Pharmacology 1

Ondansetron HCl (Zofran®) Dolasetron Mesylate (Anzemet®) Adverse Effects and Contraindications

- Both are well-tolerated - Dolasetron prolongs all ECG intervals (ondansetron less so) - Use very cautiously in patients with arrhythmias -> Including those due to electolyte abnormalities, esp. hypokalemia -> In patients undergoing chemotherapy, avoid if high, cumulative doses of doxorubicin have been used previously (dox causes cardiac damage) - Ondansetron is eliminated from the CNS by P-glycoprotein in humans - Dogs (?) - Still, use with caution in breeds known for MDR1 mutations Constipation and sedation

Neoplastic Hyperadrenocorticism - Treatment Mitotane

- Destroys zona reticularis and fasiculata - Usually doesn't reduce mineralocorticoid production. - Typically dosed until cortisol level normalize (basal and following ACTH stim test) - If dosing continues past normalization, it causes Addison's (follow-on TX coming up) The adverse effect of mitotane is creation of an Addisonian patient by ... pharmacodynamic overextension.

microtubule stabilizing agents Adverse Effects • Neurotoxicity

- Dose limiting toxicity for all drugs in this class -screw up microtuble function = screw up neural function - Mechanism is thought to be due to interaction with axonal microtubules - Vincristine > vinblastine - Signs o Hamilton et al. JAVMA. 1991 o Rapid Onset o Difficulty with locomotion, paresis, and voice change o Improvement following discontinuation of drug. (not irreversible)

S-adenosyl-methionine (SAMe) Pharmacokinetics

- Administered PO, bioavailability depends on formulation - Tolysate salts have ~1% bioavailability - 1, 4-butanedisulfonate salts have ~5% bioavailability - Most manufacturers won't tell you which it is BA at 1-5% is very low, usually wouldn't even consider giving something that low. Would normally be given IV at that low of a BA- but not what this is! NO EFFICACY STUDIES Denosyl® has been shown to reach plasma maximum in 4hrs in dogs and fasted cats. - Otherwise, per the endogenous molecule Adverse Effects and Contraindications - minimal to nonexistent (endogenous)

Disease Highlights -Dogs

- B. canis, B. gibsoni, and B. conradae - Typically in subtropical locations (gulf states) - ~20% of dogs in FL test positive for Babesia DNA - Most dogs are asymptomatic - TX: azithromycin + atovaquone (hydroxyquinolone)

Additional factors to help the selection

1. A bactericidal compound may be preferable to a bacteriostatic compound in immunocompromised patients (and on corticosteroids). 2. Toxicity and cost limit the selection of an antimicrobial drug. 3. In food-producing animals, residues in milk, eggs, and meat requiring withdrawal times before slaughter (preslaughter withdrawal times) are very important and limit the use of specific antimicrobial drugs • Animals must not be slaughtered within the preslaughter period • It should be appreciated that the plasma concentration governs the dosing intervals on a treatment regimen but it is the tissue residence times that govern the preslaughter withdrawal times in production animals.

A "Good" Ectoparasiticide Should...

1. Be an effective adulticide AND repellant 2. Persist at an effective dose on the skin for an extended period of time • Promotes compliance • 1-3 mos. is rule of thumb 3. Be stable in sunlight, shampoo, and water 4. Cause minimal contamination in the local environment • Reduces risk of resistance development

General aspects of topical ectoparasiticides

1. Commercial products combine multiple agents (not just the drug) • liquid formulations contain spreading agents (oils and alcohols) • PVC slows release of agents in collars and ear tags (remove ear tags before slaughter) -have a lot of drug in them! (for a cow for 1-3 months) 2. Individual agents are large molecular weight a. slow dermal absorption b. low systemic bioavailability - increased by ingestion following licking --can be an advantage if the drug needs to get into systemic circulation c. large volumes of distribution d. long tissue and plasma half-lives -helps keep effective dosage high 3. Advantages • Avoid degradation in the GI tract • Avoid first pass metabolism in the liver 4. Disadvantages • Risk of overdose - client non-compliance (overuse) - licking behavior (if applied topically and has low BA - never Therapeutic index - can result in toxicity • Prolonged withdrawal times in food animals

Diabetic Ketoacidosis Treatment

1. Correct dehydration a. usually 0.9% saline b. May add in glucose to prevent hypoglycemia following initiation of insulin treatment 2. Administer Short-acting Insulin a. regular human insulin (Humulin-R®, Novalin-R®) or lispro insulin (Humalog®) b. administered CRI (preferred) or IM c. immediate onset of activity, reaching a max at 30min - 2hrs. d. rate will depend on the plasma glucose concentration and decrease as glucose decreases. 3. Correct electrolyte imbalances 4. Correct acidosis

Two methods to inhibit GH secretion:

1. Decrease levels of GH-RH -and hope tumor responds 2. Increase levels of GH-IH -and hope tumor responds Always easier to increase than decrease something

Hyperadrenocorticism - Testing Low Dose Dexamethasone Suppression test

1. Dexamethasone (Azium®, Dexasone®) a. Pharmacodynamically 1) Long acting, strong glucocorticoid (30x cortisol) 2) Suppresses ACTH and CRH, should reduce circulating cortisol. b. Pharmacokinetically 1) administered IV 2) t½ ~ 2-5hrs (dogs), effective for 48hrs (measure at 4 & 8hrs) 3) ADME is uncharacterized 4) This corticosteroid is used because of the strong response and it can be discriminated from cortisol 2. Results a. If cortisol levels in 8hr samples remain high, its consistent with hyperadrenocorticism b. 4hr samples can be useful to discriminate pituitary from adrenal tumors.

Laxatives - Types and Mechanisms

1. Emollients lubricate feces (poop lube) - mineral oil 2. Surface acting agents dissolve feces (poop soap) - docusate and soapy water enema 3. Bulk forming prevent reabsorption of water/electrolytes (absorb liquid and take up space- proved hydration an promote motility -small boluses cause motility) - psyllium and canned pumpkin 4. Osmotic agents enhance secretion of water/electrolytes - polyethylene glycol 3350

Regulation of Prescription (Labeled Use)- A prescription is required if:

1. The labeled use can not be easily understood by a lay person, OR 2. A professional (ie. veterinarian) is needed to diagnose the disease AND a. monitor the patient for response to the drug OR b. adverse effects.

Recommendations for limiting resistance

1. Use drugs that are indicated for the species you're treating • Get comprehensive lists of susceptible worms from manufacturers • Stay up-to-date on which nematodes are susceptible to which agents 2. Give the full treatment course (usually two treatments) -usually two treatments; 1st reduces the reproducing adults and the 2nd removes larvae that were not mature in the 1st administration 3. Rotate between indicated drugs • After a course of one drug, consider using a different one next season 4. Treat at defined thresholds. • Plan with owners and treat at pre-arranged burdens; know the number of worm burden that is the cut-off - FEC 5. Monitor parasite levels in patient populations/herds • This is the only way to assess response to treatment -stop if not working- just causing resistance- pick something else

ELDU regulation guidelines (7)

1. Veterinarians must adhere to labeled use, unless they judge it is ineffective. 2. ELDU is ONLY allowed for FDA-approved animal or human drugs Human drugs - listed in the FDA "Orange Book" Animal drugs - listed in the FDA "Green Book" 3. A human drug can't be used if an animal drug can be used for the indication (until proved that none of the animal drugs have worked) 4. Requires veterinary supervision and an active VPCR 5. Can't be administered in food, but it can in water 6. In particular for food animals: a.) Only for therapeutic use, NOT for production b.) Can't result in any tissue residue that may be a risk to public health. c.) In the absence of scientific data on human food safety, the animal must be kept out of the food supply ex: don't know half life of gabapentin in goats, so they can never be used in production when given that drug 7. Use of an OTC in a way that isn't labeled is "technically" ELDU - consider prescribing.

Indications for use of Gonadotropin-releasing Hormone and human Chorionic Gonadotropin in males.

1. correction of cryptorchidism (Objective 3) 2. determination of remnant testicular tissue in castrated cats and dogs (Objective 4)

Indications for use of Gonadotropin-releasing Hormone and human Chorionic Gonadotropin in males

1. correction of cryptorchidism (Objective 3) 2. determination of remnant testicular tissue in castrated cats and dogs (Objective 4) draw blood- admin hCG or Gonadorelin- wait 60-90 - draw more blood - sent off to measure testosterone -low= castrated animal -testosterone spike= intact male 60-90 how long it takes to feed back and shut down that pathway

Steps of steroid hormone activity

1. diffusion through membrane lipids 2. binding to cytoplasmic receptors folllowed by nuclear translocation 3. Binding of hormone-receptor complex to DNA 4. gene activation 5. translation and protein synthesis (change, block, lead to production of RNA) 6. Target cell response either on itself or another target cell Cell now has new proteins and new functions intracellular

protamine zinc insulin (cont.) BCP - PZI

100% bovine insulin. BCP is a compounding pharmacy subsidiary of Vetpharm, Inc. • consistent manufacturing is critically important for reliable glucose control. • monitoring patients on a compounded product is critical.

Regulation of Prescription (Controlled Substances) Classes-

1970 - Comprehensive Drug Abuse Prevention and Control Act (CDAPCA) • Class I - no medical use (LSD, marijuana, heroin, etc.) (most addictive) • Class II - hydromorphone, fentanyl, pentobarbital, etc. • Class III - ketamine, Telazol®, zolazepam, etc. • Class IV - phenobarbital, diazepam, butorphanol, etc. • Class V - not many in veterinary use

Neoplastic Hyperadrenocorticism - Treatment Ketoconazole

- Inhibits 17a-hydroxylase (P450-like) - Causes idiopathic hepatopathy (esp. in cats) - Usually used as an antifungal; so, patients with fungal infections may show cortisol abnormalities

Aminoglycosides Mechanism of action Mechanism of resistance

30S, blocks initiation elicits premature termination incorp. incorrect AA acetyl, phosphoryl or adenylyl conjugation

Tetracyclines Mechanism of action Mechanism of resistance

30S, prevent binding the incoming charged tRNA "pump out"

Lactulose Pharmacokinetics & Adverse Effects and Contraindications

- The disaccharide is not absorbed by dogs and cats - Monosaccharides are absorbed and metabolized by glycolysis (Red flag!-->diabetes!) Adverse Effects and Contraindications • Flatulence, cramping, and gastric distension that abates over time with continuing treatment • Cats are adverse to liquid formulations, but will eat the crystal form when mixed with food. • Liquid formulations contain free galactose and fructose and may alter insulin requirements of diabetic patients

alkylating agents Specific Dose-Limiting Toxicities

- lomustine, mechlorethamine, melphalan, and procarbazine o myelosuppression and thrombocytopenia o CUMULATIVE myelosuppression for lomustine o Delayed effect (days to weeks) - cyclophosphamide: necrotizing hemorrhagic cystitis - cisplatin o leukopenia o lethal pulmonary edema in cats (9 out of 10 cats!) - NO CATS! o acute nephrotoxicity in dogs - carboplatin: only causes leukopenia- can be used in cats!

Adverse Effects dactinomycin

- myelosuppression (all lineages, dose-limiting) - diarrhea - ulcerative stomatitis - urate stone formation in dogs with SLC2A9 mutations (Dalmatians) - vesicant

Adverse Effects mitoxantrone (engineered to have lower toxicity)

- vomiting - diarrhea - anorexia - myelosuppression (dose-limiting)

4. Anaphylaxis Cont. - Vasodilation

-> Induces reflex tachycardia H1 receptors -- Have high affinity for histamine -- Induce NO release from endothelium -- Rapidly and short-acting on vascular smooth muscle/VSM -- Causes characteristic redness -- Blocked by competitive inhibition using H1 antagonists -diphenhydromine... in ER settings for anaphylactic shock H2 receptors (next pic) - Acts directly on VSM - Slower, sustained response; longer term response - Not typically treated with H2 antagonists Epinephrine- indirect processes that shuts down anaphylaxis

Macrolides Mechanism of action Mechanism of resistance

50S, inhibit translocation methyltransferases alter the binding site

Chloramphenicol Mechanism of action Mechanism of resistance

50S, inhibit transpeptidation inactivating acetyltransferases

Hyperadrenocorticism - Testing ACTH Stimulation test

ACTH Stimulation test 1. Cosyntropin (Cortrosyn®, in the CAC) a. Pharmacodynamically 1) amino acids 1-24 of ACTH (which has 39 total) 2) reduced immunogenicity compared to ACTH b. Pharmacokinetically 1) administered IV 2) peak effect occurs at ~60min in Dogs and cats, 30min in horses 3) ADME is uncharacterized 2. Results a. adrenals have increased capacity for cortisol production with neoplasia 1) An above normal range spike in serum cortisol levels in a hyperadrenocorticism suspect is consistent with the disease 2) False negatives are common 3) Can't discriminate AT from PDH b. Iatrogenic hyperadrenocorticism suspect is confirmed by no response to test, due to adrenal insufficiency

Short polypeptides and small proteins Pituitary gland-

ACTH, growth hormone (GH), MSH, Prolactin (PRL)

Short polypeptides and small proteins Hypothalamus-

ADH, oxytocin

b2-agonists s (albuterol) Pharmacokinetics

Absorption - Administered by inhalation in cats and horses (some absorption) - Cats dislike the taste of the drug and the hiss of the dispenser - Administered orally in dogs (well-absorbed) Distribution ??? Metabolism - hepatic Elimination - exhalation and urinary - t½ ~ 2.5-5hrs (human)

Hyperthyroid etiology and overlapping pathology

Adenomatous Hyperplasia of the thyroid • Associated with altered signaling sensitivity to TSH.- takes less hormone to get the same amount of thyroid response • Active adenocarcinomas can form in dogs and cats (much more common in cats). • High levels of dietary iodine or soy protein and chemicals used in food canning have also been implicated. -lots of causes - nothing we can point to as sole source Overlapping Pathology • A second, common, old cat disease is CKD. • Increased CO causes increased perfusion of the kidneys and increased GFR.- so may not see chronic kidney disease • Increased GFR can mask the otherwise low GFR of CKD. • Treating Hyperthyroidism can unmask cryptic CKD in an older cat.

Hypoadrenocorticism - DX

CBC/Clinical Chemistry - Selected • Sick looking dog with no stress leukogram • stress leukogram = neutrophilia, lymphopenia, monocytosis - cuz' there are no steroids • Hyperkalemia, hyponatremia, and hypochloremia -no aldosterone Pharmacological testing ACTH stim is gold standard • Cortisol levels will be low to start • ACTH won't induce any response

4. D 2/dopamine receptors

CRTZ • Agonist: apomorphine • Antagonist: chlopromazine and metoclopramide (mostly)

Maropitant Citrate (Cerenia®) Pharmacokinetics: Cats

Cats: - Linear - Bioavailability: 50% PO, 90% SC - Distribution -> 99% plasma protein bound - Hepatic Primary Metabolism (CYP1A and 3A isoforms) - Excreted via GI - t½ is age dependent -> ~15hrs in adults -> Faster in kittens <16wks

Summary

Diabetes Insipidus • vasopressin/anti-diuretic hormone Acromegaly • octreotide Milk Production • somatotropin Hypothyroidism • T4 Hyperthyroidism • methimazole • I31 Reproduction Both Genders • gonadorelin • chorionic gonadotropin • medroxyprogesterone acetate • megestrol acetate (not in US) Males Only • finasteride Females Only • progesterone • altrenogest • PGF2a • oxyto

Anthracyclines doxorubicin Chronic changes

Dilated cardiomyopathy in DOGS - oxygen radicals damage cardiomyocyte sarcoplasmic reticulum. - damage accumulation sets an upper limit on the total dose a patient can safely receive and is doselimiting - ABCB1-/- dogs are more susceptible (PGP) Chronic renal failure in CATS - oxygen radicals damage podocytes of renal glomeruli. - damage accumulates (dose limit isn't established)

Maropitant Citrate (Cerenia®) Pharmacokinetics: Dogs

Dogs: - Nonlinear - Bioavailability: Depends on dose and route - Distribution -> 99% plasma protein bound -> Accumulates with sequential administration - Hepatic primary metabolism (CYP2D15 and CYP3A12)- don't need to know - Excretion via GI - t½ is dose dependent - ~9hrs (1mg/kg, SC; labeled dose) - ~4hrs (2mg/kg)

Rabacfosadine Adverse Effects Contraindications

Contraindications • Existing Pulmonary Fibrosis • Chronic Pulmonary Disease leading to fibrosis • West Highland White Terriers (predisposed to pulmonary fibrosis) -because can cause this! Adverse Effects • Pulmonary Fibrosis and signs (eg. Tachypnea) • Cumulative Dermatopathy • Bone Marrow Suppression (all lineages at risk) • GI effects (diarrhea, vomiting, anorexia) • Lethargy • Tachycardia

Gastrointestinal Motility

Coordinated Movements - Segmentation: contractions in the small intestine, which isolate food boluses - Peristalsis moved contents caudally • Distention and obstruction cause local inhibition of contractile activity and anatomical blockage - Non-strangulating obstructions - Impactions • Pharmacological inhibition - Decreased by parasympathetic inhibition (slows motility) - Decreased by opioids - Leads to ileus

human chorionic gonadotropin Pharmacokinetics

Correction of Cryptorchidism Absorption • Digested in GI tract; so, IM administration. • Peak plasma levels occur after 6hrs. (peptides diffuse into circulation quickly but injected into muscle takes longer) Distribution • Primarily to testes in males and ovaries in females. • Large protein, ~26kDa, restricted to circulation. Metabolized in liver Elimination (Terminal t½ = 23hours) Adverse Effect is only hypersensitivity, no reported drug interactions

GnRH Pharmacokinetics

Correction of Cryptorchidism • Absorption - digested in GI tract; so, IM administration. • Distribution - Rapidly distributed to throughout the extracellular fluid following IV in pigs. • Metabolism is unknown • Elimination (t½ = 13min, pigs) No reported adverse effects or drug interactions Deslorelin (Suprelorin®) is another GnRH analog, but untested for this indication.

Corticosteroid homeostasis Adverse effects of glucocorticoid supplementation are due to pharmacodynamic overextension and look like...

Corticosteroid homeostasis is CRITICAL - imbalance in either direction is BAD HYPERADRENOCORTICISM -iatrogenic

Summary 1: Anti-Inflammatory Drugs (Atopy)

Corticosteroids -> review from last exam! • prednisolone • dexamethasone • hydrocortisone • isoflupredone • methylprednisolone • triamcinolone Janus kinase Inhibitor • oclacitinib IL-31 Inhibitor • lokivetmab Calcineurin Inhibitors • cyclosporine A • tacrolimus Dimethyl Sulfoxide 1st Generation H1 Antagonists • diphenhydramine • chlorpheniramine • promethazine • trimeprazine • hydroxyzine 2nd Generation H1 Antagonist • cetirizine (big part- does not cross BBB - good in horses)

alkylating agents Pharmacodynamics

Covalent bonding/cross-linking to DNA bases - single cross-links: procarbazine and dacarbazine (temozolamide) - double cross-links -modify both bases o cyclophosphamide, mechlorethamine, melphalan, cisplatin, carboplatin, lomustine, and mitomycin C o can form inter- and intra-base crosslinks • Guanine bases are cross-linked preferentially - deletion of modified guanines from DNA during replication - mispairing of modified guanines with thymine vs. cytosine during replication -destroys the bases, prevents replication and transcription • Ultimately, the agents cause enough mutation to induce cell apoptosis -some cancer cells that learn how to resist this • Importantly, these drugs affect cells in ALL STAGES of the cell cycle

Fleas

Ctenocephalides felis infests dogs and cats Blood sucking parasites Only leave host to lay eggs Adults live 2+ years Pupa - stable for up to a year in the environment - hatch in response to vibration Vectors D. caninum (Zoonotic tapeworm), D. reconditum, and Bartonella henselae, but not Y. pestis (vectored by X. cheopis)

Goals of cancer treatment

Cure = elimination of all cancer cells from the body (rare) • Induce remission = absence of clinical signs of disease -more common • Palliative treatment = pain reduction to improve quality of life - if remission is unattainable - if an elderly animal can have an improved quality of life and clients elect not to pursue remission • While a cure is the ideal goal, remission and palliation are both worthy goals Problem= animals present with what human physicians would call 'end stage' cancer- because we don't see all the signs

oxytocin (Oxytocin Injection and PVL Oxytocin Injectable) Indications:

Currently in the MWU clinic Indications • Induction/enhancement of uterine contractions at parturition (on label for dogs, cats, cows, and swine; extra-label in horses) • TX of retained placenta (on label in cows, swine, sheep, goats; extra-label in horses) • Postpartum metritis (on label, in cows, swine, sheep, and goats) - Persistent endometritis following mating (extra-label for horses) • Uterine involution following correction of prolapsed uterus (dogs) • Agalactia (dogs, cats, cows, swine) - most common use of this drug

Uncontrolled progression though the cell cycle is "driven" in cancer cells by mutations in...

Driver Mutations: Proto-Oncogenes o activating mutations o promote cell growth in the absence of growth signals -normal genes that become mutated and is turned on constantly - promotes cell growth in the absence of signals that tell the cell that cell growth is appropriate - Tumor Suppressor Genes o inactivating mutations o override checkpoints that prevent growth or cause cell death -take normal tumor suppressor gene and turn it off -normally suppress cells going through the cell cycle (abnormal cells) -mutations - can now get through next stage

Pyrantel pamoate/tartrate (Strongid T®, Nemex®, Drontal products®) Morantel tartrate (Rumatel®)

Drontal products, Strongid (paste), Nemex 2 (suspension) are in the MWU-CAC/EBC Indications • morantel - GI worms cows, sheep, and goats per levamisole (only live stock!) • pyrantel - GI worms - swine: A. suum, Oesophagostomum spp., and Hyostrongylus rubidus - horses: Large and small strongyles, O. equi, and P. equorum - dogs: Ancylostoma, T. canis and T. leonine - cats: T. cati and T. leonina

Calcineurin Inhibitors Cyclosporine A (Atopica®) Tacrolimus (Protopic®)

Cyclosporine A (Atopica®) - In the MWU-CAC - Labeled for atopic dermatitis - In dogs and cats - Systemic and topical formulations - Extra-label for keratoconjunctivitis sicca and autoimmune disorders --strong immunosuppressive drug Binds to cyclophilin and blocks calcinerin (which is activated when signaling occurs in a t cell) -blocks transcription and production of the IL-2 protein itself Tacrolimus (Protopic®) - Not in the MWU-CAC - Topical formulation for atopic dermatitis and auto-immune diseases - Ophthalmic formulations are compounded - All uses are extra-label (human drug)

Praziquantel Indications and Pharmacodynamics

Drontal-Plus and Drontal-Feline are currently in the MWU-CAC Indications (labeled unless otherwise indicated) • All tapeworms in dogs, cats, horses (extra-label). • Doses may vary based on age and species of the cestode. • Not approved for use in food animals. • Only drug effective against E. granulosus. Pharmacodynamics Altered intracellular calcium homeostasis, leading to.... Direct and indirect disruption of cellular metabolism, leading to... Tetanic paralysis and tegumentary (hardshell) breakdown, leading to... Host immune response, leading to... Dead tapeworms. Increases hosts immune response and breaks down shell

Anthracyclines doxorubicin - Early (<24h) -Intermediate (1d - 2w)

Early (<24h) o nausea and vomiting o histamine release w/possible anaphylaxis o ventricular arrhythmia (slow administration if it occurs) -listen to the heart while administering!! o acute GI toxicity -rapid kill of gi bacteria Intermediate (1d - 2w) o alopecia (hair re-grows; color may change) o thrombocytopenia and neutropenia (dose limiting) o tissue inflammation/necrosis (vesication) - occurs with extravasation during administration -MUST END UP IN THE VEIN - caused by oxygen radicals - mitigate with dexrazoxane (iron chelating agent) destroys tissue along fascal planes- can destroy thoracic cavity

Synergists Examples Pharmacodynamics Adverse effects

Examples • piperonyl butoxide • N-octyl bicycloheptene dicarboximide (MGK 264) Pharmacodynamics • block cytochrome P450 in insects • inhibit oxidative and hydrolytic metabolism • prevent enzymatic breakdown of pyrethrins -maintains toxicity for a longer period of time Adverse Effects • none associated with MGK 264 • piperonyl butoxide prevents breakdown of pyrethrins in cats and increases toxicity

Except for ______ and _________, all available antifungals target the cell membrane or cell wall

Except for griseofulvin and flucytosine, all available antifungals target the cell membrane or cell wall

Spinosyns

For Use in food animals For use in small animals* Spinosyn A/D (Comfortis®) For use in horses

Avermectins

For Use in food animals ivermectin (Ivomec®)† eprinomectin* (Eprinex®) doramectin (Dectomax®) For use in small animals* selamectin (Revolution®)† ivermectin (Heartgard®)† For use in horses ivermectin (Equimectrin®) *perscription dagger= in clinic

Milbemycins

For Use in food animals moxidectin (Cydectin®) For use in small animals* moxidectin (dogs only, ProHeart 6®) milbemycin oxime (Interceptor®) For use in horses moxidectin (Quest®)†

NOT TESTABLE Trypanosomiasis Disease Highlights

Four Possible Diseases: Chagas, Surra, Dourine, and Nagana Only Chagas Disease is endemic to the western hemisphere. Trypanosoma cruzi is the infectious organism. Vectored by Reduviid bugs. Infects puppies and kittens, and is ZOONOTIC. No treatments in animals approved for use in US

Administration and dosing guidelines

Glucocorticoid Replacement < Inflammatory Conditions < Immunosuppression ~Neoplasia • Cats tend to be more resistant than dogs and require higher doses Dosing Guidelines • Use the lowest effective dose and try reduction after problem is under control. • Treat for the minimum amount of time needed to control the problem. • Treated with a locally administered product instead of systemic product if available. • Use and alternating day dosing schedule if possible (reduces HPA suppression) • Plan an appropriate taper time length (monitor for HPA recovery and Addisonian crisis).

Summary

Glucocorticoids • prednisone • prednisolone • methylprednisolone (Medrol®, DepoMedrol®) • triamcinolone (Vetalog®) • dexamethasone (Azium®, Dexasone®) • hydrocortisone (Cortef®, Solu-Cortef®) • budesonide (Entocort EC®) • isoflupredone (Predef 2x®, Neo Predef®) • fluticasone (Flovent®) Mineralocorticoids • fludrocortisone (Fluorinef®) • desoxycorticosterone pivalate (DOCP; Percorten-V®) Diagnostic • cosyntropin (Cortrosyn®) • dexamethasone (Azium®, Dexasone®) Anti-adrenal agents • trilostane (Vetoryl®) • pergolide (Prascend®) • mitotane (o,p'-DDD, Lysodren®) • selegiline (l-deprenyl; Anipryl®)

Osteoarthritis

Glucocorticoids reduce the production of PGE 2 by synoviocytes and chondrocytes. Glucocorticoids directly suppress production of IL -1 and TNF - a . PGE 2, IL -1, and TNF - a all contribute to cartilage breakdown leading to synovitis and chondrocyte apoptosis.

GLUCOCORTICOIDS - anti-inflammatory actions (rapid onset)

Higher shutdown than NSAIDS -DO NOT COMBINE STEROIDS AND NSAIDS! increased risk of bleeding

Lice

Highly host specific - Species infecting dogs, cats, horses, poultry, pigs, and ruminants (do not tend to cross species boundaries) - Entire lifecycle is on the host, live on the host all year Two varieties: Chewing Lice/Mallophaga -Bovicola bovis Sucking Lice/Anoplura- Haematopinus eurysternus

A 14yo, neutered male DSH presents in your clinic with: • Polyphagia • Weight-loss associated with atrophy • Poor coat quality • Hyperactivity • PU/PD On palpation, may feel one of the thyroid lobes • Not pathognomonic, but should raise suspicion -if you don't feel it, doesn't mean you can rule out Diagnosis?

Hyperthyroidism Hyperthyroidism is the most common endocrine disorder of cats Occurs more rarely in dogs.

Oclacitinib Pharmacodynamics

In the MWU-CAC Labeled for treatment of pruritic atopic dermatitis in dogs Pharmacodynamics Competitive inhibitor of Janus kinases (Jak1 and Jak3) - Inhibits signaling in target cells due to inflammatory cytokines - No effect on Jak2 or RBC production - However, signaling between immune cells also relies on JAK1 and JAK3, and can be inhibited. IgE on mast cells-> release histamine AND cytokines -> IL-2 on Jak1 and Jak3 Jak2- intracellular molecule that binds erythropoeitin receptor - production of RBC (IL-2 little effect on Jak2)

Maropitant Citrate (Cerenia®) Indications and Pharmacodynamics:

In the MWU-CAC (Injectable and Tabs) Indications (FDA-approved) - acute vomiting in dogs and cats - motion sickness in dogs Pharmacodynamics: - Antagonist of NK1 receptors in CRTZ, Vomiting Center, and Periphery Most common anti-vomiting med used in vet

Imidacloprid(Advantage® products) Nitenpyram(Capstar®) Indications and pharmacodynamics

Indications • Fleas (fastest acting!!) - useful for fleas that are resistant to fipronil - imidacloprid = adults & larvae; kills within 1hr. - nitenpyram = adults only; kills within 30min (fastest anti-flea drug) Pharmacodynamics • Agonist of the insect postsynaptic, nicotinic AChR (NM) • Does not strongly react with the mammalian nAChR if have an animal with atopy- can give this and rule out the fleas as a cause of the atopy

Fipronil (Frontline Plus®, plus many more) Indications Pharmacodynamics Pharmacokinetics

Indications • Fleas, ticks, biting lice, ear parasites and Trombicula autumnalis Pharmacodynamics • Noncompetitive inhibitor (not reversible!) of Glutamate-activated chloride channels (GluCl) - present in nematodes, insects, and arthropods, but not mammals - causes rigid paralysis & CNS disruption (because similar to a gaba channel- inhibitor) Pharmacokinetics • Applied monthly for most applications, but sprays and eardrops are used as needed No reports of adverse effects in dogs or cats at 5x the maximum dose.

altrenogest Indications Pharmacokinetics

Indications • For luteal insufficiency in pregnant dogs and horses (extra-label) -corpus luteum does not secrete enough progesterone to maintain pregnancy • Synchronization of horses and sows (labeled) Pharmacokinetics (horses) • Administered PO • Bioavailability and volume of distribution are uncharacterized • Eliminated in the urine. • t½ = 2.5 - 4 hrs.

Nitroimidazoles

Metronidazole is in the MWU-CAC All uses are extra-label Use of these drugs in food animals is ABSOLUTELY PROHIBITED. • Due to mutagenic/carcinogenic potential Uses in treating giardiasis • Metronidazole and tinidazole used in dogs, cats, and horses • Ronidazole used in dogs Pharmacodynamics - prodrugs producing cytotoxic metabolites.

oxytocin - Pharmacodynamics Milk ejection reflex Ferguson reflex

Milk ejection reflex -Spinal Afferents activated by papillary duct stretch receptors - due to suckling- induces release of oxytocin- milk production- secretion Ferguson reflex -Spinal Afferents activated by cervical stretch receptors -oxytocin released from neurohypohysis acts on myoepithelial cells in cervix- spinal reflex acts to contract uterus

Pathology of Type 1 Diabetes mellitus

Most common cause of Diabetes mellitus in dogs • prevalence in dogs is increasing (19 - 24/10,000 between 1970 and 1999) • most recently 34/10,000 in 2014 (Mattin et al. Vet Rec. 2014) Prognosis • median survival 2 - 3 years • 80% develop cataracts within 5 - 6 months. Due to a loss of functioning beta cells • >90% loss is required before clinical signs become apparent • has a multifactorial etiology; - significant autoimmune component - genetics - acute, severe pancreatitis results is an ABSOLUTE REQUIREMENT for treatment with insulin for life

Functions of Thyroid Hormone

Neuroendocrine • Increased sensitivity to sympathetic stimulation • Increased stimulation of all other endocrine organs Cardiac • Increased CO (HR, contractility, and BP) Respiratory/Metabolic • Increased O2 and energy consumption (especially in young animals) • Increased erythropoiesis leading to increased O2 delivery • Maintains normal sensitivity of respiratory centers to O2 and CO2

Filling a Prescription/Labeling Extras:

Nice to have • Use child proof containers - especially if drug is dangerous • "Keep out of reach of children and animals" labels - also prudent

Nitrogen Mustards Platinum agents Methylating agents Other

Nitrogen Mustards • cyclophosphamide (Cytoxan®) • mechlorethamine (Mustargen®) • melphalan (Alkeran®) Platinum agents • cisplatin (Platinol-AQ®) • carboplatin (Paraplatin®) Methylating agents • dacarbazine • procarbazine (Matulane®) • temozolomide (Temodal®) Other • mitomycin C (Mutamycin®) • lomustine (CCNU, CeeNu®) These are alkylating agents

Summary

Insulins • porcine insulin zinc suspension • neutral protamine Hagedorn insulin • protamine zinc insulin • glargine insulin • detemir insulin Other • glipizide • metformin For Cataracts • Kinostat Hypoglycemia • octreotide • diazoxide

Regulation of Prescription (Compounding) Meaning: Rules:

Legalized by AMDUCA Compounding is a special form of ELDU • alteration of the original dosage form for ease of administration; or • because the labeled form is inappropriate for the intended purpose; or • because an approved drug does not exist (ex. KBr and cisapride). Rules: FDA determines what drugs can be compounded. Production must be by a licensed veterinarian or pharmacist. Production can not be from bulk drugs unless specified by the FDA.

Summary

Nitroimidazole ABX • metronidazole† • tinidazole • ronidazole Aminoglycoside ABX • paromomycin sulfate Tetracycline ABX • doxycycline† • chlortetracycline • oxytetracycline Lincosamide ABX • clindamycin† Azalide ABX • azithromycin† Ionophore ABX • lasalocid • maduramicin • monensin • narasin • semduramicin • salinomycin Sulfonamide ABX • sulfadiazine + trimethoprim • sulfadiazine + pyrimethamine • sulfadimethoxine • sulfadimethoxine + ormetoprim Benzimidazoles • albendazole • fenbendazole† • febantel† Triazine Derivatives • ponazuril • diclazuril Hydroxyquinolones • decoquinate • atovaquone Miscellaneous • imidocarb dipropionate • levamisole • nitazoxanide • meglumine antimoniate • amprolium • robenidine • halofuginone

H2 Antagonists

No FDA-approved veterinary products - Cimetidine (Tagamet®) - Famotidine (Pepcid®) in the MWU-CAC - Nizatidine (Axid®) - Ranitidine (Zantac®) Indications - PPI's have greater documented efficacy and are currently DOC - All have been used for reducing gastric acid secretion in small animals - Ranitidine has been used for ESGUS, less effective than omeprazole, but cheaper.

Psyllium Hydrophilic Mucilloid (Metamucil®)

Not in the MWU-CAC/many OTC products Indications (all extra-label) - Cats with impaction, generally resulting from insufficient fiber - Dogs -> Impaction resulting from insufficient fiber -> Idiopathic large bowel diarrhea (works by H2O absorption from the diarrhea, but doesn't treat the problem) -> Adjunct for hepatic encephalopathy (nitroginous buildup in blood because liver isn't doing its job), due to increased motility and changing GI microflora. - Horses with sand impactions -> DOC by some but known as completely ineffective by others -> Increases efficacy of mineral oil treatment -> Reduces blood glucose and insulin levels (270 g/day) in normal, non-obese, unexercised horses --> can be used as adjunct with insulin

Theophylline Adverse effects

Note: this drug has a low therapeutic index - CNS: nervousness, excitability (especially in horses), seizures - Cardiac: tachycardia to arrhythmia with very high doses - Muscular: ataxia and tremors - Urinary: PU/PD (weak diuretic) - GI: Nausea, vomiting, increased gastric pH (does NOT cause GI ulcers)

Organophosphates Carbamates

Organophosphates • Spray-ons/Dusts: fenthion, famphur • Ear tags: diazinone and pirimiphos • Collars: tetrachlorvinphos, diazinone, and dichlorvos • Dips: chlorpyriphos and phosmet Carbamates (rare group) • Shampoos/Dusts: carbaryl • Collars: propoxur

Nematodes of Veterinary Interest - 2

Other organs- -skin -> these are bigger worms -lungs- -heart- dirofilaria -eyes- horses- thelezia californiensis- frequent in cali- swim around in the vitreous fluid of eye

Other groups of drugs:

Over-the-counter (OTC) drugs -labeled use Prescription/legend drugs -labeled use -extra-labeled use -compounded -controlled Vaccines and Biologics -not really drugs -regulated completely differently

P-glycoprotein (P-gp)

P-gp is an ATP-dependent, broad specificity, cellular efflux pump. - Synonym: Cluster of differentiation 243 (CD243) - Gene: o Multidrug resistance protein 1 (MDR1, old terminology) o ATP-binding cassette sub-family B member 1 (ABCB1, current terminology) Homologues are expressed in many organisms, including most parasites In mammals, tissue expression includes: - brain capillary endothelium - small intestinal epithelium - biliary canalicular cells - renal proximal tubular cells - placenta and testes Brain- between BBB- kicks drug out, keeps blood levels higher Liver- hepatocyte takes it straight into the bile Kidney- nephron - tubules- pushes drug from blood into the urine for elimination Gut- blood gi barrier- kicked back out into the lumen

Preventing Errors- Route Abbreviations

PO - per os, by mouth SQ - subcutaneous IV - intravenous IM - intramuscular These are fine for other medical professionals, NOT CLIENTS!

Diabetic Ketoacidosis Pathology Signs

Pathology • results from prolonged, uncontrolled hyperglycemia • causes chronic ketone body formation by the liver • ketone bodies are strong acids • net result is severe metabolic acidosis Signs • lethargy/depression/coma • dehydration (can be severe due to prolonged PU) • unkempt hair coat • muscle wasting • hepatomegaly • plantigrade stance in cats, cataracts in dogs • acetone on the breath (occasionally)

I 131 Pharmacodynamics Considerations

Pharmacodynamics • Radioactive iodine concentrates in thyroid colloid. (radioactive thyroglobulin) • low energy beta particles destroy cells surrounding the colloid, but aren't powerful enough to destroy the C-Cells (significance?) -destroys ability of animal to make thyroglobulin but doesn't effect ability to regulate ca Considerations • Irreversible treatment; so the current recommendation is to treat with methimazole first to assess CKD status, because methimazole is reversible. • State regulations determine the period of time an animal must be housed following treatment to minimize client exposure to radioactivity (days to weeks) - peeing/pooping radioactive substance- which can effect owner

The Risk of Hypokalemia in DKA Patients Pharmacodynamics Adverse effects

Pharmacodynamics • prolonged PU leads to hypokalemia due to potassium wasting by renal tubules • insulin increases the activity of Na-K ATPase in cell membrane leading to cellular uptake of potassium. Adverse effects Hypoglycemia - so administer potassium solutions with dextrose.

Psyllium Hydrophilic Mucilloid Pharmacodynamics Pharmacokinetics Adverse effects

Pharmacodynamics (bulk-forming) - Non-absorbed fiber that retains water in the intestines and - Increased mass of non-digestible material in the bowel stimulates motility; decreases intestinal transit time, and increases frequency of defecation Pharmacokinetics - Administered orally, not absorbed - Slow-acting, laxative action takes up to 72 hrs Adverse effects - Esophageal obstructions in foals - Blockage and intestinal mucosal damage in rabbits - Obstruction if given with insufficient H2O (absorbs water out of GI)

Imidocarb dipropionate Pharmacodynamics Pharmacokinetics Adverse Effects

Pharmacodynamics - DNA denaturing agent Pharmacokinetics (horses) • Administered IM or SC • Rapidly distributed, undetectable in plasma after 12 hours • Metabolism is unknown • Parent drug is detectable in urine for 1.5 days and feces for 10 days following administration. - stored somewhere in the body as a depot drug is slowly released over time Adverse Effects • Injection site pain/inflammation • Cholinergic signs • Renal tubular and hepatic necrosis (rare) -make sure have good hydration

Polyethylene Glycol 3350 Pharmacodynamics Pharmacokinetics Adverse effects

Pharmacodynamics - draws water into intestines Pharmacokinetics - Administered PO (powder), naso- or oro-gastric tube (solutions) - Acts within 1hr of administration - Minimal absorption Adverse Effects: - Products without added electrolytes draw Na+, K+, Cl-, and bicarbonate into intestines (so, give with food)

Glucocorticoid Treatment of Bovine Ketosis Pharmacodynamics Specific Agents

Pharmacodynamics - induction of gluconeogenesis Specific Agents • dexamethasone - abortifacient agent, increasing levels of fetal glucocorticoids signals parturition • isoflupredone - lower risk of abortion - may cause marked hypokalemia (cause unknown) • both are labeled for use in beef and dairy cattle

Pyrantel and Morantel Pharmacodynamics Pharmacokinetics Adverse effects

Pharmacodynamics - just like levamisole (muscular nicotinic receptor agonist) so don't want to combine with levamisole!) Pharmacokinetics • Absorption - Poor (morantel is worse than pyrantel), ONLY administered PO - Maintained in the GI tract of ruminants for up to 98 days- why we don't give it to them- sits in gut and is absorbed for a long time - Better absorption when given with food in small animals, due to slowed GI transit time. • Not distributed into milk. • Elimination is up to 40% in urine; so, be aware of renal status. Adverse Effects • None at treatment doses: LD50 ~ 7xED50 (pyrantel), ~ 210xED50 (morantel) -safer drug than levamisole • Horses tend to tolerate the tartrate salt better than the pamoate salt.

Classes of Insulins Short acting:

Pharmacodynamics: acts on the same targets as endogenous insulin. Short-acting - • regular insulin • used for emergencies • administered IV • duration of effect is 1 - 4 hrs • Novolin-R is in the clinic for emergency use

Apomorphine HCl (Apokyn®) Pharmacokinetics Adverse Effects Contraindications

Pharmacokinetics - Absorbed topically (conjunctiva), IM, or IV - ~20 min is the mean time to emesis (IV) -- Range = 1 - 210 min -- Recovery ~ 50% of material -- H2O2 is pretty comparable (3%) - Hepatic conjugation - Urinary excretion Adverse Effects - Protracted vomiting (rinse conjunctiva) - Lethargy - Hypersalivation Contraindications - Seizures, obtundation, comatose - Abnormal pharyngeal/gag reflex (risk of aspiration) - Rabbits (don't vomit!)

Trilostane Pharmacokinetics Adverse Effects

Pharmacokinetics - Absorption: variable following PO administration - Metabolism: hepatic - Distribution and Elimination: poorly characterized - PU/PD resolves in ~ 4wks, skin pathologies ~4mos Adverse effects - Hypocortisolemia - lethargy, anorexia - Possible hyponatremia (may dec. aldosterone) - Gastrointestinal - vomiting, diarrhea - Adrenal gland necrosis (very rare)

N-butylscopolammonium bromide Pharmacokinetics Adverse Effects and Contraindications

Pharmacokinetics - Administered IV (slowly, FDA-approved) or IM (extra-label) - Labeled use is only a single dose --for gas colic - used to get over the gas colic - Hepatic metabolism - Eliminated in urine and feces; t½ ~ 6hrs Adverse Effects and Contraindications - Tachycardia - Transient pupillary dilation - Tacky mucous membranes - Ileus - Overdose looks like?!? --overdose of atropine, racing heart, no gi motility (makes colic worse), not sweating

Erythromycin (Gallimycin®) Pharmacokinetics Adverse Effects and Contraindications

Pharmacokinetics - Administered PO - Bioavailability depends on species, presence of food, and salt form - Well distributed, but does not cross the BBB - Hepatic metabolism - Excreted in feces, with some enterohepatic recirculation - t½ = 60 - 90 min in dogs and cats -the dose you need as an antibiotic is much larger than the dose needed for this Adverse Effects and Contraindications - Stimulation of larger food particles into the intestine may cause intestinal distress - Macrolide antibiotics may cause toxic enterocolitis in rabbits, gerbils, hamsters, and guinea pigs. - GI perforation, obstruction, or hemorrhage

Cisapride (formerly Propusid®) Pharmacokinetics Adverse Effects and Contraindications

Pharmacokinetics - Administered PO - Bioavailability: 30% on average (cats) - Widely distributed and highly bound to plasma proteins in humans - Metabolism and excretion are poorly characterized in small animals. - t ½ ~ 5hrs in cats - Promotility effect of a single dose is ~ 7hrs in dogs Adverse Effects and Contraindications - Occasional vomiting, diarrhea, or abdominal pain - Potential for increased Q-T intervals (that's why it's off market) --negative cardio effects - GI perforation, obstruction, or hemorrhage

Loperamide (Imodium®) Pharmacokinetics Adverse Effects Contraindications

Pharmacokinetics - Administered PO - Generally, per opioids - Minimal distribution across the blood brain barrier - Substrate for P-glycoprotein Adverse Effects - Constipation - Bloat - Sedation (can be) Contraindications - Ileus - Head trauma/increased intracranial pressure - Collies or other breeds with MDR1 mutations -> May cause severe depression -> Reverse with naloxone collies can't metabolize it, so when it gets into the brain, it is not pumped out (lacks glycoproteins, AKA pump) builds up and get a full opioid effect

Sulfasalazine (Azulfidine®) Pharmacokinetics Adverse Effects

Pharmacokinetics - Administered PO - Mesalazine and sulfapyridine are absorbed from the GI tract - Hepatic metabolism - Urinary excretion Adverse Effects - Potential for salicylate toxicity/hemolytic anemia in cats (rarely used) -due to glucuronidation - Keratoconjunctivitis sicca in dogs (especially Doberman Pinschers, sulfonamide toxicity) - Polysystemic immune complex disease (also Dobbies, sulfonamide toxicity)

Docusate Pharmacokinetics Adverse effects

Pharmacokinetics - Administered PO (dogs and cats, bitter taste) or via nasogastric tube (horses) - Absorption from small intestine with elimination in the bile (enterohepatic recirculation) - Amounts of absorption, metabolism, half-lives poorly defined Adverse Effects - Esophageal irritation (soap - tastes bad) - Colic, diarrhea, and intestinal mucosal damage (serious in horses with overdose) - Closely monitor patients with preexisting electrolyte or fluid abnormalities - Increased mineral oil absorption may occur in small animals when used in combination -mineral oils can cause granulomatous reaction - when drug gets into the system

Omeprazole (Gastrogard ®, Prilosec®) Pantoprazole (Protonix®, Pantoloc®) Pharmacokinetics Adverse Effects and Contraindications:

Pharmacokinetics - Administered PO (omeprazole) or IV (pantoprazole) - Omeprazole is absorbed from the gut (t½ ~ 1min in humans) (so don't crush to powder!) - Primary hepatic metabolism and elimination in the urine - Maximal efficacy requires 3-5 days (omeprazole) and 7 days for pantoprazole Adverse Effects and Contraindications: Both are well-tolerated Note: omeprazole capsules contain coated granules that protect the drug in the stomach. Crushing them will reduce efficacy.

Metoclopramide HCl (Reglan®) Pharmacokinetics Adverse effects

Pharmacokinetics - Administered PO, IM, SC - Poorly characterized Adverse Effects - Aggressive behavior (so don't use in horses) - Changes in mentation (hyperactivity/restlessness to depression) - Constipation - Increased detrusor muscle tone (increases urination)

Sucralfate (Carafate®) Pharmacokinetics Adverse effects

Pharmacokinetics - Administered PO, unpalatable - Not absorbed, so none per se. - Impairs oral absorption of many drugs, separate dosing by at least 2hrs. Adverse Effects - Occasional vomiting in cats - Constipation due to AlOH - No known contraindications

Corticosteroids (fluticasone) Pharmacokinetics Adverse effects & Contraindications

Pharmacokinetics - Administered by inhalation (30% bioavailability in humans) - Distributed everywhere (VD ~ 4.6L/kg in humans) - Metabolized by P450 enzymes in the liver - Eliminated by exhalation, and as intact drug and inactive metabolites in feces. Adverse Effects and Contraindications - Pharyngitis and upper respiratory infection - Suppression of the HPA axis (worse in dogs than cats and horses, at about a month) --why its used to get horse over the hump and then use another drug - Not for use in acute asthma attacks (may even cause bronchospasm) - Hypersensitivity - Liver insufficiency - You have to taper when switching between inhaled and systemic corticosteroids

Mineral Oil Pharmacokinetics Adverse effects

Pharmacokinetics - Administration/Absorption - nasogastric tube or rectal - absorption ranges from trace to 60% - Distribution, Metabolism, and Elimination of absorbed mineral oil is poorly characterized. --highly soluble Adverse Effects - Aspiration pneumonia (NG tube) especially with oral administration - Leaking (issue with indoor pets and rectal lesions - poop lube!) - Granulomatous reactions in liver, spleen, and mesenteric lymph nodes

Ipratropium bromide Pharmacokinetics Side Effects and Contraindications

Pharmacokinetics - Administration: Inhalation - Bioavailability: low - Distribution: low - Metabolism: low (not soluble- not a lot in circulation) - Excretion: exhalation (supplied through inhalation) Side Effects and Contraindications (Rare) Hint: Low Bioavailability ≠ No Bioavailability) Highly lipid non-soluble drug like atropine vasoconstriction increase HR increased DI motility urinary retention increased IOP so..... hypertension arrhythmias colic urinary obstruction glaucoma

Bismuth subsalicylate (Pepto-Bismol®) Pharmacokinetics Adverse effects contraindications

Pharmacokinetics - Bismuth has negligible absorption - Salicylate is rapidly and completely absorbed. -> Widely distributed -> Undergoes secondary metabolism in the liver (glucuronylation, sulfation, and conjugation with glutathione) -> t½ ~8hrs in dogs, 38hrs in cats (never give to cats due to glucuronylation) Adverse Effects Contraindications - Cats due to hemolysis - Bismuth is radio-opaque

H2 Antagonists Pharmacokinetics Adverse effects and Contraindications

Pharmacokinetics - Most are administered PO (ranitidine SC, IM, IV; IV only in horses) - Absorption is... - Species specific: High oral bioavailability in dogs, but not horses - Somewhat drug dependent - Distributed throughout the body (low plasma protein binding and CNS permeation) - Metabolized by the liver - Excreted in urine - t½ ranitidine ~ 2hrs in dogs, 1.3hrs in horses - P450 inhibition: cimetidine >>> ranitidine (negligible with others) Adverse effects and Contraindications - Hepatic or renal insufficiency

Chlorpromazine HCl (Thorazine®) Pharmacokinetics Adverse Effects Contraindications

Pharmacokinetics - Routes: IV, IM, SC - Well-distributed with 95% plasma protein binding - Hepatic metabolism - Elimination -- Half-lives and routes are poorly characterized -- Substrate for P-glycoprotein Adverse Effects - Sedation/Lethargy - Tremors/Ataxia - Diarrhea and loss of anal sphincter tone - Hypotension - Contradictory excitation - Contradictory bradycardia - Lowers seizure threshold -dropping BP with bradycardia = not good!! Contraindications - Horses - Dog breeds with predisposition to MDR1 mutations

Silymarin Pharmacokinetics and Side Effects and Contraindications

Pharmacokinetics - Varies with preparation and formulation - Poorly characterized in dogs and cats Side Effects and Contraindications - Allergy to Asteraceae/Compositae plants (includes ragweed, marigolds, daisies) -animals that allergies to any of these plants are at risk of having an allergy reaction Note - Efficacy will vary with preparation - Denamarin® is silymarin combined with S-adenosyl-methione

Oclacitinib (Apoquel®) Pharmacokinetics Adverse Effects

Pharmacokinetics Absorption - ~90% bioavailable following oral administration Distribution - Vd ~ 1L/kg, plasma and interstitial space - 60-70% protein binding Metabolism - yes, that happens Excretion - t½ ~ 4hrs Adverse Effects - Diarrhea, vomiting, anorexia, polydipsia, and lethargy - Immunosuppression, neoplasia, and skin disorders are possible --> skin disorders- skin infection IL-2 also needed for immune cell cross talk so reduction in surveillance of immune system

anti-inflammatory drugs Piroxicam Pharmacokinetics Adverse Effects

Pharmacokinetics • 100% bioavailability • confined mostly to interstitial space (0.3 L/kg) • metabolized in the liver • eliminated in the urine (t½ ~ 40h) Adverse Effects • GI ulceration and renal papillary necrosis • TI is low (adverse effects are severe at 3x treatment dose) -so low that this is the only application for this drug

Toceranib (tyrosine kinase inhibitors) Pharmacokinetics Adverse Effects

Pharmacokinetics • Administered PO, with ~80% bioavailability • 94% plasma protein binding • Distributed intracellularly in all soft tissues • Metabolized by the liver • Eliminated from the GI tract (t½ ~ 17hrs) Adverse Effects • GI (anorexia, weight loss, diarrhea, pancreatitis) • BM suppression (anemia, neutropenia) • Changes in coat color, skin color nasal depigmentation • Thromboembolic disease and inappropriate bleeding (incl. GI)

Lokivetmab (Cytopoint®) Pharmacokinetics Adverse Effects (Per manufacturer)

Pharmacokinetics • Administered SC, at 2 mg/kg • Effective in ~75% of dogs for ~49 days (based on owner survey) • Comparable efficacy to cyclosporine A • Cleared by the reticuloendothelial/macrophage system -cleared by macrophages Adverse Effects (Per manufacturer) • Erythema (8% of dogs) • Anorexia (6.2% of dogs) Very new drug, little citation available Targets signaling itself

Piperazine Pharmacokinetics Adverse effects

Pharmacokinetics • Well-absorbed following PO administration (strong base) • Distributes into most tissues (except fat) • Metabolized by the liver • Eliminated in the urine Adverse Effects • Few at recommended doses • Dogs and cats (large doses): emesis, diarrhea, ataxia, muscle tremors, behavior alteration, and head pressing. • Horses: no effects at 6-7 times the treatment dose. -so fairly safe in hands of clients

glipizide Pharmacokinetics Adverse Reactions

Pharmacokinetics • administered PO • detailed pharmacokinetics haven't been investigated • insulin concentration peaks in 15 - 30 min, and returns to baseline in 1 -"several" hours. • 20-30% of cats respond (dependence of response on factors contributing to Type 2 DM haven't been investigated). Adverse reactions • promotes formation of toxic amylin fibers that kill beta cells • reduces likelihood of being able to induce remission (<20% of cats) • transient vomiting • hepatotoxicity • hypoglycemia • contraindicated in cats with renal insufficiency

somatotropin Pharmacokinetics Adverse effects

Pharmacokinetics • administered SC at 14-day intervals (depot preparation). • VD is unknown • metabolism and excretion is per the endogenous protein (t½ ~ 20 min) (this is a cow protein - putting a cow protein in a cow) • withdrawal time = 0 days Adverse Effects • implicated in mastitis and laminitis in food animals, but not conclusive evidence • diabetes mellitus and acromegaly in dogs -overdosed pituitary dwarfism dog

Pharmacokinetics Dosing Adverse Reactions

Pharmacokinetics • depends on the type of insulin • all are metabolized by liver and kidney • can have significant dose to dose variation in individual response to the same insulin. Dosing • there are two insulins labeled for veterinary use (40 U/mL) • all other insulins are labeled for human use (veterinary use is extra-label, 100U/mL) • if you can dilute the insulin, use the manufacturer's diluent. Adverse reactions • hypoglycemia • local or systemic immune reactions

Terbinafine (Lamisil) Pharmacokinetics Adverse effects

Pharmacokinetics • oral terbinafine will lead to plasma concentrations exceeding the MICs for most fungi except Sporothrix • distributed to skin and into the sebum. • over 99% of drug in the plasma is bound to albumin. • drug in the circulation is metabolized in the liver into demethylated, deaminated, and dealkylated conjugates, which are excreted into urine. Adverse effects • unlike azoles, terbinafine does not block cytochrome P450 enzymes when administered orally or topically • appears to be well tolerated by animals

Imidacloprid(Advantage® products) Nitenpyram(Capstar®) Pharmacokinetics (Nitenpyram) Adverse Effects

Pharmacokinetics (Nitenpyram) • administered PO (100% bioavailability) • t½ ~ 2.8 hrs in dogs and 7.7 hrs in cats Adverse Effects • imidacloprid - nicotinic and hepatic effects if ingested (so admin topically) • nitenpyram - no effects when administered to dogs or cats at 4x the recommended dose

metformin Pharmacokinetics (cats) Adverse Effects

Pharmacokinetics (cats) • administered PO • bioavailability is 35 - 70% • VD = 0.55L/kg • eliminated in urine with t½ ~ 12 hrs Adverse Effects • lethargy, inappetence, vomiting, and weight loss. • overdose can cause lactic acidosis • in one trial, 20% of cats died of undetermined cause • contraindicated in cats with renal insufficiency • does not cause hypoglycemia

Misoprostol (Cytotec®) Pharmacokinetics Adverse Effects and Contraindications

Pharmacokinetics: poorly characterized in veterinary species Adverse Effects and Contraindications - Transient diarrhea, vomiting, and abdominal pain are most common - Abortion (it's a prostaglandin!) -- Increases uterine contraction frequency and amplitude -- Relaxes and thins the cervix

Neoplastic Hyperadrenocorticism - Treatment Trilostane

Present in the MWU-CAC - Labeled for use in dogs, extra-label in cats and horses - DOC for small animal hyperadrenocorticism (pituitary or adrenal tumor in origin) Pharmacodynamics - Competitive inhibitor of 3β-hydroxysteroid dehydrogenase - Reduces, but doesn't eliminate, synthesis of corticosteroids in the adrenal gland - Effective in ~75% of cases

Coccidiosis Treatment Prevention

Prevention - sanitation is most important - keep food separate from housing - don't feed raw meat (Isospora spp.) Drugs - see FARAD.org for specific use class restrictions - used metaphylactically based on history of facility (=prophylaxis but in a herd) - don't prevent infection, but o prevent clinical signs o don't interfere with development of immunity

NOT TESTABLE Neosporosis Treatments

Prevention/break the transmission cycle - keep dogs out of cattle feed; stored or otherwise - keep dogs from ingesting placentas/fetuses from abortions. Drugs for dogs - sulfadiazine-trimethoprim (TMS) + pyrimethamine - clindamycin alone - clindamycin followed by trimethoprim-sulfadiazine (TMS) + pyrimethamine - note o treatments do not eliminate tissue cysts o only slow disease progression o should be initiated before extensor rigidity occurs

Remission in cats

Return to steady-state euglycemia in the absence of insulin treatment within days to months of initiating insulin treatment. Requires the presence of functioning beta cells; so, presumed to be due to correction of glucotoxicity and lipotoxicity. Associated with choice of insulin, low-carbohydrate diet, and strict monitoring Lasts for weeks to months • some cats may be able to achieve multiple remissions • relapse is associated with all of the things that cause Type 2 Diabetes in the first place.

Pharmacodynamics macrocyclic lactones

Noncompetitive agonist of glutamate-activated, chloride channel (GluCl) - present in nematodes and arthropods, but not mammals - glutamate is an INHIBITORY neurotransmitter in nematodes - stimulation of GluCl channels by ML's induces flaccid paralysis of somatic musculature and pharyngeal pump (can't eat now) - ML's also inhibit the reproductive tract of female nematodes (unknown mechanism) -reduces burden via inhibition of reproduction as well Agonist of GABA receptors (turns on the off signal) - found in the ventral nerve cord and head of nematodes - requires much higher drug concentrations than for GluCl inhibition - effects on mammalian GABA receptors may be the cause of toxic effects of ML's. -that we see in our patients

Pyrethrins/Pyrethroids Indications Types

None in the MWU-CAC/EBC Indications • fleas and ticks • 3rd (and 4th) Generation chemicals also have some mite and lice coverage 2nd gen and higher are very toxic to cats 1st gen are also probably toxic to cats

Amitraz indications Pharmacodynamics

Not currently in the MWU clinic (OTC) Indications • Generalized Demodex in dogs and demodicosis in cats (Mitaban®) • Fleas and ticks on dogs - Promeris®, Certifect® (spot-on), and Preventic® (collar) • Ticks, mites, and lice on swine and cattle (Taktic®, can kill horses and dogs) Pharmacodynamics • MAO inhibitor that acts preferentially in mites over mammals • Causes toxic catecholamine levels in mites -Catecholamine Metabolism -Inhibition of MAO pathways causes toxicity to INSECTS

diazoxide

Not currently in the MWU clinic (requires compounding) Indication Insulinomas in dogs and ferrets (extra-label) Pharmacodynamics Opens potassium channels in beta cells, causing hyperpolarization, inhibits insulin release Pharmacokinetics • t½ ~ 5 hrs, dogs • renal elimination in humans (use carefully with CKD) Efficacy Controls clinical signs in 65 - 75% of dogs

Kinostat

Not currently in the MWU clinic (still in trials) Indicated for prevention of cataracts in diabetic dogs. Pharmacodynamics= pic • produced by Therapeutic Vision • currently in Phase II clinical studies (10 participating clinics, listed on website) • phase I clinical study results

Loperamide (Imodium®)

Not currently in the MWU-CAC -saved for cancer centers usually Indications (all are extra-label, no veterinary products) - Symptomatic treatment of diarrhea in DOGS only - Efficacy has only been shown with counteracting diarrhea associated with toceranib (Palladia®) treatment, also only dogs Pharmacodynamics - Synthetic opioid (µ-receptor agonist) - Inhibits GI motility and mucosal secretion

Emodepside

Not in the MWU-CAC Indications Labeled for Toxocara cati and Ancylostoma tubaeforme in cats Pharmacodynamics • Latrophilin receptor agonist (in nerves) (in black widow venom) - Induces release of PF1-like neuropeptide into synaptic cleft - PF1-like neuropeptide hyperpolarizes muscle cells in the nematode pharynx. - causes flaccid paralysis of muscles necessary for ingestion -> worms can't hang on or swallow their food Pharmacokinetics • Absorbed within 2hrs and reaching maximum circulating levels within 6hrs • Detectable in plasma for up to 28 days following administration Adverse Effects • Generally well-tolerated/minor, self-limiting effects in 3% or fewer in cats

Ipratropium bromide Pharmacodynamics

Not in the MWU-CAC (because used long-term for animals) - as with most of these drugs coming up All uses are extra-label Indicated for bronchoconstriction in... - horses (w/RAO, most common use) - small mammals (mostly feline asthma) Pharmacodynamics - Cholinergic Antagonist (a flavor of atropine) that - Inhibits parasympathetic tone, which increases the effect of normal sympathetic stimulation (bronchial airway expansion) - More "fight or flight" = more open airways

Corticosteroids (fluticasone) Pharmacodynamics

Not in the MWU-CAC last year Indications (all extra-label, no veterinary products) - Extra-label in dogs (upper tracheobronchial dz -AKA dog asthma) and cats (asthma) - Horses (RAO) -> $240/12g, Dosing is ~2g q12h; therefore, ~$500/wk... who does this?!? -> Alternatively, prednisolone (PO), dexamethasone (PO, IM), isoflupredone (IM) --all injectable cortical steroids -dex 30 times more potent than cortisol and no mineralocorticoid potency (no aldosterone fudging) Pharmacodynamics local, pulmonary immunosuppression reducing inflammation and epithelial damage.

Natamycin Therapeutic uses Adverse effects

Therapeutic uses • Natamycin is used topically primarily for ocular mycotic infections and is the drug of choice for treating equine fungal keratitis caused by Fusarium (in combination with other antifungals). • Extra-label • Antifungal therapy needs to be started early, be aggressive, and involve both topical and systemic therapy • A combination of topical voriconazole, oral fluconazole, and natamycin are recommended. Adverse effects • Adverse effects are rare • Corneal opacity, eye edema, tearing, eye hyperemia

Nystatin Therapeutic uses

Therapeutic uses • Nystatin is a feed additive in poultry to prevent crop mycosis and mycotic diarrhea. • Nystatin administered orally for oral or GI candida infections in dogs, cats, horses, reptiles and birds (all oral is extra-label) • Nystatin is a component of topical preparations such as Panalog, which also includes thiostrepton, a polypeptide antibiotic, and triamcinolone. Generally, nystatin is not used alone when administered topically. Many topical preparations that are veterinary labeled. Pharmacokinetics • Nystatin is not absorbed orally and is excreted in the feces. Adverse effects • Adverse effects are rare, occasional GI upset

lonophore antibiotics Therapeutic uses Pharmacokinetics. Adverse effects

Therapeutic uses • Monensin, lasalocid, and laidlomycin are administered as premixes or medicated feed for growth promotion, feed efficiency and control of coccidiosis in cattle and broiler chickens. • Salinomycin and narasin are administered as medicated feed to broiler chickens for prevention of coccidiosis. Pharmacokinetics. • ionophores are absorbed orally. Monensin absorption is 50% in ruminants. • rapidly and extensively metabolized by the liver and the numerous metabolites are excreted by bile and eliminated in the feces. • absorption is more complete and metabolism is slower in monogastric animals, especially horses, which may explain the greater toxicity in this species. Adverse effects • when used in species for which they are approved is uncommon • horses are the most susceptible species to toxic effects when accidentally exposed to ionophore-containing feeds.

Derivatives of tyrosine

Thyroid hormones secreted by thyroid gland -thyroxine (T4) Catecholamines Epi- adrenal medulla norepi- adrenal medulla dopamine -secreted by hypothalamus

TSH

Thyroid stimulating hormone from anterior lobe of pituitary gland to the thyroid gland -> thyroid hormones T3, T4

Glycoproteins -Pituitary gland:

Thyroid-stimulating hormone (TSH) Luteinizing hormone (LH) Follicle-stimulating Hormone (FSH) peptide= series of amino acids (short polypeptides= under 200)

Tulathromycin Azithromycin Clarithromycin

Tulathromycin • a single SC injection is claimed to be effective against bovine and swine respiratory infections, labeled. Azithromycin • used for susceptible infections in dogs, cats and foals • all uses are extra-label Clarithromycin • used for susceptible infections in dogs, cats, ferrets, and foals • all uses are extra-label

Ticks

Two varieties: -Hard Ticks- Dermacentor andersoni -Soft ticks- Ornithodoros coriaceus Cause disease by: - Exsanguination/Anemia - Infection 2o to bite wounds - Pruritus - Paralysis - Toxicosis - Disease Transmission

Organophosphates/Carbamates are ______ than plain-old AChE inhibitors toxicity additional concerns

WORSE Toxicity 1. SLUDGE(M) 2. Muscle spasms are followed by paralysis 3. Stimulation of the adrenergic system leading to vasoconstriction 4. Central effects leading to seizures and respiratory paralysis.... 5. ...and death. Additional Concerns 1. Sensitive breeds - Cattle: Brahman, Charolais, and Simmental - Dogs: Greyhounds and Whippets - Cats 2. Parasites are developing resistance 3. Environmental persistence- contributes to resistance 4. Highly variable withdrawal times (0-45d depending on the product)

detemir insulin

Was in the MWU-CAC last year. Use is extra-label Long-acting Insulin • duration of action is similar to glargine insulin • forms micro-precipitates following injection, like glargine, and • has increased plasma protein binding, which decreases elimination rate. Modified recombinant human insulin Does not precipitate when diluted with the manufacturer's diluent, water, or saline.

b2-agonists (clenbuterol) Pharmacodynamics Pharmacokinetics

Was in the MWU-EBC last year Labeled for treatment of bronchoconstriction in horses/RAO (no human products) Pharmacodynamics - Major action does NOT seem to be on bronchial smooth muscle - Activates b2 receptors on pulmonary macrophages (inflammation big part of RAO/bronchoconstriction), which inhibits cytokine release (IL-1b and TNF-a)- these lead to bronchoconstriction Pharmacokinetics - Absorption - ~80% bioavailability following PO administration - Distribution - 1.6L/kg (gets everywhere) - Metabolism - ??? - Elimination - urinary with a median t½ of 12.9h

Dimethylsulfoxide

Was in the MWU-EBC last year Indications - Labeled for reduction of inflammation secondary to trauma in dogs and horses (topical) - Commonly used as a systemic anti-inflammatory agent in horses (extra-label, IV) - Chronic endometritis in horses (extra-label, intrauterine) - Almost any other supposed inflammatory condition you can imagine (extra-label) - Anecdotally more effective for acute inflammation

Synergism:

When the inhibitory or killing effects of two or more antimicrobials used together are significantly greater than expected from their effects when used individually

desmopressin

Use for Treatment of CDI is extra-label (no veterinary products) Pharmacodynamics • synthetic vasopressin replacement (short half life of vasopressin is its downfall) • DDAVP: SCH2-CH2-CO-Tyr-Phe-Gln-Aln-Cys-Pro-(D)Arg-Gly-NH2 • Red groups extend life of drug in circulation. body doesn't know how to deal with D-isomers • Has 1000x more affinity for the V2 receptor than the V1 receptor and no vasoconstrictive effects

porcine insulin zinc suspension

Use in cats and dogs is FDA approved (on-label) In the MWU-CAC Intermediate-acting Insulin Produces two peaks of activity • 2 - 6 hrs and 8 - 14 hrs • due to a mixture of 30% short-acting and 70% long-acting insulin • normal insulin mixed with zinc crystals to slow absorption Porcine insulin has the same amino acid sequence as canine insulin

Prescriptions: Required Information

Your facility name, address, phone # Your name and credentials Client's name; pet's name Date Drug name and strength Quantity, refill instructions Directions for use DEA number if controlled substance -like an SSI don't include this on written prescription Your signature

Labels: Required Information; including:

Your facility name, address, phone # Your name and credentials Client's name; pet's name Date of issue and expiration Drug name and strength Quantity, refill instructions Directions for use Manufacturer Form (pill/capsule/liquid/powder) Important Warnings Don't need DEA number, In highlight = what is different from labeled

Effects on cAMP levels

activate adenylate cyclase - cAMP - activates kinase- opens ion channels and activates enzymes inhibition via- epi and norepi

Signs of AChE Inhibitor Toxicity

Salivation Lacrimation Urination Diaphoresis (sweating, except in...) GI distress (associated with diarrhea) Emesis (M)iosis and muscle spasms Additional effects 1. Bronchoconstriction (usually only asthmatics) 2. Bradycardia 3. Decreased BP (normally think of as not being a problem with parasymp stim) a. Reduced contractility b. Vasodilation

Insect Development Inhibitors Sentinel Indications Pharmacodynamics Pharmacokinetics adverse effects

Sentinel is in the MWU-CAC Indications: Fleas in dogs and cats Pharmacodynamics • Drug is consumed by fleas in blood meal and excreted, but not absorbed • Flea larvae feeding on adult flea feces ingest the drug • Drug inhibits production of chitin exoskeleton during pupal stage of development -no exoskeleton = pile of mush Pharmacokinetics • Administered PO (dogs, 40% bioavailability) and SC (cats) • Initially, accumulates in adipose tissue, and then, redistributed to plasma Adverse Effects: Injection site reactions (very severe in dogs)

Pharmacology

Study of agents used to treat, diagnose, and prevent disease Only way back to normal anatomy and physiology from disease is through pharmacology

Sulfa drugs inhibit: What organisms are highly sensitive to sulfa's?

Sulfa drugs inhibit both gram positive and gram negative organisms. The following organisms are highly sensitive to sulfa's: -Group A Streptococci, -Pneumococci, -Escherichia coli, -Nocardia (Mastitis, cutaneous/subcutaneous lesions, abscesses in organs, and pneumonia), -Actinomyces (Mastitis in sows), -Chlamydia (Conjunctivitis), -Pneumocystis jirovecii (Acute bronchointerstitial pneumonia in foals)

Sulfa -Antimetabolite

Sulfonamides, as antimetabolites, compete with paraaminobenzoic acid (PABA) for incorporation into folic acid. similar to PABA- so mimicks it to "fool" pteridine and folic acid is not synthesized

TRH TSH Idealized Diagnostics:

TRH = Thyrotropin releasing hormone TSH = Thyroid stimulating hormone (ie. Thyrotropin) Idealized Diagnostics: 1. Hypothyroid = decreased T4 and increased TSH 2. Hyperthyroid = increased T4 and decreased TSH decreased t3 and t4 -hypothalamus detects and releases TRH which acts on anterior lobe to release TSH -acts on thyroid gland to release T3 and T4 -high levels t3 and t4 supress TRH and TSH (long feedback loop)

Coccidiosis Specific Drugs (OTC options)

amprolium (all species) - pharmacodynamics: competes with thiamine (Vit B1) metabolism in parasites - pharmacokinetics: not characterized - adverse effects: thiamine deficiency, depression, anorexia, diarrhea, neurological signs (rarely) decoquinate (ruminants and birds) declazuril (birds only) robenidine - birds only - pharmacodynamics: competes with guanine metabolism in parasites- Interfering with DNA replication halofuginone - we don't know anything about how it works - birds ionophore antibiotics - ruminants and birds (monensin, lasalocid) - birds (maduramicin, narasin, semduramicin, salinomycin) dogs and cats - sulfadimethoxine + ormetoprim (dogs only) - sulfadiazine + trimethoprim sulfadimethoxine (all species)

Short polypeptides and small proteins C cells of thyroid-

calcitonin (CT)

Dimethylsulfoxide Adverse effects

can be pretty severe IV - Hemolysis and hemoglobinuria (because membrane destabilizing) - Diarrhea, muscle tremors, and colic - Odor (garlic/oyster-like) Topical - Burning sensation, erythema, vesiculation (in a high enough conc for a long enough time), local allergic reactions --> damage to corneal layer of epithelium

Lipid derivatives

carbon rings and side chains built from fatty acids or cholesterol eicosanoids steroid hormones

Life cycle of the heartworm

cats can self clear it as long as have functional immune worms susceptible to macros in L3-L4 stage

acytelcholine builds up

cause ca release- NO release- free diffusible gas- diffuses into the smooth muscle surround epithelial- activates guanylyl cyclase- activates PKG - inhibits contraction by inhibiting ca release =vasodilation and drop in blood pressure ach present in muscarinic, striated AND ganglia- symp affects if high enough concentration

Basic Synchronization Protocol

cidr device boosts estrogen - can move through esrus cycle- CL moves to CA - moves to end of ovarian cycle and remove CIDR device (all at same time) if has CL can lyse -can now all be inseminated

Treatment for anaerobic infections 1. Oropharyngeal anaerobic infections and lung abscesses (mixed)

clindamycin b-lactam/lactamase inhibitor metronidazole

The signs of acute intoxication in horses may include some or all of the following depending on dose and the individual:

colic, intermittent sweating, incoordination, muscle weakness, elevated heart rate, dark urine, kidney failure, respiratory distress and going down. Again, depending on dose and individual susceptibility, death can occur in less than 24 hours.

Short polypeptides and small proteins Adipose tissue-

leptin, resistin

Eicosanoids

lipid derivatives of arachidonic acid include: -leukotrienes -prostagladins -thromboxanes -prostacyclins Prostaglandin E Prostaglandin S2 Alpha

Bronchial tone

managed by beta 2! -direct effect on bronchodilation corticosteroids and clebuterol -inhibition of inflammatory components such as mucus secretion, inflammation and edema, smooth muscle contraction -reduce inflammation camp causes dilation component of bronchial tone -beta agonists - ATP -> AC with (+) on cAMP -cAMP broken down by phosphdiesterases (theophyline has (-) effect on PDEs- promotes dilation) theophyline also has (-) on adenosine (which causes constriction) Muscarinic antagonists (atropine) inhibits ach (which is a bronchoconstrictor)

Progestins Pharmacokinetics

medroxyprogesterone acetate (Provera®) megestrol acetate (Megase®, human product, veterinary product not marketed in US) Not in the MWU-CAC Extra-label use for all indications. Pharmacokinetics • medroxyprogesterone acetate - not determined in veterinary species. • megestrol acetate - well absorbed from GI tract - fully metabolized by liver - t½ = 8hrs in dogs

Derivative of tryptophan

melatonin secreted by pineal gland

Treatment for anaerobic infections 2. GI or female pelvic anaerobic infections (B. fragilis often)

metronidazole carbapenems moxifloxacin

Even though cephalosporins are quite effective against a wide variety of pathogens, it is important to remember that:

most Cephalosporins have no activity against the following organisms. ▪MRSA ▪List. monocytogenes ▪Enterococci ▪Atypicals (Chlamydia, Mycoplasma) (Ceftaroline is the only one effective against MRSA) because they do not have peptidoglycan cell walls

Piperazine Indications

nerve hyperpolarizing agents Not in the MWU-CAC • Rx formulations: Thenatol®, Ripercol®, Parvex®, Dyrex®, Equizole® • OTC formulations: Wazine®, Dizan®, Sergeants® Worm Away, and others Indications • Dogs and Cats: Toxocara spp. and Toxascaris leonina • Horses: Cyanthomes, ascarids, and pinworms (rarely used) • Pigs: Ascarids and nodular worms

TSH - how it works

no TSH - no t3 and t4 pendrin still able to transport I- into colloid TSH also stimulates lysosome -which breaks down TSH releases thyroglobulin into colloid

Plasma GnRH concentration

oscillates with peaks occurring every 60-90min LH and FSH driven by GNRH GNRH pulsed from hypothalamus every 60-90mins LH induces production of testosterone- induces changes responsible for male accessory sex characteristics Testosterone- neg feedback on secretion of FSH

Posterior lobe of pituitary gland secrete two hormones

oxytocin and ADH

Short polypeptides and small proteins Parathyroid gland-

parathyroid hormone

"Polyol pathway"

produces other indicators of hyperglycemia

late luteal

progesterone from ovary inhibits pituitary and hypothalamus oxytocin is secreted onto uterus PGF2a from uterus to ovary -kills corpus luteum 4-6 days corpus luteum becomes corpus albicans- no longer secretes progesterone- uterus is capable of secreted progesterone to maintain pregnancy by itself

Nematodes of Veterinary Interest - 1

roundworms- migrate to the liver then to the lungs- back to gi tract T. cati- visceral and ocular migration B. procyonis- in the brain P. Equorum- another big one

Rifampin Adverse effects

side effects are rare. hepatotoxicity may occur in animals with pre-existing liver disease. may produce red-orange colored urine, sweat, and saliva but this is not harmful

Fasciola hepatica life cycle

similar to tapeworms but snails as intermediate host

Three examples of resistance in H. contortus

small roundworm in small animals, sheep and goats 1. Number of drug targets decreases a. Expression of NM receptors is decreased in some strains b. Happened in response to treatment with levamisole c. Caused resistance to pyrantal, because of shared target (should expect resistance to morantel as well) 2. Affinity of target for the drug is decreased a. Altered b-tubulin structure occurs in some strains b. Causes resistance to albendazole 3. Elimination of the drug increases a. Increased p-glycoprotein (Pgp) occurs in some strains b. Causes resistance to albendazole and avermectins ( macrocyclic lactone)

Split Dose (3 application) Strategy

start avermectin-> NOT milbemycins because they kill so fast that they cause release of immune defense = anaphylactic response reduce activity of animal due to high risk of heart issues doxycycline at 1 month -abx -1 month prior to 1st dose melarsomine 1st melarsomine - adulticide kills all adults and juveniles that have matured (fast kill agent) -risk of anaphylaxis and thrombosis (chunks of worms floating aroung) -so cage rest and doxy to reduce inflammatory reaction 2nd and possible 3rd dose of melarsomine a month apart to kill rest of juvenile worms -stuck in cage whole time dx annually every year (test) + preventatives rest of lives Long and expensive treatment!

finasteride Pharmacokinetics

steroid hormone Absorption - Administered PO, 65% bioavailability Distribution - 90% bound to plasma proteins Metabolism - hepatic Elimination - t½ ~ 6hr No reported adverse effects, but may have interactions with anticholinergics.- atropine- can block effects of this

surge nucleus and tonic nucleus

stimulates pituitary - FSH/LH - on ovary ovary secreted estradiol Follicular- Tonic- releases gondatropin releasing hormone0 induces releases of FSH and LH - estradiol shuts down hypothalamus with estradiol Ovulation- surge nuc releases GnRH on pituitary -LH on ovary estradiol inhibits both pituitary and hypothalamus Luteal- LH on ovary- promotes secretory phase of uterus with progesterone

Role of the LIVER

stores glucose as glycogen when plasma glucose is high delivers glucose to plasma when plasma glucose levels drop. • glycogenolysis • gluconeogenesis

D. immitis "treatment gap" Timing for when to give drugs

susceptibility gap- period when nothing kills whats there Macros- L3-L4 --> only the babies are killed -alone cannot cure Melarsomine- kills adults Strategy= kill babies with macros and maintain on macros to block repro of adult worms, then kill adult worms -so have to weight for the juveniles that are not susceptible to macros to grow up into adult to be susceptible by melarsomine -maintain on macros to kill ALL babies

ADH regulated permeability channels

take osmolarity from 600 to 1200 secreted by posterior pituitary binds to ADH receptor - activates g protein - induces adenylate cyclase- atp to cAMP - protein kinase A stimulates fusion of vessicles containing aquaporin 2 with the cell, water can flow from lumen back into cytoplasm of collecting duct cell - aquaporin 3- pore allows water back into capillary from tubular cell no ADH- entire process shut down and ability to take in water is not there

Glucocorticoids at high doses

tend to hut down the immune system increased apoptosis- capable of killing immune cells (tx of bloodborne cancers)

Benign Prostatic Hyperplasia (BPH) in breeders

testosterone - enzyme 5alpha reductase leads to 5alpha-dihydrotestosterone- causes prostatic enlargement which can pinch off colon and urinary output can inhibit with finasteride - prevents production of testosterone to active form or Progestins- compete with 5a-dihydrotesterone with its receptor

Sulfacetamide

the only sulfonamide that can be prepared as the sodium salt at neutral pH and thus can be used in ophthalmic preparations.

Thyrotrope

thyroid stimulating hormone Na iodine symport in colloid- iodine tied to thyrogobulin through actvity of thyroid peroxidase becomes thyroglobulin activatefd with iodine (t3 or t4) breakdown of thyroglobulin within the lysosome - cleavage of peptide bonds - creates a t3/t4 molecule pumped into blood binding to TBG, transthyretin, and albumin

GI pathology

upper GI- vomiting -acute (infectious, induction, inhibition) or chronic (gastritis, pancreatitis, hepatitis) lower GI- constipation (impaction, obstruction (surgical) or illeus), diarrhea (infectious, drug induced, idiopathic colitis) Extra GI- tumor, obstruction, etc.

tyrosine kinase inhibitors

very commonly the receptors that respond to growth factors growth factors= one of the things cancer cells learn to ignore growth factor is needed to induce signaling -doesn't come together and signal unless GF is present cytoplasmic portions cross-phosphorylate -enzymatic function causes hydrolosis of atp -assembles signaling complex on inside of the membrane

What's really in the Bottle?

• A lot of supplements and similar products do not contain what the label says they do • They may be adulterated, poorly manufactured, etc • USP label is reassuring • DOES NOT indicate efficacy of the product US pharmacopeial convention - validates the product does what it says it does

Hallmarks of cancer

• A tumor is more than just a mass of cells progressing, uncontrolled, through the cell cycle -also include immune inflammatory cells, blood supply comes in (can't grow over a certain size without it), fibroblasts forming matrix for the tumor • Fraction of dividing cells in a tumor DECREASES as the tumor size increases - inactive cells "senesce", but can reactivate. - not all chemotherapeutic agents work on all cells

nucleotide analogs Pharmacokinetics

• Absorption - administered IV or SC (good bioavailability) - gemcitabine is IV only • Distribution - 0.67-1 L/kg (plasma and some interstitial distribution) - Amount passing into the CNS depends on administration rate (CRI > bolus) • Metabolism - converted to Ara-U (uracil) in liver and kidneys by cytosine deaminase • Elimination - urinary, t½ ~ 1.5 - 3h

Anthracyclines Pharmacokinetics

• Absorption - all are administered IV - other routes (including IP) cause local deposition • Distribution - rapid distribution to all tissues - excluded from CNS by P-gp (problem in...) - 75% is bound to plasma albumin • Metabolism - hepatic - doxorubicinol, (red death) major metabolite, retains biological activity • Elimination - doxorubicin o 40-50% of drug is excreted in feces (10% in urine) o Terminal t½ = 20-48 hours (detectable in waste for 14 days) -educate the clients about safely removing waste and limit where the go - mitoxantrone (humans) o 100% of drug is eliminated unchanged in urine o t½ ~ 5d -in environment for up to a month - dactinomycin o most is eliminated unchanged in urine and feces.

Nitroimidazoles Pharmacokinetics

• Absorption - good bioavailability following oral administration (50-100% in dogs and cats) • Distribution - extensive for metronidazole (includes bone and brain) - more restricted to circulation for tinidazole and ronidazole • Metabolized in the liver • Elimination - metronidazole t½ ~ 5-6hrs in dogs and cats - tinidazole t½ ~ 4.4hrs in dogs and 8.4hrs in cats - ronidazole t½ ~ 10hrs

Monobactams: Aztreonam (Azactam®)

drugs with monocyclic beta-lactam ring. • relatively resistant to beta-lactamases • active against gram negative rods (including Pseudomonas) • no activity against gram positives and anaerobes • parenteral administration • few side effects (phlebitis, skin rash, abnormal liver funct.) • no cross sensitivity with penicillin derivatives • all uses are extra-label

Glucose monitoring

important in management of ALL diabetic patients

vomiting center

in medulla chemoreceptor trigger zone (responds to noxious stimuli) vestibular nuclei (motion sickness) pharynx and GI tract (neural pathway) Cerebral cortex (anticipatory emesis "I think I'm going to puke")

Insulin doses increased to improve control, but... When adjusting insulin doses, be conservative, because...

increased to improve control, but... • insulin resistance should be considered when any of the predisposing conditions mentioned in the preceding discussion of Type 2 diabetes are present (ex. obesity) - glucose control is erratic and insulin doses are constantly changing - keeping glucose levels < 300 mg/dL requires > 1.5U/mL insulin in dogs or cats - inability to reduce glucose levels below 300mg/dL in a dog or cat • reduced in association with resolution of underlying causes of insulin resistance When adjusting insulin doses, be conservative, because... - hyperglycemia is rarely acutely fatal, but - hypoglycemia can be.

Amphotericin B (Fungizone R) Therapeutic uses- Administration-

• Broad antifungal spectrum; fungicidal against most organisms causing systemic mycoses including Aspergillus, Blastomyces, Coccidioides, Cryptococcus and Histoplasma spp. Generally a drug you want to reserve due to its toxicity but very good antifungal Therapeutic uses • systemic fungal infections (life threatening) and fungal keratitis in dogs, cats, horses, rabbits, reptiles and birds (all extra-label) • combined therapy with: - ketoconazole, fluconazole, or itraconazole (to reduce toxicity) - flucytosine (for CNS, bone or ocular infections) --> ampho B cannot get into CNS, eye or bone) Administration • diluted in 5% dextrose and administered IV or SC or subconjunctival injection (compounded).

3. NK 1/Substance P receptors

• CRTZ, Vomiting Center, and Periphery • NK 1 antagonist: maropitant

2. 5 -HT 3/Serotonin receptors

• CRTZ, Vomiting Center, and Periphery • 5 -HT 3 Antagonists: ondansetron, dolasetron, metoclopramide (some)

altrenogest Activation of microsomal enzymes by p450 activiated by Rifampin (used for R. equi) reduces activity. Minimal adverse effects when used as labeled. Cautions:

• Can be absorbed transdermally. • Should not be handled by people who are pregnant, have known or suspected breast carcinoma, or undiagnosed vaginal bleeding. • Should not be handled by people with estrogen dependent tumors or those that formed during use of estrogen containing products (oral birth control), among others.

Tildipirosin (Zuprevo) Warning

• Cattle intended for human consumption must not be slaughtered within 21 days of the last treatment. • Do not use in female dairy cattle 20 months of age or older.

PGF2a Tromethamine Adverse Effects and contra-indications cattle, horse, swine:

• Cattle: transient increased temperature and injection site infections. • Horses: transient decreased temperature (common), increased RR and HR, ataxia, abdominal pain, laying down (rarely) • Swine: erythema, pruritis, increased RR, dyspnea, abdominal muscle spasms, ataxia, nesting, vocalization, and salivation. • Restrictive respiratory disease (RAO and asthma) • Closed cervix pyometra • Will interact with other oxytocic agents.

Coccidiosis Disease Highlights

• Caused by - Eimeria spp. in ruminants and gallinaceous birds (birds bred for food) - Isospora spp. in dogs, cats, and pigs • Transmission - fecal-oral for both, but - consumption of rodents (intermediate host) can transmit Isospora spp. • Predisposing Factors - high density housing (dairies, feedlots, shelters, etc) - shipping stress • Clinical Signs - Diarrhea +/- blood (esp. in calves this can cause anemia) and dehydration - Poor production in food producing animals - Can be fatal in young animals • Self-limiting - For Eimeria spp., adult animals develop immunity after repeated exposure. - Isospora spp. aren't as self-limiting

NOT TESTABLE Neosporosis Disease Highlights

• Caused by Neospora caninum - transmission is fecal-oral - tissue cysts are the infective agents • Hosts - definitive = dogs - intermediate = dogs, cattle, sheep, horses, and deer - immuno-reactivity to N. caninum has been detected in people • Commonly causes abortions in dogs and cattle - abortions haven't been linked in humans • Signs - Dogs - encephalomyelitis - myositis - neuromuscular ranging from stiffness, atrophy, paresis, paralysis, and dysphagia

Chloramphenicol and Florfenicol Mechanism of Action

• Chloramphenicol reversibly binds the 50S subunit of the bacterial 70S Ribosomes and prevents transpeptidation. • Chloramphenicol usually is bacteriostatic but it can be bacteriocidal against certain common meningeal pathogens such as H. influenzae, Neisseria meningitidis, Streptococcus pneumoniae at therapeutic concentrations. • Mammalian mitochondria contain 70S ribosomes with physical and chemical characteristics similar to those found in bacterial cells. Many of the adverse effects of Chloramphenicol, including dose dependent bone marrow depression and gray syndrome appear to be a result from inhibition of protein synthesis in host mitochondria

Fourth Generation Cephalosporins

• Comparable to 3rd generation but more resistant to some b-lactamases. Cefepime (Maxipime®) • potentially useful for treating neonatal foals and dogs with serious infections

Toceranib (tyrosine kinase inhibitors) Pharmacodynamics

• Competitive antagonist of ATP binding to the kinase domain of c-kit (and about 50 more tyrosine kinases) • Receptor Tyrosine Kinase Inhibitors act on the G1 Phase of the cell cycle -gi cancer cell is sensitive to the environment competes with atp- but the atp cant bind and this blocks signaling

Veterinary Feed Directive Final Rule

• Congressional legislation passed in 2015 • intends to limit antibiotic use for THERAPEUTIC, instead of production, purposes • recommends drug manufacturers VOLUNTARILY stop labeling drugs as "promoting animal growth" • extra-label use of antibiotics (or other drugs) in feed requires a VCPR before a VETERINARIAN directs compounding.

The Hypothalamic-Pituitary-Adrenal (HPA) axis

• Cortisol and aldosterone are released from the adrenal cortex • Release is stimulated by ACTH Aldosterone: • Is mostly controlled by Angiotensin II-> ZG • Increases Na+ and H2O retention • Increases K+ excretion Feedback- cortisol on hypothalamas and ACTH on hypothalamus; dopamine from hypothalamus has neg feedback on pituitary

Resistance

• Currently uncommon, but on the increase • Most resistant organisms have mutation or increased expression of P-gp. • Ivermectin-resistant strains of - Haemochus species have been found in sheep/goats - Trichostrongylus species have been found in cattle - Treatment options o verapamil reverses P-gp and is being tested as an additive o moxidectin currently retains activity- no resistance detected yet • Low-responder strains of D. immitis are being reported in SE US.

Anthracyclines Pharmacodynamics

• Doxorubicin specifically... - combines with IRON and CATALYZES the generation of oxygen radicals - causes o marked DNA damage leading to apoptosis o lipid peroxidation of cell membrane -makes them leaky Intercalation into DNA - doxorubicin and mitoxantrone inhibit topoisomerase II o blocks DNA replication o reduces RNA/protein synthesis - dactinomycin inhibits DNA dependent RNA synthesis, does not inhibit the topoisomerase • These agents act during all phases of the cell cycle

Long-acting insulins

• Duration of action is 12 - 24 hrs • Otherwise, per intermediate-acting insulins

Intermediate-acting insulins

• Duration of action is 8 - 18 hrs • Used for maintenance • Administered SC -must alternate and vary the location of injection to avoid lipodystrophic reactions -Location is between the scapulae and last rib; dorsal thorax. • Given with a meal

Bacterial Resistance Mechanisms of resistance to penicillins:

• Inactivation of penicillin by bacterial b-lactamase (Penicillinase), the enzyme is inducible, many isoenzymes exist • Decreased permeability of bacterial cell to penicillins, which prevents it from reaching to appropriate Penicillin Binding Proteins (PBPs). -outer membrane porin channels are not big enough, so cannot get into bacterial cell wall • Alteration in PBPs which prevents the penicillin from binding. • Autolytic enzymes not being activated, thus forming "tolerant" organisms (Listeria, staphylococci). • Lack of cell wall (Mycoplasma L Forms; Chlamydia: not peptidoglycan cell wall).

nucleotide analogs: Cytarabine & Gemcitabine Pharmacodynamics

• Incorporated into the growing DNA strand DURING S-PHASE • DNA polymerase can't "read" modified sugars in the nucleosides. - bases are "repaired" leading to extensive mutagenesis - death of daughter cells • Cytarabine is regarded as more effective in most veterinary studies Ara-C is one of these drugs -get incorporated and modified -get phosphates added before being incorporated

Anthracyclines Resistance

• Increased P-gp expression for all anthracyclines • Increased glutathione expression, which reduces free radical production increases resistance to doxorubicin

Penicillin • Natural penicillin is extracted from the culture of: • Penicillin nucleus itself is the chief structural requirement for the biological activity. The antibacterial activity of penicillin resides in the: • The splitting of this ring by enzymes or acids results in the loss of:

• Natural penicillin is extracted from the culture of Penicillium chrysogenum, and semisynthetic penicillins are manufactured from the penicillin nucleus, (6-amino Penicillanic Acid - 6APA) by adding different substitutes. • Penicillin nucleus itself is the chief structural requirement for the biological activity. The antibacterial activity of penicillin resides in the intact b-Lactam ring. • The splitting of this ring by enzymes or acids results in the loss of antibacterial action. For example: b-Lactamase (Penicillinase) splits the b-Lactam ring and inactivates the penicillin.

GLUCOCORTICOIDS Endocrine System

• Negative feedback on CRH à ↓ ACTH • Antagonizes action of insulin (hyperglycemia) • ↓TSH -> ↓ thyroid hormone

Prostaglandins

• Not species specific • Extremely short half-lives • Synthesized from arachidonic acid • Specific prostaglandin is PGF2a

Tetracycline metabolism- excretion-

• Metabolism is minimal in domestic animals, except for minocycline, which is extensively metabolized by the liver. • Renal excretion by glomerular filtration is the major route of elimination for most tetracyclines but small amounts are excreted into feces via bile and/or diffusion from the blood into the intestine. • Doxycycline is unique in that intestinal excretion is the major route of elimination

• Most Cephalosporins are excreted by: • Dosage adjustment is necessary during: • Some Cephalosporins are partially metabolized in the:

• Most Cephalosporins are excreted by the kidney unchanged in a manner similar to that of penicillin • Dosage adjustment is necessary during renal insufficiency or when the renal function is impaired. • Some Cephalosporins are partially metabolized in the liver and are excreted in the bile.

Equine Protozoal Myeloencephalitis Disease Highlights

• Most common protozoal disease of horses in the US. • Caused by Sarcocystis neurona (mostly) and Neospora hughesi (rarely) • Horses are a dead-end, intermediate host -just hangs out- once in doesn't get out • Transmission probably occurs due to consumption of food or water contaminated with feces from a definitive host (opossum) • Merozoites and schizonts are the pathogenic stage • Most common sign is asymmetric ataxia

Nystatin and Natamycin Therapeutic uses

• Nystatin and natamycin are fungicidal to yeast infections caused by Candida spp. and Malassezia spp. • Both antifungal drugs are too toxic for parenteral use; administer - topically for yeast infections of the eye, ear, and skin - orally for treating mucosal yeast infections of the mouth and GI tract.

Cell cycle

• Occurs throughout development of an animal • Slows in most tissues of healthy, mature animals - cells enter G0 - reactivation with injury • Exceptions - skin & hair follicles - GI epithelium - bone marrow - male gametes Normal progression through the cell cycle is regulated by - presence of growth signals (don't grow without signals to do it) - checkpoints (maintain high fidelity of the DNA) -Happens in G1 (approp growth signals -that it should grow), S, and G2 (makes sure we made two copies) -highly controlled highly regulated

Resistance to Aminoglycosides

• One type of acquired resistance is conferred by plasmid mediated (R-Factor derived) chemical changes of enzymes that adenylate, phosphorylate or acetylate the aminoglycoside drugs. • Other types of resistance may involve alteration of bacterial ribosomes to which the aminoglycosides must attach. • The aminoglycoside fail to penetrate the bacterial cell, etc

Response to somatotropin

• Output increases by 11-30% compared to untreated cows. Causes for variability in output • Primiparous cows < multiparous cows (cows in first preg produce less milk than cows with more pregs) • Ambient temperature (higher <lower) • Feed (Consistency feed and feed-bunk management) (more milk output- need to be provided with high quality feed) keeps milk production higher for a longer amount of time

Epsiprantel (Cestex®) Pharmacokinetics

• PO Administration • Very poor absorption from the GI tract; not in the CNS -so not for granulosa • Not distributed or metabolized • Eliminated in the feces Since epsiprantel is not absorbed into the body... • its effects on cestodes are due to direct uptake of drug by the parasite • not by transport of the drug by the host to the parasite.

Excretion

• Penicillin G is probably the most rapidly excreted drug by normal kidney. • About 10% of excretion is by glomerular filtration and 90% by tubular secretion. • Tubular secretion can be partially blocked by probenecid. Probenecid may be employed to provide higher systemic level of penicillin, in severe infections

NOT TESTABLE Leishmaniasis Treatment

• Pentavalent antimony compounds meglumine antimoniate and sodium stibogluconate • Inhibit leishmania nucleotide synthesis, topoisomerases, and phosphofructokinase • Contact the CDC for accessing these agents. • Resistance to these drugs has been reported in other countries. • Relapses are common after treatment

Postantibiotic effect (PAE):

• Persistent suppression of bacterial growth after limited exposure to an antimicrobial agent (aminoglycosides, quinolones) • exact mechanisms unknown • in vivo PAE-s are longer than in vitro PAE-s, due to postantibiotic leukocyte enhancement

Benzimidazoles

• Pharmacodynamics: Inhibit microtubule formation. • Review pharmacokinetics from the lecture about anti-cestode/tremetode agents. • Kills trophozoites - not the cysts • febantel (Drontal-Plus®) for dogs and cats. • albendazole (Valbazan®) for dogs and cattle. • fenbendazole (Panacur®, Safeguard®) in dogs, cats, horses, and cattle (calves). • Note: Giardia rarely causes clinical manifestations in horse.

Hypothalamus Provides: Integrates:

• Provides highest level of endocrine control • Integrates the activities of the endocrine system (through the pituitary) and the nervous system (through the adrenal gland)

NOT TESTABLE Leishmaniasis Disease Highlights

• REPORTABLE • Two forms: visceral (occurs in the US) and cutaneous • Leishmania infantum in the US, a species of trypanosomes • Modes of transmission in US are poorly defined • Seropositivity of dogs ~0.7% in US • ZOONOTIC, no reported cases in humans in the US

octreotide Pharmacokinetics

• Rapidly absorbed following SC administration. - Animals in kidney failure may require dose adjustment. (some excretion through kidneys) - "long-acting release" (LAR) forms have been developed.-ideal in patient that needs this continuosly • Volume of distribution is not established. • Metabolism and Excretion - ~30% of the dose is excreted unchanged in dogs - unknown in cats • Elimination - t1/2 = 2h in humans (efficacy for glycemic control ~12hrs) - glycemic control reflects decrease in GH and downstream effects of lower GH not causing that breakdown of glucose USED as a marker of efficacy Adverse reactions in animals are poorly documented.

finasteride Efficacy in dogs

• Reduces DHT, but not testosterone, by 55% on average • Reduces prostate diameter by 20% on average after 16 wks - takes time due to having to shut down pathways and atrophy of already hyperplastic prostate (apoptosis) • Induces prostate involution by apoptosis • No reports of adverse semen quality or fertility in males treated with finasteride. • However, 45% recurrence- could be just temporary fix

methimazole Adverse Effects

• Unmasking cryptic CKD (30% of cats > 15yo, Bartges, VCNA, 2012) • Formation of anti-nuclear antibodies (19%, can lead to lupus, but generally doesn't)- set up an immune attack against cellular nuclei • Anorexia, vomiting, and lethargy (~10%) • Thrombocytopenia and leukopenia (up to 2.5%, causes increased risk of infection and bleeding) • Hepatopathy (1.5%) • Self-induced excoriation- scratching themselves in really damaging way All of these effects reverse following discontinuation of the drug. GI effects are reportedly reduced when using transdermal administration

Oxacillin (Prostaphlin)

• Used for the treatment of bone, skin and soft tissues infections by penicillinase producing Staphylococci • In dogs and horses • All uses are extra-label

Ampicillin (Omnipen), Amoxicillin (Amoxil)

• Used to treat sensitive bacterial infections (e.g. respiratory infections) - Amoxicillin has better oral absorption • FDA approved for dogs, cats, and cattle • All other uses are extra label

Cloxacillin (Dynapen)

• Used via intramammary infusion in dry andnd lactating dairy cattle • FDA approved

oxytocin Contraindications/Adverse Effects

• Uterine cramping, discomfort, and rupture (at high doses) • Correct hypoglycemia or hypocalcemia before use (if uterus doesn't have an energy supply for contractions then wont work) • Hypersensitivity (itchy to falls off needle to dead and everything in between) • Do not use if... - the fetus is abnormally positioned or cervico-pelvic disproportion (too small) - the cervix is not relaxed. - primary uterine inertia (animal with which uterine does not contract)

Pharmacokinetics Distribution

• VD (ivermectin) - 0.45-2.4 L/kg in cattle - 2.4 L/kg in dogs - 4 L/kg in pigs - 4.6 L/kg in sheep • Rapidly distributes to adipose - serves as a depot - slows elimination -able to maintain therapeutic concentration for longer • extensively distributed to lung and skin. -great for lung worms - high levels in lungs • permeates the BBB

Sulfasalazine

• an "enteric" sulfonamide employed in the therapy of colitis and inflammatory bowel disease in dogs and cats (extra label). • It consists of a molecule of sulfapyridine linked to a molecule of 5 -aminosalicylic acid (5 -ASA). • In the large bowel sulfasalazine is cleaved into sulfapyridine plus 5 -ASA by gut bacteria. Sulfapyridine serves as antibacterial agent while 5 -ASA elicits anti-inflammatory actions.

Therapies for the GI tract, including the liver and pancreas, are complex because, the organ system is: central to the treatment of many GI pathologies:

• anatomically diverse • extensively exposed to the environment, and • affected by a myriad of pathologies. Fluids/electrolytes, antibiotics, anti-parasitic agents, diet, and SX are central to the treatment of many GI pathologies (especially in horses & livestock). Many of the "GI drugs" discussed in this section are adjuncts used in management plans, but NOT the exclusive treatment. Some agents used for these treatments are nutraceuticals, which are defined and regulated differently than pharmaceuticals/drugs.

Sulfadimethoxine

• approved for use in dogs, cats, horses, swine and cattle • usually used for coccidiosis • can precipitate in the urine at high doses

Florfenicol

• approved in cattle and swine for the treatment of respiratory disease, and against foot rot in cattle • approved for fish • It is available as a drinking water medication in swine • extra-label for dogs and cats • administered IM in cattle and repeated 48 hours later for a total of two doses of the slow-release preparation

macrocyclic lactones Pharmacokinetics Formulation

• available in doses ranging from 3mg/kg (dogs) up to 500mg/kg • some release drug for up to 135d • some provide alternating release of ivermectin and albendazole for up to 100d -decreases risk of resistance

Posaconazole

• available orally and as an optic preparation. • Very little information on clinical efficacy and safety in vet medicine • Current use - itraconazole or fluconazole resistant infections in cats and small dogs • Cost prohibitive for most clients (Noxafil - $100/day, several months of treatment required, generic form recently became available) • Extra label Adverse Effects: • Not established; in humans GI intolerance, prolonged QT interval • Drug interactions - inhibitor of CYP3A4

Resistance may be acquire by:

• by a mutation and passed vertically by selection to daughter cells. • by horizontal transfer of resistance determinants from a donor cell, often of another bacterial species, by • transformation (incorporation of free DNA), • transduction (bacteriophages), or • conjugation (transfer of genes through sex pilus).

Adverse Effects- Toxicity to host : • renal toxicity: Agents=

• cephalosporins; • vancomycin; • aminoglycosides; • sulfonamides; • amphotericin B;

Adverse Effects: Toxicity to host: •hemopoietic toxicity: (bone) Agents=

• chloramphenicol • sulfonamides

Bactericidal agents:

• concentration dependent killing - rate and extent of killing dependent upon drug concentration (aminoglycosides, quinolones) • time dependent killing - killing is not increased with increasing concentrations above MBC (beta-lactams, vancomycin); requires a certain amount of time

Normal glucose reference ranges

• dogs 76 - 119 • cats 60 - 120 • cow 40 - 100 • horse 62 - 134 • pig 85 - 150 • sheep (goat) 50 - 80 (75)

Anthracyclines

• doxorubicin (Adriamycin®) • mitoxantrone (Novantrone®) • dactinomycin (Cosmegen®) Canine Lymphoma • Untreated: MST (mean survival time) = 4 - 6 wks • Treated with doxorubicin alone: - 5% cure - 80 - 90% have 8 - 10 mo. 1st remission --thats 8-10 months after the FIRST treatment not the last

Development of Resistance to Erythromycin

• drug efflux by an active pump mechanism (encoded by mrsA, mefA, or mefE) • ribosomal protection by inducible or constitutive production of methylase enzymes, mediated by expression of ermA, ermB, and ermC, which modify the ribosomal target and decrease drug binding; • macrolide hydrolysis by esterases produced • chromosomal mutations that alter a 50S ribosomal protein

Treatment goals

• eliminate clinical signs; • prevent short-term complications (hypoglycemia and DKA); and • enable a good quality of life; and • postpone/prevent formation of cataracts in dogs; but • NOT to maintain plasma glucose levels in the normal range.

Gentamicin

• expanded spectrum aminoglycoside with activity against Pseudomonas, Proteus, Staphylococcus and Coryne-bacterium spp., as well as Gram (-) aerobes. • labeled for use in pigs, and for uterine infusion in horses • other uses are extra-label • used in all species for the treatment of susceptible infections of the skin, respiratory tract, ear, eye, urinary tract and septicemia

Tildipirosin (Zuprevo) Uses

• labeled for the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni in beef and and non-lactating dairy cattle, • extra-label for the control of respiratory disease in beef and non-lactating dairy cattle at high risk of developing BRD associated with Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni.

Levamisole Pharmacodynamics

• levamisole is a nicotinic ACh-R (NM) agonist. • stimulation of nicotinic receptors in worm muscles causes tetanic paralysis. -strong muscular stimulation and rigid paralysis • worms are unable to maintain attachment to host. • adult GI worms are excreted in the feces paralyzed, but alive. -not the baby worms!- do not have neuromuscular junctions yet

Uniqueness of chemotherapy: -selective toxicity: -hypersensitivity and organ directed toxicity:

• selective toxicity: need greater toxicity to parasite than host • chemotherapy selects for resistant strains • hypersensitivity and organ directed toxicity is a potential problem with this class of drugs • chemotherapy lowers the microorganism load so that the Host Defense System can rid the body of foreign organisms

Amikacin

• similar to gentamicin • labeled for dogs for susceptible UTI infections • all other uses are extra-label

Tobramycin

• similar to gentamicin but has more potent anti-pseudomonal activity and reduced nephrotoxicity. • all uses are extra-label • Not used in food animals.

Antipseudomonal penicillins • spectrum includes : • major use is the treatment of: • susceptible to: • Acid sensitive? • excretion: Relative rank of antipseudomonal activity:

• spectrum includes the bacteria covered by the extended spectrum penicillins plus some additional enteric gram negative bacilli (Proteus, Enterobacter). Not Klebsiella! • major use is the treatment of Pseudomonas aeruginosa • susceptible to b-lactamase! • Acid sensitive • Renal excretion • Piperacillin (Pipracil®) • Ticarcillin (Ticar ®) Relative rank of antipseudomonal activity: piperacillin > ticarcillin

Equine Metabolic Syndrome

• Type 2 Diabetes • signs are similar to PPID, but without hirsutism • Insulin is expensive in horses (~$70/day)

Uses Tylosin

• labeled for cattle and swine for susceptible infections • other uses are extra-label

Neomycin

• labeled for cattle, sheep/goat and birds orally for the treatment of susceptible enteric infections • other uses are extra label • topically for treating skin, ear and eye infections.

Regulation of Prescription (ELDU) vs. labeled use

"Labeled Use" is a definition in the Federal Food, Drug and Cosmetic Act (FD&CA) - It applies to both prescription and OTC drugs. - Use of a drug in some manner other than the label is "Extra-Label Drug Use" (ELDU) - Use of a drug for which there is no label is also ELDU Amendment of the FD&CA in 1958 effectively made ELDU ILLEGAL! Animal Medicinal Drug Use Clarification Act (AMDUCA), 1994 - legalizes "Extra-Label" drug use (ELDU) by veterinarians - under certain conditions... 7! -can now give drugs to dogs and cats without going to jail

Third Generation Cephalosporins

(Broad-Spectrum) •Third generation agents are generally less active than first generation agents against gram-positive cocci, but they are much more active against Enterobacteriaceae, including penicillinase producing strains. • Ceftiofur (Excede) - labeled for respiratory infections for cattle, swine and horses • Cefovecin (Convenia) - labeled for cats and dogs, skin and soft tissue infections • Cefixime (Suprax®) - extra-label, skin, soft tissue, and urinary infections in dogs and cats • Cefpodoxime (Vantin®) -- labeled for skin and soft tissue infections in dogs

Second Generation Cephalosporins

(Intermediate Spectrum Cephalosporins) In general, second generation agents have somewhat increased activity against gram-negative microorganisms but are much less active than third generation cephalosporins. Cefoxitin (Mefoxin®) • all uses extra-label, parenteral Cefaclor (Ceclor®) • all uses extra-label, oral

First Generation Cephalosporins

(Narrow Spectrum) In general first generation agents have good activity against gram-positive bacteria and relatively moderate activity against gram-negative organisms. • Most gram-positive cocci (with the exception of enterococci, methicillin-resistant Staph. aureus) are susceptible. • First generation agents have good activity against E.coli; Klebsiella pneumoniae and Proteus mirabilis. •Cefazolin (Kefzol®) •Cefadroxil Monohydrate (Duricef®) •Cephalexin (Keflex®) •Cephapirin Most cephalosporins fairly resistance to penicillinase

Babesia Canis- cows

- Historically in N. America infection with B. bigemina (huge effects on production) - AKA Texas fever - Tick vector/Boophilus annulatus in the U.S. was eradicated by 1940. - REPORTABLE- if you see one of these ticks

Maropitant Citrate (Cerenia®) Adverse Effects and Contraindications

- Decrease dose in animals with hepatic insufficiency - Use with caution in combination with other drugs having high plasma protein binding - Use with caution in patients with arrhythmias, prolongs QT interval by inhibiting cardiac K+ channels - Injection site pain - Hypersalivation - Some dogs may vomit following PO administration for prevention of motion sickness

Ursodiol (Actigall®, Ursodeoxycholate) Pharmacokinetics & Adverse Effects and Contraindications

- Hindgut fermenters, rabbits, produce large amounts of lithocholate from bile acids on top of it, so limited tolerance to developing hepatoxicity - Efficacy is anecdotal

Polyethylene Glycol 3350 (PEG 3350) Products and indications

- None in the MWU-CAC - No veterinary labeled products; all uses are extra-label - Powdered products w/o added electrolytes (OTC) -> Miralax®, Glycolax®, etc. -> Used as a laxative in cats, given with food (for use as electrolytes) - Liquid products w/added electrolytes (human Rx products) -> Colyte®, GoLYTELY®, etc -> Used as a laxative in cats -> Used as colonic cleansing prior to colonoscopy (dogs and cats)

OTC- Labeled Use

- defined Dose, Frequency, Duration, and Route of Administration for a Drug (root of administration) - in a given Species - needed to treat a Specified Disease. If ALL of these features can be written down in a manner EASILY understood by a LAY PERSON, the drug may be sold without a prescription (ie OTC)

The thyroid gland produces two hormones:

1) Follicle Cells Thyroid hormones (T4, T3)- line follicular cavity that is filled with thyroid polymer 2) C-cells Calcitonin (outside of the follicles) -important in regulating calcium levels these hormones originate from Tyrosine Active form = T3 Reverse T3= inactive form of T3

Benzimidazoles Pharmacodynamics

1. Inhibits microtubule polymerization by binding to b-tubulin in all parasite stages. • binding is reversible • dissociates from parasite tubulin more slowly than from host tubulin -need these to send neural transmission, reproduce, etc. 2. Toxicity to parasites is due to... • GI secretory defects • reduced glucose uptake by the GI tract 3. Parasites DIE prior to elimination.

Questions that are helpful to aid selection of the appropriate antimicrobial agent.

1. Is an antimicrobial agent required - is there an infection that will respond to your treatment? • Avoid: 'Just in case.' 2. Where is the infection (which organ/tissue) - what are the drug access problems to be overcome? 3. Which pathogen(s) are usually found at the location of the infection? 4. Which antimicrobial agent has the necessary pharmacokinetic properties to get to the location and also will get there at a concentration above the MIC so that the MIC is below the breakpoint? 5. What dose and route is necessary to achieve the desired effect? 6. For how long should the treatment be?

Osmotic agents not used as laxatives

1. Magnesium hydroxide (milk of magnesia) - Difficult to administer orally - More often used for rumen overload or as an antacid 2. Sodium phosphate and biphosphate - Fleet Enemas - can produce hyperphosphatemia, hypocalcemia, hypernatremia -because of high salt concentrations

somatotropin - additional, off-target effects

1. May reduce prevalence of ketosis • Occurs when increased energy demands of lactation are not met by diet. • Ketosis = increased reliance on ketone bodies for energy. (occurs due to increased energy demands of lactation- energy demands not met) • Reduces milk production, can be life-threatening. • Mechanism by which GH may reduces ketosis prevalence is unclear. 2. Increases first-time pregnancy rate (good), but decreases subsequent pregnancy rates (bad) • Increases the number of days the cervix is open, (harder to detect etrus) and detection of estrous is inversely proportional to rBST dose. • Timing of insemination is more of a gamble. 3. Increases rate of twinning (bad) due to positive effects on follicle, endometrium and embryos.

Treatment for anaerobic infections 1. Oropharyngeal anaerobic infections and lung abscesses (mixed) 2. GI or female pelvic anaerobic infections (B. fragilis often)

1. Oropharyngeal anaerobic infections and lung abscesses (mixed) clindamycin b-lactam/lactamase inhibitor metronidazole 2. GI or female pelvic anaerobic infections (B. fragilis often) metronidazole carbapenems moxifloxacin

Two Major Divisions of Pharmacology:

1. Pharmacodynamics: biochemical and physiological mechanism -What the drug does to the body -Why we're using it 2. Pharmacokinetics: absorption, distribution, metabolism, elimination -What the body does to the drug

Hypoadrenocorticism Breed Dispositions:

1. Standard Poodle 2. Portuguese Water Dog 3. Nova Scotia Duck Tolling Retriever 4. Bearded Collie

Sulfas are bacteriocidal or bacteriostatic? They act by: What is necessary for the final eradication of the pathogens? Do sulfas alter the host's antibody forming mech? Do they have toxin neutralizing action?

1. Sulfa drugs are generally bacteriostatic when administered systemically in therapeutic dose. 2. They generally act by inhibiting the growth of susceptible bacteria, however, in the treatment of certain urinary tract infections, bactericidal concentration is attained. In such conditions, the sulfa drugs may become bactericidal, since a bactericidal concentration is achieved. 3. As with all antibacterial and antibiotic therapy, cellular and humoral defense mechanism of the host is always necessary for the final eradication of the pathogens. 4. As always, Sulfa drugs do not alter host's antibody forming mechanism, nor do they have any toxin neutralizing action.

Objective 7 - Filling a Prescription/Dispensing

A practice can fill prescriptions, but... - under a state's pharmacy laws, - MUST provide a prescription if requested. -https://www.avma.org/News/JAVMANews/Pages/120101i.aspx Cuts down on your clinical costs, don't need as many drugs

Antihistamines/H1 antagonists Pharmacokinetics

Absorption - Most are administered orally (promethazine is given IM to cats and IV to horses -used in an atypical situation not maintenance) - Bioavailability is highly variable (diphenhydramine = 25-60%, promethazine~10% orally - why its generally injected) Distribution - Cetirizine (2nd generation) is very low - Vd ~ 0.26 L/kg in cats (no data in other species, mostly limited to plasma compartment) - Not much crosses the blood brain barrier (10% in humans, minimal sedation) --better option for horse because less of it cross BBB so lower risk of excitatory response - 1st generation have much larger Vd's (chlorpheniramine ~ 2.8 in humans) - 70 - 95% plasma protein binding Metabolism - Mostly Hepatic - hydroxyzine is converted to cetirizine (active metabolite, not further metabolized) --hydroxy will cross BBB Elimination - Metabolites, mostly urinary - Cetirizine, urinary - Half-lives vary by drug, species, and individual - cetirizine (11hrs in cats, 6hrs in horses) - chlorpheniramine (13-43hrs in humans) - diphenhydramine (2-10hrs in humans)

Calcineurin Inhibitors Pharmacokinetics (cyclosporine A)

Absorption - Variable bioavailability following PO administration (20-45%) - Bioavailability reduced when given to dogs with food (cats are fine) Distribution is wide: liver, fat, blood cells Metabolism by P450's only -using something that inhibits the P450 system can reduce your dose (ketoconazole!!) Elimination - GI - t½ ~ 5-8hrs (dogs) and 7-40hrs (cats) Expensive!!

Clorsulon Pharmacokinetics adverse effects

Absorption • Formulated for PO administration • Oral bioavailability is 55-60% (sheep and goats) Distribution • Ingestion of blood containing the drug is the route of administration to flukes • Administered dose in livestock is just above the dose that saturates blood concentration in rats -8 weeks is about the time they start to feed on blood - why it doesn't work before 8 weeks Unmetabolized, parent drug is eliminated in the urine with t½ ~ 48hrs Adverse Effects None, LD50 in mice is 10kg/kg, PO or 761mg/kg, IP

glucocorticoids Absorption Distribution Metabolism Elimination

Absorption • desoxycorticosterone pivilate is a slow-release depot; there is a slow-release form of methyprednisolone also • fludrocortisone is well absorbed orally • prednisone is poorly absorbed from the feline (21%) and equine GI tracts -Cats- prednisolone instead • lipid soluble drugs that can redistribute systemically following local administration Distribution • lipid soluble drugs that are widely distributed • bound in plasma by albumin and corticosteroid-binding globulin Metabolism • Prodrugs - Prednisone and cortisone are inactive and must be metabolized to prednisolone and hydrocortisone, respectively - Cats also metabolize prednisone poorly - Animals in liver failure won't metabolize - Metabolism occurs in the liver, not with local administration • Inactivated by primary and secondary metabolism (glucuronidation and sulfation) Elimination - renal (at least in humans)

Praziquantel Pharmacokinetics Adverse effects

Absorption • Formulated for administration by PO, IM, and SC routes. • Completely absorbed by PO route • Poor oral bioavailability due to extensive first pass metabolism by liver. Distributed throughout the body, including the CNS -granulosa! Metabolism • Metabolites produced by dogs are biologically active. Elimination metabolite excreted in the urine, t½ ~ 3hrs (dogs) Adverse Effects None are documented at any dose tested, up to 5x the highest treatment dose.

A 12yo male, neutered, diabetic DSH presents in your clinic. Cat is on a very high dose of insulin and has become unresponsive to it

Acromegaly •Due to increased endogenous GH secretion secondary to an active pituitary adenoma. (actively secreting the hormone) •Prevalence is ~ 1 - 8/10,000 cats. Prognathonism typically seen May also see- broad facial features, weight gain (dumping GH), hepatomegaly and renomegaly, clubbed paws, respiratory stridor, systolic cardiac murmurs (heart issues what ends up killing them)

Summary

Alkylating Agents • Nitrogen Mustards - cyclophosphamide - mechlorethamine - melphalan • Platinum agents - cisplatin - carboplatin • Methylating agents - dacarbazine - procarbazine - temozolomide* • Other - mitomycin C - lomustine (CCNU) Miscellaneous • asparaginase • predinsone • piroxicam Anthracyclines • doxorubicin • mitoxantrone • dactinomycin Nucleotide Analogs • cytarabine • gemcitabine • rabacfosadine Drugs Affecting Tubulin • vincristine • vinblastine • paclitaxel Tyrosine Kinase Inhibitors • toceranib

Theophylline Pharmacokinetics

Administered PO, but bioavailability is poorly characterized Distribution - Very low plasma protein binding - Distributed throughout the body - Dosing according to lean body weight is recommended in obese animals, because of low lipid solubility Metabolism - Hepatic Elimination - gastrointestinal (t½ ~ 6 hrs in dogs and 8 hrs in cats)

oxytocin Pharmacokinetics

Administered by IV, IM, SC or IN (Intranasal) routes • Uptake by the intranasal route varies between individuals • Uterine effects begin immediately following IV administration and within 3-5 min following IM or SC administration. • Important to administer before uterine inertia (uterus has used so much energy trying to do contractions that is not longer functioning- becomes surgical issue) • Metabolized by the liver (small proteins) • t½ varies between species (3-5min in humans, 22min in goats). - Duration of action in dogs is 13-20 min.

FLUCYTOSINE (Ancobon) Administration Pharmacokinetics Adverse effects

Administration • Oral for a minimum of 4 weeks up to 1 year. Pharmacokinetics • well absorbed orally and widely distributed, including the CNS • excreted unchanged in urine Adverse effects • mild GI disturbances and, more rarely, bone marrow suppression

Griseofulvin (Fulvicin U/F) Admin- Pharmacokinetics- Adverse effects-

Administration • administered orally to dogs, cats and horses • not frequently recommended; terbinafine and azoles have largely replaced griseofulvin Pharmacokinetics • distributes to keratin precursor cells of skin, hair shafts and nails to help prevent new structures from being infected • metabolized by the liver and excreted in the urine • plasma t1/2 in dogs is <6 hours, but is stored in the growing keratin cell producing skin, hair and horn. Adverse effects • leukopenia and anemia may occur in kittens • Photosensitivity, anorexia, neutropenia, hepatotoxicity... • can also be teratogenic in cats and horses

desmopressin Pharmacokinetics

Administration and Absorption • Nasal spray - Nasal use is poorly-tolerated in animals, but well-absorbed through the conjunctiva, so use is topical - Two flavors: 0.1 mg/mL (DDAVP®, generic) and 1.5 mg/mL (Stimate®), use the lower. -- absorption varies between individuals (5-20ug controls, by this route) -- dose to effect -can use as droplets into the eye (conjunctiva) • Injectable solution (DDAVP, generic) used when conjunctival administration is not tolerated • Oral Tablets (DDAVP, generic) - poor bioavailability due to hydrolysis of peptide Pharmacokinetics Distribution, Metabolism, and Excretion in dogs and cats are poorly characterized.

Vancomycin Administration, Distribution, Metabolism Adverse Reactions Clinical Uses

Administration, Distribution, Metabolism • Not absorbed orally. • IV if parenteral use is indicated. • Primarily excreted unchanged by the kidney. • Marked accumulation toxicity occurs in the presence of renal insufficiency. Adverse Reactions • Hypersensitivity reactions including rashes and anaphylaxis. • Ototoxic and nephrotoxic reactions. • Uremia after high dose may be fatal. Clinical uses • very useful against penicillin- and methicillin-resistant Staphylococcus aureus (MRSA) infections and for treating gram-positive infections in penicillin-allergic patients. • for susceptible G+ systemic life threatening infections • all uses are extra-label Vancomycin is banned in food-producing animals

Potentiated sulfonamides Administration: Pharmacokinetics:

Administration. • Sulfonamides and potentiated sulfonamides can be administered orally or by injection, depending on species. • Frequency of dosing varies with the individual sulfonamides. Pharmacokinetics • well absorbed orally and widely distributed to tissues. Transcellular fluid concentrations are 80% of plasma concentration. • binding to plasma albumin varies with each sulfonamide but is generally 50- 75%. • metabolism by acetylation and glucuronide conjugation occurs in most species (so no cats) • acetylation does not occur in the dog • renal excretion of unchanged drug and metabolites is via glomerular filtration, active secretion and passive tubular reabsorption

Tetracyclines Administration: Pharmacokinetics:

Administration. • Tetracyclines are administered orally or IV every 8 to 12 hours. • Oral and parenterally administered therapeutic doses should be avoided in horses because of the danger of disrupting ruminal or colonic microflora. ** remember that tetracyclines are very broad spectrum so it will eliminate a high percentage of normal flora as well** Pharmacokinetics • Oral absorption of tetracyclines ranges from 60-90% of the administered dose except for chlortetracycline, which is only 35% absorbed. • Divalent or trivalent cations impair absorption and thus milk, antacids, or iron salts should be avoided three hours before and after oral administration. • Distribution is wide and includes all tissues except the CNS. • Doxycycline and minocycline are more lipid soluble than tetracycline, chlortetracycline or oxytetracycline and thus penetrate the CNS, eye and prostate at therapeutic concentrations.

Pharmacokinetics macrocyclic lactones

Administration/Absorption/Bioavailability • Administration routes: SC, IM, PO, topical (pour-on)-cows -can lick eachother- toxic!/PO* • Highly variable - highly lipophilic drugs are poorly absorbed in the ruminant GI tract- just sits in there for a longer time - ivermectin bioavailability (oral): 25-33% in cattle, but 95% in dogs - selamectin bioavailability (topical): 5% in dogs, 75% in cats (differences in skin differences) -strong coralation between skin concentration and plasma concentration -distributes equally between the skin and plasma -why this drug acts equally for treating nematodes in the GI and ecoparasites!

nucleotide analogs Adverse Effect Resistance

Adverse Effect • Myelosuppression - leukopenia is most common - anemia and thrombocytopenia also occur Resistance • Increased expression of P-gp • Increased expression of cytosine deaminase ("4" in figure) -converts cytosine's into uracil- wont be incorporated into extending dna chain- inactivation of the drug

b2-agonists s (albuterol) adverse effects contraindications

Adverse Effects - Vasodilation (b2 receptor mediated, minor) - Increased HR and contractility - There are b2 receptors in the heart (although, b1 is dominant) - Albuterol loses b2 selectivity at high doses. - Minor b2-mediated GI relaxation (exacerbates increased in hr and contractility) - Mild to marked b-mediated increase in insulin secretion, glycolysis, glycogenolysis, and lipolysis - Minor increases in IOP and accomodation to the far field Contraindications - Cardiac disease incl. hypertension - Hyperthyroidism (increased HR, contractility, and O2 consumption) - Diabetes mellitus (increased difficulty controlling blood glucose levels) - Low seizure threshold

b2-agonists (clenbuterol) Adverse effects Contraindications

Adverse Effects Acute - Tachycardia (symp agonist) - Muscle tremors and increased serum creatine kinase - Sweating, restlessness, and urticaria Chronic - Cardiac hypertrophy (tachycardia pushing the heart) - Suppression of cortisol response to exercise- so less interesting for racehorses! - Altered immune function - Reduced uterine tone and contractility - Impaired reproductive function in males Contraindications - Cardiac abnormalities - Pregnancy -> Abortions have been reported (mechanisms unclear) -> seems to be that Antagonizes PGF2a and oxytocin (late term abortion) --> Inhibits normal birth contractions --> Inhibits mammary function - Possible illicit remarketing to body-builders Tachyphylaxis develops w/in 21 days -> drug doesn't work after that

Calcineurin Inhibitors Adverse Effects Contraindications

Adverse Effects In all species: - GI initially (vomiting, diarrhea, and anorexia) - hypersensitivity - gingival hyperplasia - hypertrichosis- large amount of hair growth Dogs: diabetes mellitus (unknown reason) Cats: hepatic lipidosis (fat cat at more risk) Contraindications - HX of malignant neoplasia - use of live vaccines - FIV or FeLV positive - latent Toxoplasma gondii infection (all immunosuppressive effects) Because of degree of immunosuppression with this drug!

microtubule stabilizing agents Adverse Effects Resistance

Adverse Effects • Histamine Release - specific to paclitaxel - requires administration of antihistamines prior to treatment - produced by the vehicle in which the drug is dissolved. - occurs with rapid infusion rates (but, slower infusion rates cause myelosuppression) • Vinblastine is more myelosuppressive than vincristine Resistance • cross-resistance to vinblastine and vincristine doesn't occur, unless there are P-gp mutations. vincristine- crisps the nerves Vinblastines- blast the blasts

levothyroxine Adverse Effects Contraindications

Adverse Effects • iatrogenic hyperthyroidism/thyrotoxicosis (thyroid levels get too high and cardiac issues (increased cardiac contractility) arise - monitor T4 levels to find ideal dose - anecdotally, more common with synthetic T3 preparations- more likely to cause issues because this is the active molecule (has a little more control with T4) • anecdotally, erythema multiforme- skin disease Contraindications • Thyrotoxicosis • Acute myocardial infarction • Untreated adrenal insufficiency- can't balance out t3 t4

Pancrelipase (Viokase®) Adverse Reactions and Contraindications

Adverse Reactions and Contraindications - Pork hypersensitivity (these are pork pancreas extracts) - High doses can cause GI distress, oral ulceration, and esophageal ulceration (because of the damage of releasing unregulated digestive enzymes into these tissues that are normally protected from the gi enzymes- release of proteases in these areas- no mucosal layers) Note: - Usually added as a powder to food; so, client education is important to prevent overdoses - Efficacy is controversial; failures have resulted from -> Variability in product efficacy -> High fat in diet reduce efficacy -> Concurrent antibiotic-sensitive enteropathy - Given with PPI's in humans to prevent digestion of the enzymes, but not in pets.

Groups of drugs: Affecting the patient vs Affecting parasites

Affecting the Patient: -ANS -Cardiac -coagulation -Renal -CNS -Endocrine -GI -Respiratory Affecting the Parasites: -Antibiotics -Anti-fungals -Ati-worms agents -Macrocylic Lactones -Anti-ectoparasiticides -Anti-protozoals -Anti-neoplastic agents

Adverse Effects: Toxicity to host: • allergies:

All drugs are capable • anaphylactic shock • skin rashes • immune induced blood dyscrasias • immune hemolytic anemias

Doxycycline uses

All extra labeled Drug of choice for treating tick borne diseases in animals Cats- mycoplasma and chlamydia felis infections Dogs- Ehrlichia canis infections Often added to heartworm treatment against Wolbachia

vasopressin (argenine vassopressin) Pharmacodynamics Pharmacokinetics

All uses are extra-label (no veterinary products) (not enough central diabetes insipidus CDI) • CDI DIAGNOSIS • vasoconstriction during cardiopulmonary resuscitation or local bleeding (rarely applied) Pharmacodynamics • endogenous vasopressin replacement • AVP: Cys-Tyr-Phe-Gln-Aln-Cys-Pro-Arg-Gly-NH2 • Has equal affinity for the V1 and V2 receptors. V1 causes vasoconstriction. V2 causes activation of water being brought in • administered SC or IM • distributed throughout the interstitial space • metabolized in liver and kidneys • t½ ~ 10-20 min in humans -> too short therapeutically!

Indications Anal sac adenocarcinomas- Transitional Cell Carcinomas- Multiple myeloma- Osteosarcoma- Lymphoma- Other-

Anal Sac Adenocarcinomas - doxorubicin - mitoxantrone - toceranib Transitional Cell Carcinomas - piroxicam + mitoxantrone - piroxicam + carboplatin - piroxicam + gemcitabine - vinblastine - mitomycin C Multiple myeloma - melphalan + prednisone Osteosarcoma (single or combined) - doxorubicin - carboplatin - cisplatin - gemcitabine Lymphoma Remission/Reinduction (CHOP Protocol!) - Cyclophosphamide - Hydroxydaunorubicin (doxorubicin) - Oncovin® (vincristine) - Prednisone - Rabacfosadine (single agent or in combinations) Rescue (single or combined) - actinomycin-D/Dactinomycin - mitoxantrone - doxorubicin - dacarbazine - temozolomide - lomustine - asparaginase - mechlorethamine - vinblastine - vincristine - procarbazine - cytarabine Other - paclitaxel (SSC) - mitomycin C (SSC, horses) - toceranib (mast cell tumors)

Empirical antimicrobial therapy:

Antimicrobial agents are frequently used before the pathogen responsible for a particular illness or the susceptibility to a particular antimicrobial agent is known. It is based upon experience with a particular clinical entity • Formulate a clinical diagnosis • Obtain specimens for laboratory examinations • Formulate microbiologic diagnosis • Determine the necessity of empirical therapy • Institute treatment Choice of antimicrobial agent: depends on host factors (species, immunocompromised patients, liver damage, kidney damage, age, dosing requirements, costs, etc.)

Antibacterial prophylaxis:

Antimicrobial prophylaxis should be used in circumstances in which efficacy has been demonstrated and benefits overweight the risk of prophylaxis Applied to a HEALTHY patient! -preventative -must have reason to think that the risks outweigh the possible illness

Short polypeptides and small proteins Heart-

Atrial natriuretic peptide (ANP) Brain natriuretic peptide BNP)

Summary

Avermectins • ivermectin • selemectin • eprinomectin • doramectin Milbemycins • moxidectin • milbemycin oxime spinosad

Which of the following drugs is the best choice to treat Microsporum canis in dogs and will prevent new keratin precursor cells of skin, hair shafts and nails from being infected? A. Amphotericin B B. Griseofulvin C. Ketoconazole D. Nystatin E. Terbinafine

B. Griseofulvin

Polyene antimicrobials like amphotericin B and nystatin work by: A. Inhibition of peptidoglycan synthesis B. Interaction with sterols in the cell membrane C. Inhibition of ergosterol synthesis D. Disruption of the mitotic spindle E. Inhibition of DNA and RNA synthesis

B. Interaction with sterols in the cell membrane

Summary

Benzimidazoles • albendazole • fenbendazole NM agonists • levamisole • pyrantel pamoate • pyrantel tartrate • morantel tartrate Hyperpolarizing agents • piperazine • emodepside Other • diethylcarbamazine (anti-heartworm prev) • melarsomine (heartworm adulticide)

Gonadotropins = Glycoproteins Structurally, they are all composed of:

Beta subunits provide specificity to receptor interactions. Proteins with sugar chains attached Species-specific molecules • There is cross-over in reactivity of individual hormones between species and different hormones within species. • Cause of differing efficacy in species • Cause of hypersensitivity- variations can lead to different responses from immune Specific gonadotropins • FSH and LH from anterior pituitary • Chorionic gonadotropin (human and equine) from placenta • Anti-mullerian hormone and inhibin from gonads

Griseofulvin (Fulvicin U/F) About: Therapeutic uses:

Binds to the microtubules of certain fungi and destroys the mitotic spindle structure; fungistatic • fungistatic for dermatophytes such as Microsporum spp. and Trichophyton spp. • its action is slow as infected cells are shed and replaced with uninfected cells. Therapeutic uses • FDA-approved for use in dogs and cats to treat dermatophytic fungal infection of the hair, skin and claws, and to treat ringworm in horses (oral tablets no longer marketed in USA, oral extra label now)

Summary

Bismuth subsalicylate Lactulose Ursodiol Nutraceuticals - Silymarin - S-adenosyl-methionine - Pancrelipase

tick chart

Boophilus- eradicated in U.S -> reportable if ever seen!! Andersoni- rocky mt spotted fever, and much more otobius - more on wild life

Omeprazole (Gastrogard ®, Prilosec®) Pantoprazole (Protonix®, Pantoloc®) Indications Pharmacodynamics

Both are present in the MWU-CAC Indications - Omeprazole is FDA-approved for gastric ulcer management in horses - More effective for ESGUS than EGGUS - Efficacy of pantoprazole isn't determined - Use for gastric ulcers is extra-label in small animals for both drugs - Esophagitis Pharmacodynamics - Irreversible inhibition of the H+/K+ ATPase at the secretory surface of parietal cells

Chemotherapy selects for: Mechanisms:

Chemotherapy selects for drug resistant strains! Resistance may be: •natural and acquired •mechanisms: pathogen or cell fails to absorb drug pathogen or cell inactivates drug pathogen or cell pumps drug out (MDR) drug target is modified, thus resistant to drug increased production of target molecules altered metabolic pathway bypasses drug target •multiple drug resistance (often transmitted by plasmids)

Summary

Cestocides/Isoquinolones (tapeworms) • praziquantel • epsiprantel Flukicides (flukes) • clorsulon Benzimidazoles (all of these species and nematodes) • albendazole • fenbendazole

Heartworm Disease- Severity Scale

Class 1 Asymptomatic (+) antigen test (test isn't very sensitive!) + test means 30 FEMALE worms -- so pretty severe Class 2 Moderate Pulmonary Damage Coughing & Exercise Intolerance Class 3 Right CHF Cor pulmonale Syncope Anemia Cachexia Class 4 = Caval Syndrome All the badness of Class 3, plus... - Shock - DIC - jugular distention (palpable) - mitral regurgitation Needs to be treated right now or will die Drugs we talk about really can't be used in class 4 -> surgery is required Generally the worse in southeast -wet, mosquitos -+ arizona always bad

Hyperadrenocorticism

Common in dogs • rare in cats (only 100 reports in literature) • Pituitary Pars Intermedia Dysfunction/PPID in horses Pathology • Neoplastic • Pituitary Tumors (85%) - Cushing's Disease/Pituitary Dependent Hyperadrenocorticism (PDH) • Adrenocortical tumors (AT, 15%) • Ectopic Adrenocorticotropic hormone syndrome/neoplastic (3 reports in literature) • Iatrogenic • You should have a strong suspicion just based on the record/asking the client about current medications • Starts with as little as 2 wks treatment at labeled doses • Treat by tapering the dose of corticosteroids

Hypoadrenocorticism

Common in dogs (3-15/50) - very rare in cats (~25 reports in the literature) Pathology - Iatrogenic - Neoplastic (Pituitary Tumors destroying ACTH production) - Primary Autoimmune Disorder (~90%) - Breed Predisposition (autosomal recessive) - Gradual process that presents acutely (signs become apparent with 90% loss of adrenal cortex

H2 Antagonists Pharmacodynamics

Competitive antagonists of histamine secreted from ECL cells - Blocking H2 receptors in parietal cells reduces activation of H+ /K+ ATPase through inhibition of Gs and cAMP. - Potency: cimetidine < ranitidine < famotidine < nizatidine --move food stuffs out of stomach that leads to the acid secretion when the food bolus causes stimulation Ranitidine and nizatidine are prokinetic - Mild inhibition of AChE in synaptic junctions of the myenteric plexus increases parasympathetic tone.

Concentration-dependent killing Post-antibiotic effect

Concentration-dependent killing • increasing concentrations kill an increasing population of bacteria, and at a more rapid rate • adverse effect are time dependent Post-antibiotic effect • aminoglycosides have a significant PAE • antibacterial activity persists beyond the time that the antibiotic is measurable • single, large dose has better efficacy than multiple smaller doses

Rabacfosadine Use Pharmacodynamics

Conditionally labeled for canine lymphoma • Still in FDA-efficacy trials • Absolutely illegal to use extra-label -risk to human population Pharmacodynamics • Guanine nucleotide analog • Active form is incorporated into DNA chain of replicating cells • Does not have a ribose base that DNA polymerase recognizes • Terminates replication of DNA chains during Sphase of the cell cycle hard stop in replication of DNA during s phase -triggers apoptosis

GI conditions amenable to medical management and their agents

Constipation - Impaction laxatives and N-butylscopolammonium bromide (flavor of atropine- causes relaxation to allow impaction to move) Diarrhea - Nonspecific/Idiopathic Chronic Colitis - Drug-Induced (eg. Chemotherapeutics) sulfasalazine, loperamide Acute Vomiting - Inhibition - Induction anti-emetics emetics and adsorptive agents Chronic Vomiting PPI's, H2 Blockers, pro-motility drugs, and cytoprotectants - Gastritis (Small animal, Equine) -> Drug-Induced -> Infectious/Helicobacter - Pancreatitis - Chronic Hepatitis misoprostol (drug induced gastritis), bismuth subsalicylate, nutraceuticals, nutraceuticals and lactulose

Flucytosine is often combined with other antifungal drugs for the treatment of meningeal cryptococcosis because of which of the following drug properties? A. Flucytosine inhibits CYP3A, resulting in plasma concentrations that exceed the MIC for Cryptococcus B. Flucytosine is fungistatic and safer in immunocompromised animals. C. Flucytosine inhibits Cryptococcus ergosterol synthesis resulting in fungal cell death. D. Flucytosine penetrates the central nervous system of infected animals.

D. Flucytosine penetrates the central nervous system of infected animals.

Cestodes/Tapeworms of Veterinary Interest

DO NOT memorize the table Definitive host= undergoes sexual reproduction Intermediate= no reproduction cycle- just there for the ride If not reproducing- very hard to kill (aka intermediates!) Echinococcus- can cause granulomatous inflammation in the brain (HUMANS) flea and lice are capable of carrying the disease and transfer to other species

anti-inflammatory drugs Piroxicam Pharmacodynamics

DOC for Transitional Cell Carcinoma (TCC) in dogs • reduces tumor volume in 66% of dogs with TCC • may be beneficial in SCC, TVT, and mammary adenocarcinoma Pharmacodynamics • nonspecific cyclooxygenase inhibitor • Induces tumor cell apoptosis possibly by reducing angiogenesis (requires PGE2) -deprived of blood supply= death • cell cycle independent

Silymarin (Milk Thistle, Silybin, Marin®, Denamarin®)

Denamarin® is in the MWU-CAC Indications - Chronic Hepatitis in dogs and cats -> Efficacy studies are generally lacking -> Provides some hepatoprotective effects in cats with acetaminophen toxicity - Extra-label Pharmacodynamics - Antioxidant: scavenges free radicals and inhibits lipid peroxidation (so is broadly antioxidant and anti-inflamatory) - TNFa inhibition: reduces cytotoxic/apoptotic and inflammatory effects - Alters hepatocyte membrane permeability to toxic agents (preventative effect) NOTE- looks very similar to yellow star thistle plant

S-adenosyl-methionine (SAMe, Denosyl®, in Denamarin®)

Denosyl® and Denemarin® are in the MWU-CAC Indication: - Any form of liver disease, but efficacy studies for none (remember- dietary supplement- no efficacy studies required) - Extra-label Pharmacodynamics Normal product of the liver that is a cofactor in three pathways: - Transmethylation which is involved in phospholipid synthesis - Aminopropylation which produces anti-inflammatory molecules - Transsulfuration which is necessary for glutathione production (necessary for producing free radicals) endogenous molecule

4 cabinent level positions that regulate drugs:

Dept. of ag (USDA) Dept. of health and human services (USDHHS) Dept. of justice (USDOJ) Environmental Protection Agency (EPA)-> pesticides

Trichomoniasis

Disease Highlights • Caused by Trichomonas foetis In cats - causes large bowel diarrhea - prevalence ~ 31% - self-limiting, but can take up to 2 years. - drug of choice is RONIDAZOLE In cattle - transmitted by sexual intercourse - bulls are persistently infected and usually culled - self-limiting in cows -NO DRUGS due it being self limiting

Giardiasis

Disease Highlights • Infection occurs due to contaminated food or water • Has 2 primary life stages (pathogenic trophozoite and a cyst) • Interferes with absorption in the lumen of the small intestine • Infects dogs, cats, horses, and cattle • ZOONOTIC Treatments • benzimidazoles (dogs, cats, horses, and cattle)= roundowrms, flukes, giardia • nitroimidazoles (dogs, cats, and horses)

Benzimidazoles Pharmacokinetics

Distribution - not well-described Metabolism - liver produces active metabolites Elimination - fenbendazole in sheep, cattle, & pigs - 45-55% eliminated unchanged in feces, <1% eliminated unchanged in urine -so in environment Adverse Effects - All benzimidazoles: hypersensitivity reaction to antigens from dying worms - Fenbendazole: pancytopenia - Albendazole: -- aplastic anemia (implied, not proven) in dogs, cats, and humans. -- potentially teratogenic; consider fenbendazole in pregnant animals

Musculoskeletal/Joint Injections Drugs Adverse effects

Drugs • triamcinolone (labeled in horses) • isoflupredone (labeled in swine and cows) • flumethasone (labeled in horses and dogs) • methylprednisolone and betamethasone (extra-label) Adverse Effects • causes muscle atrophy (increased circulating amino acids) • causes osteoporosis • increased calcium excretion and decreased Vitamin D activation • inhibits osteoblast function • inhibits fibrocartilage growth (don't use in growing animals)

Filling a Prescription/Labeling

Drugs that require a prescription are labeled drugs Requirements Prescription Number Label must include a valid "legend" ◦ "Rx only" (human legend only) ◦ "Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian" -->"For Animal Use Only" -->"For Veterinary Use Only"

Pathology of Type 2 Diabetes mellitus

Due to acquired resistance of tissues to insulin • problems with insulin binding to its receptor (anti-insulin antibodies) • problems with the function of the insulin receptor (anti-insulin receptor antibodies or downregulation) • problems with downstream signaling from the insulin receptor Causes of mild or fluctuating insulin resistance • obesity, hyperlipidemia • concurrent disease (hyperthyroid cats and hypothyroid dogs) • chronic inflammation (infection, pancreatitis, gingivitis) • renal, hepatic, or cardiac insufficiency Causes of severe persistent insulin resistance • diestrus induced increase in GH • Cushing's disease • diabetogenic drugs (progestins and glucocorticoids) • acromegaly (~10% of diabetic cats) Dogs can develop Type 2 diabetes • they can have many of the predisposing causes • insulin resistance in a Type 1 diabetic dog can complicate treatment Cats normally develop Type 2 Diabetes Mellitus • prevalence is 25 - 200/10,000 (much higher than in dogs)

Summary

Ectoparasite Nervous System Stimulants: Pyrethroids (know effects of each category) • allethrin (1st gen) • etofenprox (1st gen) • phenothrin (2nd gen) • resmethrin (2nd gen) • permethrin (3rd gen) • fenvalerate (3rd gen) • cyfluthren (4th gen) • cypermethrin (4th gen) Synergists • piperonyl butoxide • N-octyl bicycloheptene dicarboximide Organophosphates/carbamates • fenthion • famphur • tetrachlorvinphos- most OTCs • carbaryl • propoxur Neonicotinamides • imidacloprid • nitenpyram Miscellaneous • fipronil • amitraz Insect growth regulators Juvenile Hormone Analogs • methoprene • pyriproxyfen Insect development inhibitors • lufenuron Repellents • butoxypolypropylene • di-n-propyl isocinchomeronate • diethyl-m-toluamide

Glycoproteins- Kidneys:

Erythropoietin (EPO)

Collie - related breeds that have MDR-1 mutations

Essentially don't make p-gp • have a 4bp, inactivating deletion (ABCB1-1D) • homozygotes do not have a functional P-gp • ivermectin levels in brains of ABCB1-/- : WT mice = 87 : 1 • Increase [ivermectin] brain may activate mammalian GABA receptors -stimulation of gaba receptors in dogs that cannot get rid of the drug Circulating plasma levels are really high and they can get into the brain much easier Mixed breeds- fairly low percentage of homozygotes (ones we really worry about) Anything over 3 is at a higher risk 4 that really stand out= australian shepherd (+mins); Collie, Longhaired whippet -also border collies, waller dogs

In the absence of pregnancy, the female reproductive tract is regulated by 3 cycles

Estrous/Behavioral Cycle -proestrus, estrus, metestrus, diestrus, anestrus Ovarian Cycle -Follicular Phase- proestrus and estrus cycle, Luteal Phase - mestrus and diestrus Uterine Cycle -Menses Proliferation Secretory Dominant Hormones -Estradiol Progesterone LH surge- release of embryo- moves down folloppian tube- can be fertalized, development of corpus luteum (red one- corpus hemorragicum) - corpus luteum- eventually turns to corpus albicans

Follicular Cysts/Cystic Ovary Disease (in cattle) Etiology Pathology

Etiology • Caused by lack of synchrony between follicle maturation and LH surge -if LH surge doesnt trigger estrus- lots of estradfiol in system- builds up - causes pressure atrophy in ovary and destroys remaining follicles present- animal now useless for reproduction • Results in continuously high systemic estradiol levels due to a persistent tertiary follicle Pathology • Early: Endometrial edema and cystic hyperplasia • Chronic: Mucometra, endometrial atrophy and squamous metaplasia, myometrial atony (uterus doesn't contract normally), and cystic Gartner's ducts and Bartholin's glands. can artificially induce another LH surge by giving gonadotropin to push animal out of cystic phase- restart button

Repellents -examples -effects -adverse effects

Examples - butoxypolypropylene (Stabilene®) - di-n-propyl isocinchomeronate (MGK 326) - diethyl-m-toluamide (DEET®) Effects - Reduce insects landing on/entering the hair-coat of animals - Interfere with ectoparasite feeding - Ectoparasite disorientation (drunk ectoparasites) Adverse effects DEET may increase dermal absorption and increases adverse effects of primary ectoparasiticides in cats.

Equine Protozoal Myeloencephalitis Tx:

FDA-Approved - ponazuril or diclazuril (triazine derivatives) +/- - Sulfadiazine-pyrimethamine - 60% effective Investigative (Not FDA approved yet) - decoquinate (hydroxyquinolone/electron transport chain inhibitor) + levamisole (imidothiazole) - 90% effective Patients tend to relapse - no consensus on protocol for horses that relapse - most report adding new anti-protozoal drugs to cocktail

Integument Conditions (Skin, Eyes, and Ears)

Frequently used systemically and topically for these indications. The differential diagnosis list for pruritus is as long as those for diarrhea or vomiting. Most important to know the MAJOR REASONS NOT to use them (rule-outs). 1. Cutaneous Food Allergies (rare in herbivores) 2. Infectious or parasitic a. bacterial or fungal skin infections, viral infections with eye involvement in any species (ex. feline herpes virus 1) b. flea allergy dermatitis...even in cats c. grey areas 1) horses - short course (~ a week) as an adjuncts in TX of biting/burrowing parasites causing marked inflammatory reactions (Habronema, Oxyuris, Culicoides, Hypoderma, etc) 2) cattle - dexamethasone only for insect bites (extra-label)

Hyperadrenocorticism - Other Scaries

Gastric Ulcers and colonic perforation • inhibition of PLA2 leading to reduced prostaglandin production Slow Wound Healing • inhibition of collagen synthesis • inhibition of platelet aggregation (thromboxane inhibition) • inhibition of fibroblast growth Growth retardation in immature animals • hypothyroidism • muscle atrophy • inhibition of osteoblasts & chondroblasts • inhibition of growth hormone Infections • increased susceptibility due to immuno-suppression • inhibition of inflammation masks signs • Typically UTI and pyoderma Suppression of HPA axis • Adrenals will reduce glucocorticoid and mineralocorticoid production • Adrenals may atrophy • ONLY occurs with IATROGENIC hyperadrenocorticism • Tapering glucocorticoids at the end of the treatment regimen allows adrenal recovery

Steroid hormones Gonads- Adrenal cortex- Kidneys- Example-

Gonads-androgens, estrogens, progestins Adrenal cortex- mineralcorticoids, glucocorticoids, androgens Kidneys- calcitriol Example- estradiol, an estrogen

somatotropin

Growth hormone itself Approved for use to increase milk production by dairy cattle. Other Applications: • Increased growth rate and improved meat quality in pigs (not approved) • Increased lean-to-fat ratio in beef cattle (not approved) • Pituitary dwarfism in dogs (porcine somatotropin, extra-label) These are all ELDU- wouldn't do these in food animals then!

Helicobacter spp. in small animals

H. pylori is common in humans, and is associated with gastric ulcers and neoplasia - Rare in small animals Several species of Helicobacter have been identified in small animals - H. heilmannii, felis, bizzozeronii, and salomonis are identified in cats and dogs - Can co-colonize the GI tract - Indistinguishable microscopically - Larger than H. pylori Contribution of Helicobacter spp. to vomiting and gastritis is uncertain. - Experimental infection in animals causes only mild signs - Eradication of Helicobacter spp. has been associated with improvement, but not resolution, of clinical signs.

Antihistamines/H1 antagonists Pharmacodynamics Histamine is involved in... 1. Gastric acid secretion 2. Neurotransmission

Histamine is involved in... 1. gastric acid secretion - inhibited by H2-receptor competitive antagonists - we'll discuss more in upcoming lectures 2. neurotransmission Stimulatory/excitatory neurotransmitter mediated by H1-, H2-, and H3-receptors located in the hypothalamus --> so inhibiting stimulatory= sedative -located in the hypothalamus - activation promotes wakefulness - Competitive inhibition prevents vomiting, which we'll discuss in upcoming lectures, and may cause sedation.

Antihistamines/H1 antagonists Pharmacodynamics Histamine is involved in... 3. Allergy

Histamine is involved in... 3. Allergy - Basophils and mast cells -> Surface bound IgE's react to antigens/allergens - >Allergen binding induces histamine release - Localized release causes atopic dermatitis - Can also cause asthma and rhinitis, mostly humans - Competitive inhibition can block pruritus -Primary use for this drug in this lecture

Antihistamines/H1 antagonists Pharmacodynamics Histamine is involved in... 4. Anaphylaxis

Histamine is involved in... 4. Anaphylaxis - Effects are caused by histamine released from mast cells and basophils - Contraction of endothelial cells in postcapillary venules- lateral contraction not vasoconstriction (retracting and decreasing surface - are making spaces and exposing BM -facilitates extravasation -> Mediated by H1 receptors -> Facilitates extravasation of circulating cells -> Increases permeability to plasma proteins and fluid -> Causes edema/wheals -> Can be reduced by competitive inhibition using H1 antagonists

Hypoadrenocorticism - TX

Hormone Replacement Remember- "all, never, & sometimes"

Effects on Ca levels

Hormones, and drug analogs of hormones, acting through surface receptors... • act rapidly, - receptors are always there • the components in the signaling pathway are always present. Examples: -epinephrine and norepinephrine (a1 receptors) -oxytocin -Regulatory hormones of hypothalamus -several eicosanoids activates g protein which activiate phosopholipase C - DAG - PKC - opens ca channels and release of stored ca - ca second messenger - calmodulin - activates enzymes

Hypoglycemia- Pathologies-

Hypoglycemia - glucose below the normal limit (<70 mg/dL in a dog is exciting, <60 mg/dL is definitive) Pathologies • insulin overdose • low diabetogenic homones (ie. catecholamines, etc), usually secondary to Addison's disease • sepsis • malnutrition in neonates and toy breeds • liver pathologies - portal shunt -end stage liver disease • cancer - hepatic neoplasia - leiomyosarcomas - beta cell tumors/insulinomas (most common in dogs and ferrets, can occur in cats)

A 6yo spayed female Doberman Pinscher walks into your office Bilateral alopecia Rear leg weakness and lethargy Mildly aggressive Diagnosis

Hypothyroidism common in dogs, rare in cats common= doberman -goldens, sheepdogs, great danes, beagles, borzois

Prescriptions

Order for a medication, device, or feed issued by a licensed veterinarian Methods of issuance: ◦ Preprinted forms handed to client ◦ Electronically submitted to pharmacy ◦ Phoned to a pharmacy for most drugs Kept as part of the patient's record

Review of Glucocorticoids Actions

Immune System • Anti-inflammatory • ↓heat, erythema, swelling, tenderness • ↓PLA2, COX2, cytokines • Immunosuppressive • Neutrophilia, lymphopenia, and monocytosis (stress leukogram) • Decreased leukocyte function (increased risk of infection) Cardiovascular System • Increased sensitivity to sympathetic stimulation (vasoconstriction) • Increased aldosterone leading to retention of Na+ and H2O (hypervolemia) • Leading to... • Increased BP • Decreased Baroreceptor Reflex • Decreased ADH secretion • Dilute Urine, PU/PD Endocrine System • Negative feedback on CRH à ↓ACTH • Insulin antagonism (hyperglycemia) • ↓TSH à ↓ thyroid hormone (hypothyroidism) Metabolism • Increased circulating amino acids (contributes to muscle atrophy) • Increased circulating fatty acids (associated with fat redistribution and contributing to thin skin and "potbelly") • Increased gluconeogenesis (hyperglycemia)

N-butylscopolammonium bromide (Buscopan®)

In the MWU-CAC Atropine Indications - Spasmodic colic, flatulant colic, or simple impactions in horses (FDA approved) - Extra-label uses in horses - Choke/esophageal obstruction - Aid to performing rectal exams - Detomidine-induced bradycardia - RAO Pharmacodynamics: per Atropine

Misoprostol (Cytotec®) Indications Pharmacodynamics

In the MWU-CAC Indications - NSAID-induced gastric ulceration (incl. EGGUS) Pharmacodynamics - Synthetic prostaglandin E1 analogue that inhibits H+/K+ ATPase by stimulating Gi and inhibiting cAMP production - Promotes bicarbonate and mucus production by gastric epithelial cells - Increases gastric blood supply and turnover of gastric epithelium

Sucralfate (Carafate®) Indications Pharmacodynamics

In the MWU-CAC Indications - Ulcers in any GI location (oral to duodenum) or cause (except NSAID induced) - Has been used in dogs, cats, horses, ferrets, and reptiles - Extra label in all species Pharmacodynamics - Stomach acid promotes polymerization of the sucrose octasulfate and aluminum hydroxide - Binds to protein exudates and basement membranes of cells in ulcer - Little effect on acid

Ursodiol (Actigall®, Ursodeoxycholate Indications and Pharmacodynamics

In the MWU-CAC Indications (all extra-label) - Chronic hepatitis in dogs an cats - Gallbladder mucoceles in dogs - Cholangiohepatitis in horses - Feline triaditis (disease with concurrent cholangiohepatitis, pancreatitis, and IBD)- very difficult management problem Pharmacodynamics - Solubilizes gall stones by reducing hepatic secretion and intestinal absorption of cholesterol - Increases bile flow - Reduces hepatocellular inflammatory change and fibrosis (protective to the liver itself) This is BILE!

Lactulose (Cephulac®, Kristalose®) Indications and Pharmacodynamics

In the MWU-CAC Indications (extra-label) - Reduction of circulating ammonia levels in small animals with hepatic encephalopathy - Osmotic laxative Pharmacodynamics - Indigestible disaccharide composed of galactose and fructose - Metabolized by gut bacteria into lactic, formic, and acetic acids - The sugars act as laxatives by providing an osmotic gradient that draws H2O into the GI lumen - Metabolism of sugars by gut bacteria produces lactic, formic, and acetic acids -- The acids reduce colonic pH leading to protonation of NH3 (Nh3 to NH4) -- The charged NH4 + doesn't diffuse across the colonic epithelium and is eliminated in the feces. -- Metabolism of aspartate and glutamate by GI bacteria is the source of NH3, not endogenous metabolism of these amino acids. Most important drug in this set!

Apomorphine HCl (Apokyn®) Pharmacodynamics and indication

In the MWU-CAC Indications - Emetic for dogs (primarily for ingested toxins, extra-label) - Available in human Rx injectable formulation or compounded pills Pharmacodynamics - Agonist of D2 receptors in the CRTZ - Fewer D2 receptors in feline CRTZ than canine CRTZ, use xylazine for cats - apo- means "related to" or "derived from" - apomorphine is related to morphine, but isn't an opioid, and - doesn't interact with opioid receptors "like morphine"

Metoclopramide HCl (Reglan®) Indications Pharmacodynamics

In the MWU-CAC, new this year Indications - General antiemetic for most purposes in dogs (no efficacy studies) - Gastric ulceration (due to promotility effects) (in addition to preventing vomiting it also has pro-motility effects) Pharmacodynamics - Antagonism of D2 receptors in the CRTZ (much less effect in cats) - Some 5-HT3 receptor antagonism in the CRTZ, Vomiting Center, and Periphery - Sensitizes upper GI smooth muscle to parasympathetic stimulation (rest and digest- where pro-motility effects are coming from) - Increases gastric contraction and duodenal and jejunal peristalsis - Increases lower esophageal motility in cats - Increases lower esophageal and decreases pyloric sphincter pressures - Some of these effects can be attenuated by antagonism of D2 receptors in the GI tract

octreotide

Indication Insulinomas in dogs and ferrets (use is extra-label) Pharmacodynamics Inhibits insulin gene expression Pharmacokinetics See notes in lecture on Hypothalamic and Pituitary Hormones Efficacy • anecdotal in ferrets • improvement of clinical signs in 75% - 100% of dogs • dogs may become refractory

b2-agonists (terbutaline)

Indications - All uses extra-label (no veterinary products) - Acuter bronchoconstriction in cats, birds, and reptiles (asthma or bronchospasm) - Bradyarrhythmias in dogs and cats (b2 agonist) - Premature labor (tocolytic effects/suppression of uterine contractions) - Testing for anhidriosis in horses (lack of sweating) -increasing symp tone should induce sweating Pharmacodynamics - Per albuterol Pharmacokinetics - poorly defined, similar to albuterol -Given IV, SC, or IM; so, usually used only during admissions. -not a maintenance drug usually Adverse Effects and Contraindications - per albuterol, but more marked due to route of administration

b2-agonists (albuterol) Pharmacodynamics

Indications - Treatment of bronchoconstriction in dogs, cats, and horses - Extra-label, no veterinary labeled products - Primarily considered a drug for treating emergent respiratory exacerbations in humans (rescue drug not maintenance drug) - Risk of pulmonary fibrosis with long-term, repetitive use of b2-agonists due to increased inflammation Pharmacodynamics - Directly stimulates relaxation of the bronchial smooth muscles through b2 receptors - More sympathetic stimulation = more "Fight or Flight" = more open airways

Sucralfate (Carafate®) Indications Pharmacodynamics

Indications - Ulcers in any GI location (oral to duodenum) or cause (except NSAID induced) - Has been used in dogs, cats, horses, ferrets, and reptiles - Extra label in all species Pharmacodynamics - Stomach acid promotes polymerization of the sucrose octasulfate and aluminum hydroxide - Binds to protein exudates and basement membranes of cells in ulcer - Little effect on acid

Antihistamines/H1 antagonists Indications 1st Generation 2nd Generation

Indications • Sedation (cats and horses are opposite!- excitatory effect) • Prophylaxis of Atopic Dermatitis • Aseptic Laminitis (cattle) • Blood Transfusions • Anaphylaxis • Adjunct for treating mast cell tumors (mast cells secrete histamine) • Motion sickness (dogs only) All uses are extra-label (human drugs) ... except Temaril-P in dogs for pruritus. 1st Generation • diphenhydramine HCl (Benedryl®) - In the MWU-CAC • chlorpheniramine maleate (Chlor-Trimetron®) -has been used in dogs • promethazine HCl (Phenergan®) -has been used in dogs • trimeprazine tartrate (Temaril-P®) -Was in the MWU-CAC last year - P = prednisolone- so be aware of long-term effects -atopic dermatitis -basophils (leukocytes) corticosteroids have inhibitory effects on lymphocytes (downregulation of basophils) • hydroxyzine HCl (Atarax®) - In the MWU-CAC 2nd Generation • cetirizine (Zyrtec®) - Was in the MWU-EBC last year

Epsiprantel Indications and pharmacodynamics

Indications (labeled) • Dogs: Dipylidium caninum and Taenia pisiformis • Cats: Dipylidium caninum and Taenia taeniaeformis. • Not approved for use in food animals. Pharmacodynamics - per praziquantel

Vomiting - Guidelines for Intervention Induction and inhibition

Induction - Within 1hr of toxin ingestion (after that point- messing with electolytes) - Don't induce animals that have ingested strong acids or bases or sharp objects Inhibition - Intractable - Risk of Aspiration - Onset of acid-base disorders - Onset of electrolyte disorders

Others Inflammatory Indications for Glucocorticoids

Inflammatory Bowel Syndrome • multifactorial disease, first managed with diet modification and antibiotic TX • prednisolone if diet and antibiotics fail • budesonide has been used in dogs, but has significant adverse effects. Bronchoconstrictive Disorders • coming in Antihistamine and Respiratory Agents Lecture - Next Block

Vancomycin (Vancocin):

Inhibits cell wall synthesis by: • binding to the D-Ala-D-Ala terminus of the peptidoglycan peptide, preventing cross linking of the peptidoglycan chains; • it also inhibits transglycosylation which inhibits elongation of the peptidoglycan and chain.

Polyene antifungal agents Mechanism of Action

Interaction with sterol of fungal membrane, ergosterol, that results in the loss of intracellular components - pore formation Amphotericin B (Fungizone) Nystatin (Mycostatin) Natamycin (Natacin)

Interstitial Cells = Sustentacular Cells =

Interstitial Cells = Leydig Cells • They produce testosterone. • They are stimulated by LH. Sustentacular Cells = Sertoli Cells • They produce inhibin. • They are stimulated by FSH.

levothyroxine

It is T4 In the MWU-CAC (was last year) Approved for use in dogs, cats, horses, birds, and (reptiles -all extra-label) Pharmacokinetics • Absorption PO - Bioavailability is reduced by giving with food (so give before breakfast) - Bioavailability of the liquid formulation (Leventa®) ~ 2x pill formulation • Distribution - largely confined to vasculature due to plasma protein binding - 0.1% of T4 is free, 1.0% of T3 is free • Metabolism is hepatic (glucoronylation, sulfation, and deamination). • Elimination, t½ (terminal) ~ 8 hrs (dogs) and 11hrs (cats).

What is an integral part of folic acid? What happens to susceptible bacteria in the presence of sulfas? Mammalian cells and sulfas?

It is crucial to remember that PABA is an integral part Folic acid, which is necessary for purine and DNA synthesis by the bacteria. In the presence of sulfa drugs, susceptible bacteria cannot multiply, grow and survive. This mechanism is not applicable to mammalian cells. Mammals require pre - formed folic acid since they do not synthesize their own folic acid. Thus, a competitive antagonism between PABA and sulfa drugs is inconsequential in humans.

Pharmacokinetics: It is important to reach and maintain ________ in order to prevent the development of resistance. Maintenance of constant ________ is more important with bacterio_____ than bacterio_______ agents

It is important to reach and maintain adequate blood levels in order to prevent the development of resistance. Maintenance of constant blood levels is more important with bacteriostatic than bactericidal agents.

"AZOLES" Includes: Mechanism of Action: Therapeutic uses for azoles:

Ketoconazole (Nizoral) Fluconazole (Diflucan) Voriconzole (Vfend) Clotrimazole (Lotrimin) Miconazole (Monistat) Itraconazole (Sporanox) Posaconazole (Noxafil) Mechanism of action - Inhibits the synthesis of ergosterol- leads to the depletion of ergosterol in the cell membrane and accumulation of toxic intermediate sterols, causing increased membrane permeability and inhibition of fungal growth Therapeutic uses for azoles: fungistatic for most pathogenic fungi causing systemic infections such as Blastomyces, Coccidioides, Cryptococcus and Histoplasma spp.

Melarsomine

Labeled for Dirofilaria immitis > 5mos* in dogs in stable Class I, II, or III disease (NOT CLASS 4!) • only approved adulticide in the US • labeled for use in hospital settings only (it's in the MWU-CAC) • ABSOLUTELY CONTRAINDICATED in dogs with Caval Syndrome. Pharmacodynamics: • Unknown mechanism of action • RAPID KILL agent - risks of pulmonary thromboembolic events - risks hypersensitivity reactions - AVOIDING these possible side effects is the ENTIRE POINT of HW treatment strategy

protamine zinc insulin

Labeled for cats In the MWU-CAC Long-acting insulin (6 - 28 hrs in dogs and 6 - 24 hrs in cats) • uses protamine to slow absorption. Mixed-source insulin (90% beef and 10% pork) • induces insulin antibody production in ~45% of dogs • promotes insulin resistance in dogs. Only one amino acid difference between the sequences of feline and bovine insulin.

PPID Treatment- Pergolide mesylate

Labeled for use in horses Not in the MWU-CAC Pharmacodynamics • highly potent dopamine receptor agonist Pharmacokinetics • Rapid absorption following oral administration • Widely distributed • t½ ~ 27hrs, but highly variable between individuals Adverse effects are rare • ~10% have decreased appetite during 1st week of treatment • colic and diarrhea have been reported

Therapeutic uses Tetracycline

Large animals. Tetracycline, chlortetracycline, and oxytetracycline are used in the treatment of local and systemic bacterial, chlamydial, rickettsial, and protozoal infections in cattle, sheep, and swine (labeled) and as feed additive/growth promoters in cattle swine, and poultry. Small animals. Doxycycline, minocycline, and tetracycline are used in the treatment of respiratory and urinary tract infections in dogs and cats and as specific therapy for Borrelia (Lyme disease), Brucella, Haemobartonella, and Ehrlichia spp. infections. They are also effective in the treatment of psittacosis in birds (extra-label). Abscesses in cats. Doxycycline and minocycline have been used against abscesses that do not respond to b-lactams even though b-lactams are part of the antibiogram for the pathogen cultured from the abscess. These abscesses are thought to contain L-form bacteria that lack cell walls and are sensitive to tetracyclines. Contracted tendons in foals. Tetracyclines inhibit collagen-based contraction in myofibroblasts. This accounts for their efficacy against contracted tendons in foals. (a non-antibacterial use)

Summary

Laxatives - must give with water!!!! - know about granulomatous reactions!!! - Mineral Oil - Docusate - Psyllium - Polyethylene glycol ANS agent - N-butylscopolammonium bromide Opioid - Loperamide Anti-inflammatory - Sulfasalazine

Mineral Oil (white petrolatum, liquid paraffin) Laxatone, petrolatum

Laxatone was in the MWU-CAC last year Many OTC products Notes on uses - Used in dogs, cats, small mammals, and horses - All uses are extra-label - Can be combined with psyllium or docusate to increase efficacy - Used for hair-ball treatments in cats and small mammals Pharmacodynamics = lubrication

Therapeutic uses. Lincomycin Clindamycin

Lincomycin • approved for cats and dogs for susceptible infections • used in swine for the control and treatment of swine dysentery, • treatment of staphylococcal, streptococcal, and mycoplasmal infections. Clindamycin • approved in dogs and cats for periodontal disease, osteomyelitis, dermatitis, and deep soft tissue infections caused by Gram(+) organisms. • used for treating toxoplasmosis in dogs and cats and neosporosis (N. caninum) in dogs. Pirlimycin labeled for the treatment of bovine mastitis

Two major pathways of feedback regulations in hormones typically

Long and short both released from anterior lobe (also posterior lobe) secreted hormone itself will act back on hypothalamus to supress stimulator and stimulate inhibitory high levels of prolactin- causes inhibition feedback Long pathway- intervening organ sends up-regulating or down-regulating signals

Lincosamides (lincomycin, clindamycin, pirilmycin) Mechanism of Action Antibacterial activity

Mechanism of Action • bind to the 50S ribosomal subunits of the bacteria, which inhibits protein synthesis. Antibacterial activity • Active against a wide range of aerobic gram-positive cocci as well as several anaerobic gram-negative and gram-positive organisms. • Many species of streptococci, and staphylococci except for enterococci, are extremely susceptible. • Effective in combination with pyrimethamine treating toxoplasmosis

FLUCYTOSINE (Ancobon) Mechanism of Action Therapeutic uses

Mechanism of Action Metabolic antagonism of fungal DNA and RNA. Flucytosine is converted to 5-fluorouracil which interferes with fungal DNA and RNA synthesis. (Reaction is only performed in fungal and bacterial cells, not mammalian) 2 Major actions: inhibition of DNA synthesis and inhibition of protein synthesis Therapeutic uses • fungicidal against Cryptococcus, Candida and Aspergillus spp. • combined with amphotericin B for synergistic action in the treatment of cryptococcosis (especially meningeal cryptococcosis) in dogs and cats (extra label) • Frequent dosing and cost are issues

Cephalosporins Mechanism of Action of Cephalosporins Bacterial Resistance Clinical Pharmacology

Mechanism of Action of Cephalosporins • Same as penicillins Bacterial Resistance • Same as penicillins Clinical Pharmacology •Oral Administration •Parenteral Administration

Fasciola hepatica pathology

Metecercariae --> Immature flukes • penetrates GI and traverse peritoneum to liver- bury through; 4 days • migrate through and feed on liver tissue causing damage - may disseminate Clostridium novyi throughout liver- bad liver damage and peritoneum - at ~8 wks, penetrate main bile ducts --> Flukes mature (~10-12 wks) • feed on blood, • cause biliary hyperplasia and progressive occlusion -not breaking down food

Polymyxin B Mechanism of action Therapeutic uses Pharmacokinetics Adverse effects

Mechanism of action • interacts with phospholipids in the bacterial cell membrane to produce a detergent-like effect and membrane disruption • rapidly bactericidal to Gram(-) organisms. Therapeutic uses • used topically to treat Gram (-) bacterial infections of the skin, eye and ear in all species • usually combined with bacitracin for broad-spectrum antibacterial effects. • administered orally to cattle and swine for the treatment of Gram(-) enteric infections Pharmacokinetics • not absorbed orally • too nephrotoxic for parenteral use, except when warranted in severe cases in horse. Adverse effects • does not produce systemic toxicity when administered topically or orally • nephrotoxicity following parenteral administration

Metronidazole Mechanism of Action Therapeutic uses

Mechanism of action • is taken up by anaerobic bacteria and protozoa and reduced to a cytotoxic metabolite, which disrupts DNA • It is bactericidal against most obligate anaerobes and is active against protozoa including Giardia and Trichomonas spp. Therapeutic uses • use is banned in food producing animals. • used in dogs, cats and horses for the treatment of severe infections caused by anaerobic pathogens especially brain abscesses and pelvic, genitourinary tract, and respiratory infections. • also used to treat protozoal infections such as giardiasis and trichomoniasis in dogs and cats. • Metronidazole is combined with clindamycin in order to prevent pseudomembranous colitis

Rifampin Mechanism of action. Therapeutic uses. Administration.

Mechanism of action. • inhibits DNA-dependent RNA polymerase, which prevents initiation of RNA synthesis • bactericidal for mycobacteria and Gram(+) pathogens. • effective against intracellular infections. Therapeutic uses. • combined with erythromycin (or another macrolide) in the treatment of Rhodococcus equi infections in foals. • used in combination with antifungal agents to treat fungal infections such as aspergillosis or histoplasmosis in dogs and cats with CNS infections Administration. • administered orally three times a day in foals, dogs, and cats.

Terbinafine (Lamisil) Mechanism of action: Therapeutic uses:

Mechanism of action: • Interferes with sterol biosynthesis; inhibits squalene monooxygenase; build-up of squalene is toxic to fungi. • Fungicidal against dermatophytes (Microsprorum, Trichophyton) and fungistatic against yeast (Candida). Therapeutic uses: • when administered orally or topically, terbinafine is useful for treating dermatophytic infections in dogs and cats (extra label). • Oral - useful for treating birds for systemic mycotic infections such as aspergillosis (extra label).

- somatotropin pharmacodynamics

Metabolic (GH acts on liver causing:) 1. Increased fat utilization by organs Which makes sugars available to be used in the milk), and 2. Increased glycogen hydrolysis 3. Increased glucose available for milk Mammary Gland 1. Increased blood flow 2. Increased nutrient extraction -leads to increase in milk production Increased Cardiac Output

Pharmacokinetics Metabolism Elimination

Metabolism • 5 - 25% of administered dose is metabolized in liver (sheep and cattle) Elimination • t½ ~ 2d (dogs), 2-3d (cattle), 2-7d (sheep), and 0.5d (pigs) (long!) • 95% fecal and 5% urine (parent compound) - 20% of doramectin and metabolites undergo enterohepatic recirculation in sheep - avermectins are eliminated in milk and use is restricted to non-lactating animals, except: o eprinomectin (topical) is poorly partitioned into milk (plasma/milk = 10) -eprinomectin concentration in plasma is 10x higher than it is in milk o moxidectin (topical) can be given to lactating cows • P-glycoprotein is required to move drug out of tissues

Levamisole Indications

NM agonists Not in the MWU clinic (available OTC) Indications (FDA - Approved) • cattle (beef and non-lactating dairy), sheep and goats (all use classes) - mature and larval lung worms: Dictyocaulus spp. - mature stages of GI worms: Haemonchus spp., Ostertagia spp., Cooperia spp., Oesophagostomum spp. Trichostrongylus spp., Nematodirus spp., and Bunostomum spp. • swine (all use classes) - mature stages of GI worms: Oesophagostomum spp., Strongyloides ransomi, Stephanurus dentatus, and Metastrongylus No indications for worms in horses, dogs, or cats

Thiazine derivatives Pharmacodynamics:

Neither is currently in the MWU-CAC Pharmacodynamics: May interfere with apicoplast function, which may be needed for... • fatty acid synthesis • amino acid synthesis • starch storage So it is the "liver" of the apicoplast

methimazole is a "slow" drug.- why? Adverse effects

Normalization of T4 levels occurs in 3-4 wks with PO administration. • Requires concentration in the thyroid colloid to an effective dose. • Does not affect circulation T3 and T4 levels. Adverse effects become apparent in weeks to months. • Self-excoriation begins in 6 wks. • Lupus risk peaks at 3 mos. and anti-nuclear antibodies begin in 6 mos. need to monitor! • The thrombocytopenia and leukopenia can be rapid and transient or slow and prolonged. need to monitor -these effects are due to the transcription in different cell lines Resolution of adverse effects occurs over weeks. • Jaundice and abnormal liver chemistry tests can take weeks to resolve. • Thrombocytopenia and leukopenia requires new cell synthesis- about a week for thrombocytopenia (time to synthesize new platelets), longer for leukopenia

Progestins (hormone of pregnancy)

Not currently available in the MWU clinic Pharmacodynamics - prolong diestrus by effectively maintaining high progesterone levels -synchronizing cattle -companion animals- maintaining preg with uterine insufficiency 4 flavors 1. medroxyprogesterone acetate (Provera®) • Suppression of estrus in dogs, cats, and horses (all are extra-label) 2. megestrol acetate (Megase®) - not in US • Suppression of estrus in dogs and cats (all are extra-label) 3. progesterone (Eazi-Breed Controlled Internal Drug Release/CIDR®) • Labeled for synchronizing estrus in beef and dairy cattle, heifers, and sheep. • Currently, there isn't a labeled product for use in goats in the US. -keeps animal in state of diestrus

Atovaquone Pharmacodynamics Pharmacokinetics

Not currently available in the MWU-CAC Use is extra-label Pharmacodynamics - electron transport chain inhibitor Pharmacokinetics - poorly described - absorption is doubled when oral administration is accompanied by a fatty meal - significant binding to plasma proteins.

PGF2a Tromethamine (Dinoprost Tromethamine, Lutalyse®) Prostaglandin F2 alpha Tromethamine Indications:

Not currently in the MWU clinic Cloprostenol Sodium (Estrumate®) is a synthetic PGF2a, (only labeled for use in cows; indications below). Indications • Synchronization of estrus in cows and estrus induction in horses (labeled), sheep and goats (extra-label) • Lysis of LUTEAL cysts - Occurs when pressure atrophy kill the granulosa cells of other ovarian/FOLLICULAR cysts - Leads to luteinized thecal cells that in turn produce high systemic progesterone levels - Causes prolonged anestrus- as long as progesterone levels are high- animal cannot cycle pgf2a kills a luteum- kills a follicular cyst (driving normal phys that leads to the lysis of the follicle • Abortifacient in feedlot and non-lactating dairy cows (labeled), sheep, goats, and small animals (off-label) -table= there are three groups of animals in which pgf2a can cause an abortion group 1- never works (cats and dogs) group 2- sometimes works -sheep, cows, horses group 3 - always works after 4-6 days (need 4-6 days before you have pgf2a receptors that are being secreted by corpus luteum)- pigs after 10-12 days receptors are available- if you give pgf2a in those 10-12 days -causes abortion -pigs and goats • Induction of parturition in swine • Pyometra in feedlot and non-lactating dairy cows (labeled); however, evidence of effectiveness in endometritis is lacking. • Hydro- or muco-metra in sheep and goats (extra-label) • Silent estrous in lactating dairy cows (labeled), sheep and goats (extra-label)

glipizide Pharmacodynamics

Not currently in the MWU clinic Indicated for extra-label use in Type 2 DM (usually cats) • possible alternative for owner who refuses to give injections. • cat well-maintained on a low dose of insulin, and the owner wants an alternative Pharmacodynamics • inhibits ATP-dependent K+ channels • increases beta cell secretion of insulin • enhances insulin sensitivity of extrahepatic tissues

metformin Pharmacodynamics

Not currently in the MWU clinic Indicated for treatment of Type 2 DM • primarily cats, but • some conflicting studies in horses • extra-label use Pharmacodynamics Reduces glucose by: • increasing glucose uptake by the liver, and • inhibiting gluconeogenesis (30 - 95% of glucose output) by opposing glucagon signaling

Clorsulon indications and pharmacodynamics

Not currently in the MWU clinic Indications • Fasciola spp. in cattle (labeled) and sheep (extra-label) • NOT EFFECTIVE against flukes BEFORE 8wks post-infection • Ivomec Plus® contains both clorsulon and ivermectin macrocyclic lactone); so, it also covers nematodes. Pharmacodynamics Stops glycolysis by inhibiting phosphoglyceromutase and phosphoglycerate kinase. -fluke cannot make ATP- dies

pralidoxime chloride Pharmacodynamics Pharmacokinetics

Not in the MWU clinic Use is extra-label in all species Pharmacodynamics -after aging process- doesn't work - so give asap at exposure Pharmacokinetics Administration • slow IV (dogs, cats, and horses) • IM all others • Best within 3hrs, but depending on exposure up to 36hrs has been used Distribution • primarily extracellular water • does not cross BBB -peripheral affects of ach being high but not the central (seizures!) Metabolized by liver and excreted in urine Don't use unless indicated; 2-PAM also inhibits AChE and causes neuromuscular blockade

Albendazole indications

Not in the MWU clinic (available OTC) Labeled Indications • cats and dogs: Giardia only • cows: stomach worms (Ostertagia ostertagi, incl. 4th stage larvae), intestinal worms, and lung worms • also approved for use in: sheep, goats, and rodents. benzimidazoles

Docusate (Colase®, dioctyl sodium sulfosuccinate/DSS)

Not in the MWU-CAC Indications (all extra-label) - Dogs, cats, and horses only - Used in combination with mineral oil for colonic impactions in horses Pharmacodynamics - Anionic detergents (charged) that soften stool by increasing the mixing of water and lipids in digestive fluid - Increases cAMP concentrations in colonic mucosal cells, which increases ion secretion and fluid permeability of the cells

Sulfasalazine (Azulfidine®)

Not in the MWU-CAC Indications (extra-label, no veterinary products) - Nonspecific chronic colitis in dogs and cats - Subtype of irritable bowel syndrome (IBD) Pharmacodynamics - Hydrolyzed by GI bacteria into... - 5-aminosalicylic acid/mesalazine, nonspecific competitive COX inhibitor (1 and 2) - Sulfapyridine, a sulfonamide antibiotic (shifts GI microbiome)

Erythromycin (Gallimycin®) Indications Pharmacodynamics

Not in the MWU-CAC Indications (sub-antimicrobial doses, all extra-label) - Primary gastroparesis - Esophageal reflux - Colonic motility disorders - Only in dogs and cats Pharmacodynamics - Stimulates motilin receptors in cats - Stimulates 5-HT3 receptors in dogs

Theophylline Pharmacodynamics

Not in the MWU-CAC Indications: Indicated for bronchoconstriction in dogs and cats (extra-label) Primarily used for coughs of unknown origin (ie. when all else fails) Pharmacodynamics Inhibits smooth muscle contraction by inhibiting - phosphodiesterase IV, which causes increased cAMP - Gs-linked adenosine receptors, which increase Ca2+

Cisapride (formerly Propusid®)

Not in the MWU-CAC - Compounded only - Current status is uncertain pending new FDA-CPG Indications - Primary gastroparesis - Esophageal reflux - Constipation and megacolon in cats Pharmacodynamics - Modulates Serotonin receptors - Agonist of presynaptic 5-HT4 receptors that directly increases release of ACh - 5-HT1, 5-HT2a, 5-HT3 receptors have less central roles - Stimulates gastric emptying and lower esophageal motility and sphincter pressure

Pancrelipase (Viokase®) Indication and pharmacodynamics

Not in the MWU-CAC Indication: - Exocrine pancreatic insufficiency - Extra-label Pharmacodynamics - Combination of lipase, amylase, and protease intended to promote digestion of nutrients Pharmacokinetics: ???? -like steak- high amounts of proteins- results in pepsin breakdown - does it actually do anything other than that though?

Juvenile Hormone Analogs Methoprene and Pyriproxifen Indications Pharmacodynamics Adverse effects

Not in the MWU-CAC Indication: Fleas in dogs and cats Pharmacodynamics • Hormones that induce flea maturation when they DECREASE - maintaining high levels prevents insect maturation -a hormone that is kept at a high to keep the flea from maturing • Pyriproxyfen also concentrates in flea ovaries and creates non-viable eggs • Pyriproxyfen in more stable to UV light than methoprene Adverse effects: Very safe by themselves, but are included in combination products that have permethroids- toxic in cats; so, be sure to use only cat products in cats

Chlorpromazine HCl (Thorazine®) Indications and Pharmacodynamics

Not in the MWU-CAC Indications - Antiemetic in dogs and cats - Inhibits apomorphine-induced (dogs only) and morphine-induced emesis (blocks vomiting pathways at multiple points) - May be useful for motion sickness in cats - Significant adverse effects (so used rarely) Pharmacodynamics - Primarily, antagonism of D2 receptors in the CRTZ - Also has anti-histaminic, anti-cholinergic, and anti-alpha adrenergic effects

Bismuth subsalicylate (Pepto-Bismol®) Indications and Pharmacodynamics

Not in the MWU-CAC Indications - Helicobacter spp. associated gastritis in cats, dogs, and ferrets - Diarrhea in cats, horses, pigs, and cattle - There are products for veterinary use, but no FDA-approval Pharmacodynamics - Cleaved into bismuth and salicylate - Bismuth (a heavy metal) is weakly anti-endotoxic and antibiotic - Salicylate is a nonspecific competitive COX inhibitor

Ondansetron HCl (Zofran®) Dolasetron Mesylate (Anzemet®)

Ondansetron is in the MWU-CAC (injectable and tabs) Indications - Vomiting (cats and dogs) - All uses are extra-label; no veterinary products - Ondansetron increases efficacy of dexmedetomidine and buprenorphine combinations (when used as sedatives) Pharmacodynamics: - Antagonists of 5-HT3 receptors in the CRTZ, Vomiting Center, and Periphery

Nutraceuticals and Dietary Supplements

Nutraceuticals • Foods, or parts of food, that provide health benefits, including the prevention and treatment of disease • Regulated by the FDA as drugs, foods, food ingredients, or dietary supplements depending on marketing claims Dietary Supplements • Products taken by mouth that contains a "dietary ingredient" intended to supplement the diet (Dietary Supplement Health and Education Act/DSHEA of 1994). • Not regulated for efficacy* by the FDA; but manufacturing facilities must register with FDA • May not claim to treat a disease or condition • Labelling must state: "These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease."

Hyperadrenocorticism - Signs

PU/PD • Due to CV derangements Polyphagia • Desirable with cancer cachexia • If you had muscle wasting, fat redistribution, and hyperglycemia, you'd be hungry too. • Consistently occurs in dogs only Muscle Weakness • Due to atrophy resulting from increased circulating amino acids • Insulin antagonism decreases available energy Pot-bellied abdomen w/hepatomegaly • Fat redistribution to the liver and mesentery • Increased GNG in the liver Skin Pathologies • Thinning (12% of cases) • Due to fat redistribution • Can occur with both high systemic levels and chronic topical use • Hyperpigmentation (43% of cases) • Bilateral & Symmetric Alopecia (80% of cases) Laminitis in horses (hyperglycemia)

Fenbendazole (a benzimidazole) Indications

Panacur C is in the MWU-CAC Labeled Indications • dogs: roundworms (T. canis and leonina), hookworms (A. caninum), and whipworms (T. vulpis). • cats: roundworms, hookworms, strongyloides, lung worms, and Giardia • cows: lung worms, stomach worms (Ostertagia ostertagi, incl. 4th stage larvae), intestinal worms (Haemonchus) • horses: strongyles (large and small), pinworms, and ascarids (P. equorum) • also approved for use in: bears, large cats, rodents, ferrets, swine, sheep, goats, camelids, birds and reptiles benzimidazoles

Penicillin Toxicity Penicillin Allergy

Penicillin Toxicity Other than allergy, penicillins are probably the most non-toxic and safest drugs available. Penicillin Allergy • All forms of hypersensitivity reactions • Anaphylactic (immediate) • Cytotoxic (autoimmune) • Arthus (immune complex) • Cell mediated (delayed) IgE hypersensitivity reaction -most seen - just give epinephrine

Dimethylsulfoxide Pharmacodynamics Pharmacokinetics

Pharmacodynamics - DMSO traps hydroxyl radicals (free radicals drive inflammation) - Dimethylsulfide (DMS, active metabolite) trap oxygen radicals - Presumably,... this reduces neutrophil and macrophage activity -> Inhibits some prostaglandin synthesis -> Inhibits alcohol dehydrogenase Pharmacokinetics - Absorption: 80-100% following topical application (very hydrophobic!! - so very sensitive) - Distribution: extensive, freely diffuses into cells - Metabolism: Hepatic - Elimination: -> Urinary, GI, and respiratory -> t½ ~ 9hrs in horses and 36hrs in dogs cheaper

Pyrethrins/Pyrethroids Pharmacodynamics Toxicity

Pharmacodynamics • Activates Na+ channels in nerves- in insect • Causes repetitive depolarizations leading to parasite death (of insect!) • 100-1000x more selective for parasite vs. mammalian Na+ channels -can still do this to mammals but due to the selectivity for parasites- preferentially effect parasites Toxicity • 2nd Generation and greater are ABSOLUTELY toxic to cats. - Ingestion by grooming - Metabolism requires glucuronidation -even if dog at home- still don't give because if cat licks dog- toxicity • Signs (similar to organophosphate toxicity) - Salivation, Lacrimation, Urination, Defecation, GI distress, and Emesis (SLUDGE) - also miosis, tremors/convulsions, and dyspnea - all signs occur at toxic levels in all animals

Organophosphates Pharmacodynamics Pharmacokinetics

Pharmacodynamics • Long-lasting inhibitors of AChE • Becomes irreversible with "aging"- binds to active site of ach- HF comes off, H combines with F- stablizes oxygen phosphate bond- ach inactive- long lasting bond -when hydrolyses happens - becomes irreversible until body makes a new one • We "HOPE" that the parasite nervous system is more sensitive that the mammalian nervous system. Pharmacokinetics • Many routes of entry- mucosa, gi, etc • Highly lipid soluble -long life span in an animal

Summary 2: Drugs for treating bronchoconstriction

Phosphodiesterase Inhibitor • theophylline b2 Agonists • albuterol (Ventolin®) • clenbuterol (Ventipulmin®) • terbutaline (Brethine®) Cholinergic Antagonist • ipratopium (Atrovent®) Corticosteroids • fluticasone (Flovent®) • prednisolone • isoflupredone • dexamethasone

Pituitary Gland = Anterior pituitary = Posterior pituitary =

Pituitary Gland = Hypophysis • Anterior pituitary = Adenohypophysis (derived from oral mucosa) • Posterior pituitary = Neurohypophysis (derived from neural ectoderm) red stained- secretory glands of anterior pituitary

Thiazine derivatives Ponazuril and Diclazuril Pharmacokinetics

Ponazuril - absorption o 30% bioavailability following oral administration in water; enhanced when dissolved in DMSO o CSF:plasma = 1:20 - elimination t½ ~ 80 hrs - adverse effects: blisters (nose and mouth), rash, diarrhea, mild colic, seizures Diclazuril - 5% bioavailability following oral administration, CSF:plasma = 1:20 - elimination t½ ~ 43-65 hrs - No reported adverse effects

Summary

Pregnancy and lactation are contraindications for many of these agents and extra care must be taken to in these cases. focus on drugs he focused on -but be able to pick the others up out of a line up -know specific adverse effects doxirubicin- mostly talked about pyrimidine- very similar vincristine vs vinblastine

Hypothyroidism Etiology Drug-induced hypothyroidism

Primary hypothyroidism due to lymphocytic thyroiditis (autoimmune disease) (common). • Increased circulating anti-thyroglobulin antibodies -attacking the colloid Primary hypothyroidism due to congenital hypothyroidism (rare) • Autosomal recessive mutations in thyroid peroxidase gene (can't make T3 and T4) • Signs include large heads, macroglossia, short thickened necks, shortened limbs, hypothermia (don't have normal sympathetic stimulation), ataxia, and more! (developmentally abnormal) • Terriers Hypothyroidism secondary to lots of other diseases or nutritional status (I, Se, and Zn) Drug-induced hypothyroidism • Trimethoprim/sulfonamides- bad in doberman -other species as well with actual signs • Glucocorticoids (alters T4, but rarely produces signs) • Phenobarbital (alters T4, but rarely produces signs)

Preventing Errors- Frequency Abbreviations

Q24hr = once a day; not SID ◦ Likewise, Q48hrs; not QOD BID = twice a day (Q12hrs is better) TID = three times a day (Q8hrs) QID = four times a day (Q6hrs) PRN (pro re nata) = as needed These are fine for other medical professionals, NOT CLIENTS!

desmopressin Rate of response- Pharmacokinetics cont. Adverse Effects

Rate of response • In Dogs • Peak effect occurs 2-6hrs post-conjunctival application • Duration of effect is 10-27hrs • Other species include cats and horses, effects not well-documented Adverse Effects • DDAVP causes increased Factor VIII and von Willebrand Factor in dogs. - coag proteins • Use with care in patients at risk of thrombotic events.

tyrosine kinase inhibitors c-kit -CD117, stem cell growth factor receptor.. etc.

Receptor tyrosine kinase that normally drives leukopoesis • induces cell cycle activation and protein synthesis when stimulated • greatest proliferative effect is on mast cells c-kit is a proto-oncogene • mutated in 25-50% of canine mast cell tumors • mutant c-kit signals continuously (constitutively), even in the absence of the ligand • sufficient to cause unregulated cell proliferation (driver mutation) in mast cell tumors

Central Tenants:

Regulations for drug use in animals began 110 years ago and are frequently revised (most recently in 2014). Central Philosophy of drug regulation for animal use: - To protect the public from inadvertent consumption of harmful amounts of drugs given to livestock. -->to protect population from what they eat - To allow livestock producers to protect the health of their animals with minimal oversight.

Fluoroquinolones Resistance and Adverse effects:

Resistance • Development of bacterial resistance is emerging due to mutations in genes encoding DNA gyrase and topoisomerase. Adverse effects • reversible erosion of articular cartilage in young dogs and foals particularly if used at high doses for longer than 14 days in rapid growth phase of the animal. • enrofloxacin has also been reported to produce seizures in dogs on phenobarbital for epilepsy • retinal degeneration has been reported in cats and it is due to acute, diffuse, and irreversible retinal damage. • Orbifloxacin and marbofloxacin are the least toxic

Type of Insulin and diabetic remission in cats

Roomp and Rand. J Feline Med Surg. 2012 • comparison of cats treated with either detemir or glargine • all cats had been previously treated with other insulins • remission - 67% overall, but 81% if started within 6 mos of diagnosis - no significant differences in outcomes between the two groups Hoelmkjaer, Spodsberg, and Bjornvad. J Feline Med Surg. 2015 • retrospective study of response of 14 cats to detemir in a practice setting • clinical signs of 13/14 cats were well-controlled, - including 5 that were unresponsive to other insulins - better than indicated by serum glucose and fructosamine levels. - 4 went into remission (time after diagnosis?)

Prescriptions: Controlled Substances

Schedule II ◦ No Refills ◦ Must be a WRITTEN prescription Schedule III - V ◦ 5-refill maximum ◦ prescription only good for 6 months -most prescriptions are good for a year Prescriptions must not be pre-printed (don't do this anyway)

Antihistamines/H1 antagonists Adverse Effects

Sedation, except when it causes.... - Excitation (esp. Diphenhydramine in cats and horses) - Anticholinergic effects (colic!, like atropine) -> Only with 1st generation antihistamines -> GI effects - Iatrogenic Cushing's DZ with Temaril-P®

Ulcers in small animals

Signs - Weight loss and anorexia - Sporadic, chronic vomiting, possibly with blood - Abdominal Pain - Anemia and melena (leaking blood in gi- digested and through gi) - Secondary esophagitis (really with any vomiting) -vomiting acid and damaging muscosa • Causes - drug-induced (NSAIDS) - Helicobacter pylori, controversial

Toxoplasmosis Signs and treatment

Signs - in healthy, adult cats, diarrhea (rarely chronic) -asymptomatic - in kittens or immuno-suppressed, adult cats o fatal extra-intestinal/disseminated toxoplasmosis. o depression, anorexia, fever followed by hypothermia, icterus, dyspnea, and ascites - dogs o immuno-suppression may lead to disseminated toxoplasmosis o signs and treatment are the same as Neosporosis. Treatment (small animals) • sulfadiazine-trimethoprim (TMS), or • clindamycin

Hypoglycemia signs and tx

Signs Lethargy/depression, head-tilt, seizures, and coma Signs associated with catecholamine release (tachycardia, etc.) • catecholamines are diabetogenic and will act to correct hypoglycemia Treatment at home: • discontinue insulin until hyperglycemia recurs; then use adjusted insulin dose. • KaroTM syrup on the gums and bring in immediately if symptomatic. in clinic: • IV fluids containing dextrose for emergency cases and adjust insulin.

Signs of Diabetes mellitus Clinical Chemistry

Signs of Diabetes mellitus • PU/PD • weight loss in the face of polyphagia/hunger • cataracts in dogs and neuropathy in cats (chronic changes) Clinical Chemistry • blood glucose above normal range • glucosuria • when blood glucose is greater than kidneys capacity to reabsorb • 180-220 mg/dL in dogs and 250-290 mg/dL in cats • increased fructosamine levels

Hepatozoonosis Treatments

TICK PREVENTION Drugs • sulfadiazine-trimethoprim (TMS) + clindamycin + pyrimethamine • imidocarb dipropionate has also been used. • decoquinate (Deccox®, hydroxyquinoline) Decoquinate • used as a stand-alone to prolong remission following TX • electron transport chain inhibitor • acts on the schizont/infective stage to prevent further development Only clindamycin is available in the MWU clinic.

Sulfamethazine (Sulmet)

Slowly excreted, therapeutic levels maintained for 24 hours • Used to treat: • bacterial pneumonia and bovine respiratory disease • foot rot and diphtheria in cattle • acute mastitis in cattle • bacterial pneumonia in swine • coccidiosis in chicken -Coccidiosisis an intestinal disease that occurs when a protozoa attaches itself to the intestinal lining of a chicken. The disease starts with an unsporulated oocyst passed through a chicken's droppings.

Guidelines for cat owners (esp. pregnant or immuno-suppressed)

T. gondii causes abortion, mental retardation, hydrocephalus, and ocular pathologies in humans • House cats indoors • Cover outdoor sandboxes • Use plastic liners in litterboxes and sanitize regularly. • Feed cats cooked or commercially processed food. • Filter or boil water from non-community sources • Wash hands and/or wear gloves when handling cats, cleaning litterboxes, gardening, or preparing food.

Production of thyroid responsive proteins and changes in cell activity

T3 and T4 get transported into cells, T4 converted to T3 T3 activates intracellular receptor that alters transcription in the cells - puts new pathways in place (takes time to happen) management in animals with low levels t3 and t4 takes time

Benzimidazoles

Tapeworms Albendazole is FDA-approved against Moniezia spp. in cattle (non-lactating) Fenbendazole is effective against T. pisiformis in dogs and cats Flukes Albendazole is effective against F. hepatica in cattle at labeled dose. • 12+ weeks post-infection • Comparable to clorsulon (70-99%) Febendazole is 95% effective against F. gigantica in sheep at the labeled dose. Roundworms and Giardia Approved in dogs, cats, horses, and cattle (specifics in upcoming lectures)

Routes of Absorption for Topical Agents 3 major

Trans-epidermal can be... - Intracellular diffusion- confined to the interstial space - Transcellular, -active transport - Epidermal thickness: pigs > cattle > dogs > cats Trans-follicular is both: - Trans-epidermal and - Sweat pore -- due to accumulation in sebaceous glands -- Variation in this route due to hair structure of different species. Not shown: Lateral diffusion- not generally a path of absorption -not the way the drug is spread from the nose to the tail of the animals -diffusion of an oily mixture of the drug spread 1-3 inches of application -doesn't spread drug all the way through the animal absorption very important process - into blood stream

Disease Highlights Babesiosis

Transmitted by ticks • Specific tick species are regional. • TICK PREVENTION is mainline action. -1st thing to do Pathogenic stages infect RBC's, which are destroyed by immune attack Signs include: anemia, splenomegaly, depression, and anorexia Horses • Not currently a problem in the US, but we have known tick vectors; so, it's only a matter of time • TX: imidocarb dipropionate (B. caballi) • TX: chlortetracycline (Theileria/Babesia equi)

octreotide Pharmacodynamics

Use is Extra-label Pharmacodynamics • synthetic, 8aa, long-acting analog of human somatostatin - Somatostatin = GH-IH (growth hormone inhibitory hormone) - Highly conserved: identical sequence of the active 14aa peptide from humans to angler fish. • Used to exogenously increase the amount of GH-IH, which induces a decrease in the amount of circulating GH 1. Short acting preparations of octreotide are reportedly ineffective for feline acromegaly. 2. In humans, ~65% of patients have improved GH and IGF-1 levels with longacting release (LAR) preparations of octreotide 3. Long-acting/depot preparations of the somatostatin analog Pasireotide induces diabetic remission in 3/14 cats -not a cure, but pos result that indicates therapy worth following up on variation- may not have receptors in adenomas

glargine insulin

Use is extra-label Long-acting insulin • acts for 12 - 16 hrs in cats • acidic solution that is neutralized when injected SC, which causes microprecipitates to form that dissolve at a constant rate. • modified recombinant human insulin Dilution • induces precipitation • no loss of effect when this is done IMMEDIATELY PRIOR to injection.

Objective 6 - Preventing Errors Keys:

Use prescription software ... or write legibly Be specific about drug names and use generic names. Include ◦ the diagnosis, ◦ the indication for drug, and ◦ any supplemental instructions. Use metric units (ml, not tsp.) 0.1, not .1; 5, not 5.0 100 units, not 100U microgram (or mcg), not µg Ampoules- how many, dose? By client: Write directions for use in plain English Specify how often and how many Do not use abbreviations Clarity of Instruction helps ensure client compliance.

Propranolol Use of propranolol

Used for thyrotoxicosis- too much thyroid hormone • Decreased HR (b1 inhibition, main reason) • Promotes inactivation of T3 by blocking Types I and III monodeiodinases (additional possible benefit) -blocks conversion to active form not the inactive form -reducing levels of active t3 b1 and b2 inhibitor- reduces cardiac output reverse t3= inactive

neutral protamine Hagedorn insulin

Used in dogs only, extra-label In the MWU-CAC Intermediate-acting insulin Mixed with protamine to slow absorption Single peak of activity at 8.5 hrs (median) Human recombinant insulin (~5% of dogs have immune reactions)

Organophosphates uses

Uses Pesticides - Mosquito control (diazinon, malathion) - Agricultural Use (malathion, chlorpyrifos, dimethoate, etc) - Livestock Use -- Ear-tags (diazinon, pirimiphos) -- Anti-nematodal agents (famphur and fenthion) - Flea collars (dichlorvos, diazinon, etc) - Sprays, Dusts, and Dips (coumaphos and phosmet) Nerve Gases (Sarin, Tabun, VX, etc.)- militarized EPA enforcement is patchy....

Uses: Cefazolin (Kefzol®) Cefadroxil Monohydrate (Duricef®) Cephalexin (Keflex®) Cephapirin (many veterinary formulations)

Uses: Cefazolin (Kefzol®) • surgical prophylaxis, • parenteral • extra-label Cefadroxil Monohydrate (Duricef®) • approved for susceptible infections of the skin, soft tissues and GU in dogs and cats • oral Cephalexin (Keflex®) • labeled for susceptible skin infections in dogs • all other uses are extra-label • oral Cephapirin (many veterinary formulations) • approved for mastitis in lactating and dry cows

Piperacillin (Pipracil), Ticarcillin (Ticar)

Uses: • Combined with penicillinase inhibitors • Effective against many penicillinase producing isolates, anaerobic and mixed infections • All uses are extra-label

PPID/Equine Cushing's Disease

Usually seen in older horses (> 15 yrs) Pathology - tumor formation in the pars intermedia causes pressure atrophy of dopaminergic neurons in the hypothalamus - reduced inhibition of ACTH release by pituitary induces cortisol release by adrenal glands Physical exam/signs - abnormal fat deposition - muscle wasting over hindquarters - PU/PD - increased likelihood of infections - hirsutism - laminitis

Hypoadrenocorticism Physical Exam/Signs

Usually vague/nonspecific.... • Poor body condition/weight loss • Lethargy Can be severe.... • Bradycardia • Hypovolemic shock (weak pulses, decreased CRT) • Anemia- not stimulatingblood production • Humans are unable to respond to stress, but this is less true in dogs Adrenal gland may have deficient cortisol and aldosterone production

Summary

Vomiting (CNS) - 5-HT3 inhibitors - Ondansetron - Dolasetron - Maropitant - D2 agents - Apomorphine (agonist) - Chlorpromazine - Metoclopramide - H1 Antagonists - Diphenhydramine, etc. PPI's - Omeprazole - Pantoprazole H2 Antagonists - Cimetidine - Famotidine - Nizatidine - Ranitidine Promotility Agents - Erythromycin - Cisapride - Ranitidine - Nizatidine - Metoclopramide Cytoprotectants - Sucralfate - Misoprostol

Adverse Effects dogs

Vomiting, Tremors, Ataxia, Mydriasis, Blindness, and Seizures • Wild Type - ivermectin becomes toxic at > 160x normal dose. - deaths begin occurring at 6000x normal dose (LD50 = 12,000x) so if a normal drug- this is relatively safe -no MDR1 -trouble! • ABCB1-/- - ivermectin becomes toxic at < 2x normal dose (signs begin within 4hrs of treatment) - safer alternate macrocyclic lactones o selamectin has no adverse effects in ABCB1-/- collies at 6.5x normal dose (Novotny et al. Vet Parasitol. 2000) o milbemycin oxime causes adverse effects at 2x the dose used heartworm prevention (Barbet et al. Vet Dermatol. 2009) Combination with spinosad increases BBB permeability... ...and toxicity

Adverse Effects cats, horses, cattle, pigs

Vomiting, Tremors, Ataxia, Mydriasis, Blindness, and Seizures Cats • signs start within 10hrs of overdose • no signs noted in kittens at 4x normal cat dose • no signs in adult cats at 30x normal cat dose Horses - signs start between 9-10x normal dose Cattle - signs start at ~12x normal dose (SC injection) Pigs • adults: Signs start at 100x normal dose • piglets: more sensitive; so, dose accurately In ALL species, with ANY of the ML's... HYPERSENSITIVITY reactions may occur in animals with large worm burdens! What is your frontline approach to this problem? -slow kill agent + steroids

Sulfachlorpyridazine

a rapidly absorbed and rapidly excreted sulfonamide • approved orally in calves (excluding veal calves) according to FARAD under one month of age and in swine for the treatment of respiratory and enteric infections, especially colibacillosis. Peak levels occur in 1-2 hours in non-ruminants and in preruminant calves.

Cancer Incidence in companion animals

don't tend to treat cancer in FA- can harm humans Breast cancers- really big in dog and cats- spay and neuter has helped reduce this Skin cancer Connective tissues Testicular cancers - neuter Lymphoid Malignant melanomas GI Bone - fairly low but very dramatic

L-asparaginase Pharmacodynamics

asparaginase acts at the G1 phase of the cell cycle effects metabolism and specifically used in dogs with lymphoma (rescue drug) Normal- ASP into cell and converted to ASN by Asb synthetase Lymphoid cell- Aspartate- cannot be converted (low Asn synthetase levels) Asparaginase- destroys circulating levels of asparginase- tumor cells die because no way of converting

How do these work? b-lactam antibiotics: Glycopeptides: Bacitracin:

b-lactam antibiotics (penicillins, cephalosporins, carbapenems and monobactams) prevent the cross-linking reaction called transpeptidation -bind to the transpeptidase enzyme - prevent cross-link Glycopeptides: (vancomycin) sterically inhibit the addition of subunits to the peptidoglycan backbone. Bacitracin: inhibits the conversion to its active form of the lipid carrier that moves the water soluble cytoplasmic peptidoglycan subunits through the cell membrane to the cell exterior

Bacteriostatic vs. Bactericidal activity:

bactericidal - no remarkable difference between bacteriostatic and bactericidal concentrations -As you increase the concentration further and further- then at a certain point, the bacteria start to die bacteriostatic - bacteriostatic concentrations are much lower than bactericidal -bacteriostatic much lower concentration -bacteriocidal concentration is too high -too much toxicity to be able to use

Flies

blood feeding -culicidae = mosquitos -stable flies= big problem non-biting -cow grubs burrow into the skin and cause large welt in the skin of a cow -cuterebra similar to cow grubs in cats -can also transmit other diseases

Ondansetron HCl (Zofran®) Dolasetron Mesylate (Anzemet®) Pharmacokinetics

both very similar * PO is ineffective with acute, intractable vomiting, dolasetron pill doses are too large for small animals

Mite chart

burrowing and non-burrowing types sarcoptes- super itchy- burrow in skin, defecate, hypersensitivities set off

ADH and hematacrit

decrease in blood pressure from peeing out a hiuge amount of water- reduced renal blood flow, reduced o2 flow to kidneys induces renin release- causes conversion of angiotensinogen - angiotensin 1 - 2 - aldosterone secreted (increased na retention), ADH secreted, thirst stimulated - increased fluid retention, increased fluid intake- increased blood pressure and volume reduced o2 to kidneys causes erythropoietin release, increased red blood cell production - increased blood pressure and volume

A 6yo male, neutered boxer cross is presented in your senior clinic with marked PU/PD. Clinical Chemistry • isosthenuria (SG < 1.012) -not concentrating urine at all • negative urine glucose -not diabetic (diabetic has high glucose in sugar which crashes over into urine, causes excessive urination, drinking a lot) • normal creatinine • mildly increased hematocrit • unremarkable radiographs and bladder U/S • negative culture Rule-outs include

diabetes insipidus Two forms central and nephrogenic.

Trematodes/flukes of veterinary interest

flukes tend to live in areas with a lot of water 3 main = hepatica (main one we see), gigantica, magna Intermediate host= main = snail salmincola- fish- harbors protozoa- neoricketsia- death

GLUCOCORTICOIDS - anti-inflammatory actions (delayed onset)

glucocorticoids look like steroids -bind to the glucocorticoid receptors and cause new transcription pathways (increased transcription of anti-inflammatory genes) and decreased pro-inflammatory- foot on break for inflammatory

Release of growth hormone

glucose-sparing effect- stimulates adiopose cells to break down stored fat, fueling growth effects Increased uptake of amino acids from blood- enhances cellular proliferation and reduces apoptosis Diabetogenic effect- GH stimulates liver to break down glycogen

Fluconazole and Itraconazole

have replaced ketoconazole in most treatment regimens for the systemic mycoses because of their longer t1/2 , greater activity, and lower toxicity. • Fluconazole penetrates the CNS - useful for Cryptococcal meningitis • Fluconazole achieves high urinary concentration - useful for fungal UTI • Fluconazole is more cost effective than itraconazole; highly prescribed for valley fever (Coccidioides) Administration • Fluconazole can be given with or without food; itraconazole requires an acidic environment for oral absorption • Itraconazole - ophthalmic ointment for fungal keratitis in horses (compounded) Fluconazole and itraconazole - oral or IV (1-3 months) for dogs, cats, horses, rabbits, birds for systemic mycoses. • All extra label. Fluconazole- adverse effects = Better tolerated and fewer drug interactions Itraconazole- adverse effects= Hepatic toxicity, vasculitis, depression (cats), anorexia (dogs)

Adverse Effects: Toxicity to host: idiosyncrasies:

hemolytic anemias: • sulfonamides • nitrofurantoin photosensitivity: • tetracyclines • fluoroquinolones

Generalized nematode life cycle

ingestions/infection- migrate through the definitive host - into liver, lungs, gi- elimination another possible route- instead of being eliminated - can be ingested by intermediate host- which transmit (vector) to next host

Glycoproteins Reproductive organs:

inhibin

Fluoroquinolones Mechanism of action Mechanism of resistance

inhibiting topoisomerase change in sensitivity of TI "pump out"

Beta lactams Mechanism of action Mechanism of resistance

inhibition of bacterial cell wall synthesis penicillinase; modification of PBP-s; change of porins

Sulfonamides Mechanism of action Mechanism of resistance

inhibition of folic acid synthesis decreased sensitivity of the target enzymes, increased formation of PABA, use of exogenous folate

Vancomycin Mechanism of action Mechanism of resistance

inhibition of peptidoglycan chain elongation change in pentapeptide, D-ala-Dlactate

Rifampin Mechanism of action Mechanism of resistance

inhibits DNA dependent RNA polymerase change in enzyme

methimazole Pharmacokinetics

inhibits thyroid peroxidase and thyroglobulin -reducing addition of iodine -t3 and t4 without iodine -not active Available in the MWU clinic ~90% efficacy with PO administration (Trepanier, VCNA, 2007)- higher efficacy with pilling ~60% efficacy with transdermal administration (Lecuyer, CVJ, 2006) Pharmacokinetics (Cats only) • Administered PO or transdermally (requires compounding) -Bitter tasting • Absorption/Bioavailability - 45-98%, with an average of 80%, lower with transdermal -Distribution: VD = 0.12 - 0.84 L/kg (concentrates in the thyroid colloid) - Metabolism: Not documented, but there is probably liver involvement. - Elimination - t1/2 ~ 2 - 10 hrs (8 - 9hrs in dogs)

Short polypeptides and small proteins Pancreas-

insulin, glucagon

Tapeworm life cycle

intermediates- encyst in the muscle - don't do anything Definitive Host- infective stages

Groups of Parasites

internal -- external Yellow= macrocycliclactones

Vancomycin (cont'd) Resistance:

• If the terminal D-Ala-D-Ala is replaced by D-Ala-D-Lactate (Mutation!) vancomycin cannot bind. • vancomycin resistant strains are often resistant to other antibiotics • Gram negatives are resistant Synergistic effect with aminoglycosides, also synergistic toxicity!

alkylating agents Pharmacokinetics

• Absorption - most are administered IV - lomustine, melphalan, procarbazine, and cyclophosphamide are administered PO (prodrugs) Pro-drugs - have to be PO • Distribution - rapidly distributed throughout the body - platinum agents are most strongly absorbed by liver, bone, and GI tissue - procarbazine and active metabolites of lomustine cross the BBB - plasma protein binding is variable (~90% of cisplatin binds to albumin, but carboplatin does not) • Metabolism - platinum compounds are not actively metabolized- break down in circulation - dacarbazine is a prodrug (the active drug is temozolamide) - lomustine and cyclophosphamide are pro-drugs that are metabolized to their active forms - melphalan is metabolized in the plasma by hydrolysis - procarbazine is NOT metabolized to dacarbazine (they are separate drugs- not a prodrug) • Elimination - platinum compounds undergo active RENAL secretion o both parent drug and free platinum. o t½ ~ 24h (terminal t½ ~3 days) (eliminating parent chemotherapeutic into the environment!- must discuss with owners) - cyclophosphamide t½ ~ 1h - lomustine t ½ ~ 15m

L-asparaginase Pharmacokinetics

• Absorption - typically administered IM, SC (IV administration can be fatal)- because is a protein with an enzymatic activity - 50% bioavailability when administered SC • Distribution (humans) - confined to the plasma (135kDa ->big), but rapidly becomes undetectable - asparagine levels remain low for 23d post-administration • Metabolism and Elimination - hydrolyzed to amino acids and used for new protein synthesis

Levamisole Pharmacokinetics

• Absorption - well-absorbed following oral, topical, or SC administration - bioavailability: SC > Oral > topical • Widely distributed - found in all tissues - enters the milk of cattle within 1 hour following SC administration (not approved in lactating dairy). • Rapidly metabolized in the liver • Elimination - 90% within 24 hours (t½ ~ 4-6 hours in cows and pigs) --> 5-10% is excreted unchanged in the urine and feces. - 60% of metabolites are eliminated in the urine and 30% in feces

microtubule stabilizing agents Pharmacokinetics

• Absorption - Administered IV • Distribution - plasma protein binding (75% for vinca alkaloids, up to 98% for paclitaxel) - excluded from CNS in P-gp. o Increased toxic effects in ABCB1-/- dogs o vincristine (worse) > vinblastine • Metabolism - hepatic • Elimination - GI - t½ is biphasic, suggests slow elimination following tissue accumulation (slow release from depot tissue) - vincristine slowest t½ ~ 75min

Treatment of Organophosphate/Carbamate Poisoning

• Administer atropine until pupils dilate and repeat q3-6hours as needed (atropine is best!) • Administer 2-PAM (pralidoxime) if less than 3-4 hours since exposure and repeat q8hrs as needed. • Maintain respiration until organophosphate effect reversed (intubation and ventilator) • Remove the source of toxicity ASAP (bathe animal or SX)- ate the saturated collar Treatment of carbamates... • they have reversible binding to AChE; so, no 2-PAM needed, and... • carbamates don't have a reactive phosphate; so, 2-PAM won't work anyway, but... • you probably won't know which it is when the animal presents; so, use 2-PAM anyway.

Rabacfosadine Pharmacokinetics

• Administered IV • Prodrug that has to be metabolized into the active form • Distribution • Active form concentrates in lymphoid tissue and PBMC's • Does not cross the BBB • t½ ~ 60hrs (urine and feces) (eliminated into environment for a long time

anti-inflammatory drugs Prednisone/Prednisolone

• Administered at a high dose (typically 20x that used for glucocorticoid replacement) • Induces apoptosis of most immune cell lineages -kills neutrophils and macrophages, eosinophils, basophils, mast cells, TH1 and TH2) -reduces number of circulating lymphoma cells • Apoptosis induction is independent of cell cycle

Chemotherapy as a treatment modality Advantages and disadvantages-

• Advantages - treatment of diffuse disease (metastases) - treatment of areas in difficult anatomic locations - improved surgical outcome (by reducing tumor burden before surgery or after surgery can treat field if isolated primary and no metastases- may be able to catch the cells that were out of the surgical field) • Disadvantages - solid tumors (>1mg of tissue) are resistant - selection for resistant cells - adverse effects (taking to the edge of death and bring back.. again and again...) - expensive o local lesions in horses are amenable, but not large or systemic disease o livestock aren't safe for food use after chemotherapy

Aminoglycosides

• All of these antibiotics contain amino sugars in glycosidic linkage (Aminoglycosidic antibiotics). • They are poly cations Their polarity is responsible for their pharmacokinetic properties (absorption, distribution, etc.) • None is absorbed adequately after oral administration. • None penetrates CSF readily. • The normal kidney rapidly excretes all. • All act by inhibiting protein synthesis of susceptible microorganisms (by inhibiting the function of 30S subunit of bacterial ribosomes). • These aminoglycosides are used almost exclusively to treat infection caused by susceptible gram-negative enteric bacteria or when there is a suspicion of sepsis or endocarditis. • Bacteria that acquire resistance to one aminoglycoside may exhibit cross-resistance to the other aminoglycosides. • Used mostly in combination Oxygen dependent active transport into the bacterial cell is necessary Under aerobic conditions, they are bactericidal - mechanism not clear

Chloramphenicol and Florfenicol Adverse effects

• Anemia, which is dose-related, may occur in animals and humans. Chloramphenicol may inhibit the uptake of iron in mitochondria present in erythropoeitic cells in bone marrow. • A second type of anemia may occur in humans treated with chloramphenicol. It is idiopathic, dose- independent, and rare but the resulting aplastic anemia is often fatal. This phenomenon is the basis for the chloramphenicol ban in food-producing animals, and caution should be exercised when handling this drug. Aplastic anemia has not been observed with florfenicol. • Iatrogenic endotoxicosis may occur due to a rapid killing of Gram (-) bacteria. • Florfenicol is not known to produce aplastic anemia and its use is permitted in beef cattle and swine.

Febantel

• In Drontal-Plus and Drontal-Feline (in the MWU-CAC) • prodrug that is metabolized to fenbendazole following absorption • pharmacokinetics haven't been reported • indications are per fenbendazole in dogs and cats only benzimidazoles

Fluoroquinolones Therapeutic uses: -Enrofloxacin -Danofloxacin -Difloxacin -Orbifloxacin and Marbofloxacin -Moxifloxacin

• Enrofloxacin is used in the treatment of dermal, respiratory and urinary tract infections (including prostatitis) in dogs, cats, and birds and in respiratory infections in cattle. • Danofloxacin is used for the treatment of bovine respiratory infections including Mannheimia species. • Difloxacin is used for treatment of dermal, respiratory, and urinary tract infections in dogs according to FARAD). Good for Pasteurella; otherwise, all others tend to have lower MIC's for everything else. Not listed in the most recent Plumbs. • Orbifloxacin and Marbofloxacin are used for the treatment of dermal, respiratory and urinary tract infections of dogs and cats. Orbifloxacin is used for susceptible Gram(-) infections in horses. • Moxifloxacin is effective against anaerobic infections, used in small animals Extra-label use of fluoroquinolones in food animals is banned.

Macrolides -Erythromycin

• Erythromycin and similar agents are macrolide antibiotics containing macrocyclic lactone ring to which sugars are attached. • They are effective alternative agents to penicillin when the patient is allergic to penicillin and/or when kidney is in failure. • Other members of macrolide group include such drugs as tylosin, tilmicosin, azithromycin, tulathromycin, and clarithromycin

Hallmarks of cancer Contribution of mutations to cancer- Acting on the "microenvironment

• Evading growth suppressors • Avoiding immune destruction • Tumor promoting inflammation (promote local inflammation to help growth) • Inducing angiogenesis • Activating invasion and metastasis supports the cancer

Fluoroquinolones Administration

• Fluoroquinolones are administered orally or parenterally once or twice a day in all species. • Enrofloxacin can be administered once daily for up to 5 days in cattle (beef or non-lactating dairy only) or as a single high dose for treatment of respiratory infections in cattle and pigs. BRD (M haemolytica, P multocida, H somni, and M bovis) and SRD (A pleuropneumoniae, P multocida, H parasuis, B bronchoseptica, and M hyopneumoniae) respectively. • Danofloxacin is approved as a single dose administration or administration twice, 48 hours apart for treatment of respiratory infections in cattle. (nonveal calves and beef cattle only; BRD due to M haemolytica and P multocida only)

NOT TESTABLE Cryptosporidiosis (Cryptosporidium spp.) Treatments

• Food animals - supportive - halofuginone reduces shedding, but nothing prevents it (in Smith, 5th ed) • Dogs and cats (should really never need to treat) - paromomycin sulfate o only available in 250mg capsules for humans o aminoglycoside antibiotic o causes a high incidence of AKI, cataracts, and deafness - nitazoxanide (cats) o causes severe vomiting and diarrhea o induces a carrier state, which is reactivated with corticosteroid treatment

Ruminants

• Formulations and labeling are species specific. • There is significant overlap in antiparasite action between ML's in ruminants -means overlap in resistance as well • Details - Topicals are more effective against biting lice - Not indicated/labeled for, but effective against horn flies (these cause huge production loss) o Haematobia irritans o ivermectin and eprinomectin o Up to 4w depending on formulation ecto and endo parasites pic just = how much it can kill

Piperazine Pharmacodynamics

• GABA receptor agonist -inhibitory neuron - hyperpolarizes muscle cells -->pushing the electrical signal in the opposite direction from activation- more cl- inside or K outside (hyperpolarized) causes cell to be less likely to have an AP - makes them less responsive to signaling through nicotinic acetylcholine receptors - causes flaccid paralysis of worm muscles • Pharmacodynamic competition with pyrantel, morantel, and levamisole has been demonstrated. - do not mix- cancel each other out • Not effective against nematode eggs - it works on the nervous system (no nervous system in eggs) - like levamisole and tetrahydropyridines

Hallmarks of cancer Contribution of mutations to cancer- Acting on cancer cells:

• Genome instability and mutation (mutations begets mutations) • Resisting cell death (override apoptosis) • Deregulating cellular energetics • Sustained proliferative signaling • Enabling replicative immortality (override replicative limit and become essentially immortal) Broken cells- easier for them to acquire more mutations passenger mutations- don't drive the cancer but not inactive- direct effects that can cause cancer cells to form

Natural penicillins are a drug of choice for a variety of bacteria such as:

• Group A beta hemolytic Streptococci • Many G+ anaerobes • Spirochetes • G- aerobic cocci There are OTC and prescription products available Some uses are FDA approved for cattle, sheep, horses, and swine Use in other species are extra-label

Resistance qualities

• Has been observed with ALL classes of anti-nematode agents • Resistance to one member of a drug class tends to cause resistance to all members of a drug class • All mechanisms involve altered genetics and are heritable • Reversion/loss of resistance has not been observed in parasites

Correction of Cryptorchidism Limitations of this approach

• Has to be administered within the normal period of testicular descent (first 8wks- no later!) • No reports, case study or case-control, that quantify efficacy - in humans, hCG is 45% effective in causing testicular descent without guarantee normal function) - in humans, gonadorelin is used to improve testicular function in patients having received orchipexy • In animals there are no reports that this treatment reduces risk of Sertoli Cell tumor formation or rescues fertility (and it's still a heritable disorder) -Don't want to breed these dogs go to is to cut out teste

L-asparaginase Adverse Effects

• Hypersensitivity - pruritus, urticaria, dyspnea, hypotension (decreased contractlity- death) - vomiting and diarrhea • Protein synthesis abnormalities - hepatotoxicity - defective coagulation factor production o coagulation defects o hemorrhagic pancreatitis - hyperglycemia (low insulin production) --because damaging pancreas

Lokivetmab (Cytopoint®) Pharmacodynamics

• IL-31 promotes pruritus through activation of the JAK1/2 pathways • Cytopoint® is a "caninized" monoclonal antibody against IL-31 -engineered antibody that only works in dogs - Only works in dogs - Unlikely to cause hypersensitivity • Binds IL-31 (also targets jak1 jak2 pathway) and prevents receptor binding (function blocking) • Reduces the perception of itch by reducing a circulating mediator of the itch response -treating cause of itch but not doing anything to reduce the allergen or allergen response (just perception of itch)

alkylating agents Resistance Mechanisms

• Increased production of molecules that inactivate drugs - aldehyde dehydrogenase inactivates cyclophosphamide -cancer cells upregulate expression of aldehyde dehydrogenase - glutathione competes with DNA for the drugs (reduced glutathione is a free radical scavenger) --Broad mechanism • Increased expression of DNA repair enzymes --cells increase repair and get better at fixing it • Reduction of intracellular drug concentrations by... - reducing expression of enzymes that transport the drug into the cell, or o melphalan is taken in by the leucine transport system o mechlorethamine is taken in by the choline transport system - increasing expression of enzymes that export the drug (P-gp)- takes all the drug out of the cell- Broad Spectrum • Notes - these mechanisms occur in the cancer cells - resistance to one alkylating agent does not imply resistance to all alkylating agents, but... - resistance to one alkylating agent does not PRECLUDE resistance to other agents.

Melarsomine (Diroban®, Immiticide®) Adverse Effects (of the drug, not the treatment)

• Increased risk of occurrence with IV and SC injections. • Dogs - injection site inflammation that takes weeks to resolve (30%), - coughing/gagging (22%),- dead worms in lungs - lethargy (15%), - inappetence (13%), - fever (7%), - lung congestion (6%), - vomiting (5%), - paresis/paralysis (<3%). Basically every dog will have an adverse effect • Very toxic in cats.

GLUCOCORTICOIDS Metabolism-

• Increases circulating amino acids • Increases circulating fatty acids • Increases gluconeogenesis

GLUCOCORTICOIDS CV system-

• Increases sensitivity to sympathetic stimulation (increase HR, contractility and CO) • Increases aldosterone release (retention of Na+ and H2O)- increase preload on heart- CO

Toxoplasmosis Disease Highlights

• Infectious agent is Toxoplasma gondii • Definitive host is any felid (incl. lions) - seroprevalence among US domestic cats is ~32% - normally lives in the GI tract • Intermediate host is any mammal (ZOONOTIC) • Transmission - fecal-oral - ingestion of tissue cysts - cats shed oocysts for 3-21 days after infection - oocysts survive for months to years in the environment and resist most disinfectants.

Hepatozoonosis. Disease Highlights

• Infects dogs and coyotes (usually in rural areas) • Emerging disease spread throughout the continental US • Caused by Hepatozoon americanum in North America - transmitted by ingestion of infective oocysts in ticks (Amblyomma maculatum) or paratenic hosts - schizonts and gamonts are the pathogenic stages • Signs include: - severe neutrophilic lymphocytosis - marked joint pain associated with myositis and periosteal proliferation

Theileriosis

• Infects ruminants • Infectious Organisms - Theileria parva in Africa and India (East Coast Fever, high mortality) - T. annulata in the Mediterranean and Middle East (Tropical Theileriosis, high mortality) - T. sergenti in Korea and Japan - T. mutans in the US (mostly in the southwest, relatively non-pathogenic) • Vectored by ticks • Treatment: We don't in the US

Tetracyclines Mechanism of Action

• Inhibition of bacterial protein synthesis is the overall mechanism of antibacterial action of all tetracyclines. • Like aminoglycosides, tetracyclines bind reversibly to 30S ribosomes and prevent the access of aminoacyl tRNA to the receptor site on the mRNA-ribosome complex. This prevents the addition of amino acids to the growing peptide chain. • Tetracyclines are generally bacteriostatic in therapeutic concentration. • They are bacteriostatic and broad spectrum. • Their antimicrobial spectrum includes Gram (+) and Gram (-)aerobes and anaerobes, Rickettsiae (such as Anaplasma spp. and Haemobartonella spp.), Spirochetes, Chlamydiae, Mycoplasma and some protozoans. • Because uptake by bacteria is oxygen-dependent, tetracyclines poorly penetrate anaerobes.

Antagonism:

• Inhibition of cidal activity by static agents (pneumococcal meningitis: penicillin + chloramphenicol). • Induction of enzymatic inactivation: some gram-negative bacilli (Enterobacter, Pseudomonas, Serratia, Citrobacter) contain inducible beta lactamases

Hormones controlling testicular descent

• Insulin-like growth factor 3 (Insl3) • Anti-mullerian hormone (AMH) • Androgens hCG can stimulate interstitial cells to secrete testosterone as well

Chloramphenicol and Florfenicol Therapeutic uses (all extra-label)

• It is ILLEGAL to use chloramphenicol in food-producing animals because the potential danger of residue-induced toxicity in humans (see below). • It is used in dogs, cats, horses and birds for local and systemic infections, inducing respiratory, CNS and ocular infections, and infections caused by anaerobes and Salmonella spp.

Toxicity and Adverse Reactions of Erythromycin

• Large animals: Diarrhea is the most common adverse effect • Hyperthermia in foals • Small animals: vomiting, diarrhea (motilin receptors) • Rodents and rabbits: severe often fatal diarrhea

Adverse effects. • Lincosamides

• Lincosamides are contraindicated in horses, rabbits, hamsters and guinea pigs because they may produce a severe, often fatal diarrhea due to altered GI flora involving Clostridium difficle. • Side effects are rare in dogs, cats, cattle and swine except for neuromuscular blockade at high doses or when used with anesthetics. • Metronidazole is often used in combination with clindamycin in order to avoid the C. difficle-mediated pseudomembranous colitis associated with clindamycin in dogs.

Neoplastic Hyperadrenocorticism - Treatment Selegiline

• MAO-B inhibitor that reduces dopamine metabolism • Dopamine inhibits release of ACTH by the pituitary • More effective for treatment of pituitarydependent hyperadrenocorticism (85% of cases) than other etiologies

Major difference between bacterial and mammalian cells: The structure conferring cell wall rigidity and resistance to osmotic lysis in both gram positive and negative bacteria is:

• Major difference between bacterial and mammalian cells is the presence in bacteria of a rigid wall external to the cell membrane. • This wall protects bacterial cells from osmotic rupture, which would result from the fact, that the cell is usually markedly hyperosmolar (by up to 20 atm) to the host environment. • The structure conferring cell wall rigidity and resistance to osmotic lysis in both gram positive and negative bacteria is peptidoglycan, a large, covalently linked sacculus, that surrounds the bacterium. • In gram-positive bacteria, peptidoglycan is the only layered structure external to the cell membrane and is thick (20 - 80 nm); in gram negative bacteria, there is an outer membrane external to a very thin (1 nm) peptidoglycan layer.

Potentiated sulfonamides Adverse effects

• Renal crystalluria due to precipitation of sulfonamides in neutral or acidic urine may occur with large or prolonged doses or inadequate water intake, especially with the older, less soluble sulfonamides such as sulfathiazole. • Keratoconjunctivitis sicca (KCS) may be observed in dogs • Hypoprothrombinemia, thrombocytopenia and anemia occur rarely and are probably immune-mediated reactions. • Arthritis can be a sequela of sulfonamide therapy in Dobermans, especially with sulfasalazine. • Sulfonamides are contraindicated in male dogs used for breeding since the drug can reduce sperm counts. • Sulfonamides are not effective in abscesses • Trimethoprim and ormetoprim (i.e., benzylpyrimidines) can cause a decrease in plasma levels of thyroid hormones.

Gastrointestinal Fluid Handling

• Secretion of water and electrolytes - Stomach - Liver - Pancreas • Reabsorption of water and electrolytes - Small intestine - Colon • secretions > reabsorption (diarrhea) • secretion < reabsorption (impaction)

Polypeptides

• Short chains of 8-10 amino acids • Sequences are species specific • Have shorter half-lives than glycoproteins • Specific polypeptide hormones - Gonadotropin-releasing hormone (GnRH) secreted by the hypothalamus to the anterior pituitary - Oxytocin secreted by the hypothalamus to the posterior pituitary

Hyperadrenocorticism - Selected CBC/Chemistry Abnormalities

• Stress Leukogram (Neutrophilia, Lymphopenia, Monocytosis) • Increased Blood Pressure - Due to CV abnormalities - Check IOP • Low urine specific gravity (<1.020) due to CV abnormalities • Hypothyroidism due to decreased TSH • Hyperglycemia due to increased GNG and insulin antagonism

Steroids

• Synthesized from cholesterol (cholesterol produces progesterone which get shunted into the creation of testosterone which is shunted into the production of estradiol) -progesterone also gets shunted into production of cortisol- type hormones • Not species specific • Produced throughout the reproductive tract - Gonads - Uterus & Placenta - Hypothalamus • Short half-lives, but long durations of action due to transcriptional activation. (reduce transcriptional chains) • Potency may vary by species

human Chorionic Gonadotropin (hCG, Chorulon®) Indications

• TX of FOLLICULAR CYSTS in cows (labeled) • Induction of estrus in prepuberal gilts and noncycling sows (labeled) • Can also use equine Chorionic Gonadotropin (eCG, PMSG, PG600®). - functional overlap between equine and human hCG • eCG is available OTC, but hCG is RX only. • These molecules have both LH and FSH effects, but the LH effects are used for this indication.

GnRH (Gonadorelin) Indications

• TX of FOLLICULAR CYSTS in cows (labeled) and dogs (extra-label) • Synchronization of estrus in cows (labeled) • Detect ovarian remnants in cats following OVH (extra-label)

Signs of Thyrotoxicosis

• Tachycardia +/- arrhythmia • Hypertension (leading to retinal damage & blindness) • Tachypnea (if progressed to LS-CHF) • Hypokalemia (unknown cause, muscle weakness and cervical ventroflexion) • Venous Thromboembolism • Seizures, depression, sudden death

Other lipid hormones (ex. prostaglandins) tend to be:

• Tend to be fast acting, like peptides and proteins, because the signal pathways are always in place.

Steroid Hormones

• Tend to induce signaling pathways slowly, because they act by creating new signaling pathways, which requires transcription and translation and new protein synthesis. • Different cells synthesize and degrade proteins at different rates; so, not all effects of a steroid will be apparent at the same time. (full effect of drug may take a while and may not be full response yet, important- effects managing of client expectations- clients may want to see immediate effect, may also not be aware of the change when it happens, very slow)

Preslaughter of oxytetracycline, in food animals.

• The Food Animal Residue Avoidance Databank (FARAD) recommends, in cattle, an extra-label withdrawal of 28 days for intrauterine treatment. It also recommends testing milk after intrauterine treatment, as there is interanimal variability in the residue elimination profiles in milk. • FARAD recommends an extralabel preslaughter withdrawal of 28 days in sheep and goats after IM or SC oxytetracycline administration. - A milk withdrawal of 96 hours is recommended for sheep and goats. • For swine, FARAD recommends an extralabel preslaughter period of 14 days following administration of tetracycline product in feed or water to swine.

Adverse effects • The tetracyclines

• The tetracyclines (except for doxycycline and minocycline) are potentially nephrotoxic and should be avoided if renal function is impaired. • Permanent staining of unerupted teeth may occur in young animals due to the formation of a tetracycline-calcium phosphate complex in enamel and dentine. This seems to be less prevalent for doxycycline and minocycline. • Superinfections of fungi, yeast, or resistant bacteria may occur in the GI tract with prolonged administration of broad-spectrum antibiotics such as the tetracyclines. • GI adverse effects are seen frequently in cats. • Oral tetracyclines should not be used long-term in herbivores because of serious effects on ruminant digestion. • Anti-anabolic effects are seen at high doses because of binding to mitochondrial ribosomes. This may result in an elevated BUN especially with pre-existing renal disease. • Photosensitivity and hepatotoxicity are rare side effects in animals.

Transduction occurs by the intervention of a: If this genetic material includes a gene for drug resistance, a newly infected bacterial cell may become: particularly important in the transfer of:

• Transduction occurs by the intervention of a bacteriophage (a virus that infects bacteria) that contains bacterial DNA incorporated within its protein coat. •If this genetic material includes a gene for drug resistance, a newly infected bacterial cell may become resistant to the agent and capable of passing the trait on to its progeny. • particularly important in the transfer of antibiotic resistance among strains of Staph. aureus, where some phages can carry plasmids that code for: • penicillinase, • resistance to erythromycin, tetracycline, or chloramphenicol.

NOT TESTABLE Cryptosporidiosis Disease Highlights

• Transmitted through ingestion of contaminated water • Pathogenic stage is schizonts • C. parvum infects ruminants (5-35 days old) and humans (ZOONOTIC) • Rarely infects dogs and cats (C. canis and C. felis, respectively) • Signs - Food animals: anorexia, weightloss, diarrhea, and tenesmus - Dogs & cats: usually none

alkylating agents Toxicity/Adverse Effects

• Vesication (blistering & erosion, not vesiculation; iatrogenic) - severe tissue damage resulting from the drug getting out of the circulation (extravasated)- super reactive drug! o pro-drugs (administered PO) aren't vesicants until they are converted to the active form - lower risk o active drugs (administered IV) are always vesicants - higher risk, requiring CAREFUL catheter placement - mechanism o all active alkylating agents are free radicals. o free radicals cause severe tissue damage outside of the circulation. • Dose-Limiting Toxicity - the most severe toxic effect of a drug that doesn't lead to acute death (edge of death and back) - corresponds to the highest dose of a drug that can be given without killing the patient (highest tolerable dose) - this is the dosing goal for anti-neoplastic drugs. o kills the most cancer cells o reduces the risk of developing resistant cancer cells

5. a2* receptors

• Vestibular system and Vomiting Center • Agonist: xylazine and dexmedetomidine • Antagonists: yohimbine and atipamezole (reversible agents for the agonists)

1. H 1 receptors

• Vestibular system and Vomiting Center • H 1 Antagonists (ex. diphenhydramine, etc.) • Motion sickness in dogs

microtubule stabilizing agents Drugs affecting Tubulin Dynamics

• Vinca Alkaloids - vincristine (Oncovin®) - vinblastine (Velban®) • Taxanes - paclitaxel (Taxol®) stabilize microtubles

Benzimidazoles Pharmacokinetics - Absorption

• Water insoluble compounds - formulated as pastes, suspensions, and pellets - administered PO (FDA - approved) • Efficacy is increased by longer GI residency times (good in ruminants- sit in there for a long time) - not really for SA if moving through quickly - increased time in the GI = increased absorption - absorbed drug is toxic to the worms (not the drug in the GI tract lumen) • Differences in GI physiology dictate differences in dosing frequencies. - ruminants: o rumen is a reservoir - mixing and long residency solubilizes drug o acid pH of the abomasum solubilizes drug o dosing: one dose followed by possible retreatment 4-6wks later - monogastrics (incl. pigs, not horses): o absorption is decreased due to rapid GI transit times o acid pH of the stomach solubilizes drug o dosing: q24hrs for 3 days minimum (may vary depending on nematode)

General Aspects

• William Campbell and Satoshi Omura were awarded the 2015 Nobel Prize for the discovery and development of these drugs (ivermectin specifically) -for livestock and domestic -helped alleviate food problems around the world • Originally purified from Streptomyces spp. (yeast) • Three related groups: avermectins, milbemycins, spinosyns • Endectocides - these drugs are "cidal" and very long acting - have activity against BOTH nematodes AND ectoparasites.

Amitraz Adverse Effects

• a2-adrenergic agonist in mammals - mechanism of adverse effects is different than that for parasite toxicity - sedation (most common) - bradycardia - may also cause vomiting, diarrhea, and ataxia • PO administration is most common cause of toxicity - swallowing dip or impregnated collar - endoscopic/SX removal of impregnated collars is recommended. • Toy breeds, dogs < 4mos, cats, and rabbits are particularly susceptible • Reversal DOC? Atipamezole

Rifampin Pharmacokinetics

• absorbed orally and rapidly distributed to cells and tissues. • metabolized in the liver to a metabolite which also has antibacterial activity. • both the metabolite and parent drug are excreted primarily in the bile, but up to 30% may be excreted in the urine. • the parent drug is substantially reabsorbed in the gut, but the metabolite is not. • elimination t1/2 for various species are: 6-8 hours (horses), 8 hours (dogs), 3-5 • hours (sheep). • rifampin can induce hepatic microsomal enzymes, elimination rates may increase with repeated doses.

Pharmacokinetics Florfenicol

• absorbed rapidly from IM sites in cattle • widely distributed, including the CNS, similar to chloramphenicol. • Serum t1/2 is 18 hours in cattle and 2/3 of a dose is excreted as the parent drug in the urine and 1/3 is metabolized by the liver.

microtubule stabilizing agents Pharmacodynamics

• act to stabilize microtubules • prevents proper breakdown of mitotic spindle during cytokinesis -can't breakdown spindle- can't provide dna into daughter cells • induces apoptosis and immune clearance. • act during M-phase of the cell cycle • vincristine and vinblastine sites are the same. • vincristine and paclitaxel sites differ - these drugs act synergistically

Properties of ICWS:

• activity against gram positives • spectrum • activity against Pseudomonas aeruginosa • activity against anaerobes • penicillinase resistance • acid resistance - oral absorption (can you give orally?) • main route of elimination • CNS penetration

Combination products with b lactamase inhibitors • addition of b-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam) to ampicillin, amoxicillin, ticarcillin or piperacillin extends: • bacteria may develop resistance independently upon:(e.g. altered PBP production). • Not active against: -What drugs are included?

• addition of b-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam) to ampicillin, amoxicillin, ticarcillin or piperacillin extends the spectrum of these agents to include many organisms that are resistant by virtue of b-lactamase production not all b-lactamases are inhibited by these products • bacteria may develop resistance independently upon b-lactamase production (e.g. altered PBP production). • Not active against methicillin-resistant, penicillinase-producing Staphylococci! • Ampicillin; Sulbactam (Unasyn®) (parenteral) • Amoxicillin; Clavulanic Acid (Augmentin®) (oral) • Piperacillin; Tazobactam (Zosyn®) I.V. • Ticarcillin; Clavulanic Acid (Timentin®) I.V. All uses are extra label

PGF2a Tromethamine Pharmacokinetics

• administered IM (never IV) • widely distributed- small lipid like molecule • rapidly metabolized in the lungs (70-98% on first pass, depending on species). • meat withdrawal times in cows and swine is 0 days.

Uses Erythromycin

• administered orally or IM • labeled for cattle for bovine respiratory disease (BRD) • other uses are extra-label • used for susceptible infections in dogs, cats, ferrets and birds

Adverse Effects: Toxicity to host: • ototoxicity: Agents=

• aminoglycosides • vancomycin • minocycline (vestibular only)

Specific considerations- Extralabel use in FA: Third gen cephalosporins: Voluntary band on the use of ALL _______ in FA because:

• extralabel use of specific antimicrobial drugs in food animals is prohibited for reasons of safety or limitation of resistance. • these drugs include the fluoroquinolones, chloramphenicol, nitroimidazoles, furazolidone, nitrofurazone and other nitrofurans, sulfonamide drugs in lactating dairy cattle (except approved use of sulfadimethoxine) and vancomycin • third-generation cephalosporins are not to be used in an extra-label manner in food-producing animals for prevention of disease Note, there is a voluntary ban on the use of ALL sulfonamides in food animals, because they accumulate in the kidney and withdrawal times can be long and highly variable.

Diabetes mellitus in other species

• ferrets, guinea pigs, and birds are treated with insulin (with variable effect) • insulin is expensive for larger animals

Potentiated sulfonamides -Fixed combination of: -cidal or -sitic? -preparations include:

• fixed combinations of a sulfonamide with trimethoprim or ormetoprim. This results in a synergistic action via sequential blockade of folate synthesis, • and this synergism is often bactericidal • potentiated sulfonamides have a broader spectrum of action and a reduced rate of development of bacterial resistance. • preparations include sulfadiazine + trimethoprim, sulfamethoxazole + trimethoprim and sulfadimethoxine + ormetoprim. They are used in the treatment of susceptible infections in all species. • trimethoprim and ormetoprim are organic bases in contrast to the organic acid nature of the sulfonamides. • trimethoprim plasma t1/2 is 2-3 hours in most species and it concentrates in the prostate, which is the basis for its use against prostatitis in the dog.

Gamithromycin (Zactran)

• for subcutaneous injection in beef and non-lactating dairy cattle only. Not for use in female dairy cattle 20 months of age or older or in calves to be processed for veal Uses • labeled for the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni and Mycoplasma bovis in beef and non-lactating dairy cattle • extra-label for the control of respiratory disease in beef and non-lactating dairy cattle at high risk of developing BRD associated with Mannheimia haemolytica and Pasteurella multocida.

Mutations may occur in the

• gene encoding the target protein, altering its structure so that it no longer binds the drug; • in a protein involved in drug transport; or • in a regulatory gene or promoter leading to altered expression of the target, • an inactivating enzyme.

Antibacterial Spectrum and Indications

• generally active against gram-negative rods (Enterobacteria, Proteus, Pseudomonas, and Serratia). • effective particularly against P. aeruginosa. • synergistic with beta-lactams against many Gram positives • used for Gram negative infections in all species

Diabetogenic/Glucose Releasing Hormones

• glucagon (secreted from a cells) • catecholamines • cortisol • growth hormone

Natural penicillins: highest antibac activity against certain: coverage: readily inactivated by: no ___ activity eliminated by: CNS penetration? Types:

• highest antibacterial activity against certain gram positive bacteria some gram negative coverage • some anaerobic coverage • readily inactivated by b-Lactamase (penicillinase) • no antipseudomonal activity • eliminated by active transport in the kidney • poor CNS penetration (except inflammation) • Penicillin V acid resistant to gastric acid Penicillin G potassium (IV, IM) Penicillin G benzathine (IM depot) Penicillin G procaine (IM) Penicillin V (relatively acid resistant, orally useful)

Fluoroquinolones Mechanism of action.

• inhibit bacterial DNA gyrase and topoisomerase enzymes that control DNA supercoiling as the replicating strands separate • broad-spectrum and bactericidal agents • anaerobes tend to be resistant to the fluoroquinolones used in veterinary medicine.

Antidiabetic Hormone

• insulin (secreted from b cells)

Bacitracin

• interferes with the final dephosphorylation step in the phospholipid carrier cycle, which causes impedance of mucopeptide transfer to the growing cell wall • active mainly against gram-positive bacteria, • Parenteral bacitracin is used rarely due to the risk of serious nephrotoxicity • Bacitracin most commonly is used topically (usually combination with neomycin and polymyxin) to prevent superficial skin and eye infections following minor injuries

Cats (labeled) • ivermectin • selamectin • milbemycin oxime • spinosad

• ivermectin - Dirofilaria immitis (prevention) • selamectin - Dirofilaria immitis (prevention), fleas (C. felis), Otodectes spp., T. cati, and A. tubaeforme (hookworms) -broadest approval • milbemycin oxime - Dirofilaria immitis (prevention), GI roundworms, and hookworms • spinosad (spinosyn A/D) - fleas (dosing is higher than in dogs)

Dogs (labeled use unless indicated otherwise) • ivermectin • selamectin • milbemycin oxime • moxidectin • spinosad

• ivermectin - Dirofilaria immitis (prevention; all macrocyclic lactones are effective against stage 3 and 4 larvae) - Extra-label: Generalized demodicosis, Cheyletiella spp. (Zoonotic), Sarcoptes scabiei (selflimiting zoonosis), Otodectes spp., Pneumonyssus spp./Pneumonyssoides spp. (nasal mites) • selamectin - Dirofilaria immitis (prevention), fleas (C. felis), Otodectes spp., Sarcoptes scabiei, Dermacentor variabilis -ear mites, ticks • milbemycin oxime - Dirofilaria immitis (prevention), GI roundworms, hookworms (Zoonotic), and whipworms • moxidectin - Dirofilaria immitis (prevention) and hookworms only • spinosad (spinosyn A/D) - fleas These are what the manufacturing tested - not nec. only what they kill

Horses (labeled) ivermectin and moxidectin

• ivermectin and moxidectin: as labeled by manufacturer, GI roundworms - ivermectin is better against Gastrophilus intestinalis - moxidectin is better against Cyanthostomum spp. (gi round worms)

Pigs (labeled) ivermectin: doramectin:

• ivermectin: GI roundworms, lungworms, lice, and Sarcoptic mange • doramectin: as indicated by manufacturer (it's a long list)

Melarsomine (Diroban®, Immiticide®) Pharmacokinetics

• labeled for IM administration in 2, 3, or 4 applications • rapidly absorbed following IM injection. • Vd ~ 0.7L/kg, gets everywhere • Metabolism - yeah, that happens. • t½ ~ 3hrs

Uses Tilmicosin

• labeled for cattle (BRD), sheep and swine • other uses are extra-label

Penicillinase Resistant Penicillins (Antistaphylococcal Penicillins) Lower activity against: resistance to: Coverage: drug of choice against: More than __% of s. aureus isolates are resistant metabolism = excretion = types:

• lower activity against certain gram-positive bacteria • resistant to penicillinase • some gram negative and anaerobe coverage • some are acid stable and highly protein bound. • drugs of choice against penicillinase producing Staphylococcus aureus. • more than 20% of S. aureus isolates are resistant (MRSA)! • hepatic metabolism and renal excretion • Oxacillin (Prostaphlin®) (liver metabolism) • Cloxacillin (Dynapen®) (liver metabolism) • Methicillin -nephrotoxicity- only used as a diagnostic tool -if a bacteria is resistant to penicillin, test it with methicillin - then the resistance is due to penicillinase enzyme -If not- resistance is due to penicillin binding protein

Extended spectrum penicillins coverage • ______ coverage when combined with penicillinase inhibitors • no ____activity • resistance: • susceptible to _____ • acid resistant? • excretion types:

• lower gram pos. coverage • extended gram negative coverage (E. coli, Salmonella, Shigella, H. influenzae, Proteus). • Anaerobic coverage when combined with penicillinase inhibitors • no antipseudomonal activity • resistance develops frequently • susceptible to b-lactamase • acid resistant • urinary excretion Ampicillin (Omnipen®) Amoxicillin (Amoxil®)

Progestins -medroxyprogesterone -megestrol Adverse Effects

• megestrol - increased appetite, weight gain, lethargy behavior change, acromegaly, adrenocortical suppression (severe in cats), diabetes (cats), and Addison's syndrome (cats) • medroxyprogesterone - increased appetite, increased body weight, lethargy, behavior change, adrenocortical depression, diabetes, hypothyroidism, temporary inhibition of spermatogenesis These drugs are becoming unpopular due to effects on human females: increased risk of mammary and uterine neoplasia and risks of fetal abnormalities considered to outweigh any possible benefits (category X for use during pregnancy.) -so should probably stay away from these drugs as well

Development of superinfections:

• most frequently observed with the broad spectrum antibiotics • pathogens resistant to the antibiotic grow • e.g. fungal superinfections

Amphotericin B (FungizoneR ) Pharmacokinetics

• not absorbed from the GI tract. • slowly distributes to most tissues except the CNS, eye and bone. (so accumulates in kidney) • elimination is biphasic with plasma t1/2 of 24-48 hours and 1-2 weeks. • approximately 65% of amphotericin B is excreted unchanged into urine (20%) and feces (45%). • Excreted slowly by the kidney (nephrotoxicity) • Can be detected in the urine for several weeks after therapy

Role of Wolbachia

• obligate, intracellular, gram (-), bacteria/rickettsia • Wolbachia is associated with - survival of filaria - production of filaria - infectivity of filaria (L3 stage) - pulmonary and renal inflammation (via WSP surface protein) • doxycycline sensitive - current recommendation is to TX with doxycycline for 30d prior to melarsomine (reduces all associated issues above) - reduces worm burden prior to adulticide (CRITICAL) --reduces risk of thrombosis and anaphylactic reaction!! - TX with doxycycline alone holds promise as a sole adulticide in dogs for which melarsomine is contraindicated.

Antibacterial spectrum • Vancomycin is very useful against

• penicillin- and methicillin-resistant Staphylococcus aureus (MRSA) infections and for • treating gram-positive infections in penicillin-allergic patients (parenteral).

lonophore antibiotics Mechanism of action.

• polyether antibiotics derived from Streptomyces used primarily in poultry and swine for feed efficiency and anticoccidial activity • they include monensin, lasalocid, laidlomycin, salinomycin, and narasin. Mechanism of action. • the net effect for monensin is a trans-membrane exchange of sodium ions for protons; the consequence of this exchange is the neutralization of acidic intracellular compartments • in the rumen, ionophores selectively affect Gram (+) organisms resulting in a shift to Gram(-) populations in the rumen microflora. • this increases production of propionic acid and decreases production of acetic and butyric acids by rumen bacteria. • this change in volatile fatty acids increases feed efficiency by reducing bacterial energy losses to CO2 and methane, thereby increasing the energy content per unit of feed

Equine Gastric Ulcer Syndrome (EGUS)

• poor appetite, lethargy, weight loss, poor performance • race horses are very prone (60% prevalence) • Equine Squamous Gastric Ulcer Syndrome (ESGUS) - Associated with going off feed - Glandular stomach constantly produces acid that is buffered by feed (not squamous though!) - Restricted access to hay decreases gastric pH • Equine Glandular Gastric Ulcer Syndrome (EGGUS) - Associated with a breakdown in gastric mucus layer of the stomach - NSAIDS are the main culprit (flunixin meglomine, ketofren)

Fluoroquinolones Pharmacokinetics

• rapid oral absorption, with peak plasma concentrations at 1 hour in dogs. • distribution is wide and includes the CNS, bone and prostate. • dome hepatic metabolism occurs and both parent drug (15-50%) and metabolites are excreted in urine and bile. • plasma t1/2 for enrofloxacin is 3-5 hours in dogs, 6 hours in cats and horses. elimination t1/2 for difloxacin and marbofloxacin are 9-12 hours in dog and cats and for orbifloxacin 6 hours in dogs and cats and 9 hours in horses

Pharmacokinetics Chloramphenicol

• rapidly absorbed from the GI tract and widely distributed to all tissues including the CNS and eye. • hepatic metabolism by glucuronide conjugation occurs slowly for 75% of the administered drug in cats, but faster to 90% in dogs. • elimination t1/2 is 1-1.5 hours for dogs and horses and 4-5 hours in cats.

Nitrofurantoin

• reduced by bacteria to reactive intermediates that inhibit nucleic acid synthesis occasionally used in the treatment of lower urinary tract infections in dogs and cats. • administered orally every 6-8 hours and is most effective in acidic urine. Nitrofurazone is used topically as an antibacterial ointment, powder and water-soluble wound dressings in all species. Nitrofurans are banned in food-producing animals.

Amphotericin B (Fungizone R ) Adverse effects

• renal toxicity is a serious side effect. Amphotericin B produces renal vasoconstriction, decreased GFR, and damage to tubular epithelium. Due to the potential for severe toxicity, amphotericin B should only be considered for progressive, potentially fatal fungal infections. Weekly monitoring of renal function is required. Exception! Lack of nephrotoxicity in birds due to shorter half life

Levamisole Adverse Effects/Toxicity

• stimulates NM receptors in the host, but • Toxic signs look like SLUDGE (NN (neuronal) activation and AChE inhibition may be involved) -In ganglia of autonomic nervous system- so unregulated signaling of both parasympathetic and sympathetic nervous system -AChe- drives up systemic of parasympathetic and musculature -SLUDGE = salivation, lacrimation, urination, defecation, GI, emesis • Signs may be apparent at as low as 2xED50, but LD50 ~ 2-6xED50 -Signs potentially = DEATH - toxicity may be increased by concurrent treatment with pyrantel, morantel, or cholinesterase-inhibitors - depends on route of administration (SC is more dangerous than PO), and - species notes (extra-label use) o dogs are more tolerant than ruminants and pigs with PO administration o horses are very intolerant

mutation occurring in a previously susceptible cell and antibiotic selection of this resistant mutant:

• streptomycin (ribosomal mutation), • quinolones (gyrase gene mutation), and • rifampin (RNA polymerase gene mutation)

Adverse Effects: Toxicity to host: •hepatotoxicity: Agents=

• tetracyclines; •erythromycin; •clindamycin; •sulfonamides; •amphotericin B;

Ketoconazole

• used in dogs, cats (controversial), horses, reptiles and birds for systemic mycoses and severe yeast infections. • Broad spectrum • Advantage - cost; Disadvantage - adverse effects (hepatic toxicity) Administration • topical, shampoos for dermatophytes - labeled for dogs and cats, some for horses • oral (3-6 months) for systemic mycotic infections - all extra-label Adverse effects: • Anorexia, vomiting and diarrhea may occur, esp. in cats treated with ketoconazole. • Hepatic toxicity (cats most sensitive), thrombocytopenia • Many drug interactions - potent inhibitor of CYP3A12; often combined with cyclosporine to reduce cyclosporine dosage (reduce cost).

Voriconazole

• used in dogs, cats (with caution), horses and birds for systemic Blastomyces, Cryptococcus and Aspergillus. • High bioavailability • penetrates the CNS • Expensive, little data on clinical experiences in veterinary medicine Administration • Ophthalmic; penetrates cornea, must be compounded (equine fungal keratitis) • Oral and IV • All extra-label Adverse Effects: Not well established; cats are very susceptible (azotemia, lethargy, weight loss) and should be used as a "last resort" drug in cats

Clotrimazole and Miconazole

• used in the treatment of Candida, Aspergillus, Malassezia and dermatophyte infections. • Not effective for treating dermatophytosis in cats Administration • Clotrimazole • spray and ointment is available OTC, or Rx when combined with betamethasone and or gentamicin - labeled for otic use in dogs Miconazole • 1% ophthalmic solution, compounded, extra label equine fungal keratitis • Topical - very effective against Malassezia dermatitis. Adjunctive systemic treatment usually required • Miconazole nitrate labeled for dogs, cats and horses (OTC and Rx)

Azoles Pharmacokinetics: Adverse effects for all:

• well absorbed in the presence of food that stimulates bile flow. • widely distributed, particularly in tissues high in lipid content; however, minimal amounts are found in cerebrospinal fluid (except for fluconazole and voriconazole which have excellent CNS penetration). • metabolized by microsomal enzymes of the liver and excreted in bile. Adverse effects- Anorexia, vomiting and diarrhea - all oral azoles Adverse effects most prominent in cats

Sulfonamides Derivatives of: Produced by: Difference between the individual agents: What is important for anti-bacterial action?

•All Sulfa drugs are derivatives of Benzene sulfanilamide (Sulfonamide) having basically similar antibacterial action. •They are produced by substitution at the amino group (R-NH-SO2 ). •The difference between the individual agents is based on such properties as rate of absorption, excretion and solubility in the urine, etc... •It is important to remember that for antibacterial action, a free para-amino group is essential.

Macrolide Absorption, Metabolism and Excretion

•Gastric acids rapidly destroy erythromycin base • modified formulations are necessary, such as, erythromycin stearates and estolates, which are acid resistant. •Enteric coated or film-coated preparations are preferable. •Erythromycin passes through the placenta, penetrates into prostatic fluid, but not into CNS. •Large amounts of erythromycin are lost in feces. Only 5% is excreted in the urine. •A portion of the drug excreted in the bile, is reabsorbed from the intestine. •Excretion (primarily fecal) - 2-5% unchanged drug is found in the urine after oral route, whereas 12-25% is unchanged in the urine after IV.

Carbapenems: Imipenem; Cilastatin (Primaxin®), Meropenem (Merrem®)

•Imipenem is rapidly inactivated by renal tubule dehydropeptidases and must be given with cilastatin, a dehydropeptidase inhibitor. • meropenem is not inactivated by dehydropeptidases • these agents are given I.V. and have broad spectrum activity including anaerobes, gram positive organisms, gram negative rods. • imipenem can cause seizures in high levels and should be used cautiously in patients with brain lesions, head trauma, or a history of CNS disorders such as seizures • meropenem is less likely to cause seizures • all uses are extra-label

Macrolide Mechanism of Action

•Inhibition of protein synthesis of susceptible bacteria ( mostly gram positive). •Erythromycin binds reversibly to 50S ribosomal subunits to prevent translocation of amino acids and thereby interferes with the protein synthesis. •Incidentally, chloramphenicol and clindamycin binding site is situated close to this site (on 50S ribosomal subunit). Thus one can anticipate interference and an antagonistic action if erythromycin & chloramphenicol is administered at the same time.

Adverse effects:

•Overextension of pharmacologic actions •Organ directed toxicity •Hypersensitivity reactions

Conjugation The passage of genes from cell to cell by: Genetic transfer by conjugation occurs: Conjugation can take place in the intestinal tract between:

•The passage of genes from cell to cell by direct contact through a sex pilus or bridge is termed conjugation. •DNA that codes for resistance to multiple drugs may be so transferred. •Resistance could be easily transferred to sensitive strains of both Shigella and other Enterobacteriaceae. •R-determinant plasmid. • resistance transfer factor, or RTF, •Genetic transfer by conjugation occurs predominantly among gram-negative bacilli • Conjugation can take place in the intestinal tract between nonpathogenic and pathogenic microorganisms.

Virtually all antibiotics that inhibit bacterial cell-wall synthesis are: They eventually result in the cell's death due to: much of the loss of cell-wall integrity following treatment with cell-wall active agents is due to In the presence of agents that inhibit cell wall growth, ___________ occur Protein synthesis inhibitors (e.g. chloramphenicol) prevent:

•Virtually all antibiotics that inhibit bacterial cell-wall synthesis are bactericidal. • they eventually result in the cell's death due to osmotic lysis. • much of the loss of cell-wall integrity following treatment with cell-wall active agents is due to the bacteria's own cell wall remodeling enzymes (autolysins) that cleave peptidoglycan bonds in the normal course of cell growth. •In the presence of agents that inhibit cell wall growth, autolysis proceeds without normal cell-wall repair; weakness and eventual cellular lysis occur. •Protein synthesis inhibitors (e.g. chloramphenicol) prevent the action of the cell wall synthesis inhibitors.

Transformation involves incorporation of: molecular basis of:

•involves incorporation of DNA that is free in the environment into bacteria. •molecular basis of penicillin resistance in Pneumococci and Neisseria. •Penicillin-resistant pneumococci produce altered penicillin binding proteins (PBPs) that have low-affinity binding of penicillin

Linezolid (Zyvox) (all uses extra-label) Mechanism of action: Pharmacokinetics: Adverse reactions: Uses

•new class of synthetic antibiotics known as fluorinated oxazolidinones. •predominant activity of linezolid is against aerobic gram-positive organisms Mechanism of action: •inhibits bacterial protein synthesis by interfering with translation. Pharmacokinetics: •administered by intravenous infusion or orally; •metabolized via oxidation but the oxidative metabolism of linezolid is nonenzymatic and does not involve the hepatic microsomal oxidative system Adverse reactions: •usual side effects and interactions as the MAO inhibitors! •superinfection can occur Uses • bacterial pneumonia, • skin and skin structure infections, • vancomycin-resistant enterococcal (VRE) infections • methicillin-resistant staphylococci (MRSA)

Linezolid (Zyvox) (all uses extra-label)

•new class of synthetic antibiotics known as fluorinated oxazolidinones. •predominant activity of linezolid is against aerobic gram-positive organisms

Regulation of Prescription (Controlled substances) Records Rules:

◦ Must be kept for a minimum of 2-years (invoices, credit memos, dispensing transactions, administration records, disposal records, and prescriptions) ◦ Records for Schedule II drugs are kept separately from others. ◦ Schedule II drugs require a special order form (DEA-222) or online access (DEA CSOS system)

Regulation of Prescription (Controlled substances) Storage at facility:

◦ Must be secured (in a locked container, preferably fixed to the foundation) ◦ Prescription pads should also be kept secure ◦ Theft or loss must be reported to DEA and state pharmacy board