veterinary medications Drugs were unsafe unless FDA approved All ELDU (extra label drug use) became illegal

Answer 222

Legalized extra-label drug use (ELDU) under specified conditions Because vets complained that they could do ELDU but it was illegal Requirements for ELDU: Permitted only by or under supervision of a veterinarian. FDA approved animal and human drugs Valid Veterinary Client Patient Relationship (VCPR) You examine and diagnose animal and client has agreed to treatment For therapeutic purposes only (i.e., not for production purposes) ELDU must not result in violative drug residues in food animals Food animal and non-food animal algorithms Legalized compounding (provided starting material is FDA approved) but not from bulk chemicals

Answer 223

Drug used as labeled or identical or human drug Human or animal drug used extra-Label Compounding- Cost is NOT a valid reason

Answer 224

Drug used as labeled Food animal drug used extra-label Extended withdrawal time Non-food animal or human drug used extra-label Compounding ELDU prohibited for certain medications! Chloramphenicol Clenbuterol Diethylstilbesterol Dipyrone Gentian Violet Nitroimidazoles Nitrofurans Phenylbutazone (adult dairy cattle) Sulfonamides (lactating cows) Fluoroquinolones Glycopeptides

Answer 225

Drugs are altered in dosage, form and/or flavor to accommodate the needs of a particular patient Federal Food, Drug and Cosmetic Act ELDU Regulations AMDUCA Relevant state laws

Answer 226

Modification of approved drug to sufficiently treat a patient Flavorings Different strength Changing form Ie. tablet → suspension Patient or species is sensitive to an ingredient within the formulation Approved drug not currently commercially available Cost is not a justification for using a compounded product

Answer 227

Standard setting body Expert committees write standards Quality, purity of drugs and foods Non-enforcement Standards enforced by pharmacy boards

Answer 228

Legal under AMDUCA: Permitted only by or under supervision of a veterinarian. FDA approved animal and human drugs Valid Veterinary Client Patient Relationship (VCPR) For therapeutic purposes only No animal drug approved for the intended use or not in appropriate formulation/concentration. ***Should never compound copies of an FDA approved drug***

Answer 229

a substance used to make a drug that becomes an active ingredient in the finished dosage form of the drug. Bulk substance is not an FDA approved product Final product is not the equivalent of an FDA approved product. ***Using an approved finished dosing form for compounding offers a major advantage to bulk substances.

Answer 230

By/under supervision of vet or pharmacist in licensed pharmacy Should only be done if FDA-approved drugs are not medically appropriate to treat the animal All substances meet USP standards Should not be a copy of an approved marketed drug Office stock should not be compounded from bulk substances except in limited instances Specific labeling requirements: “This is a compounded drug. Not an FDA approved drug.” Report adverse events to FDA

Answer 231

Only bulk drug substances identified on the FDA’s List of Bulk Drug Substances for compounding drugs for use in food producing animals. Copper glycinate is the only bulk compound listed for this use Includes drugs with sufficient scientific information to establish a WDT.

Answer 232

Present human or animal health concerns For Food producing animals Copies of FDA-approved or indexed products Distributed as office stock

Answer 233

Office Use- Obtaining a compounded medication not pursuant to a patient-specific prescription to keep on hand for use in future patients Compounded products are unique medications to address a specific patient’s needs Not regulated like manufactured products Sometimes necessary to have on hand to allow therapy to start immediately Don’t have a lot on hand → like a drug distributor Can have office stock compounded from FDA approved products on-hand If compounded from bulk, must be on approved list and only for non-food producing animals.

Answer 234

Lacks stability Stability: “extent to which a dosage form retains, within specified limits and throughout its period of storage and use, the same properties and characteristics that it possessed at the time of its preparation” USP 34/NF 29 Too much Drug/too little drug Compounding can change how much drug concentration there is Toxic excipients Not bioavailable Failure of Drug Delivery Reformulation generates a new product Usually affects absorption Oral Formulations Are there FDA approved oral formulations? Destruction by gastric acid Extensive first pass effect Physiochemical properties of the drug

Answer 235

Expiration dates - FDA drugs Determined based on product-specific studies Specific formulation Specific container Possible conditions Conventionally manufactured drug Product Beyond-Use Dates- Compounded drugs Full stability studies generally not performed Based on data for similar products or USP default dates Compounded product Both- Indicates when a drug should no longer be used Whichever is shorter should be used as reference

Exam 2 Flashcards

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