Lit Pharmacology, Toxicology

Question 1

What were in the differences in pharmacokinetics of IV ampicillin between azotemic and healthy dogs?

Answer 1

Monaghan JVIM 2021
Azotemic dogs had higher peak ampicillin concentration (~4.5x), greater half-life (~6x), greater AUC (731.04 vs 33.57), significantly lower clearance & lower volume of distribution vs healthy dogs.
*Consider dose/frequency adjustment in azotemic dogs.

Question 2

What are the potential effects of dexmedetomidine sedation on abdominal US changes in dogs, and the risk factors?

Answer 2

Seitz JVIM 2021
Transient GB wall thickening (>2mm) in 24% dogs, and peritoneal effusion.
Risk factors - longer duration of sedation sig associated with GB wall thickening, but NOT recumbency.

Question 3

Which plasma extracellular vesicle (EV)-associated microRNAs (miRNAs) were affected during/post administration of doxorubicin in dogs with sarcoma?

How did changes in these biomarkers correlate to other traditional cardiac biomarkers & echo findings?

Answer 3

Beaumier JVIM 2020

Downregulation of miR-107 & miR-146a vs upregulation of miR-502.

miR-502 upregulation was detected before 3rd chemo dose + before significant changes in cTnI or echo parameters.
*Significant cTnI changes occurred only 1 month post-tx completion, correlated with LV ejection fraction & LVIDd.

Question 4

1) What were the common clinical signs & CBC abnormalities in dogs following anthracycline overdose?
2) What was the short-term outcome for these dogs?

Answer 4

Lawson JVIM 2021
1) CSx: D+ (63%), anorexia (56%), V+ (38%), lethargy (31%), nausea (25%)
CBC: neutropenia (94%) - usually high-grade, not responsive to filgrastim; thrombocytopenia (88%), anemia (63%).
2) Death uncommon (12.5% or 2/16 dogs), most recovered with supportive care (mostly hospitalised).

Question 5

What adverse effects were associated with robenacoxib administration in cats for management of chronic MSK disease?

Answer 5

King JVIM 2021
Overall well tolerated when given over 4-12 wks. Incidence of AE similar in RCXB vs placebo cats (47% vs 41%).
Increased creatinine (but subclinical)
Mostly GIT (V+, D+, anorexia)

Question 6

What was one major adverse effect noted in cats that received frunevetmab?

Answer 6

Gruen JVIM 2021
Skin lesions (alopecia, lumps) in most cats resolved with topical or systemic tx (abx, anti-histamines, topical steroids), small % did not improve.

Question 7

DDAVP - MOA, indications, SE?

DDAVP administration to dogs on prednisolone treatment to alleviate PUPD may result in what complication?

Answer 7

Galati JVIM 2021
Synthetic ADH analogue. Central DI. Hyponatremia (excessive free water retention).

Hyponatremia (worry about excessive free water if no PUPD observed with prednisolone + receive DDAVP. USG also remains concentrated).

Question 8

Mycophenolate mofetil (MMF) - MOA?

Adverse effects - incidence & which? in dogs receiving MMF to treat IMD?

Answer 8

Fukushima JVIM 2021
MOA: mycophenolic acid is a metabolite of MMF - selectively and reversibly inhibits inosine 50-monophosphate dehydrogenase (IMPDH), which is a rate limiting enzyme of de novo synthesis of the nucleotide guanine. As rapidly growing cells like lymphocytes have a high demand for guanine nucleotide, inhibition of IMPDH results in arrest of proliferation of both T & B lymphocytes –> immunosuppression

Incidence ~25.9% (34/131) dogs.
GI AE most common (24.4%).
Also hematologic (neutropenia 4%, anaemia 4%, thrombocytopenia 4%) & dermatologic 1.5%.
No sig diff among dogs with/without potential AEs wrt sex, age, BW, MMF dosage.

Question 9

1. What is the MOA of zolendric acid (ZA), indications, and potential AE?
2. What adverse effects were noted with IV ZA in dogs for the abovementioned indications?

Answer 9

Brewer JVIM 2021
1. Nitrogen-containing bisphosphonate or aminobisphosphonate. Inhibits bone resorption.
Indications - management of bone pain (ostealgia) & hypercalcemia (of malignancy) in dogs.
AE - AKI, hypophosphatemia, hypokalemia, hypocalcemia (reported in humans).

2. Progressive azotemia in 8 dogs (8.4%) - not associated with cumulative dose. V+ (2 dogs, 2%), pancreatitis (1 dog, 1%), cutaneous ulceration (1 dog), D+ (1 dog).

Question 10

Which 2 body systems are affected with grape/raisin toxicity in dogs?
What clinical manifestations?
Survival rate?

Answer 10

Schweighauser JVIM 2020
Renal + neuro.
Renal - severe (grade 4-5) AKI.
Neuro - Severe forebrain, cerebellar, or vestibular signs –> reversible functional brain injury. 73% dogs.
53% survival (similar to non-GRT causes of AKI).

Question 11

In cats receiving doxorubicin for tx of various neoplasms, what was the
a) incidence of creatinine elevation >/=30% from baseline?
b) average time to onset of a), and
c) risk factors associated with a)?

Answer 11

Kopecny JVIM 2020
a) 34%
b) 4 months
c)
- Single-agent doxo (vs multi agent CHOP)
- Pre-existing CKD
- Neutropenia or anemia during chemo
- No. of RT treatments under GA.

Question 12

a) Which 2 of 3 acid suppressants evaluated were superior (achieved goals established for treatment of gastroduodenal ulceration in people – based on increasing the gastric pH ≥3 for 75% of the day) during the first 72 hours of treatment in dogs?

b) What were the differences in time effect for mean pH, mean percentage time (MPT) intragastric pH >4, MPT >3 between use of 3 gastroprotectants in a population of healthy dogs?

Answer 12

Kuhl JVIM 2020
a) No sig differences

b) Famotidine CRI (1mg/kg followed by 8mg/kg IV CRI) & esomeprazole. VS pantoprazole (standard doses).

Question 13

What was the effect of metronidazole on a) time to resolution of diarrhoea, and b) detection rate of C. perfringens in faecal cultures of dogs?

Answer 13

Langlois JVIM 2020
MTZ tx can shorten duration of D+ & decrease faecal culture detection of C. perfringens in some dogs with acute non-specific D+.

Question 14

MOA & effects of the following drugs on gastric emptying (GE) & motility index (MI) of antral contractions in healthy cats?
- Metoclopramide
- Erythromycin
- Exenatide

Answer 14

Husnik JVIM 2020
- Metoclopramide: shorten GE, increase MI. MOA: sensitises upper GI s.m. to ACh effects. NB: does not stimulate gastric, pancreatic, biliary secretions, nor colonic motility.

• Erythromycin: shorten GE, increase MI. MOA - motilin agonist, initiates interdigestive type III migrating motor complexes (MMCs).
• Exenatide: delays GE initially. MOA GLP-1 analogue (incretin, reduces post-prandial hyperglycemia).

Question 15

What is calprotectin?

What was the effect of omeprazole administration on faecal calprotectin & GI dysbiosis index (DI) n dogs receiving carprofen without risk factors for GI bleeding?

Answer 15

Jones JVIM 2020

Calprotectin aka S100A8/A9 = protein complex expressed & released into the extracellular space by activated macrophages & neutrophils at sites of inflammation.

Coadministration of omeprazole & carprofen significantly increased faecal calprotectin concentration & DI vs baseline/carprofen alone.

Question 16

What clinical manifestation is common in dogs following envenomation by the European adder (Vipera berus)?

Which quantitative clinical parameter had an association with this clinical manifestation?

Answer 16

Harjen JVIM 2020
Ventricular arrhythmias (57% dogs)

CTnI concentration. Dogs with arrhythmias had sig higher CTnI at 12, 24 & 36hrs.

Question 17

Which immunosuppressive drugs had significant effects on IL-2 & IFN-γ expression in dogs?
What are the clinical implications during treatment?

Answer 17

Archer JVIM 2020
Prednisone & cyclosporine. Mean IL-2 & IFN-γ values were significantly lower before vs after treatment - with cyclosporine being more suppressive than prednisone.
(NOT azathioprine, mycophenolate or leflunomide)

Use of these 2 drugs have the ability to influence results when utilizing pharmacodynamic monitoring of cyclosporine tx.

Question 18

What was the impact of prophylactic gastroprotectants (omeprazole and/or famotidine) on GI signs in dogs with neoplasia treated with single-agent piroxicam?

Answer 18

Shaevitz JAVMA 2021
Both omeprazole (~85%) & famotidine (80%) were associated with more frequent & severe GI AEs in these dogs vs placebo (36%) by 8 weeks.

DO NOT recommend prophylactic PPIs & H2-blockers in dogs with cancer receiving NSAIDs.

Question 19

What gene mutation was identified in cats that dveloped neurotoxicity following topical eprinomectin administration?

Answer 19

Mealey JAVMA 2021
Eprinomectin = macrocyclic lactone.
Homozygous for ABCB11930_1931del TC mutation.

Question 20

Lamotrigine toxicosis in dogs
- Clinical manifestations
- Tx?

Answer 20

Lamotrigine = anti-epileptic drug (humans), lipophilic.
CSx - seizures, obtundation, tachyarrhythmias (VPCs/VTach > VFib if severe), death possible
Tx - IV lipid emulsion, supportive care

Question 21

In dogs with α-amanitin toxicity, describe:
- Typical clinicopathologic abnormalities
- Prognosis
- Negative prognostic factors

Answer 21

Kaae JAVMA 2021
- Clin path: mild-marked ALT elevation (97%), hypoglycemia (78%), prolonged coags (91%).
- 22% survived to discharge with complete recovery. Many dogs rapidly decompensated & died.
- Poor px especially if tx is not immediate (often the case).
- Neg px factors - marked hypoglycemia, coagulopathy.

Question 22

Discuss similarities or differences in efficacy in inducing emesis & safety profile between apomorphine SC vs IV in dogs.

Answer 22

Fischer JAVMA 2021
Similar efficacy (80-82% dogs V+) with SQ/IV.
Sig shorter time to emesis for IV admin (2mins) vs SQ (13mins).

Question 23

Non-survival rate to discharge for dogs receiving antivenom tx for crotalid evenomation?
Risk factors associated with non-survival?
Differences between 3 antivenom products used wrt patient survival?

Answer 23

Crotalid = pit viper.
96% survived to discharge.
2 fractionated Ig products (F[ab’]) & 1 whole Ig product (IgG).
No sig diff in survival rates amonst all 3 products. Higher % of dogs receiving IgG product only needed 1 unit

Question 24

What is the half-life & bioavailability of a single dose of oral gabapentin in cats?
Is its PK altered by repeated dosing?
Were there significant differences in drug efficacy with different routes of administration?

Answer 24

Adrian JVIM 2018
3.6 hours, 95% bioavailability.
No, so dose adjustments are unnecessary with long term tx.

Transdermal gel formulation not appropriate based on this study.

Question 25

Why are carbapenems effective in treating MDR infections? Which bacteria?

What was the rate of resistance to carbapenems in cases with reported susceptibility based on C&S in a veterinary hospital?

Answer 25

Smith JVIM 2019

Effective as carbapenems are relatively resistant against destruction via hydrolysis of many β-lactamases.

MDR Enterobacteriaceae (E. coli & Salmonella) - NOT Enterococcus.

3%.

Question 26

Adverse effects of minocycline in cats?
What dose is recommended based on PK studies?

Answer 26

Tynan JFMS 2016

V+ most common. Transient lethargy & tachypenea (during IV infusion).

Dose 8.8mg/kg q24hr (~1x 50mg capsule)

NB: 62% PO bioavailability. 60% protein bound, may need to adjust for protein binding)

Question 27

xxxx Is minocycline an alternative to doxy for E canis infection?

Answer 27

Jenkins JVIM 2018

Assessed in subacute infections in dogs. Demonstrated negative PCR after 28 days of therapy (doxy in this study cleared by 3 weeks). Long term follow up not performed so cannot confirm if suppression or true clearance (negative at 7 days)

Question 28

What is the bioavailability & half-life of oral posaconazole in healthy cats? Based on this what dosing regimens have been recommended?

Answer 28

Mawby JVIM 2016

15.9% (low!)
T1/2 38hrs (IV much higher @ 57hrs)

PO dosing options - 30mg/kg loading then 15mg/kg q48hrs, OR 15mg/kg loading followed by 7.5mg/kg q24hrs. Target trough concentrations 0.5-0.7ug/mL.

Question 29

What is the difference in PK between oral compounded & reference itraconazole in healthy cats?

Answer 29

Mawby JAVMA 2018

Compounded forms had poor & inconsistent absorption. Relative absorption was only 2-8% of reference formulations.

Question 30

xxx What has higher bioavailability in dogs, the liquid or tablet itraconazole?

Answer 30

Liquid. However, overall concentrations similar, elimination half lives identical and no recommendation to alter dose based on formulation

Question 31

Why should periodic urinalyses be performed in cats receiving chlorambucil?

Answer 31

Reinert JFMS 2016
Monitor for euglycemic glucosuria. Drug-associated Fanconi syndrome reported in 4 cats (also documented aminoaciduria).

Question 32

What were the effects of glucocorticoids on serum cystatin C in dogs? Did this differ between endogenous vs exogenous sources?

Answer 32

Muñoz JVIM 2017
Pred PO increased sCysC in a dose-dependent manner.
Endogenous steroids (PDH) did not alter sCysC concentrations.

Question 33

What are some side effects associated with leflunomide? Are they dose dependent? What is the recommended starting dose & clinical response rate in dogs with immune-mediated disease?

Answer 33

Sato JVIM 2017
D+, lethargy, unexplained haemorrhage, thrombocytopenia & increased liver enzymes. Dose-dependent.
2mg/kg/day recommended based on this paper.
70.5% clinical response rate. No difference in doses between dogs that responded vs not.

Question 34

What are the signs of immune-mediated destruction consistent with IMHA?

Answer 34

ACVIM consensus statement
Spherocytes (dogs), positive agglutination (with/without washing - washing more significant), positive direct antibody test (Coombs test).

Question 35

Gapriprant (brand Galliprant) - MOA & side effects? What is its reported efficacy?

Answer 35

Rausch-Derra JVIM 2016
Prostaglandin E2 EP4 receptor antagonist (NSAID). Does not inhibit COX like other NSAIDs.
SE: GI upset, increased ALT & ALP (also reported decreased TP/alb, increased Ca). **Contraindicated with concurrent steroids or NSAIDs. **
In this study reported improved clinical scores in dogs with OA (48%) vs placebo (31%) by Day 28.

Question 36

(3 papers)
What is an antibody target for a pain relief injection in cats with OA? What is the half life and recommended dose?

What is its canine counterpart?

Answer 36

Gruen JVIM 2016 (pilot study)
Frunevetmab (brand Solensia)
Felinized anti-nerve growth factor monoclonal antibody (anti-NGF mAb). Nerve growth factor (NGF) has an important role in nociceptor sensitization. Drug binds to NGF, sequestering it & preventing interaction with NGF receptors.
- Study dose 0.4 or 0.8mg/kg SQ.
- Increased activity 2-6 weeks after treatment.
- No SE documented.

Gearing JVIM 2016 (inflammation induced in research cats)
- Dose 2mg/kg SQ.
- Decreased signs of lameness on day 2-7.
- T1/2 7-15 days.

Gruen JVIM 2021 (superiority study; naturally occurring OA cats)
- Dose 1mg/kg SQ q28d x3 doses
- Sig improvement cf placebo at D28 & D56 for owner + vet-assessed joint pain.
- SE: skin disorders more frequent in tx cats (17% vs 8% placebo).

• Canine anti-NGF mAb = bedinvetmab (brand Librela or Beransa).

Question 37

What has higher oral bioavailability in dogs, the liquid or tablet itraconazole? Did this correlate with drug concentrations?

Answer 37

Hasbach JVIM 2017
Liquid (capsule 85% bioavailability of liquid). But overall drug concentrations & elimination T1/2 (33hrs) were similar. Recommend loading dose 20mg/kg then 10mg/kg PO q24 regardless of formulation.

Question 38

Did the frequency & severity of neutropenia differ between administration of compounded vs FDA-approved formulations of lomustine in dogs?

Answer 38

Burton JVIM 2016
100% dogs tx with FDA-approved CCNU developed neutropenia, of which 71% were grade 3+. 25% dogs tx with compounded lomustine developed neutropenia, of which 12.5% were grade 3.
Highly variable potency of CCNU from 5 compounding pharmacies ranged from 50 to 115% of the labelled concentration - study highlighed need for greater oversight of compounded products.

Question 39

Empirical use of which two antibiotic classes of high importance were administered to dogs/cats in Australia based on a 2017 survey?

Answer 39

Hardefeldt JVIM 2017
FQ in dogs (for otitis externa) & 3rd-generation cephalosporins in cats.

Question 40

Vancomycin - MOA, time or concentration dependent? Susceptibility & safety profile in animals?

Answer 40

DeStefano JVIM 2019
Time-dependent. Bactericidal (activate bacterial cell wall autolysins) + bacteriostatic (vs enterococci, by binding to the D-alanyl-D-alanine portion of cell wall precursors).
Susceptible - Strep, Enterococcus, MRSA, MRSP. NOT G- bacteria.
Used to tx various infections.
AE - AKI in 16% patients (but study could not prove direct cause).
Neutropenia or allergic rxn not observed (occurs in people).
70% survived to discharge. Most cases (95%) had alternative effective abx.

Question 41

What pH of solution ensure stability of torsemide?

Answer 41

Adin JVIM 2017
Alkaline (pH 8.3 of injectable form, also 5mg/mL compounded formulation buffered to this pH was validated/stable.

Question 42

What considerations should there be when sedating dogs with the ABCB1-1 mutation (both homozygotes & carriers)?

Answer 42

Deshpande JVIM 2016
Homozygotes - dose reduce (higher sedation scores with ACP noted in this study). No diff in sedation scores between normal dogs & carriers. No diff in CVS parameters amongst all groups.

Question 43

What anti-epileptic drug can be useful to address anxiety & fear associated with noise phobia in dogs? MOA for this drug?

Answer 43

Engel JVIM 2019
Imipetoin.
Acts centrally as a low-affinity partial agonist at the BZD-binding site of the GABAA-receptor –> potentiates neuronal inhibition –> anxiolytic & anticonvulsant effects.

Question 44

What rare but severe AE (reported in people) may occur with chronic bisphosphonate treatment? What is the MOA?

Answer 44

Larson JVIM 2019 (cat) & Lundberg JVIM 2016 (dog)
Osteonecrosis of the jaw.

Phosphate & hydroxyl groups of bisphosphonates allow preferential binding to hydroxyapatite crystals within the
bone matrix –> bisphosphonates accumulate in bone matrix –> osteoclast apoptosis, decreased bone resorption & subsequent
accumulation of necrotic bone

Question 45

What (susceptible) breakpoint should be considered when administering ciprofloxacin 25mg/kg PO SID to dogs? What patient factor may affect plasma drug concentrations?

Answer 45

Papich JVIM 2017
</= 0.06ug/mL
Patient size (larger dogs achieve lower plasma drug [ ] despite similar mg/kg dose).

Question 46

What are the clinical manifestations of diphenhydramine toxicosis in dogs? Mortality rate?
What type of adverse drug reaction does this cause (dose-dependent vs idiosyncratic)?

Answer 46

Worth JAVMA 2016
Neuro (lethargy, hyperactivity, agitation, hyperthermia, ataxia, tremors, and fasciculations) & CVS (tachycardia) - mild & uncommon (23.5%). 3/621 dogs died.
Dose-dependent.

Question 47

What is the main indication & MOA of Isoniazid? What are clinical manifestations of isoniazid toxicosis? What antidote may reduce risk of seizures? Negative px indicators?

Answer 47

Schmid JAVMA 2017
1st line anti-mycobacterial agent used to treat tuberculosis in people & animals. Inhibits synthesis of mycolic acids, a component of mycobacterial cell walls.
98% dogs were clinical. CNS signs +/- seizures, GI > CVS, urogenital > respiratory.
Pyridoxine (vit B6) IV - dose-dependent effect against seizures & death (adm 1:1 ratio to isoniazid).

Ingested dose & presence of seizures, not receiving pyridoxine IV (dogs received were 29x more likely to survive) were associated with non-survival.

Question 48

Treatment options for digitalis toxicity? Is dialysis effective?

Answer 48

Galton JFMS 2020, also Ettinger
- Acute ingestion - cholestyramine or activated charcoal (reduce absorption)
- Digoxin-neutralizing IgG antibody (Fab) fragments = treatment of choice for life threatening toxicity (or oleander).
- Digoxin is NOT dialyzable

Question 49

What are the clinical signs of ozone exposure in cats?

Answer 49

Caudal JAVMA 2018
Acute dyspnea/tachypnea with pulmonary crackles. TXR - NCPO. Tx frusemide & bronchodilator, supplemental O2

Question 50

What is duloxetine and what clinical manifestations are more likely to occur with dogs ingesting >20mg/kg?

Answer 50

James JAVMA 2019
Anti-depressant, serotonin & norepinephrine
reuptake inhibitor.
CSx in 15%. Lethargy, mydriasis, V+, trembling

Question 51

What clinical signs are noted with minoxidil toxicity? What is a potential treatment?

Answer 51

Jordan JAVMA 2018
Minoxidil = hair growth promoter solution.
CVS (tachycardia, hypotension, ECG -narrow complex tachycardia)
IVLE (minoxidil is lipophilic)

Question 52

What clinical manifestation is common in dogs following envenomation by the European adder (Vipera berus)?

Which quantitative clinical parameter had an association with this clinical manifestation?

Answer 52

Harjen JVIM 2020
Ventricular arrhythmias (57% dogs)

CTnI concentration. Dogs with arrhythmias had sig higher CTnI at 12, 24 & 36hrs.