Presents: CLINICAL PHARMACOLOGY

Chicago Veterinary Medical Association Shaping the Future of Veterinary Medicine - Promoting the Human-Animal Bond Presents: CLINICAL PHARMACOLOGY With: LAUREN TREPANIER DVM, PHD, DACVIM, DACVCP MAY 8, 2013

TOP TEN POTENTIAL DRUG INTERACTIONS IN DOGS AND CATS Lauren A. Trepanier, DVM, PhD, Dip. ACVIM, Dip. ACVCP University of Wisconsin-Madison, School of Veterinary Medicine, Madison, WI In humans, the risk of adverse drug interactions multiplies as the number of administered drugs increases. Interactions can occur during IV drug administration, during oral absorption, at the target site, or during hepatic or renal elimination, and may lead to loss of efficacy or increased toxicity. Although most of our knowledge of drug interactions is from data in humans, many of these interactions are likely to occur in dogs and cats as well. 1. Cimetidine Cimetidine is a major P450 enzyme inhibitor, and also decreases renal excretion of some drugs by inhibiting transporter pumps. Cimetidine therefore decreases the clearance of many drugs in humans: Theophylline and aminophylline: theophylline toxicity seen in humans Lidocaine: could lead to GI and neurologic side effects Midazolam: increased plasma midazolam concentrations with cimetidine Warfarin: do not use cimetidine in suspected warfarin toxicity patients Propranolol (but not atenolol) Because of many potential cimetidine interactions, alternative H 2 blockers such as ranitidine, famotidine, or nizatidine (which are not P450 inhibitors at therapeutic concentrations), should be chosen over cimetidine. Ranitidine and nizatidine have the added advantage of possible prokinetic effects, which may counteract gastric atony in clinically ill patients. 2. Sucralfate Aluminum-containing drugs such as sucralfate can form complexes with many other drugs in the GI tract, markedly decreasing drug absorption: Fluoroquinolones: poor bioavailability even 2 or more hours after sucralfate in humans Tetracycline: marked inhibition of oral absorption Theophylline, aminophylline, digoxin, azithromycin: sucralfate may decrease efficacy H 2 blockers: sucralfate delays, but does not decrease the extent of, the absorption of H 2 blockers; therefore staggering of dosing is probably not required This is a physicochemical interaction that is likely to occur in dogs and cats as it does in humans. It is recommended that sucralfate be avoided in patients on multiple oral drugs, particularly tetracycline and fluoroquinolones. If sucralfate must be given orally with drugs other than H 2 or pump blockers, the sucralfate should be given 2 hours after the other drugs (not vice versa), and at least 6-8 hours before subsequent dosing of other drugs that day. Because of the difficulty in coordinating dosing at home, I avoid sucralfate on an out-patient basis unless the only other drugs given are H 2 or pump blockers. 3. Ketoconazole Ketoconazole and itraconazole are best absorbed at acidic ph; therefore, do not combine these drugs with antacids such as: Omeprazole, H 2 blockers, or aluminum hydroxide o However, antacids do not affect the absorption of fluconazole (Zimmermann 1994) Ketoconazole inhibits a specific cytochrome P450 enzyme, CYP3A, that has a wide substrate range and high potential for drug-drug interactions. This has been shown in both dogs and cats. Ketoconazole is also an inhibitor of p-glycoprotein, the important drug efflux transporter in the Clinical Pharmacology Lauren Trepanier DVM, PhD, DACVIM, DACVCP Page 1 of 41

gut, kidney, biliary tree, and brain. Ketoconazole can therefore decrease the bioavailability and/or clearance of many drugs: Cyclosporine: a favorable interaction; ketoconazole can allow lower doses of cyclosporine. Recommended dosages: cyclosporine, 5 mg/kg/day; ketoconazole, 10 mg/kg/day. Monitor ALT and clinical response. Whole blood cyclosporine can be measured at steady state (by one week). Target levels for immunosuppression in humans are 400-600 ng/ml, but dogs with perianal fistulas may respond to much lower concentrations. Ivermectin: ketoconazole doubles ivermectin exposure (AUC) in dogs (Hugnet 2007); neurologic toxicity has not been reported, but could occur if ketoconazole were combined with high dosages of ivermectin (e.g. in treating sacroptic mange), or in p- glycoprotein deficient breeds. Clomipramine, amitriptyline, midazolam, fluoxetine: decreased clearance with ketoconazole; could increase sedation Warfarin: ketoconazole may prolong its toxicity Note: Itraconazole, like ketoconazole, also inhibits the P450 metabolism of these same drugs in humans. Fluconazole has less P450 inhibition, but can still affect drug clearance at dosages > 3 mg/kg/day in humans. 4. Fluoroquinolones Oral absorption of fluoroquinolones is impaired by drugs that contain divalent or trivalent cations, such as: Sucralfate, aluminum hydroxide, aluminum carbonate Calcium carbonate Oral zinc (in the milk thistle supplement Marin ; 17-45 mg zinc per tablet) Oral iron or magnesium (e.g. in vitamin supplements) In humans and dogs, fluoroquinolones inhibit the metabolism, by CYP1A2, of theophylline. This has led to theophylline toxicity in humans. In dogs, enrofloxacin leads to higher plasma theophylline concentrations by about 30-50% (Intorre 1995), while marbofloxacin at 5 mg/kg decreases theophylline clearance to a lesser extent (about 26%; Hirt 2003) Fluoroquinolones also inhibit the clearance of pentoxifylline (shown in mice). 5. Metoclopramide As a dopaminergic (D2) antagonist and prokinetic agent, metoclopramide has several important drug interactions: Enhanced absorption of acetaminophen, aspirin, and alcohol overdoses via increased gastric emptying (shown in humans). Increased plasma concentrations of cyclosporine (by 30%) in humans (possibly due to enhanced gastric emptying). o However, this was not seen in dogs after a single dose of metoclopramide (Radwanski 2011) Extrapyramidal side effects (tremor) in combination with phenothiazines (e.g. chlorpromazine, acepromazine) or selective serotonin reuptake inhibitors (e.g. fluoxetine) Tremor in patients with renal insufficiency, unless dosage is reduced. Metoclopramide reduces the amount of propofol needed for anesthetic induction in humans by 20-25% (Page 1997; mechanism unknown). Clinical Pharmacology Lauren Trepanier DVM, PhD, DACVIM, DACVCP Page 2 of 41

As a D2 antagonist, metoclopramide should not affect D1-mediated vascular effects of administered dopamine: No effect on dopamine systemic pressor effects in dogs (Hahn 1980) However, metoclopramide (1 mg/kg) did attenuate dopamine-mediated renal vasodilation in dogs, but only for 30 minutes (Hahn 1980) 6. Cisapride Like ketoconazole, cisapride is a substrate of CYP3A. High plasma concentrations of cisapride, caused by drug interactions, have led to fatal cardiac arrhythmias (prolonged QT syndrome) in humans. Azole antifungal drugs (fluconazole, itraconazole, ketoconazole) that inhibit CYP3A could increase cisapride concentrations and increase the risk of cardiac side effects, as shown in humans. However, the margin of safety appears to be higher in cats than in humans. Prolongation of the QT interval has been shown in cats at very high cisapride dosages (30 mg/kg BID). This would be a concern primarily for accidental drug overdose. Erythromycin increases cisapride concentrations in humans, but does affect cisapride in dogs (Al-Wabel 2002), and is not an inhibitor of CYP3A in cats (Shah 2009). Mosapride, a newer prokinetic drug, does not affect the QT interval on ECG measurements in cats (Kii 2001). o The pharmacologically effective dosage of mosapride in dogs is 0.75 2.0 mg/kg BID (Tsukamoto 2011); this has not been evaluated in cats. 7. Furosemide Several drug combinations with furosemide can lead to enhanced toxicity: Aminoglycoside nephrotoxicity is enhanced by furosemide. (Adelman 1979) o Mannitol may be preferable to furosemide for treatment of acute renal failure due to aminoglycosides such as amikacin and gentamicin. Enalapril and benazapril may cause hemodynamic changes leading to acute renal failure when combined with high doses of furosemide. o Delay the start of ACE inhibitors until fulminant heart failure is resolved and furosemide dosages are lowered to maintenance dosing Digoxin: furosemide increases risk of digoxin toxicity o Furosemide can lead to pre-renal azotemia and decreased digoxin excretion. o Furosemide can also lead to hypokalemia and hypomagnesemia, both of which exacerbate the cardiac toxicity of digoxin. o Serum digoxin levels need to be monitored in all dogs treated with digoxin. Renal function and serum electrolytes should be routinely evaluated in all patients on furosemide. Other drug combinations with furosemide can affect efficacy: Lidocaine o Hypokalemia secondary to furosemide can blunt the antiarrhythmic effects of lidocaine. Serum potassium should be evaluated in patients with ventricular arrhythmias, and potassium supplementation should be considered if patients do not respond to lidocaine. Bromide o Furosemide administration will increase the renal loss of bromide, and can lower serum bromide concentrations, leading to seizure breakthrough. Clinical Pharmacology Lauren Trepanier DVM, PhD, DACVIM, DACVCP Page 3 of 41

8. Omeprazole Omeprazole is an inhibitor of some P450 s in humans (mostly CYP2C19), and may inhibit the clearance, and possibly increase the toxicity, of: Diazepam, midazolam, warfarin, and carbamazepine. Omeprazole also impairs conversion of clopidogrel to its active metabolite, leading to decreased anti-platelet efficacy in humans o Proton pump inhibitors have led to adverse cardiovascular events (loss of clopidogrel efficacy) in human patients (Bhurke 2012) Omeprazole may also lead to digoxin toxicity, possibly via inhibition of p-glycoprotein efflux of digoxin (Kiley 2007). As an inhibitor of gastric acid secretion, all proton pump blockers can decrease the absorption of: Iron supplements, oral zinc Ketoconazole and itraconazole o But not fluconazole, which does not require an acidic ph for absorption It is wise to discontinue antacids when ketoconazole and itraconazole are being given. Alternatively, if antacids cannot be stopped, fluconazole should be considered, if indicated. 9. Phenobarbital Phenobarbital is a major P450 enzyme inducer in humans and dogs. Phenobarbital speeds the metabolism of many drugs in dogs, including: Glucocorticoids but does not affect LDDST testing Ketoconazole, chloramphenicol Clomipramine Theophylline Digoxin, propranolol, lidocaine Mitotane o Dogs on phenobarbital, that are given mitotane for hyperadrenocorticism, often need much higher loading and maintenance dosages of mitotane. However, phenobarbital causes minimal cytochrome P450 enzyme induction in the cat (Maugras 1979; Truhaut, 1978), and therefore P450-mediated drug interactions with phenobarbital are unlikely in the cat. 10. Clomipramine As a tricyclic antidepressant, clomipramine inhibits both norepinephrine and serotonin reuptake. Clomipramine can lead to serotonin accumulation and serotonin syndrome (twitching, tremor, tachycardia, myoclonic movements, hyperthermia) in humans, when used in combination with drugs such as: Monoamine oxidase inhibitors (MAOIs, which decrease the breakdown of serotonin) o Deaths reported in humans given clomipramine plus MAOIs; well established interaction o Veterinary MAOIs include: L-deprenyl (selegiline) Amitraz: found in tick dips and some collars AVOID these drugs in dogs taking clomipramine Serotonin reuptake inhibitors (which increase synaptic serotonin concentrations) o Fluoxetine (Prozac, Reconcile) Clinical Pharmacology Lauren Trepanier DVM, PhD, DACVIM, DACVCP Page 4 of 41

o Fluoxetine has been associated with serotonin syndrome in combination with clomipramine in human case reports Other drugs that affect serotonin: o Tramadol: inhibits serotonin reuptake; potential interaction with clomipramine o Dextromethorphan (in Robitussin): inhibits serotonin reuptake; potential interaction with clomipramine Clinical Pharmacology Lauren Trepanier DVM, PhD, DACVIM, DACVCP Page 5 of 41

Drug Cimetidine Sucralfate Ketoconazole Drug interactions in Humans that may also affect Dogs and Cats May increase the toxicity of: Theophylline, lidocaine, midazolam, propranolol Cyclosporine, warfarin, digoxin, amitriptyline, midazolam, cisapride May decrease the efficacy of: Ketoconazole, itraconazole, iron supplements Fluoroquinolones, tetracycline, theophylline, digoxin Toxicity may be increased by: Efficacy may be decreased by: Antacids, H 2 blockers, omeprazole Fluoroquinolones Theophylline Sucralfate, iron, calcium, aluminum, magnesium Metoclopramide Furosemide Cisapride Omeprazole Ethanol, aspirin, or acetaminophen overdoses; propofol? ACE inhibitors, digoxin, aminoglycosides Diazepam, warfarin, digoxin Bromide, lidocaine (via hypokalemia) Ketoconazole, itraconazole, iron supplements Aceprozamine, fluoxetine (tremor) Aminoglycosides Azole antifungals, fluoxetine Some NSAIDs Phenobarbital Clomipramine Selegiline, amitraz, fluoxetine Mitotane, clomipramine, lidocaine, propranolol, theophylline, digoxin Fluoxetine, ketoconazole, itraconazole; possibly tramadol, dextromethorphan Clinical Pharmacology Lauren Trepanier DVM, PhD, DACVIM, DACVCP Page 6 of 41

DRUG DOSE ADJUSTMENT FOR DISEASE Lauren A. Trepanier, DVM, PhD, Dip. ACVIM, Dip. ACVCP University of Wisconsin-Madison, School of Veterinary Medicine, Madison, WI There is considerable evidence to support the adjustment of drug dosages in human patients with heart failure, hepatic failure, or renal insufficiency. In contrast, similar studies are lacking in dogs and cats. This presentation will discuss veterinary situations in which drug dose adjustments may be warranted. I. Heart failure A. Decreased cardiac output 1. Leads to preferential shunting of blood to brain and heart a) May enhance cardiac toxicity (arrhythmias) and central nervous system toxicity (nausea) from digoxin 2. Leads to prerenal azotemia a) Requires lower doses of enalapril, digoxin, furosemide b) Benazepril clearance is not affected by mild to moderate azotemia in dogs and cats B. Gastrointestinal changes 1. GI edema a) May lead to erratic oral drug absorption in fulminant heart failure 2. Delayed gastric emptying a) Shown in mouse models of heart failure b) Attributes to high concentrations of natriuretic peptides, including BNP c) May delay absorption of oral drugs C. Decreased hepatic blood flow 1. Decreased clearance of hydralazine (Johnston, 1992) D. Many potential drug interactions 1. Furosemide and digoxin: a) Hypokalemia and dehydration from furosemide can enhance digoxin toxicity 2. Angiotensin converting enzyme (ACE) inhibitors and furosemide a) ACE inhibitors will impair the patient s ability to respond to dehydration from furosemide 3. Furosemide and lidocaine a) Hypokalemia from furosemide can impair the efficacy of lidocaine 4. Spironolactone and ACE inhibitors a) Possible hyperkalemia when used in combination b) Important to monitor serum electrolytes in patients taking spironolactone 5. Diltiazem and beta blockers (propranolol or atenolol) a) Enhanced risk of atrioventricular block and bradycardia with combination b) Avoid use of diltiazem and beta blockers together II. Hepatic insufficiency A. Decreased metabolism of some drugs with advanced liver disease 1. In humans with inflammatory liver disease without cirrhosis, hepatic drug metabolism is fairly well conserved 2. With cirrhosis, drugs that are normally extensively metabolized are not cleared as readily a) Veterinary diseases with comparable hepatic dysfunction: (1) Severe hepatic lipidosis Clinical Pharmacology Lauren Trepanier DVM, PhD, DACVIM, DACVCP Page 7 of

(2) Acute hepatic necrosis (3) Cirrhosis in dogs 3. Based on human data, dosages of the following drugs should probably be reduced in dogs and cats with severe hepatic dysfunction: a) Diazepam or midazolam (1) Use 25-50% of regular dose and use sparingly if treating encephalopathic seizures b) Propranolol (1) Decrease dose by 50% or more c) Chloramphenicol (1) Use with caution and monitor CBC, or choose another drug d) Metronidazole (1) Dose for HE is ~50% of antimicrobial dose B. Hypoalbuminemia 1. Possible risk of increased acute effects from highly protein drugs such as NSAIDs and benzodiazepines C. Ascites 1. Water soluble drugs will distribute to ascites fluid a) Use the total body weight (including ascites fluid) to calculate dosage of relatively water-soluble drugs: (1) Aminoglycosides (2) Fluoroquinolones (3) Morphine (a) Relatively polar opioid with polar active glucuronide metabolites in (b) dogs Leads to decreased efficacy in humans if dosed on non-ascitic body weight 2. Lipid soluble drugs will not distribute to ascites fluid a) Use the normal body weight (minus estimated ascites fluid weight) to calculate dosage of lipid-soluble drugs such as: (1) Propofol (2) Fentanyl (3) Vitamin K 1 D. Increased sensitivity to CNS depressants 1. Opioids: reduce dosage or use reversible agents 2. Benzodiazepines, acepromazine: avoid or use reduced dosages 3. Barbiturates: avoid or use reduced dosages a) For encephalopathic seizures, use phenobarbital at 20-30% of standard doses and titrate upwards E. Hepatic encephalopathy 1. Avoid stored whole blood and packed red blood cell transfusions (can contain high ammonia levels) 2. Avoid non-steroidal anti-inflammatory drugs (NSAID s) a) Risk of GI bleeding (1) GI bleeding can worsen encephalopathy 3. Avoid furosemide a) Hypokalemia, dehydration, azotemia, and alkalosis from furosemide can all exacerbate encephalopathy b) Consider spironolactone / hydrochlorthiazide instead for ascites (1) 1 mg/kg twice daily Clinical Pharmacology Lauren Trepanier DVM, PhD, DACVIM, DACVCP Page 8 of

4. Avoid 0.9% saline IV a) Often leads to edema, worsens ascites b) Consider 1/2 strength saline with 2.5% dextrose, and added potassium, for patients with liver disease accompanied by hypoalbuminemia c) Use Hetastarch for volume expansion 5. Avoid glucocorticoids a) Catabolic (1) Enhance deamination of proteins and release of NH 3 6. Consider lactulose and neomycin over metronidazole a) Less likely to cause neurologic signs III. Renal failure A. Leads to: 1. Decreased filtration of renally eliminated drugs and active metabolites 2. Decreased tubular secretion of some drugs a) Digoxin, famotidine, trimethoprim 3. Decreased renal P450 metabolism and conjugation of some drugs 4. Decreased binding of acidic drugs to albumin a) Furosemide, sulfamethoxazole, aspirin 5. Reduced tissue binding of some drugs a) Digoxin B. There are very few studies regarding dose adjustments for renal failure in dogs or cats 1. Creatinine clearance is used to make rational dosage adjustments in azotemic humans, but this measurement is almost never available for veterinary patients 2. Drug dosage adjustments are often made in humans with creatinine clearances less than around 0.7 to 1.2 ml/min/kg (depending on the drug) a) Corresponds to a serum creatinine of ~ 2.5 to 3.5 mg/dl in dogs and cats 3. Adjustments are made to reduce dose or extend dosing interval a) Reducing the dose, with the same dosing interval, minimizes fluctuations in plasma concentrations b) Extending the dosing interval, while keeping each dose the same, maximizes peak concentrations and minimizes trough concentrations (1) This is most appropriate for aminoglycosides (2) Also recommended for fluoroquinolones (Czock, 2005) c) See dosage adjustment table at end of handout, extrapolated from human data C. Drugs that merit dose reductions in renal failure: 1. Penicillins a) Dose reduction is appropriate, but toxicity is unlikely for ampicillin, penicillin, and amoxicillin b) Dose reduction is appropriate and will decrease the cost of more expensive beta lactams and related drugs (ticarcillin, aztreonem, meropenem) in azotemic patients 2. Cephalosporins a) Cephalothin and cefazolin are nephrotoxic at high doses in animal models, so dose reduction of these two drugs in renal failure should be considered in dogs and cats (1) Consider decreasing dose and maintaining the same dosing interval in renal failure b) Cephalothin can also be nephrotoxic in combination with aminoglycosides to elderly humans 3. Fluoroquinolones a) Most fluoroquinolones are renally cleared Clinical Pharmacology Lauren Trepanier DVM, PhD, DACVIM, DACVCP Page 9 of

b) Given the risk of retinal toxicity in cats, always think twice about enrofloxacin dosing in cats with renal insufficiency (1) Choose less retinotoxic fluoroquinolones (2) Retinotoxic potential in cats is marbofloxacin and pradofloxacin < orbifloxacin << enrofloxacin c) Extend the dosing interval (Hartmann 2010) (1) This will maximize peak concentrations for this concentration-dependent antibiotic class 4. Aminoglycosides a) Use other agents whenever possible (marbofloxacin, ticarcillin, cefotetan, aztreonem, meropenem) b) When necessary for use in patients with pre-existing renal failure: (1) Extend the dosing interval (2) Always rehydrate and use concurrent fluid therapy (IV or SC) (3) Consider possibly less nephrotoxic aminoglycosides (Christensen 1977) (a) Amikacin 15 mg/kg SC q. 24h (standard dosage) with interval adjustment (4) Monitor for tubular damage by examining fresh urine sediments for granular casts daily (5) Do not use furosemide or NSAID s concurrently (6) Do not use aminoglycosides in patients with urinary obstruction (7) Limit aminoglycoside therapy to 5 days or less whenever possible 5. Tetracyclines a) Use doxycycline, not tetracycline (1) No adjustment needed with renal insufficiency b) Tetracyclines can increase BUN, independent of any renal damage, due to protein catabolism (increase is reversible) c) Never use outdated tetracyclines (breakdown products are nephrotoxic) 6. Chloramphenicol a) In cats, 25% or more is excreted unchanged in the urine b) Avoid use in cats with renal insufficiency or monitor CBC for dose-dependent leukopenia 7. Potentiated sulfonamides a) Decreased renal clearance in renal failure (1) Rehydrate first and dose accurately b) Avoid sulfadiazine (in Tribrissen) in renal failure (1) Sulfadiazine forms drug crystals in the renal tubules and can lead to hematuria in humans (2) Avoid with urinary acidifiers (promote sulfadiazine precipitation in urine and tubular damage in humans) 8. Digoxin a) Decreased renal filtration, tubular secretion, and skeletal muscle binding leads to increased serum concentrations in uremia b) Reduce dose in azotemia c) Measure serum digoxin concentrations (1) Steady state after about 1 week in dogs (2) Draw level 6 to 8 hours after dosing (3) Therapeutic target: 0.8 1.2 ng/ml 9. Furosemide a) Avoid in renal failure Clinical Pharmacology Lauren Trepanier DVM, PhD, DACVIM, DACVCP Page 10 of

b) Can lead to dehydration, hypokalemia, acute renal decompensation c) If needed for concurrent heart failure, use lowest dosages needed and monitor carefully (1) Serial BUN, creatinine, potassium, packed cell volume (PCV), and total protein (TP) 10. Cimetidine / ranitidine / famotidine a) CNS disturbances reported in elderly humans with decreased GFR when H 2 blockers are given without appropriate dose reductions b) Reduce dosage in renal failure c) Either decrease dose or extend dosing interval (either method used in people) 11. Metoclopramide a) Standard CRI dosages (1-2 mg/kg/day) may cause tremor and ataxia in azotemic patients b) Consider 0.25-0.50 mg/kg/day in renal failure, and titrate to dosage that controls emesis without tremor c) Or substitute maropitant as an antiemetic (but this lacks prokinetic effects) 12. Atenolol a) Renally cleared (unlike propranolol) b) Given at 25-50% of standard dosages in humans with moderate to severe renal insufficiency c) Consider similar dosage adjustments in azotemic cats, with monitoring of heart rate and blood pressure 13. Angiotensin converting enzyme inhibitors (ACEi) a) Benazepril is preferred over enalapril in azotemic patients (1) Benazepril undergoes some hepatic clearance, and does not accumulate in mild to moderate azotemia in dogs or cats b) All ACE inhibitors have potential adverse effects on glomerular filtration rate (GFR) (1) Efferent arteriolar dilation can drop GFR (2) May lead to worsened azotemia, particularly with: (a) Concurrent NSAIDs (b) Concurrent furosemide (c) High ACEi dosages (d) Anesthesia c) Monitor BUN, creatinine, and electrolytes in patients on ACE inhibitors, especially those with pre-existing azotemia 14. NSAID s a) Decreased renal clearance and adverse effects on GFR b) Coxibs have same potential to adversely affect GFR (1) COX-2 is also expressed in the kidney c) Coxibs are not safer than classical NSAIDs in renal insufficiency d) Use alternatives to NSAIDs in azotemic patients with osteoarthritis: (1) Tramadol (2) Buprenorphine (3) Cosequin (4) Omega-3 fatty acids (5) j/d diet (6) Physical therapy (7) Acupuncture (8) S-adenosylmethionine (SAMe)? (a) Some efficacy for osteoarthritis in humans Clinical Pharmacology Lauren Trepanier DVM, PhD, DACVIM, DACVCP Page 11 of

(b) Not effective as stand-alone therapy for OA in dogs (Imhoff 2011) e) If NSAID is required for pain control and quality of life, use conservative NSAID dosages, and monitor frequently for: (1) Dehydration, inappetance, and increases in BUN or creatinine Clinical Pharmacology Lauren Trepanier DVM, PhD, DACVIM, DACVCP Page 12 of

Drug Table 1: Empirical recommendations for drug dosage adjustment in renal failure (based on human studies, a few veterinary studies, and adapted from expert opinion (Margo Karriker, PharmD) presented at the 2006 Advanced Renal Therapies Symposium at the Animal Medical Center) Standard dosage Amikacin 15 mg/kg q. 24h Amphotericin B 1 mg/kg IV three times weekly Atenolol 0.25 mg/kg q. 12h Azithromycin 5-10 mg/kg q. 24h Benazepril 0.5 mg/kg q. 12h Method for adjustment IRIS Stage II renal disease (creatinine 1.4-2.0 mg/dl) Interval q. 24-48h *Avoid if possible *Adjust interval for trough concs. < 2 ug/ml Use liposomal formulation only IRIS Stage III renal disease (creatinine 2.1-5.0 mg/dl) q. 48h *Avoid if possible *Adjust interval for trough concs. < 2 ug/ml Use liposomal formulation only IRIS Stage IV renal disease (creatinine > 5.0 mg/dl) Not recommended Not recommended Dose/Interva 0.19 mg/kg q. 12-0.125 mg/kg q. 0.06 mg/kg q. l 24 h 12-24 h 24h - No adjustment No adjustment No adjustment Dose No adjustment 0.25 mg/kg q. 12h 0.125 mg/kg q. 12h Doxycycline 5 mg/kg q. 12h - No adjustment No adjustment No adjustment Enalapril 0.5 mg/kg q. 12h Dose 0.375-0.5 mg/kg q. 12h 0.25-0.375 mg/kg q. 12h 0.25 mg/kg q. 24 h Enrofloxacin 5 mg/kg q. 24h Interval 5 mg/kg q. 24-48 h 5 mg/kg q. 48h (not recommended in cats) 5 mg/kg q. 48-72h (not recommended in cats) Famotidine 1 mg/kg q. 12h Dose/Interva No adjustment 1 mg/kg q. 24 h 0.5 mg/kg q. 24 h l Fluconazole 5 mg/kg q. 12h Interval 5 mg/kg q. 12-24h 5 mg/kg q. 24-48 h 5 mg/kg q. 48-72 h Gentamicin 6-8 mg/kg q. 24h Not recommended Ketoconazole 10 mg/kg q. 12h Maropitant 1 mg/kg SC q. 24h Metoclopramide 1-2 mg/kg/day CRI Interval q. 24-48h *Avoid if possible *Adjust interval for trough concs. < 2 ug/ml q. 48h *Avoid if possible *Adjust interval for trough concs. < 2 ug/ml - No adjustment No adjustment No adjustment Negligible renal clearance (Benchaoui 2007) Dose No adjustment No adjustment No adjustment 1.0 mg/kg/day CRI 0.5 mg/kg/day CRI; monitor for tremors 0.25 mg/kg/day CRI; monitor for tremors Clinical Pharmacology Lauren Trepanier DVM, PhD, DACVIM, DACVCP Page 13 of

Metronidazole 7.5-15 mg/kg q. 12h Ondansetron 0.1-0.2 mg/kg q. 6-12h Propranolol 0.1-0.2 mg/kg q.8h Spironolactone 1.0 mg/kg q. 12h Tramadol 1-4 mg/kg q.8-12h Dose No adjustment No adjustment 3.75-7.5 mg/kg q. 12h Dose No adjustment 0.05-0.1 mg/kg 0.025-0.05 q.6-12h mg/kg q.6-12h Dose No adjustment No adjustment 0.08-0.16 mg/kg q. 8h Dose/Interva 0.5-1.0 mg/kg 0.25 mg/kg q.24h Not l q.24h recommended Dose/Interva 0.5-2 mg/kg q. 0.5-1 mg/kg q. 0.5-1 mg/kg q. l 12h 12h 24h Clinical Pharmacology Lauren Trepanier DVM, PhD, DACVIM, DACVCP Page 14 of

RATIONAL USE OF PRE-SURGICAL ANTIBIOTICS Lauren A. Trepanier, DVM, PhD, Dip. ACVIM, Dip. ACVCP University of Wisconsin-Madison, School of Veterinary Medicine, Madison, WI Pre-surgical antibiotics are indicated for specific types of surgical procedures and in patients with certain risk factors for infection. In other situations, peri-operative antimicrobials are not rational, only add to the cost of hospitalization, may lead to adverse reactions or drug interactions, and can encourage the selection of resistant bacteria in an individual patient or on a hospital wide basis. I. CASES FOR WHICH ANTIMICROBIALS ARE NOT INDICATED: A. Patients undergoing uncontaminated, short surgical procedures 1. For example, ovariohysterectomy, castration, skin mass removal, some splenectomies 2. If less than an hour in duration, these cases do not require prophylactic antimicrobials. a) In one study of 122 dogs undergoing short duration, clean surgical procedures, there was no difference in the rate of infection in those animals given ampicillin compared to those given placebo II. Cases for which antimicrobials are indicated: A. Surgical sites with expected contamination 1. Even if contamination can be controlled, contaminated surgery sites warrant prophylactic antibiotics. 2. This includes all procedures that enter the GI, lower urogenital, oropharyngeal, or respiratory tracts, such as: a) Gastrotomy, enterotomy, subtotal colectomy b) Urethrostomy, vaginoplasty c) Oral tumor removal, palate surgery d) Dental surgeries e) Larynx, tracheal or lung surgery 3. This includes sites that are difficult to decontaminate, which also warrant prophylaxis a) Ocular surgeries b) Ear canal ablations B. Surgical procedures of prolonged duration 1. Prolonged anesthesia alone has been correlated with an increased risk of infection in dogs and cats a) This may be due to hypothermia, hypotension, and decreased tissue perfusion 2. Procedures greater than 60-90 minutes in duration warrant prophylactic antimicrobials. a) Infection risk doubles for every 70 minutes of surgery, according to one study of more than 1000 surgeries in dogs and cats in Switzerland 3. In dogs undergoing elective orthopedic surgery, prophylactic antibiotics have been shown to decrease the rate of postoperative infection compared to placebo a) Preventing infection in orthopedic procedures is particularly important, since infection at the site of bone healing can have disastrous consequences for return to function. Clinical Pharmacology Lauren Trepanier DVM, PhD, DACVIM, DACVCP Page 15 of 43

C. Preexisting infection at the surgical site 1. an obvious indication for intra- and post-operative antimicrobial treatment but this is therapy, not prophylaxis. 2. If the infection is long-standing or recurrent, tissue should always be submitted for culture and sensitivity. a) Always include an aerobic and anaerobic culture if the wound is deep or walled off. 3. If devitalized tissue is present, it should be debrided appropriately, since antibiotics will not penetrate tissue without adequate blood flow. 4. Topical antibiotics are not useful in such instances, because they will be inactivated in the presence of necrotic debris. D. The presence of devitalized tissue, tissue dessication, or traumatic tissue handling 1. Intra-operative tissue dessication or traumatic tissue handling increases the risk of post-surgical infection. 2. In one study, antimicrobials were not necessary in preventing infection in surgeries performed by experienced veterinary surgeons, but antimicrobials did reduce the incidence of infections in surgeries performed by inexperienced veterinary students 3. For practicing veterinarians, it makes more sense to focus on good surgical technique than to rely on antimicrobials to compensate for poor tissue handling. E. A compromised host 1. Immunodeficiency a) Immunodeficient human patients have a higher risk of surgical infections and poor wound healing b) In veterinary patients, feline leukemia (FeLV) or feline imunodeficiency virus (FIV)- infected cats, or patients with neutropenia, may benefit from antimicrobial prophylaxis prior to surgery. (1) This is particularly important for procedures for which the gastrointestinal tract, lower urogenital, or upper respiratory tract are entered. (2) In these patients, bactericidal antibiotics provide a theoretical advantage. 2. Endocrinopathies a) Diabetes (1) Human patients with diabetes mellitus have a higher risk of surgical infections (2) However, diabetic humans develop peripheral vascular disease but diabetic dogs and cats do not appear to (3) Increased infection risk in humans may not translate directly to diabetic dogs and cats. b) Hyperadrenocorticism and hypothyroidism have been associated with increased surgical site infections in dogs (1) Although no studies have been published comparing surgical infection rates in dogs with controlled versus uncontrolled hyperadrenocorticism, delayed wound healing and incision dehiscence are common surgical complications in dogs with untreated hyperadrenocorticism (2) Whenever possible, hyperadrenocorticism should be treated and controlled before elective surgeries III. Timing of antimicrobial therapy A. The following recommendations are the standard of care in humans (National Surgical Infection Prevention Project): Clinical Pharmacology Lauren Trepanier DVM, PhD, DACVIM, DACVCP Page 16 of 43

1. Parenteral antimicrobials within one hour before incision 2. Re-dose every 1-2 elimination half-lives during prolonged procedures 3. Discontinuation of prophylactic antimicrobials after wound closure IV. SELECTION OF AN ANTIMICROBIAL REGIMEN A. Orthopedic procedures: 1. Coverage should be targeted at skin flora (i.e. Staph. pseudintermedius) that may cause deeper wound contamination. 2. Cefazolin has been shown to be effective in preventing infection after orthopedic procedures in dogs when given at 20 mg/kg at induction, followed by 20 mg/kg IV every 90 minutes thereafter until wound closure. a) The same study demonstrated that potassium penicillin G was also effective, compared to placebo, in this setting b) However, cefazolin, and related first generation cephalosporins, remain the standard for orthopedic prophylaxis because of their spectrum against many betalactamase-producing Staph. B. Dental procedures: 1. There are two considerations with dental procedures: a) Treatment of pre-existing gingival or periodontal infections (1) Treatment of pre-existing infection prior to definitive dental procedures may decrease tissue inflammation and bleeding at the time of oral surgery (2) Amoxicillin-clavulanate and clindamycin are each effective against Gram positive and anaerobic gingival flora in dogs and cats. b) Control of bacteremia during dental prophylaxis (1) Probably not a concern in most animals (a) Healthy animals are able to overcome this bacteremia without the use of systemic antibiotics (American Veterinary Dental College position statement, 2004) (2) Antibiotic therapy prior to dental prophylaxis is only recommended for human patients with: (a) Joint prostheses (b) Artificial heart valves (c) Prior endocarditis (d) Prior cardiac transplant (3) The American Veterinary Dental College recommends antibiotics at the time of dental prophylaxis only in animals that are immune compromised, have underlying systemic disease (such as clinically-evident cardiac, hepatic, and renal diseases) and/or when severe oral infection is present. c) For dental prophylaxis in at-risk patients, antibiotics should be given one hour prior to the dental procedure (1) Note: long acting antibiotics, such as Convenia, are inappropriate in this setting (2) Additional treatment after the procedure is not indicated unless there is a clear underlying infection C. Gastric, biliary, and small intestinal surgery: 1. Because these procedures involve entering a contaminated body cavity, antimicrobial prophylaxis is warranted. Clinical Pharmacology Lauren Trepanier DVM, PhD, DACVIM, DACVCP Page 17 of 43

a) Treatment prior to incision is the key to efficacy. 2. Coverage should be aimed primarily at anaerobes and routine Gram negative enterics such as E. coli. a) Ampicillin, cefazolin, or cefotetan are reasonable choices, given within 30 minutes prior to incision 3. For soft tissue surgeries, a bolus dose of 20 mg/kg cefazolin IV given at the time of surgery, followed by a second dose of 20 mg/kg SC 6 hours later, was shown to provide adequate drug concentrations at the surgical wounds for more than twelve hours postoperatively in experimental dogs. a) However, based on data in humans, the second injection 6 hours later is probably unnecessary (and was not tested separately) D. Colonic surgery: 1. Surgery involving the colon carries a relatively high risk of surgical site infection and bacterial peritonitis. 2. In humans, the standard of care for colorectal surgery is both oral and intravenous antibiotic prophylaxis. a) Systemic coverage for anaerobes and Gram-negative enterics is warranted. b) Typical regimens include oral neomycin and erythromycin given in divided doses the day before surgery, followed by ampicillin-sulbactam, cefotetan, or metronidazole / cefazolin, given IV one hour prior to incision. c) Human studies do not support the administration of additional antimicrobials beyond wound closure. 3. If surgery is urgent, cefotetan (a broad spectrum second generation cephalosporin) can be administered at induction and for 24 hours postoperatively. 4. Although mechanical irrigation prior to colonic procedures makes intuitive sense, and is widely used in both human and veterinary patients, it has shown no benefit in reducing postoperative complications in humans. a) Notably, mechanical irrigation has actually been associated with an increased risk of abdominal infections in colorectal surgeries in humans, possibly due to mucosal inflammation and loss of colonic mucus. E. Bladder surgery: 1. Prophylactic antibiotics do not reduce the incidence of wound infection after bladder surgery in immunocompetent humans. a) However, antibiotic prophylaxis is recommended for immunocompromised patients (patients on chemotherapy, with Cushing s, or with neutropenia) prior to cystotomy (1) Consider a single dose of a cephalosporin or fluoroquinolone 2. For stable patients with documented or suspected pre-existing urinary tract infections, there are two options prior to bladder surgery: a) Culture urine pre-operatively, and treat infection for a week or more prior to elective surgery, or b) Obtain cultures at surgery, and treat based on results 3. If postoperative urinary catheterization is necessary: a) Minimize duration of catheterization (intermittent clean catheterization may be preferred over indwelling catheter, if possible, e.g. in male dogs) b) Use scrupulous clean technique c) Always use a closed collection system 4. Treat with antimicrobials if clinical signs of urinary tract infection, with bacteriuria, develop Clinical Pharmacology Lauren Trepanier DVM, PhD, DACVIM, DACVCP Page 18 of 43

a) Do not treat asymptomatic bacteriuria diagnosed during or immediately after urinary catheterization b) Consider culturing urine 3 days after catheter removal (1) If cystocentesis is contraindicated (i.e. recent bladder surgery), collect a mid-stream voided sample and request a quantitative culture (2) > 10,000 cfu/ml is significant growth in a cultured mid-stream voided sample V. Other prophylactic measures to prevent peri-operative infections A. Shave animals after anesthetic induction 1. Shaving animals prior to anesthetic induction has been associated with an almost 3-fold higher incidence of surgical site infection compared to dogs and cats clipped after anesthetic induction. 2. This has also been demonstrated in humans shaved the night before surgery, and is most likely due to small skin nicks that have time to become colonized by bacteria. B. Use care with multi-dose vials 1. The use of multi-dose 20 ml vials of propofol, without preservatives, has been associated with higher rates of SSI in dogs and cats, compared to patients not given propofol, under conditions in which vials were shared among patients or syringes were pre-filled more than 6 hours prior to use C. Maintain core body temperature during surgery 1. Hypothermia increases wound infection rates a) Hypothermia causes secondary vasoconstriction and decreased blood flow to the wound site b) Hypothermia leads to impaired innate immune function 2. Supplemental warming during anesthesia reduces postoperative infection by 5-14% in human patients D. Minimize the number of people in the operating room 1. For each additional person in the surgical suite, veterinary patients were found to be 1.3 times more likely to develop post-operative infections E. Adhere to consistent, high quality postoperative nursing care 1. Alcohol-based hand sanitizers between every patient 2. Exam gloves when examining every incision 3. Get recumbent dogs up to walk and urinate frequently Clinical Pharmacology Lauren Trepanier DVM, PhD, DACVIM, DACVCP Page 19 of 43

IDIOSYNCRATIC DRUG TOXICITIES Lauren A. Trepanier, DVM, PhD, Dip. ACVIM, Dip. ACVCP University of Wisconsin-Madison, School of Veterinary Medicine, Madison, WI I. Mechanisms of Toxicity A. Dose-dependent 1. Increasing toxicity with increasing dose, in one or more species 2. Virtually all members of a population or species will be affected at high enough dosages 3. Relatively predictable a) Therapeutic drug monitoring helpful 4. May be due to property of parent compound, or to a metabolite that is reliably generated in that species 5. May or may not be related to the desired pharmacologic action of the drug 6. Requires dose reduction but usually not drug discontinuation B. Idiosyncratic 1. Toxicity at therapeutic dosages, in a small proportion of the species or population 2. Toxicity does not increase with dose in the general population (therefore not considered dose-dependent ) a) but toxicity probably does increase with dose among susceptible individuals 3. Relatively unpredictable a) Therapeutic drug monitoring generally not helpful 4. May be due to property of parent compound or of a metabolite that is variably generated in that species 5. Usually not related to desired pharmacologic action of the drug 6. May or may not involve an immunologic response 7. Usually requires discontinuation of the suspect drug II. Idiosyncratic toxicity - targets A. Liver 1. Susceptibility of liver a) Site of first-pass clearance of many orally administered drugs b) Site of P450-mediated bioactivation of some compounds to more reactive metabolites 2. Types of adverse effects on hepatic function caused by drugs: a) Acute: (1) Cytotoxic (a) Often due to reactive metabolite (b) May lead to haptenization with immune response (2) Cholestatic (a) Inhibition of transporters (3) Mixed (a) Cytotoxic and cholestatic b) Chronic: (1) Many patterns could result from chronic drug injury: chronic hepatitis, steatosis, vacuolar degeneration, granulomatous change, or cirrhosis B. Bone marrow 1. Susceptibility a) Large tissue mass (including circulating cells) Clinical Pharmacology Lauren Trepanier DVM, PhD, DACVIM, DACVCP Page 20 of 43

b) Rapidly dividing cells. c) Bone marrow precursors and peripheral blood cells are metabolically active (1) Cytochrome P450 (2) Myeloperoxidases (3) Cyclooxygenases (a) Can bioactivate drugs to reactive intermediates 2. Idiosyncratic drug-induced blood dyscrasias include: a) Thrombocytopenia b) Neutropenia (1) Agranulocytosis if severe c) Hemolytic anemia d) Pure red cell aplasia e) Aplastic anemia 3. Mechanisms of idiosyncratic bone marrow damage include: a) Reactive drug metabolite leading to: (1) Cytotoxic destruction of stem or circulating cells (2) Haptenization with immune response directed at stem or circulating cells b) Suppression of hematopoiesis due to deranged cytokine production C. Skin 1. Susceptibility a) Large tissue mass b) Keratinocytes can bioactivate some drugs c) Large number of antigen-presenting cells in skin (Langerhans cells) 2. Idiosyncratic skin eruptions caused by drugs: a) Vasculitis (1) Examples: Meloxicam, sulfadiazine b) Pemphigus foliaceus (1) Example; potentiated sulfonamides c) Erythema multiforme (1) Localized detachment of the epidermis d) Stevens-Johnson syndrome (1) Widespread lesions but less than 10% of epidermis is detached e) Toxic epidermal necrolysis (1) Widespread lesions with more than 30% of epidermis is detached 3. Mechanisms of skin lesions: a) Haptenization of keratinocytes > targeting of altered self by antibodies and/or T cells b) Association with HLA genotypes (MHC I and MHC II) in humans III. Drugs implicated in idiosyncratic drug toxicity A. Phenobarbital 1. Toxicity in humans: idiosyncratic toxicity not a major side effect 2. Hepatotoxicity in dogs: a) Probably better described as dose-dependent with individual modifiers b) Ranges from asymptomatic increases in bile acids, to overt cirrhosis c) Possible mechanism of toxicity: (1) Induction of P450 enzymes with secondary bioactivation and hepatotoxicity of other substances (drugs, dietary components, environmental toxins) Clinical Pharmacology Lauren Trepanier DVM, PhD, DACVIM, DACVCP Page 21 of 43

(2) Direct cytotoxic effect is unlikely, since hepatotoxicity has not been seen with loading doses of phenobarbital d) Risk factors: (1) Prolonged duration and high dose (2) Prior therapy with primidone or phenytoin e) Management: (1) Phenobarbital discontinuation or dose reduction (2) Maintenance dose of KBr at 40-60 mg/kg/day (a) KBr loading dose of 400-600 mg/kg if brittle epilepsy and no hepatic encephalopathy (3) Rapid taper of phenobarbital over 1-2 weeks (4) Both felbamate and zonisamide are also associated with hepatotoxicity in dogs (a) Not ideal rescue drugs for phenobarbital hepatotoxicity until more is known about mechanisms f) Prevention of phenobarbital hepatotoxicity: (1) Use combination antiepileptic therapy to avoid chronic high dosages of phenobarbital (2) Screen patients on phenobarbital with serum bile acids every 6-12 months (3) Monitor for: (a) Increases in ALT > SAP (b) Hypoalbuminemia (c) Increased bilirubin (even if mild) (d) Clinical illness (e) Increased sedation (may indicate impaired hepatic clearance of phenobarbital) (f) Bile acids increased to the abnormal range 3. Phenobarbital and superficial necrolytic dermatitis a) Phenobarbital is associated with almost 45% of cases of superficial necrolytic dermatitis b) Liver biopsies show steatosis with nodular regeneration and fibrosis c) Mechanism unknown 4. Phenobarbital has also been associated rarely with blood dyscrasias a) To include thrombocytopenia, neutropenia, anemia, or myelofibrosis (Jacobs 1998; Weiss 2002; Weiss 2005). b) Possible mechanisms include: (1) Antibody or T cell responses to drug haptens (2) Cumulative marrow toxicity from reactive metabolite (3) Deranged folate metabolism c) Responds to drug discontinuation and supportive care unless advanced myelofibrosis has developed B. Potentiated sulfonamide antibiotics 1. Idiosyncratic toxicity in humans and dogs: a) Classically a delay in onset from 5-14 days post exposure b) Fever (1) 50% of cases c) Hepatotoxicity (1) Hepatocellular necrosis, cholestasis, or both Clinical Pharmacology Lauren Trepanier DVM, PhD, DACVIM, DACVCP Page 22 of 43

(2) In the past, 20% of FDA-reported drug hepatopathies in dogs were due to potentiated sulfonamides d) Thrombocytopenia, neutropenia, IMHA (1) Neutropenia associated with sulfonamides is an early, transient finding and is usually modest e) Skin eruptions (1) Vasculitis (2) Pemphigus foliaceus (White 2002) (3) Erythema multiforme, Stevens-Johnson syndrome toxic epidermal necrolysis f) Polyarthopathy, proteinuria g) Uveitis 2. Mechanisms of toxicity a) P450- or myeloperoxidase-generated oxidized metabolite (hydroxylamine), which is further converted to another oxidized metabolite (nitroso) that covalently binds to proteins and acts as a hapten b) T cell mediated cytotoxicity shown in humans c) Anti-drug antibodies documented in dogs and humans (1) Anti-sulfonamide antibodies cross-react across sulfamethoxazole, sulfadiazine, and sulfadimethoxine in about 30% of dogs (2) In humans and dogs, anti-platelet antibodies recognize non-covalent drugplatelet complexes (a) Some of these antibodies require continuous presence of sulfonamide drug in order to bind to platelets d) Some dogs have antibodies to myeloperoxidase, which suggests that oxidative activation of the sulfonamide by myeloperoxidase contributes to hypersensitivity e) No good evidence of cross-reactivity with other drugs containing sulfonamide moiety (e.g. furosemide, acetazolamide) 3. Risk factors: a) Familial risk in humans (1) Under investigation in our laboratory b) Breed risk in dogs (1) Dobermans (arthropathy, thrombocytopenia, proteinuria) (2) Schnauzers, Samoyeds over-represented in our series of 40 dogs with sulfonamide hypersensitivity (a) May indicated dosing bias c) Tribrissen, Primor, and generic TMP-sulfamethoxazole all implicated in dogs d) AIDS in humans (1) Glutathione and ascorbate depletion (2) Down regulation of drug detoxification enzymes? 4. Management: a) Stop potentiated sulfonamide at first sign of illness!! b) Ascorbic acid (1) Ascorbate decreases haptenization of sulfonamides to dog liver proteins in vitro (2) 90 mg/kg/day ascorbate IV (empirical dosage) c) N-acetylcysteine (1) Glutathione also decreases haptenization of sulfonamides to dog liver proteins in vitro (2) 140 mg/kg loading IV, then 70 mg/kg every 6 hours for 7 treatments Clinical Pharmacology Lauren Trepanier DVM, PhD, DACVIM, DACVCP Page 23 of 43

(3) Dilute 10 or 20% N-acetylcysteine sterile oral solution to 5% in D5W (4) Give each IV dose over 30-60 minutes to minimize vomiting d) IV IgG (1) Anecdotal success for sulfonamide-associated bullous skin eruptions in humans (Nuttall 2004) C. Methimazole 1. Toxicity in humans: a) Chlolestasis or hepatic necrosis b) Neutropenia or agranulocytosis 2. Toxicity in cats: a) Hepatocellular necrosis (increased ALT) or cholestasis (increased SAP) b) Blood dyscrasias (thrombocytopenia, neutropenia) c) Skin eruptions (facial excoriations) (1) Biopsies typically not performed 3. Mechanisms of toxicity: a) Hepatotoxicity is due to N-methylthiourea metabolite (1) Glutathione depletion is risk factor experimentally b) In humans, methimazole-induced neutropenia is associated with an arrest in myeloid progenitors in the bone marrow (1) Anti-neutrophil antibodies documented (a) May suppress granulocyte-macrophage CFU s (2) Association with certain HLA haplotypes (3) Some studies have shown an increased risk of these reactions at higher methimazole doses 4. Management in cats a) Evaluate cat at first sign of illness (1) Rule out blood dyscrasia (CBC) (2) Rule out renal decompensation (3) Rule out hepatotoxicity (ALT, bilirubin, SAP) (a) Make sure to compare to liver enzymes pre-treatment (often reversibly increased in hyperthyroid cats) b) If simple GI upset (normal blood work), reduce dose or switch to transdermal methimazole c) If idiosyncratic hepatopathy, blood dyscrasias, or facial excoriation, discontinue methimazole (1) Transdermal route not beneficial in reducing risk of idiosyncratic toxicity from methimazole D. Diazepam 1. Toxicity in humans: a) Hepatotoxicity not a recognized side effect of diazepam in humans (or in dogs) 2. Toxicity in cats: a) Fulminant hepatic necrosis with marked increases in ALT 3. Mechanism of toxicity: a) Not known b) Delay of 8-9 days from exposure to onset of signs (reported initially) suggests immune component, but some cats have been affected within 96 hours of first exposure 4. Risk factors: Clinical Pharmacology Lauren Trepanier DVM, PhD, DACVIM, DACVCP Page 24 of 43