May 2009

Pharmacology

Lauren A. Trepanier, DVM, PhD, Dip. ACVIM, Dip. ACVCP
University of Wisconsin-Madison




Top Ten Potential Drug Interactions in Dogs and Cats

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 decreases the clearance of many drugs:
  • Chloramphenicol: dose-dependent leukopenia
  • Metronidazole: neurologic side effects
  • Lidocaine: GI and neurologic side effects
  • Theophylline and aminophylline: theophylline toxicity
  • Warfarin, propranolol, diazepam, midazolam, many others….
    Because of many potential cimetidine interactions, alternative H2 blockers such as ranitidine, famotidine, or nizatidine (which are not P450 inhibitors at therapeutic concentrations), should be chosen over cimetidine for patients treated with multiple drugs. Ranitidine and nizatidine have the added advantage of 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 6 hours after sucralfate in humans
  • Tetracycline and doxycycline: marked inhibition of oral absorption
  • H2 blockers: sucralfate delays, but does not decrease the extent of, the absorption of H2 blockers; therefore staggering of dosing is probably NOT required
  • Theophylline, aminophylline, digoxin, azithromycin: sucralfate may decrease efficacy.
    This is a physicochemical interaction that is likely to occur in dogs and cats as it does in humans.

    3. Ketoconazole

    Ketoconazole and itraconazole are best absorbed at acidic pH; therefore, do not combine these drugs with:
  • Omeprazole, H2 blockers, or antacids
  • Interestingly, increased gastric pH does not affect the absorption of fluconazole 1
    Ketoconazole inhbits a cytochrome P450 enzyme, CYP3A, with a wide substrate range and high potential for drug-drug interactions. Ketoconazole is also an inhibitor of p-glycoprotein, an important drug efflux transporter in the gut, kidney, and biliary tree. Ketroconazole 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.
  • Digoxin: ketoconazole can lead to digoxin toxicity
  • Amitriptyline, midazolam: ketoconazole could increase sedation
  • Warfarin: ketoconazole may prolong its toxicity
    Note: Itraconazole, like ketoconazole, also inhibits the P450 metabolism of the same drugs in humans.

    4. Fluoroquinolones

    The absorption of oral fluoroquinolones is markedly impaired by drugs that contain divalent or trivalent cations, such as:
  • Sucralfate, aluminum hydroxide, aluminum carbonate
  • Calcium carbonate
  • Oral iron, zinc
    In humans and dogs, fluoroquinolones inhibit the CYP1A2 metabolism, of theophylline. This has lead to theophylline toxicity in humans. In dogs, enrofloxacin leads to higher plasma theophylline concentrations by about 30-50%.2

    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).
  • Enhanced extrapyramidal side effects (tremor) in combination with phenothiazines (e.g. chlorpromazine, acepromazine) or selective serotonin reuptake inhibitors (e.g. fluoxetine), or with renal insufficiency.
  • Metoclopramide reduces the amount of propofol needed for anesthetic induction in humans by 20-25% (mechanism unknown).
    It has been suggested that metoclopramide may antagonize the effects of dopamine on renal hemodynamics. However:
  • Metoclopramide has no effect on low dose dopamine-induced increases in GFR or effective renal plasma flow in humans.
  • Dopamine increases urine output in cats 3 as in humans, but this is not inhibited by dopamine antagonists. 4

    6. Cisapride

    Like ketoconazole, cisapride is a substrate of CYP3A. High plasma concentrations of cisapride can lead to potentially fatal cardiac arrhythmias in humans. Drugs that inhibit CYP3A may increase cisapride concentrations and increase the risk of cardiac side effects in humans:
  • Clarithromycin, erythromycin (but not azithromycin)
  • Fluconazole, itraconazole, ketoconazole
    Note: in one study in dogs, erythromycin did not alter cisapride pharmacodynamics.5

    7. Furosemide

    Several drug combinations with furosemide can lead to enhanced toxicity:
  • Amikacin and gentamicin: nephrotoxicity is enhanced by furosemide; mannitol may be preferable to furosemide for treatment of acute renal failure due to aminoglycosides.
  • Enalapril, benazapril: may cause hemodynamic changes leading to acute renal failure, when given with full doses of furosemide. Use conservative initial doses of ACE inhibitors when also starting furosemide
  • Digoxin: furosemide increases serum digoxin levels (independent of dehydration). Furosemide can also lead to hypokalemia and hypomagnesemia, both of which exacerbate the cardiac toxicity of digoxin. In addition, furosemide can lead to prerenal azotemia, leading to decreased digoxin excretion. All of these interactions can lead to digoxin toxicity unless serum digoxin levels are monitored.
  • Renal function and serum electrolytes should be routinely evaluated in all patients on furosemide.
    Other drug combinations with furosemide can affect efficacy:
  • Lidocaine: 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 instituted if patients do not respond to lidocaine.
  • Bromide: furosemide administration will increase the renal loss of bromide, and lower serum bromide concentrations, which may lead to seizure breakthrough

    8. Omeprazole

    Omeprazole is an inhibitor of some P450's in humans, and may inhibit the metabolism, and possibly increase the toxicity, of:
  • Diazepam, midazolam
  • Warfarin
    As an inhibitor of gastric acid secretion, omeprazole can also decrease the absorption of:
  • Iron supplements
  • Ketoconazole and itraconazole (but not fluconazole, which does not require an acidic Phillotson for absorption)

    9. Phenobarbital

    Phenobarbital is a major P450 enzyme inducer in humans and dogs. Phenobarbital speeds the metabolism of many drugs in dogs, including:
  • Glucocorticoids
  • Mitotane
  • Ketoconazole
  • Clomipramine
  • Chloramphenicol
  • Lidocaine
  • Etodolac
  • Theophylline
  • Digoxin, propranolol, and many others…
    However, phenobarbital causes minimal cytochrome P450 enzyme induction in the cat, 6,7 and therefore these P450-mediated drug interactions are unlikely in the cat.

    10. Clomipramine

    As a tricyclic antidepressant that inhibits norepinephrine reuptake, clomipramine can have pharmacologic interactions with monoamine oxidase inhibitors (which decrease the breakdown of norepinephrine and serotonin)
  • L-deprenyl (selegiline): MAO inhibitors like L-deprenyl used in combination with clomipramine or amitriptyline can lead to "serotonin syndrome" (twitching, tremor, seizures) in humans
  • Amitraz: an MAO inhibitor found in tick dips and collars; potential for interaction with tricyclic antidepressants like clomipramine. The metabolism of clomipramine can be inhibited by:
  • Fluoxetine (Prozac): can lead to increased clomipramine levels and cardiac conduction disturbances in humans
  • Ketoconazole, itraconazole

    Drug interactions in humans that may also affect dogs and cats

    Drug May increase the
    toxicity of:
    May decrease
    the efficacy of:
    Toxicity may be
    increased by:
    Efficacy may
    be decreased
    by:

    Cimetidine Metronidazole, lidocaine,
    theophylline,
    diazepam,propranolol
    Ketoconazole,
    itraconazole, iron
    supplements
       
    Sucralfate   Fluoroquinolones,
    tetracyclines,
    erythromycin,
    theophylline,
    digoxin
       
    Ketoconazole Cyclosporine, warfarin,
    digoxin, amitriptyline,
    midazolam, cisapride
        Antacids, H2
    blockers,
    omeprazole
    Fluoro-
    quinolones
    Theophylline     Sucralfate,
    iron, calcium,
    aluminum,
    magnesium
    Metoclopramide Ethanol, aspirin, or
    acetaminophen
    overdoses; propofol?
    Probably does not
    counteract the renal
    effects of dopamine
    Aceprozamine,
    fluoxetine
    (tremor)
     
    Furosemide ACE inhibitors, digoxin,
    aminoglycosides
    Bromide, lidocaine
    (via hypokalemia)
    Aminoglycosides NSAID's
    Cisapride     Clarithromycin,
    erythromycin,
    azole antifungals,
    fluoxetine
     
    Omeprazole Diazepam, warfarin,
    digoxin
    Ketoconazole,
    itraconazole, iron
    supplements
       
    Phenobarbital   Glucocorticoids,
    clomipramine,
    lidocaine,
    theophylline,
    digoxin,
    propranolol…
       


    Cited references
    1. Zimmermann, et al. The influence of gastric pH on the pharmacokinetics of fluconazole: the effect of
      omeprazole. Int J Clin Pharmacol Ther 1994;32:491-496.
    2. Intorre, et al. Enrofloxacin-theophylline interaction: influence of enrofloxacin on theophylline steadystate
      pharmacokinetics in the beagle dog. J Vet Pharmacol Ther 1995;18:352-356.
    3. Wassermann, et al. Dopamine-induced diuresis in the cat without changes in renal hemodynamics.
      Naunyn Schmiedebergs Arch Pharmacol 1980;312:77-83.
    4. Wright, et al. Pharmacokinetics of gentamicin after intravenous and subcutaneous injection in obese
      cats. J Vet Pharmacol Ther 1991;14:96-100.
    5. Al-Wabel, et al. Electrocardiographic and hemodynamic effects of cisapride alone and combined with
      erythromycin in anesthetized dogs. Cardiovasc Toxicol 2002;2:195-208.
    6. Maugras, et al. The hepatic cytochrome level in the cat (Felis catus): normal value and variations in
      relation to some biological parameters. Comp Biochem Physiol B 1979;64:125-127.
    7. Truhaut, et al. [Induction of cytochrome P 450 by phenobarbital in cats]. C R Acad Sci Hebd Seances
      Acad Sci D 1978;286:371-373.


    Choosing Therapy for Chronic Liver Disease

    Making a diagnosis
    It is important to obtain a liver biopsy whenever possible. Specific biopsy findings that can drive therapy include: degree of fibrosis (mild, moderate, severe); predominant type of inflammatory infiltrates (neutrophils vs. lympocytes and plasma cells); degree of necrosis (mild, moderate, severe); presence of cholestasis (mild, moderate, severe); and presence of cirrhosis (distortion of architecture by fibrosis and nodular regeneration). The location of inflammation may indicate the underlying source. For example, in portal hepatitis, inflammatory cells (esp. neutrophils) are found around portal areas without necrosis or fibrosis. This may indicate inflammation secondary to extrahepatic causes, such as septicemia, GI neoplasia, or inflammatory bowel disease. Such cases may not need aggressive primary hepatic therapy, but instead, attention to underlying abdominal disease.

    When are antimicrobials indicated?

    Antimicrobials are obviously indicated for active hepatic or biliary infection, ideally based on results of culture of bile or liver. Bile cultures can be obtained from gall bladder aspiration under ultrasound guidance, or swabs at laparotomy. If you biopsy the liver, always culture the bile, and submit both aerobic and anaerobic samples (e.g use A.C.T. I agar tubes (Remel); good for 24 hours for both aerobic and anaerobic culture). Bile may be a more sensitive site to document hepatobiliary infection (versus liver tissue). In almost 250 cases of liver and bile cultures from dogs and cats at the University of Wisconsin, the most common isolates were E. coli, Enterococcus spp, Clostridium spp, and Staphylococcus. [Wagner, 2007] These bacteria can be treated with a combination of a fluoroquinolone and either amoxicillin/clavulanate, clindamycin, or metronidazole and amoxicillin. The empirical recommended duration is 2 to 4 weeks of therapy, but this has never been evaluated.

    When are glucocorticoids indicated?

    The rationale for glucocorticoids (anti-inflammatory, antifibrotic, and choleretic effects) should always be weighed against potential side effects in each patient. Recommendations have been based on experience in humans with hepatitis, with no controlled clinical trials in dogs or cats. Consider glucocorticoids for predominantly lymphocytic-plasmacytic or eosinophilic inflammatory infiltrates on liver biopsy. Glucocorticoids may be used empirically (without biopsy) if the owner refuses biopsy, progressive increases in ALT are noted, and infectious and neoplastic causes have been ruled down with ultrasound and serologies. Prednisolone is preferred in cats due to apparent poor conversion of prednisone to prednisolone. Prednisolone has a theoretic advantage in dogs with liver disease, but cytochrome P450-mediated activation of prodrugs such as prednisone is actually well conserved in liver disease unless overt failure is present. Budesonide may be less likely to induce SAP and cause other side effects in dogs. It can, however, still cause significant PU/PD and adrenal suppression in some dogs; in these patients, this relatively expensive glucocorticoid has no real advantage over prednisone.

    Precautions with glucocorticoids

    Glucocorticoids are contraindicated in patients with uncontrolled hepatic encephalopathy, ascites, active GI ulceration, hepatic lipidosis, and active hepatobiliary infection. Always stabilize patients and treat for encephalopathy and GI ulcers before starting glucocorticoids. Add glucocorticoids as a single change (e.g. 2 weeks after other supportive care has been started) and monitor carefully for improvement or decompensation. If ascites is present, substitute dexamethasone (at 1/7 the dose) for prednisone, since dexamethasone has no mineralocorticoid activity.

    Immunomodulatory and antioxidant therapies

    Most recommendations for these agents are extrapolated from experience in humans, and are ideally based on a patient's individual liver biopsy findings. Ursodiol (ursodeoxycholic acid) is a choleretic bile acid that also reduces hepatocellular injury and fibrosis in humans and animal models. In patients with moderate to severe cholestasis without obstruction, ursodiol is indicated as a choleretic. It is also the drug of choice for primary biliary cirrhosis in humans, which resembles feline cholangitis. Ursodiol is dosed at 10-15 mg/kg/day; 250 mg tablets or 300 mg capsules can be reformulated for cats and small dogs. Ursodiol should not be used unless bile duct obstruction has been ruled out (based on normal bilirubin or via ultrasound).
    S-Adenosyl-methionine (SAM-e; DenosylTM SD4; Denamarin™ with milk thistle) is a modified amino acid, important for methylation reactions in the liver and elsewhere. Methylation of membrane lipids modulates membrane fluidity and surface cell interactions. SAMe protects membranes from bile salt damage, and enhances bile excretion from hepatocytes (shown in vitro). SAMe is also an indirect precursor of glutathione; SAMe administered to dogs helps to counteract liver glutathione depletion that occurs with liver disease or with corticosteroid administration. There are no controlled clinical trials of efficacy in dogs with naturally occurring liver disease, but SAMe has been shown to prolong survival in alcoholic cirrhosis in humans. Empirical indications include chronic hepatitis or cholangitis with significant component of necrosis. Recommended dosing is 18-20 mg/kg, on an empty stomach. Enteric-coated tablets should not be broken open.
    Milk thistle (Silybum marianum; Silymarin; also found in Marin™ and Denamarin™ with SAMe) is another hepatoprotective compound, which has been used for hepatic disorders since the time of the ancient Romans. It is thought to scavenge reactive oxygen species, and may have anti-inflammatory effects via inhibition of 5-lipoxygenase. Milk thistle has been shown experimentally to protect dogs against Amanita mushroom hepatotoxicity. There are no controlled clinical trials, but milk thistle may be used in patients with significant inflammation and necrosis on biopsy, in addition to, or instead of, SAMe (if clients prefer a "natural" product). The empirical dosage is 4 to 8 mg/kg/day. Marin™ (if dosed by label) provides 1.5 to 4 mg/kg/day. Product formulation and potency may vary significantly from one manufacturer to another.
    Vitamin E (also found in Marin™) is a critical membrane antioxidant that protects hepatocytes against the toxic effects of bile acids in vitro. Its use has been advocated for empirical therapy for any inflammatory hepatopathy, especially hepatopathies with significant necrosis. Vitamin E may be used in addition to SAMe or silymarin, an is empirically dosed at 150 - 600 I.U. per dog per day. If significant cholestasis is present, use water soluble forms (Nutra-E-Sol, Liqui E). Overdoses of vitamin E can lead to a coagulopathy, [Abdo, 1986] and even modest doses (approximately 15 IU/kg in humans) can lead to subclinical decreases in the function of prothrombin, a vitamin K-dependent coagulation factor.[Booth, 2004] Although the exact mechanism is not understood, it is hypothesized that high dose vitamin E may antagonize the effects of vitamin K.[Booth, 2004] Further, vitamin E has been shown to exacerbate the anticoagulant effect of warfarin in dogs. [Corrigan, 1979] Until more is known, vitamin E supplementation in veterinary patients suspected of having a vitamin K-dependent coagulopathy should be based on strong rationale and should be monitored carefully. In addition, vitamin E supplementation should be avoided in patients treated with, or exposed to, warfarin or related anticoagulant rodenticides.

    Antifibrotics

    Three major anti-fibrotics are in common use: glucocorticoids, zinc, and colchicines.
    Glucocorticoids inhibit fibroblast proliferation, and may be adequate for treatment of mild to moderate fibrosis accompanied by inflammation. Zinc inhibits collagen synthesis and decreases hepatic fibrosis in animal models. As a cofactor for superoxide dismutase (which scavenges superoxide free radicals), zinc also may have antioxidant effects. Zinc also impairs copper absorption. Zinc may therefore be useful for dogs with chronic hepatitis with moderate fibrosis, especially if mild to moderately increased copper is present. The empirical dosage is 15 mg/kg of elemental zinc per day, (or 200 mg elemental zinc per medium sized dog per day, tapered to 50 to 100 mg per dog per day based on serum zinc levels). The goal is for serum zinc levels of 200 to 500 ug/dl (2-5 ug/ml). Zinc should ideally be given on an empty stomach (1 hour before or after a meal); mix with tuna oil if nausea noted.
    I prefer that add zinc in as a single drug after stabilization of the patient with hepatoprotective agents and glucocorticoids (if indicated). Formulations include: Marin™: 45 mg of zinc per tablet (1 to 2 mg/kg of elemental zinc at label dose); zinc gluconate (14.3% zinc) 10 mg, 15 mg, 50 mg, 78 mg tabs; and zinc acetate (35% zinc; no commercial product; can have capsules made from reagent grade zinc acetate). GI upset is common (zinc acetate may cause less GI upset than sulfate or gluconate forms). Hemolysis can occur if serum zinc exceeds 1000 ug/dl.
    Colchicine inhibits microtubule function and decreases collagen synthesis. It may be useful in dogs with chronic hepatitis and moderate to severe fibrosis, or with portal hypertension with ascites. The dosage in dogs is 0.03 mg/kg PO SID (do not use probenicid-containing formulations, which increase the risk of toxicity). Occasional GI upset usually responds to a 50% dose reduction. High dosages can cause leukopenia or peripheral neuropathy.
    D-penicillamine is primarily a copper chelator, but may also inhibit fibrosis by preventing cross-linking of collagen, It is indicated for dogs with a biopsy diagnosis of copperassociated hepatopathy (Bedlingtons, some Westies, Dalmations), with quantitative hepatic copper levels > 3000 ug/gm. The recommended dosage is 15 mg/kg twice daily, 30 minutes prior to feeding. Efficacy may take several months for decoppering of liver and improvements in ALT. Some clinicians treat with D-penicillamine for 2 months, then switch to zinc. GI upset is also common with D-penicillamine.

    Anti-ulcer therapy

    Empirical anti-ulcer therapy is recommended for all acute and chronic liver disease. Liver disease is a common predisposing factor for GI ulceration, due to impaired mucosal blood flow from portal hypertension, decreased hepatic clearance of histamine and active gastrin fragments, and bile acid stimulation of gastric acid secretion. Either H2 blockers or pump blockers can be used, although famotidine (1 mg/kg BID) has minimal drug interactions.

    Management of hepatic encephalopathy

    A check list for acute management of hepatic encephalopathy includes: 1) Lactulose (orally, or by enema if stupor or seizures); 2) NPO for 12 to 24 hours; 3) If no response, add metronidazole orally at 15 mg/kg/day; 4) If no response, add neomycin orally at 20 mg/kg PO three times daily. Provide IV fluids with potassium (and dextrose for patients with portosystemic shunts or severe cirrhosis). Add anti-ulcer therapy (GI bleeding is a protein load in hepatic encephalopathy), and add vitamin K1 if jaundiced. Withhold any glucocortiocids until encephalopathy is resolved! Give as much dietary protein as tolerated; increase the lactulose dosage if needed.

    Management of ascites

    In patients with liver disease and ascites, avoid drugs with mineralocorticoid activity
    (prednisone, prednisolone, hydrocortisone, anabolic steroids). If glucocorticoids are indicated for primary liver disorder in the presence of ascites, substitute dexamethasone.
    Spironolactone/hydrochlorthiazide (Aldactizide) is an excellent diuretic for hepatic ascites. It is more potent than spironolactone alone, but causes less hypokalemia and dehydration than furosemide. The empirical dosage, based on the spironolactone component, is 0.5 -1.0 mg/kg PO twice daily. Furosemide mobilizes fluid well but often leads to hypokalemia and hypovolemia. If used, use only low dosages for short periods, such as 0.5 mg/kg once or twice daily for 2-3 days. Watch for hypokalemia, hypovolemia, and weakness. Furosemide can produce metabolic alkalosis, which exacerbates hepatic encephalopathy.
    Therapeutic abdominocentesis is indicated if significant ascites is refractory to medical management and is impairing mobility or causing respiratory compromise. Supplement with colloids during centesis (e.g. 10 mls/ kg of plasma or Hetastarch) to prevent hypovolemia and worsened hypoalbuminemia as fluid shifts back into the abdomen. Monitor body weight, hydration, and abdominal girth (measure girth at level of L2 with a measuring tape) to document improvement in ascites.

    Assessing response to therapy

    When using prednisone or prednisolone in dogs, you cannot rely on SAP to monitor response, since it is induced by glucocorticoids. SAP is reliable in cats. ALT may also increase with prednisone, but will usually decrease overall as inflammation subsides. Other parameters to monitor include albumin and bilirubin; body weight, body condition score, and abdominal girth (in dogs); and clinical status (appetite, energy, resolution of vomiting and diarrhea, avoidance of severe PU/PD and panting).

    Empirical treatment recommendations for chronic hepatitis in dogs


    Biopsy finding Treatment options
    Neutrophilic inflammation Antimicrobials based on liver or bile culture
    Empirical: Clavamox plus fluoroquinolone
    Lymphoplasmacytic
    inflammation
    Prednisone, prednisolone, or budesonide
    Mild to moderate fibrosis Glucocorticoids (if also lymphoplasmacytic inflammation)
    Zinc if also copper accumulation
    Moderate to severe
    fibrosis
    Colchicine
    Necrosis SAMe
    Milk thistle
    Cholestasis Ursodiol


    Empirical treatment recommendations for cholangitis/cholangiohepatitis in cats

    Biopsy finding Treatment options
    Neutrophilic inflammation Antimicrobials based on liver or bile culture**
    Empirical: Clavamox plus fluoroquinolone
    Lymphoplasmacytic
    inflammation
    Prednisolone or budesonide
    Fibrosis Glucocorticoids (if also lymphoplasmacytic inflammation)
    Ursodiol
    (Colchicine not recommended in cats)
    Necrosis SAMe
    Milk thistle
    Cholestasis Ursodiol

    ** bile cultures strongly recommended in cats



    Pitfalls in Appropriate Antibiotic Use

    Is there good evidence of bacterial infection?
    The first step in empirical antimicrobial therapy is to first critically ask whether there is good evidence of a bacterial infection. Too often, antimicrobials are prescribed on a "just in case" basis or because an owner resists additional diagnostics. There are several very real drawbacks of "just in case" antimicrobials: they add to the cost of the visit or hospitalization, without contributing to a diagnosis; they may lead to diarrhea, inappetance, or vomiting that obscure the underlying problem; they can cause adverse reactions or drug interactions; and importantly, they encourage the selection of resistant bacteria, both globally, in your hospital, and in that patient.

    Fever alone is inadequate criteria for prescribing an antimicrobial. If the probable source of fever cannot be localized during a physical exam, it is not possible to choose an appropriate spectrum of bacterial coverage or decide how long to treat. Physical exam findings that support the use of antibiotics without additional diagnostics are usually straightforward, such as a carnasial tooth root abscess, skin pustules or epidermal collarettes, or a traumatic wound with purulent exudate. Cytology should be performed on all exudates in all areas endemic for Blastomycosis or other fungal infections, prior to considering antibacterials.

    Leukocytosis alone is not a good justification for antimicrobials, since leukocytosis can result from stress, inflammation, glucocorticoid administration, or hyperadrenocorticism. If a left shift and toxic change are present with leukocytosis, then a source of infection or significant inflammation should be pursued. Fever with neutropenia, however, is an established indication for empirical antimicrobials, at least in humans. Meta-analyses of studies in humans suggest that the benefit of antibacterials in neutropenic patients, even prior to fever, outweighs the negative effects of selecting for bacterial resistance. 1 A beta lactam and fluroquinolone combination is recommended in humans, which provides coverage against gut flora to include anaerobes and Enterococcus (beta lactam) and gram negatives (fluoroquinolone).

    Antimicrobials are inappropriate in most cats with lower urinary tract signs. There is a < 5% incidence of positive urine cultures in cats with lower urinary tract disease overall. 2 Clients' money is better spent on a urinalysis and bladder imaging for stones. Cats at higher risk for bacterial urinary tract infections are those with diabetes mellitus (13% prevalence),3 perineal urethrostomies, CRF, or in older cats with dilute urine.2 For these cats, urine culture is a good investment.

    For cats with upper respiratory infections, there are no good studies comparing antimicrobials to placebo. Although Mycoplasma is commonly isolated from pharyngeal swabs, underlying viral infection is typical, and cats have similar recovery rates whether antimicrobials with and without activity against Mycoplasma are used. 4 When active Mycoplasma or Chlamydia infection are documented or suspected, doxycycline remains the drug of choice. Suspension is preferable to capsules to decrease the risk of esophagitis. 5-7

    Diarrheas in dogs and cats are usually not caused by pathogenic bacteria. For example, in dogs with acute diarrhea, the prevalence of Salmonellosis (2%), Campylobacter (5%), and Clostridium difficile toxin (10%) is low. 8 Empirical antimicrobials, such as amoxicillin or fluoroquinolones, are not indicated for acute diarrheas. Fiber and a short-term diet change may be a better choice.

    Finally, pancreatitis is usually sterile in dogs and cats. Antimicrobials are not indicated unless peritonitis, pancreatic abscess, or loss of intestinal mucosal integrity (bloody diarrhea with mucosal sloughing) develops. In humans, antimicrobials in severe (necrotizing) pancreatitis do not reduce the incidence of secondary pancreatic infection or decrease mortality. 9

    Helpful diagnostics in lieu of culture

    Pyuria with bacteria in a urine sediment provides a strong indication for antimicrobials, although bacteriuria can be overdiagnosed. If cocci are frequently diagnosed in your in-house urine sediments, be cautious; stain precipitates can mimic cocci. The majority of urinary pathogens in dogs are gram negative rods. 10 In cats, gram positive and gram negative pathogens occur at approximately the same rate; however, urinary tract infections are much less common in cats overall.

    The finding of intracellular bacteria on cytology is a strong rationale for antimicrobials. A gram stain, which is immediate and cheap, narrows the spectrum to gram positive, gram negative, or mixed. Gram stains are underutilized in companion animal practice. This simple technique is described at:
    http://www.life.umd.edu/classroom/bsci424/LabMaterialsMethods/GramStain.htm.

    Deciding about cultures

    Cultures are not, in the practical sense, necessary for first time empirical treatment of many routine bacterial infections, to include acute contaminated wounds, carnasial tooth abscess, infectious tracheobronchitis, superficial pyoderma, cat bite abscess, or first time bacterial cystitis in an adult dog.

    Cultures are very important for any second line antimicrobial treatment, to include lack of response to empirical treatment, relapse after treatment discontinuation, or waxing and waning signs. Examples of this include suspected bacterial bronchopneumonia, urinary tract infections, or non-responding pyoderma. Avoid antibiotic roulette in these cases! With recurrent urinary tract infections, serial cultures can be very helpful. Repeated culture of the same organism suggests inadequate clearance (e.g. poor compliance, uroliths, pyelonephritis, or accompanying prostatitis with inadequate drug penetration). Repeated culture of different organism suggests new (usually ascending) infection (e.g. an anatomic defect such as an ectopic ureter or urethral incompetence, vulvar fold pyoderma, or poor perineal hygiene in debilitated or obese animals).

    Cultures and cytology are also important for first time treatment of long-standing infections, such as fistulous tracts, possible chronic foreign bodies, or non-healing wounds, as well as for serious or life-threatening infections, such as pyothorax, suspected endocarditis, osteomyelitis, joint sepsis, renal failure with suspected pyelonephritis, or suspected sepsis. Cultures are also recommended for suspected hospital-acquired infections (those developing > 72 hours after admission), since nosocomial bacteria may have multi-drug resistance patterns, 11 and hospitalized patients may be more susceptible to sepsis because of IV lines, urinary catheters,12 invasive procedures, and immunocompromise.

    Practical culture techniques

    For aerobic culture, our microbiologist at UW-Madison (Faye Hartmann) recommends BBL CultureSwab Plus (Amies gel formulation without charcoal; available from Fisher Scientific). This system is not ideal for anaerobes in our hands (despite the label). Urine is ideally set up for culture within 15 to 30 minutes of collection, but this is impractical in many settings. Alternatively, a sterile syringe containing urine can be capped and refrigerated immediately, for up to 12 hours prior to culture. While some fastidious bacteria may not survive storage > one hour, this approach is adequate in most situations, and also allows quantitative culture by the laboratory. Fluids for culture should not be placed in heparin or EDTA.

    For anaerobic (along with aerobic) cultures, which are recommended for bile, body fluid, and pus, transport media should be used. A.C.T. II agar tubes (Remel) contain a nonnutritive semisolid medium to which you can add fluid, or, if using swabs, insert one swab each for aerobic and anaerobic culture. Organisms should be stable for 24 hours for both aerobic and anaerobic culture set up. Mycoplasma cultures, which are recommended for tracheal wash samples, 13 can be run from either BBL CultureSwab Plus (without charcoal) or A.C.T. II agar tubes.

    If your available laboratory does not provide cultures at an affordable price or with a useful turnaround time, talk to the laboratory manager about your concerns. In-house cultures are also an option, and may not require an incubator. One author recommends inoculation of blood agar and McConkey plates with a sterile calibrated loop or pipette, followed by incubation eleven cm under a 60W bulb for 24 hours. 14 Positive plates are submitted for identification and susceptibility, while negative plates are discarded. This can reduce costs to the client and make cultures an affordable habit in your practice.

    Empirical first line regimens

    There are several principles to follow when using empirical antimicrobials. First, use the narrowest spectrum drug for the suspected organism. For example, choose amoxicillin or penicillin, instead of amoxicillin-clavulanate, for a cat abscess, and doxycycline, rather than a fluoroquinolone, for suspected Bordetella infectious tracheobronchitis. 15 Fluoroquinolones are over-used as first line antimicrobials in both human and veterinary medicine. Common reasons for misuse in humans include the wrong disease indication and the availability of narrower spectrum first line agents. 16

    Second, consider tissue penetration. It should be assumed that urinary tract infections in male dogs involve the prostate, and antimicrobials with good prostatic penetration, such as fluoroquinolones,17 doxycycline, chloramphenicol, or potentiated sulfonamides, should be chosen. For bronchitis without pneumonia, drugs that achieve high concentrations in bronchial secretions should be prescribed, to include fluoroquinolones, doxycycline, azithromycin, or potentiated sulfonamides. For endophthalmitis or ocular trauma, azithromycin and fluoroquinolones show excellent ocular penetration. Beta lactams and aminoglycosides, which are relatively polar, have poor penetration into the prostate, eye, testes, or bronchial secretions.

    Finally, treat for the shortest effective period possible. Shorter courses of appropriate antibiotics decrease the emergence of resistant organisms in humans, and there is a trend towards the use of shorter courses of antimicrobials, with equivalent efficacy compared to longer regimens, in human patients. 18 For example, acute sinusitis,19 pneumonia,20 or uncomplicated urinary tract infections 21 are treated effectively with only a 3 to 7-day course of antibiotics in humans. Bacterial otitis in children can be treated with a single dose of azithromycin (as effective as multiple dosing over 7 days), and for community-acquired pneumonia, treatment regimens are tailored to patient response, and are continued for only 2 to 3 days beyond resolution of fever.18 In veterinary medicine, the recommended duration of treatment for many infections is entirely empirical, and there has been little work to determine whether the longer courses that are recommended in textbooks are actually necessary. Consider using these shorter regimens, with a follow-up recheck and culture one week after discontinuation. Shorter treatment regimens are less expensive for clients (allowing more resources for diagnostics and follow-up), and are associated with better compliance. Most importantly, shorter courses of antimicrobials lead to significantly less bacterial resistance. 18

    Common isolates from bacterial infections in dogs


    Indication Most common organisms Empirical antimicrobial
    Bacterial cystitis E. coli (51%) 10 Amoxicillin/clavulanate (female)
    Fluoroquinolone (male)
    Endocarditis* Gram positives (51%; esp. Strep canis)22
    Gram negatives (22%)
    Bartonella (20%)
    Cephalexin plus
    fluoroquinolone, awaiting
    culture and serologies
    Hepatobiliary 72% negative cultures (bile)
    E. coli, gram positives, anaerobes 23
    Amoxicillin/clavulanate plus
    fluoroquinolone
    Joint sepsis* Staph. sp. 24,25 Cephalexin
    Osteomyelitis* Staph. and Strep 26 Cephalexin
    Pneumonia Young dogs: Bordetella, other gram
    negatives 27
    Doxycycline (apparently low
    risk of enamel discoloration vs.
    tetracycline)
    Prostatitis E. coli Fluoroquinolone
    Pyometra E. coli 28 Fluoroquinolone
    Superficial pyoderma Staph intermedius Cephalexin

    (* Cultures strongly recommended at first presentation)

    Common isolates from bacterial infections in cats

    Abscess Pasteurella, anaerobes 29 Amoxicillin (95% efficacy)29
    Hepatobiliary 64% negative cultures (bile)23
    Mixed gram positives, negatives, and
    anaerobes
    Amoxicillin/clavulanate plus
    fluoroquinolone
    Pyelonephritis* E.coli, Enterococcus 30 Base on urine sediment
    Pyothorax* Anaerobes, Pasteurella 31 Penicillin (awaiting culture)

    (* Cultures strongly recommended at first presentation)

    Typically effective antimicrobials for different microorganisms

    Gram positive aerobes
    Commonly effective

    Penicillin
    Amoxicillin, ampicillin
    Clindamycin (except Enterococcus)
    Cephalexin (except Enterococcus)
    Chloramphenicol

    Typically ineffective

    Metronidazole
    Beta-lactamase producing gram positive aerobes
    Commonly effective

    Amoxicillin/clavulanate
    Cephalexin
    Clindamycin
    Fluoroquinolones (Staph > Strep)
    Potentiated sulfonamides

    Typically ineffective

    Penicillin
    Amoxicillin, ampicillin
    Metronidazole
    Gram negative aerobes
    Commonly effective

    Fluoroquinolones
    Aminoglycosides
    Amoxicillin/clavulanate (57% E. coli sensitivity)32
    Cephalexin
    Chloramphenicol
    Potentiated sulfonamides

    Typically ineffective

    Clindamycin
    Azithromycin
    Metronidazole
    Anaerobes
    Commonly effective

    Metronidazole
    Amoxicillin/clavulanate
    Penicillin
    Clindamycin
    Azithromycin
    Chloramphenicol
    (Penicillin, if not beta lactamase producing)

    Typically ineffective

    Fluoroquinolones
    Aminoglycosides
    Cephalexin
    Spirochetes, rickettsiae, protozoa
    Borrelia

    Doxycycline
    Pencillin, ampicillin, amoxicillin
    Azithromycin
    Fluroquinolones (but MIC90 > 2 ?g/ml for cipro)33

    Leptospira

    Doxycycline
    Pencillin, ampicillin, amoxicillin
    Fluoroquinolones
    Chloramphenicol (higher MICs than for others)

    Rickettsiae

    Doxycycline
    Chloramphenicol (inferior to doxycyline in
    humans)34
    Fluoroquinolones (RMSF and Anaplasma, not E.
    canis) 35

    Toxoplasma

    Clindamycin
    Azithromycin
    Other organisms
    Mycoplasma,

    Doxycycline
    Chloramphenicol
    Clindamycin
    Fluoroquinolones

    Chlamydia

    Doxycycline
    Amoxicillin/clavulanate
    Azithromycin (does not eliminate Chlamydia carrier) 36

    Bordetella

    Doxycycline
    Chloramphenicol

    Bartonella

    Doxycycline
    Azithromycin
    Fluoroquinolones

    Initial concept for table courtesy of Dr. Jill Maddison, Royal Veterinary College, University of London

    References
    1. Paul M, Leibovici L. Systematic reviews and meta-analysis of febrile neutropenia. Mayo Clin Proc 2005;80:1122-1125.
    2. Bailiff NL, Westropp JL, Nelson RW, et al. Evaluation of urine specific gravity and urine sediment as risk factors for urinary tract infections in cats. Vet Clin Pathol 2008;37:317-322.
    3. Bailiff NL, Nelson RW, Feldman EC, et al. Frequency and risk factors for urinary tract infection in cats with diabetes mellitus. J Vet Intern Med 2006;20:850-855.
    4. Ruch-Gallie RA, Veir JK, Spindel ME, et al. Efficacy of amoxycillin and azithromycin for the empirical treatment of shelter cats with suspected bacterial upper respiratory infections. J Feline Med Surg 2008;10:542-550.
    5. German AJ, Cannon MJ, Dye C, et al. Oesophageal strictures in cats associated with doxycycline therapy. J Feline Med Surg 2005;7:33-41.
    6. McGrotty YL, Knottenbelt CM. Oesophageal stricture in a cat due to oral administration of tetracyclines. J Small Anim Pract 2002;43:221-223.
    7. Trumble C. Oesophageal stricture in cats associated with use of the hyclate (hydrochloride) salt of doxycycline. J Feline Med Surg 2005;7:241-242.
    8. Chase HP, Beck R, Tamborlane W, et al. A randomized multicenter trial comparing the GlucoWatch Biographer with standard glucose monitoring in children with type 1 diabetes. Diabetes Care 2005;28:1101-1106.
    9. Hart PA, Bechtold ML, Marshall JB, et al. Prophylactic antibiotics in necrotizing pancreatitis: a metaanalysis. South Med J 2008;101:1126-1131.
    10. Ball KR, Rubin JE, Chirino-Trejo M, et al. Antimicrobial resistance and prevalence of canine uropathogens at the Western College of Veterinary Medicine Veterinary Teaching Hospital, 2002-2007. Can Vet J 2008;49:985-990.
    11. Ogeer-Gyles J, Mathews K, Boerlin P. Nosocomial infections and antimicrobial resistance in critical care medicine. J Vet Emerg Crit Care 2006;16:1-18.
    12. Ogeer-Gyles J, Mathews K, Weese JS, et al. Evaluation of catheter-associated urinary tract infections and multi-drug-resistant Escherichia coli isolates from the urine of dogs with indwelling urinary catheters. J Am Vet Med Assoc 2006;229:1584-1590.
    13. Chandler JC, Lappin MR. Mycoplasmal respiratory infections in small animals: 17 cases (1988-1999). J Am Anim Hosp Assoc 2002;38:111-119.
    14. Bartges JW. Diagnosis of urinary tract infections. Vet Clin North Am Small Anim Pract 2004;34:923-933, vi.
    15. Speakman AJ, Dawson S, Corkill JE, et al. Antibiotic susceptibility of canine Bordetella bronchiseptica isolates. Vet Microbiol 2000;71:193-200.
    16. Mean M, Pavese P, Vittoz JP, et al. Prospective assessment of fluoroquinolone use in a teaching hospital. Eur J Clin Microbiol Infect Dis 2006;25:757-763.
    17. Dorfman M, Barsanti J, Budsberg SC. Enrofloxacin concentrations in dogs with normal prostate and dogs with chronic bacterial prostatitis. Am J Vet Res 1995;56:386-390.
    18. Niederman MS. Principles of appropriate antibiotic use. Int J Antimicrob Agents 2005;26 Suppl 3:S170-175.
    19. Falagas ME, Karageorgopoulos DE, Grammatikos AP, et al. Effectiveness and safety of short vs. Long duration of antibiotic therapy for acute bacterial sinusitis: a meta-analysis of randomized trials. Br J Clin Pharmacol 2008.
    20. Dimopoulos G, Matthaiou DK, Karageorgopoulos DE, et al. Short- versus long-course antibacterial therapy for community-acquired pneumonia: a meta-analysis. Drugs 2008;68:1841-1854.
    21. Lutters M, Vogt-Ferrier NB. Antibiotic duration for treating uncomplicated, symptomatic lower urinary tract infections in elderly women. Cochrane Database Syst Rev 2008:CD001535.
    22. Sykes JE, Kittleson MD, Pesavento PA, et al. Evaluation of the relationship between causative organisms and clinical characteristics of infective endocarditis in dogs: 71 cases (1992-2005). J Am Vet Med Assoc 2006;228:1723-1734.
    23. Wagner K, Hartmann F, Trepanier L. Bacterial culture results from liver, gall bladder, or bile in 248 dogs and cats evaluated for hepatobiliary disease. J Vet Intern Med 2007;21:417-424.
    24. Clements DN, Owen MR, Mosley JR, et al. Retrospective study of bacterial infective arthritis in 31 dogs. J Small Anim Pract 2005;46:171-176.
    25. Marchevsky AM, Read RA. Bacterial septic arthritis in 19 dogs. Aust Vet J 1999;77:233-237.
    26. Caywood DD, Wallace LJ, Braden TD. Osteomyelitis in the dog: a review of 67 cases. J Am Vet Med Assoc 1978;172:943-946.
    27. Radhakrishnan A, Drobatz KJ, Culp WT, et al. Community-acquired infectious pneumonia in puppies: 65 cases (1993-2002). J Am Vet Med Assoc 2007;230:1493-1497.
    28. Hagman R, Greko C. Antimicrobial resistance in Escherichia coli isolated from bitches with pyometra and from urine samples from other dogs. Vet Rec 2005;157:193-196.
    29. Roy J, Messier S, Labrecque O, et al. Clinical and in vitro efficacy of amoxicillin against bacteria associated with feline skin wounds and abscesses. Can Vet J 2007;48:607-611.
    30. Litster A, Moss S, Platell J, et al. Occult bacterial lower urinary tract infections in cats-Urinalysis and culture findings. Vet Microbiol 2008.
    31. Walker AL, Jang SS, Hirsh DC. Bacteria associated with pyothorax of dogs and cats: 98 cases (1989-1998). J Am Vet Med Assoc 2000;216:359-363.
    32. Oluoch AO, Kim CH, Weisiger RM, et al. Nonenteric Escherichia coli isolates from dogs: 674 cases (1990-1998). J Am Vet Med Assoc 2001;218:381-384.
    33. Kraiczy P, Weigand J, Wichelhaus TA, et al. In vitro activities of fluoroquinolones against the spirochete Borrelia burgdorferi. Antimicrob Agents Chemother 2001;45:2486-2494.
    34. Buckingham SC. Tick-borne infections in children: epidemiology, clinical manifestations, and optimal management strategies. Paediatr Drugs 2005;7:163-176.
    35. Branger S, Rolain JM, Raoult D. Evaluation of antibiotic susceptibilities of Ehrlichia canis, Ehrlichia chaffeensis, and Anaplasma phagocytophilum by real-time PCR. Antimicrob Agents Chemother 2004;48:4822-4828.
    36. Owen WM, Sturgess CP, Harbour DA, et al. Efficacy of azithromycin for the treatment of feline chlamydophilosis. J Feline Med Surg 2003;5:305-311.


    Therapeutic options for inflammatory bowel disease

    I. Defining inflammatory bowel disease (IBD)

    A. Criteria for diagnosis (WSAVA GI Standardization group, 2005)
    1. www.wsava.org/StandardizationGroup.htm
    2. GI signs > 3 weeks in duration (vomiting, diarrhea, weight loss)
    3. Incomplete response to diet trials and deworming
    4. Histologic lesions of mucosal inflammation
    5. Response to immunomodulatory therapies
    B. Underlying pathogenesis
    1. Likely a disturbance in GI mucosal immunity with loss of mucosal tolerance to intestinal antigens (commensal bacterial, dietary components)
      1. Consistent with this:
        1. Upregulation of MHC class II molecules found in enterocytes of IBD cats (Waly 2004)
        2. These allow presentation of foreign antigen to the immune system by enterocytes
    2. Bacterial adherent to intestinal mucus in affected cats correlate with: (Janeczko, 2008)
      1. Abnormal duodenal architecture on histopathology
      2. Macrophage and T lymphocyte infiltrates
      3. Upregulation of inflammatory cytokines
        1. Especially IL-8
      4. Number of clinical signs
    II. Getting a definitive diagnosis

    A. Mucosal biopsies
    1. Endoscopic gastric and duodenal biopsies
    2. May miss a diagnosis of lymphoma in cats
      1. Missed in 4 out of 10 cats (Evans 2006), especially cats with intestinal but not gastric lymphoma involvement
    3. Cannot reach consistently ileocecocolic junction, common site of lymphoma
    4. Use WSAVA standardization group forms to record biopsy findings at endoscopy (www.wsava.org/StandardizationGroup.htm
    B. Full thickness biopsies
    1. By laparotomy or laparoscopy
    2. Ask your pathologist to follow the WSAVA standardization group guidelines for IBD histopathoogy
      1. Day et al. J Comp Pathol 2008 138 Suppl 1: S1-S43.
    3. Histopathology should describe degree of:
      1. Crypt distortion
      2. Villous blunting and fusion
      3. Fibrosis
    III. Treating without a biopsy

    A. Abdominal palpation and abdominal ultrasound
    1. Thickened intestines and mesenteric lymphadenopathy cannot distinguish between more severe IBD and lymphoma
    2. Loss of normal intestinal wall layering suggests severe infiltrative IBD or lymphoma
      1. Gastric lymphoma may have normal ultrasonographic appearance
    3. Intestinal adenocarcinoma has ultrasonographic appearance of mixed echogenicity, segmental, intestinal wall thickening (Rivers 1997)
    B. Long duration of signs (> one year) does not rule out GI lymphoma

    C. If treating without a biopsy, make sure that owner would not pursue chemotherapy for lymphoma, if present

    IV. Treatment options

    A. Diet
    1. Novel protein diets
      1. Most commercial elimination diets are also milk-, corn-, and wheatfree
        1. Highly digestible, moderate soluble fiber
      2. Efficacy of novel protein diets
        1. Up to 50% of referred cats with idiopathic GI signs will respond to an elimination diet trial (e.g. venison and rice; Guilford 2001)
          1. Improvement within 2 to 3 days
          2. Some of these cats relapsed after re-challenge with original diet, within 3 to 4 days, and some stayed in remission despite re-challenge for a week
        2. 60% of referred dogs with idiopathic GI signs will respond to an elimination diet trial (e.g. salmon and rice; Luckschander 2006)
          1. Improvement within one week
          2. Improved canine IBD activity index (CIBDAI)
      3. Predictors of response
        1. Concurrent skin and GI signs may increase likelihood of response to diet elimination
        2. Eosinophilia is unreliable
        3. About half of diet responders had "IBD" changes on duodenal biopsy, and about half did not
        4. Serum IgE screens for dietary allergens not predictive of response to elimination diets (Guilford 2001)
          1. False positives and false negatives common
          2. Not thought to be IgE-mediated in most dogs and cats
    2. Hydrolyzed protein diets
      1. Goal is decreased antigenicity of dietary protein
      2. Examples
        1. z/d (Hill's)
        2. Royal canin feline hypoallergenic diet
      3. Consider in patients with lack of response to elimination diets, or for use during initial glucocorticoid induction
      4. Diarrhea, lack of palatability are problems
      5. No efficacy studies
    B. Immunosuppressive agents
    1. Prednisone/prednisolone
      1. Indications:
        1. Histologic evidence of moderate to severe lymphoplasmacytic or eosinophilic infiltrates with clinical signs
        2. Dosing
          1. Use anti-inflammatory to immunosuppressive dosages (1-3 mg/kg/day) initially
          2. If in remission, gradually (q. 2-4 weeks) taper to lowest dose that controls signs
        3. Always accompany with novel protein, highly digestible diet
        4. Consider / rule out lymphoma first!
    2. Budesonide
      1. Glucocortioid with high hepatic clearance (therefore, low systemic blood levels)
      2. Fewer systemic side effects than other oral glucocorticoids
      3. Anecdotal reports of efficacy for inflammatory bowel disease in cats
      4. 3 mg enteric coated gelcaps.
        1. 0.5 to 0.75 mg capsule (reformulated) per cat
        2. 0.5 to 2.0 mg (reformulated) per dog to start
      5. May still cause systemic side effects of glucocorticoids, but may be less so than oral prednisone or prednisolone
    3. Dexamethasone
      1. Allows SC glucocorticoid administration in patients with severe malabsorption
      2. Can be used to induce remission and allow transition to oral prednisolone or budesonide
      3. Give 1/7 of prednisolone dose when using dexamethasone, to account for increased potency of dexamethasone
    4. Cyclosporine
      1. Inhibitor of T cell function
        1. Inhibits IL-2 production by T cells
      2. Immunosuppressive agent; may deplete T cells in inflammatory diseases
      3. Efficacious in dogs with IBD refractory to glucocorticoids (12 out of 14 dogs; Allenspach 2006)
        1. Decreased clinical disease activity
        2. Decreased T cells in duodenal biopsies
      4. Dosage: 5 mg/kg once or twice daily
      5. Side effects:
        1. Vomiting, inappetance
          1. Dose dependent
        2. Gingival lesions (reported in dogs)
        3. Secondary fungal infections
          1. Observed anecdotally in dogs given both glucocorticoids and cyclosporine
          2. Important to minimize dosages of both
    5. Chlorambucil
      1. Alkylating agent
        1. Cross-links DNA
        2. Less potent than cyclophosphamide
      2. Efficacy, with prednisone, for small cell GI lymphoma in cats (Kiselow 2008)
        1. Option for IBD refractory to diet and glucocorticoids, or for severe lymphoplasmacytic IBD that is difficult to differentiate from low grade lymphoma
      3. Dosing
        1. 2 mg per cat, every 48 to 72 hours
        2. Taper to lowest effective dose and interval
      4. Side effects
        1. Leukopenia at higher dosages
        2. No risk of hemorrhagic cystitis
        3. Myoclonus (reversible) reported in one cat with dosing interval error (Benitah 2003)
    C. Probiotics and prebiotics
    1. Probiotics
      1. Defined as live microorganisms that lead to a beneficial microbe balance in the intestinal tract, with positive effects on overall health
      2. Non-pathogenic organisms
        1. Resistant to gastric acid and bile
        2. Adhere to the intestinal mucosa
        3. Ideally originated from species to be treated
      3. Examples
        1. Lactobacillus spp.
        2. Enterococcus faecium
        3. Bifidobacterium spp.
        4. Saccharomyces
        5. Effects are strain- and dose-specific
      4. Potential benefits
        1. Modulation of gut flora
        2. Inhibition of colonization by pathogenic bacteria
        3. Inhibition of bacterial translocation
      5. Mechanisms of action
        1. Decreased intestinal lumen pH (lactic and butyric acid formation)
          1. May inhibit pathogenic anaerobes
        2. Butyrate may also have anti-inflammatory effects
          1. Inhibits NF-?B translocation and pro-inflammatory inflammatory cytokine expression (Segain 2000)
        3. Production of bacteriocins
          1. Peptides that kill other bacterial populations
        4. Enhanced mucosal barrier function
      6. Clinical evidence for probiotic efficacy
        1. In humans
          1. Decreased incidence of antibiotic-induced diarrhea
          2. Some efficacy for maintenance of remission in ulcerative colitis (Hedin 2007)
        2. Evidence in dogs
          1. Decreased fecal Clostridial counts in healthy dogs given Enterococcus faecium probiotic (Enteroferm) (Vhjan 2003) or Lactobacillus (Baillon 2004; Biagi 2007)
          2. Increased expression of duodenal IL-10 in canine biopsy samples exposed to Lactobacillus ex vivo (Sauter 2005)
          3. No advantage of probiotic cocktail over limited antigen diet alone in 21 dogs with IBD (Sauter 2006)
        3. Evidence in cats
          1. Decreased Clostridial counts and plasma endotoxin concentrations in healthy cats given Lacotbacillus acidophilus (DSM12341, Waltham) (Marshall-Jones, 2006)
      7. Products
        1. Proviable™ (Nutramax)
        2. Fortiflora™ (Purina)
        3. Many other marketed veterinary probiotics have been shown not to contain viable organisms as labeled (e.g. Nutrigest) or to have no label claims and low viable counts as tested (Probiotic paste from Pet Perfection, Pediatric Health tabs from Pet Perfection, Fel-Addase, Can-Addase) (Weese 2002)
    2. Prebiotics
      1. Non-digestible food ingredient that promotes growth of certain populations of bacteria in the gut
        1. Usually selectively fermentable short chain carbohydrates
      2. Examples
        1. Soluble fiber
          1. Beet pulp, psyllium
          2. Fermented to butyrate (short chain fatty acid)
            1. Nutrient for colonocytes
            2. Decreased pro-inflammatory cytokines
        2. Fructo-oligosaccharides
        3. Lactulose
      3. Efficacy
        1. No overall changes in duodenal bacterial flora in healthy cats supplemented with fructo-oligosaccharides for 32 weeks (Sparkes 1998)
    3. Veterinary prebiotic and probiotic products
      1. Purina Fortiflora
        1. Encapsulated Enterococcus faceium (strain SF68)
        2. Decreased fecal concentrations of Clostridium perfringens in treated kittens
        3. Decreased incidence of outbreak diarrhea in treated kittens
      2. Nutramax Proviable ?
        1. Cocktail of Enterococcus, Streptococcus, Lactobacillus, and Bifidobacterium, plus prebiotics
        2. Encapsulated
    D. Adjunct therapies
    1. Cobalamin
      1. Low serum cobalamin common in patients with chronic small intestinal diarrhea, particularly cats
        1. Especially catswith low body condition score (Reed 2007)
        2. Low cobalamin impairs normal enterocyte function
      2. Causes
        1. Ileal malabsorption
        2. Pancreatitis
          1. Impaired release of pancreatic intrinsic factor, necessary for cobalamin absorption
          2. Impaired secretion of bicarbonate into the duodenum
            1. Neutralization of gastric acid in duodenum necessary for cobalamin binding to intrinsic factor
      3. Associated abnormalities
        1. Hypocobalaminemia associated with low serum folate and low serum phosphorous levels in cats (Reed 2007)
        2. Macrocytosis is not a reliable marker of low cobalamin in cats, but has been reported (Simpson 2001)
      4. Treatment
        1. Cobalamin (B12) 250 ug SC weekly
        2. Treatment associated with weight gain, increased appetite, and diminished vomiting in affected cats (Ruaux 2005)
        3. Circulating cobalamin half-life of approximately 5 days in treated sick cats (Simpson 2001)
    2. Metronidazole
      1. Anecdotal efficacy for mild IBD or as adjunct to glucococorticoids
      2. Response may be related to finding of Clostridium spp. in duodenal epithelia of cats with IBD (Janeczko 2008)
      3. No real effect on immune function in vitro at therapeutic concentrations (Anderson 1979)
      4. Dosing
        1. 15 mg/kg per day
      5. Side effects
        1. Unpalatable, anorexia
        2. Neurologic toxicity at high dosages in both dogs and cats
          1. > 55 mg/kg/day
    3. Omega-3 polyunsaturated fatty acid (PUFA) supplementation
      1. Decreased generation of leukotrienes such as LTB4, a potent neutrophil chemotactant and pro-inflammatory molecule
      2. Effective in maintaining remission in people with Crohn's disease in some studies (Belluzzi 1996), although not supported by metaanalyses (Feagan 2008)
      3. Dosing
        1. Very empirical
          1. Eicosapentanoic acid 22 mg/kg/day (recommended for dogs with atopy)
          2. Dietary omega-6 : omega-3 PUFA ratio of 5:1 (recommended for dogs with chronic renal disease)
        2. Add as single agent and titrate dose
      4. Side effects
        1. Unpalatable
        2. Diarrhea common
    E. IBD treatment failures
    1. Dietary compliance?
      1. Need to individualize diet
      2. May need to try several diets in series
      3. One to two week trials adequate based on response data in cats with IBD (Guilford, 2001)
    2. Is the dosage of prednisone / prednisolone adequate?
    3. Is the prednisone / prednisolone being absorbed?
      1. Consider SC dexamethasone to induce remission in severe malabsorption cases
    4. Is there accompanying disease?
      1. Cobalamin deficiency
      2. Occult parasites or bacterial overgrowth
      3. Undiagnosed GI lymphosarcoma
      4. Pancreatitis
      5. Chronic hepatitis or cholangiohepatitis
      6. Diabetes
        1. May emerge during glucocorticoid therapy
        2. Have owners check for glucosuria periodically
          1. Purina Gluco-test strips in litter for cats every 2 weeks


    Update on Transdermal Drugs: What Do We Know?

    The transdermal delivery of drugs to the systemic circulation has been in use in humans for more than 25 years. Transdermal nitroglycerin and scopolamine were first developed to bypass the problems of variable bioavailability, short duration of action, and peak side effects seen after oral administration. Since then, a large number of drugs have been developed for transdermal administration in humans. Although nitroglycerin ointment has been in use for veterinary patients for decades, only recently have veterinary transdermal formulations been available for a wide variety of drugs through custom compounding pharmacies. For the vast majority of these formulations, however, absorption and efficacy data is absent, and the clinician should keep a clear view of the pros and cons of transdermal delivery when considering this route of administration.

    I. Transdermal vs. topical

    A. Transdermal: goal is therapeutic drug concentrations in the systemic circulation

    B. Topical: goal is local therapeutic drug concentrations in surface organs (skin, eye, ear canal)

    II. Potential advantages and disadvantages of the transdermal route


    Feature of transdermals Potential advantage Potential disadvantage
    Do not require "pilling" or injections May be better accepted by many cats Some cats resent sensation of gel or patch
    No direct gastric or intestinal contact Decreased direct G.I. irritation Inappropriate route for drugs acting locally in the GI tract
    Avoid first pass oral biotransformation by the gut and liver May avoid variable absorption seen with the oral route May be inappropriate for prodrugs dependent on biotransformation for efficacy
    Absorbed slowly from depot formed in skin May provide longer duration of action May never reach therapeutic plasma concentrations
    Avoid high peak plasma concentrations May decrease acute dosedependent side effects Lack of immediate effect for most drugs needed in an emergency setting
    Require custom formulation Concentration can be tailored to patient's size Often more expensive than commercially available formulations; stability data often unavailable


    III. Transdermal formulations

    A. Mechanisms of permeation enhancers
    1. Change in lipid fluidity in the stratum corneum
    2. Solubilization of lipids between corneocytes
    3. Generation of pores on the surface of corneocytes
    4. Actual exfoliation of the stratum corneum
    B. Commonly used permeation enhancers
    1. PLO (Pluronic lecithin organogel)
      1. Pluronic F127
        1. Polymeric surfactant
        2. Enhances drug micelle formation
          1. Shown to enhance the skin permeation of many drugs in vitro and in vivo.
      2. Lecithin
        1. Increases fluidity of stratum corneum
        2. Leads to exfoliation of stratum corneum and low grade inflammation with chronic use
      3. PLO separates at cold temperatures
        1. Do not refrigerate
        2. Do not send through mail during cold months
    2. Lipoderm
      1. Proprietary formula (PCCA) containing lecithin
      2. Less greasy than PLO
      3. Can be refrigerated
    3. VanPen
      1. Proprietary formula (PCCA) used for more lipophilic drugs
    C. Other permeation enhancers
    1. Oleic acid, propylene glycol, ethanol, and glycol ethers
      1. Many good permeation enhancers are also irritating
      2. Lower-dose combinations of enhancers have been used to decrease irritation from any single agent
    2. Glycol ether/isopropanol
      1. Used in Revolution® for transdermal absorption of selamectin
    3. DMSO
      1. Not recommended
      2. Local irritation, odor
      3. Inadvertent absorption of skin contaminants
    D. Patches
    1. Matrix-type patches
      1. Contain high concentrations of drug in a matrix or solvent, with one or more permeation enhancers
      2. Rely on skin permeability to regulate drug delivery
    2. Reservoir-type patches
      1. e.g. Duragesic® fentanyl patch
      2. Additional semi-permeable membrane that controls the rate of drug delivery
    IV. What formulations work for humans?

    A. Ideal transdermal drug candidates
    1. Small compounds (i.e. molecular weight less than 500 g/mole)
    2. Low melting point
    3. Low polarity
    4. Relatively high lipophilicity
    B. Total daily dosages less than 50 mg per day (for 70 kg. person)
    1. Existing patches limited in size to 50 cm2 (less than 3 inches square)
    2. Stratum corneum barrier limits transdermal delivery to about 1 mg per cm2 of skin surface area
    3. Commercially available human transdermals:
      1. Fentanyl patch
      2. Contraceptives
      3. Hormone replacement therapy
      4. Nicotine
      5. Oxybutynin, clonidine, and testosterone.
    V. Absorption and efficacy of transdermal veterinary drugs

    A. Nitroglycerin ointment
    1. Effective venodilator to reduce preload in acute heart failure
    2. Absorbed transdermally
      1. Small molecule
      2. Local venodilation, increased blood flow
    B. Fentanyl patch
    1. Well established method of post-operative pain relief in dogs and cats
      1. Spay, declawing, orthopedic procedures
      2. Less sedation or hypothermia compared to injectable narcotics
    2. 25, 50, 75, 100 ug/hr sized patches
    3. Applied to shaved skin that is cleaned with warm water and alcohol, and dried thoroughly before application
    4. Dose: 3-5 ug/kg/hr
      1. For cats smaller than 4 kg, consider exposure of only half of a 25 ug/hr patch (Do not cut patch!) (Davidson, 2004)
    5. Drawbacks of fentanyl patch:
      1. Variable absorption
      2. Must be applied prior to need for analgesia
        1. Cats
          1. In cats, apply 12 hours prior to surgery
          2. Analgesic concentrations sustained for 3-5 days
        2. Dogs
          1. Apply 18-24 hours prior to surgery
          2. Analgesic concentrations sustained for 1-3 days
          3. Hypothermia decreases absorbed fentanyl concentrations (e.g. under anesthesia)
          4. Heating pad in contact with patch can lead to exaggerated fentanyl absorption
    C. Single dose pharmacokinetic studies
    1. Fluoxetine
      1. Fluoxetine (15% in PLO, = 150 mg/ml) is only 10% bioavailable relative to oral fluoxetine (Ciribasssi, 2003)
      2. Roughly comparable AUC values for fluoxetine and its active metabolite, norfluoxetine, can be obtained by dosing transdermal fluoxetine at 10 mg/kg (compared to the 1 mg/kg oral dose)
      3. Slower absorption and lower peak serum concentrations with the transdermal route
      4. Skin irritation with repeated doses
    2. Fentanyl and morphine in PLO
      1. Essentially undetectable (below limit of quantitation) serum levels after single transdermal doses of 0.88 mg/kg of transdermal fentanyl (almost 90 times the IV dose) and 2 mg/kg of transdermal morphine (almost 7 times the IV dose) (Krotscheck, 2004)
    3. Dexamethasone
      1. No significant absorption after single transdermal dose in PLO (0.05 mg/kg) (Willis-Goulet, 2003)
      2. Multiple dose studies needed
    4. Buspirone, amitriptyline in cats
      1. Poor transdermal absorption after single transdermal doses (Mealey, 2004)
      2. Multiple dose studies needed
    5. Diltiazem
      1. Poor transdermal absorption after a single dose of 7.5 mg per cat (DeFrancesco, ACVIM, 2003)
      2. Bioavailability 10% that of IV diltiazem
      3. Diltiazem is stable in Lipoderm for 60 days at 100 mg/ml (Burr 2005)
    D. Multiple dose studies
    1. Methimazole
      1. Poor absorption after a single dose, but….
      2. Effective in lowering serum T4 with chronic administration in hyperthyroid cats
        1. Methimazole in PLO, no DMSO; 50 mg/ml (5 mg per 0.1 cc)
        2. 2.5 mg q. 12 h. to inner pinna
        3. Owners wear exam gloves or finger cots
        4. Alternate ears with each dose
        5. Remove crusted material before next dose
      3. Fewer GI side effects (4% of cats) compared to oral (24%) methimazole (Sartor, 2004)
      4. No difference in incidence of facial excoriation, neutropenia,, thrombocytopenia, or hepatotoxicity
      5. Somewhat lower efficacy (67% euthyroid by 4 weeks) compared to oral methimazole (82% euthyroid by 4 weeks)
      6. Drawbacks of methimazole in PLO
        1. Erythema at dosing site in some cats
        2. Increased cost due to formulation
        3. Stability guaranteed for only 2 weeks
    2. Atenolol
      1. 6.25 mg transdermally BID for one week in propylene glycol/glycerin/Tween
      2. Lead to therapeutic concentrations in 2 out of 7 cats (MacGregor 2008)
      3. Heart rate did decreased overall in cats treated transdermally
      4. Transdermal dose needs to be optimized, but drug was absorbed
    3. Amlodipine
      1. Amlodipine 0.625 mg per cat once daily on Lipoderm
      2. Given to hypertensive cats for one week after control with oral amlodipine for one week
      3. Plasma concentrations were about . of those seen after oral administration
      4. Blood pressure control was not maintained as well, but did not return to hypertensive baseline
    E. EMLA (topical analgesia)
    1. Euctectic mixture of local anesthetics (lidocaine and prilocaine)
    2. Effective in our hands for topical/local analgesia in cats
    3. Essentially no transdermal (systemic) absorption of lidocaine or prilocaine (and no side effects) in healthy or sick cats when dosed at 1 gram of cream over 10 cm2 area, with one hour of occlusion (Gibbon, 2003; Wagner, 2005)
    VI. Dosing of transdermal drugs without absorption or efficacy data

    A. There is no single useful rule to extrapolate an oral dose to a transdermal dose
    1. Transdermal dose needed may be much higher (if skin penetration is poor)
    2. Transdermal dose may be the same (if transdermal and oral absorption are comparable)
    3. Transdermal dose may be much lower (if oral drug is subject to a lot of first pass hepatic metabolism)
    B. Choose only drugs with a quantitative therapeutic endpoint
    1. Start with a low dose, and titrate to therapeutic effect
    C. The transdermal route is not recommended for empirical dosing of antimicrobials
    1. Dosage usually exceeds 50 mg rule
    2. Dose titration to therapeutic effect could lead to microbial resistance
    D. The transdermal route is not recommended for empirical dosing of drugs for conditions that require immediate efficacy
    1. Significant hypertension
    2. Bronchospasm
    3. Seizures
    4. Arrhythmias
    5. Hyperkalemia
    6. Heart failure
    VII. Other approaches: besides permeation enhancers

    A. Physical disruption of the stratum corneum
    1. For presently available patches and solvent systems in humans, all drugs that can be delivered are small (< 500 g/mole), relatively lipophilic, and effective at low total daily doses.
    2. For delivery of larger or more polar molecules, physical disruption of the highly ordered lipid bilayers of the stratum corneum is necessary.
    B. Sonophoresis
    1. Brief (10 second) pre-treatment of the skin with low frequency ultrasound waves
    2. Has been shown to speed the onset of action of EMLA cream (lidocaine/prilocaine) in humans, reducing the time needed for local analgesia from 60 minutes to only 5 minutes.
    C. Microneedles
    1. Tiny arrays of microneedles to either directly allow drug diffusion from a drug-impregnated patch ("poke with patch") or to act as drug carriers through needles surface-coated with drug ("coat and poke")
    2. Reported to be painless by human subjects.
    3. Has been studied for transdermal delivery of insulin and desmopressin.
    D. Iontophoresis and electroporation
    1. Use an electric field to enhance the skin penetration of polar drug molecules
    2. Has been studies for transdermal delivery of:
      1. Peptides such as insulin, calcitonin, vasopressin, PTH, and octreotide
      2. Non-peptide drugs such as opioids, non-steroidal antiinflammatory agents, and anti-emetics.
      3. Chemotherapeutic drugs
        1. Local delivery to surface tumore
    3. Compact, battery-operated, and well tolerated by human patients (e.g. Iontopatch™ 80, Sammons Preston Rolyan, Bolingbrook, IL).

    Checklist for the use of transdermal medications without absorption or efficacy data
  • Is there a quantitative endpoint that can be measured?
    o T4
    o Heart rate
    o Blood pressure
    o Blood glucose
    o Plasma drug levels
  • Does the drug have a relatively large therapeutic window?
  • Are proven routes (oral or parenteral) not possible in this patient?
  • Can you wait for a therapeutic response?
    o Empirical transdermal administration is not appropriate for conditions that require immediate efficacy
  • Have you informed the client that the appropriate dosage is not established for this route, and that other, better established routes are available?
  • Will your pharmacy tell you what is in the formulation?
  • Can your pharmacy provide you with a shelf life for the formulation?
  • Do you have a rationale for your dose?
    o For example, starting with the oral dose and titrating to quantitative endpoint (only acceptable for drugs with large margins of safety)



    Drug Dose Adjustments for Disease

    There is considerable evidence to support the adjustment of drug dosages in human patients with heart failure, hepatic failure, renal insufficiency, or immaturity. 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


    Decreased cardiac output
    1. Leads to preferential shunting of blood to brain and heart
    2. May enhance cardiac toxicity (arrhythmias) and CNS toxicity (nausea) from digoxin
    B. Prerenal azotemia
    1. Requires lower doses of enalapril, digoxin, furosemide
    2. Benazepril clearance not affected by azotemia in dogs and cats
    C. Gastrointestinal edema
    1. May lead to erratic oral absorption of some drugs in fulminant heart failure
    D. Many potential drug interactions
    1. Furosemide and digoxin:
      1. Hypokalemia and dehydration enhance digoxin toxicity
    2. Furosemide and ACE inhibitors
      1. ACE inhibitors impair ability to response to dehydration from furosemide
    3. Furosemide and lidocaine
      1. Hypokalemia impairs efficacy of lidocaine
    4. Spironolactone and ACE inhibitors
      1. Possible hyperkalemia
    5. Diltiazem, and propranolol or atenolol
      1. Enhanced risk of AV block
      2. Do not use together
    II. Hepatic insufficiency

    A. Decreased metabolism of some drugs
    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
      1. Veterinary diseases with comparable hepatic dysfunction:
        1. Severe hepatic lipidosis
        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:
      1. Propranolol (decrease dose by 50% or more)
      2. Chloramphenicol (use 25% of regular dose, or choose another drug)
      3. Metronidazole (use 25-50% of antimicrobial dose)
        1. Or substitute:
          1. Lactulose or neomycin (for encephalopathy)
          2. Amoxicillin/clavulanate (for systemic anaerobic therapy)
      4. Diazepam or midazolam (use 25-50% of regular dose and use sparingly if treating encephalopathic seizures)
    B. Hypoalbuminemia
    1. Increased acute effects from highly protein drugs such as NSAIDs and benzodiazepines
    C. Ascites
    1. Use the total body weight (including ascites fluid) to calculate dosage of relatively water-soluble drugs:
      1. Aminoglycosides
      2. Fluoroquinolones
      3. Morphine
        1. Relatively polar opioid with polar active glucuronide metabolites
        2. Leads to decreased efficacy in humans if dosed on non-ascitic body weight.
    2. Lipid soluble drugs will not distribute to ascites fluid
      1. Use the normal body weight (minus estimated ascites fluid weight) to calculate dosage of lipid
        soluble drugs such as:
        1. Propofol
        2. Vitamin K1
    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
      1. 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 (high ammonia levels)
    2. Avoid NSAID's
      1. Risk of GI bleeding
    3. Avoid furosemide
      1. Hypokalemia, dehydration, azotemia, alkalosis all exacerbate encephalopathy
      2. Consider spironolactone / hydrochlorthiazide instead for ascites (1 mg/kg BID)
    4. Avoid 0.9% saline IV
      1. Often leads to edema, worsens ascites
      2. Consider 1/2 strength saline with 2.5% dextrose, and added potassium, for patients with liver disease accompanied by hypoalbuminemia
      3. Use Hetastarch for volume expansion
    5. Avoid glucocorticoids
      1. Catabolic
      2. Enhance deamination of proteins and release of NH3
    6. Consider lactulose and neomycin over metronidazole
      1. 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
      1. Digoxin, cimetidine, trimethoprim, quinidine
    3. Decreased renal P450 and conjugative metabolism of some drugs
    4. Decreased binding of acidic drugs to albumin
      1. Furosemide, sulfamethoxazole, aspirin
    5. Reduced tissue binding of some drugs
      1. Digoxin
    B. Few good 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 is almost never known for our patients
    2. Drug dosage adjustments are often made in humans with creatinine clearances less than around 0.7 ml/min/kg (depending on the drug)
      1. Corresponds to a serum creatinine of about 2.0 to 2.5 mg/dl in dogs and cats
    C. For many drugs, a crude dose reduction can be made by adjusting the amount given based on the serum creatinine, assuming a normal creatinine of 1.0 mg/dl
    1. Divide the dose by the serum creatinine in mg/dl (i.e. less drug given at same intervals)
    2. Roughly accurate for serum creatinine concentrations up to 4 mg/dl
    3. Exception is aminoglycosides (and probably fluoroquinolones), for which the dose interval should be extended instead (see below)
    D. Drugs that merit dose reductions in renal failure:
    1. Penicillins
      1. Toxicity unlikely, but dose reduction is appropriate and will also decrease the cost of using more expensive beta lactams and related drugs (such as ticarcillin, aztreonem, meropnem) in patients with azotemia
    2. Cephalosporins
      1. Cephalothin and cefazolin can be nephrotoxic at very high doses in humans, so dose reduction of these two drugs in renal failure may be important in dogs and cats
      2. Cephalothin and cefazolin can also be nephrotoxic in combination with gentamicin to elderly humans; avoid this combination in older dogs and cats
    3. Fluoroquinolones
      1. Most fluoroquinolones are renally cleared.
      2. Given the risk of retinal toxicity in cats, always think twice about fluoroquinolone dosing in cats with renal insufficiency.
      3. Although the optimal method is not established, consider extending the dosing interval of enrofloxacin
        1. e.g. enrofloxacin 5 mg/kg every 48 hours instead of every 24 hours
      4. Or choose less retinotoxic fluoroquinolones
        1. Retinotoxic potential in cats is marbofloxacin < orbifloxacin << enrofloxacin
    4. Aminoglycosides
      1. Use other agents whenever possible (fluoroquinolones, ticarcillin, cefotetan, aztreonem, meropenem)
      2. When necessary for use in patients with pre-existing renal failure:
        1. Always rehydrate first
        2. Always use concurrent fluid therapy (IV or SC)
        3. Consider possibly less nephrotoxic forms of aminoglycosides
          1. Amikacin 15 mg/kg SC q. 24h
          2. Netilmicin 6-8 mg/kg SC q. 24h
        4. Monitor for tubular damage by examining daily fresh urine sediments for granular casts
        5. Reduce the dose by multiplying the dose interval by the serum creatinine
          1. e.g. For a serum creatinine of 2.0 mg/dl, dose every 48 hours instead of every 24 hours
        6. Do not use aminoglycosides in patients with urinary obstruction
        7. Do not use furosemide or NSAIDs concurrently
        8. Limit aminoglycoside therapy to 5 days or less whenever possible
    5. Tetracyclines
      1. Use doxycycline, not tetracycline
        1. No adjustment needed with renal insufficiency
      2. Tetracyclines can increase BUN, independent of any renal damage, due to protein catabolism (increase is reversible)
      3. Never use outdated tetracyclines (breakdown products are nephrotoxic)
    6. Chloramphenicol
      1. In cats, 25% or more is excreted unchanged in the urine
      2. Avoid use in cats with renal insufficiency
        1. Or consider reducing the dose or monitoring CBC for dose-dependent leukopenia
    7. Potentiated sulfonamides
      1. Decreased renal clearance and decreased protein binding in renal failure
        1. Reduce dose in renal failure
      2. Rehydrate first
      3. Dose accurately
      4. Avoid sulfadiazine (in Tribrissen)
        1. Sulfadiazine forms drug crystals in the renal tubules and can lead to hematuria in humans
      5. Avoid use with methotrexate (combination can precipitate in urine and cause tubular damage)
      6. Avoid urinary acidifiers
    8. Digoxin
      1. Decreased renal filtration, tubular secretion, and skeletal muscle binding leads to increased serum concentrations in uremia
      2. Reduce dose in azotemia
      3. Measure serum digoxin concentrations
        1. Steady state after 1 week in dogs
        2. Draw level 6 to 8 hours after dosing
        3. Therapeutic level: 0.8 - 1.2 ng/ml
    9. Furosemide
      1. Can lead to dehydration, hypokalemia, acute renal failure
      2. Use conservative dosages and monitor carefully
        1. Serial BUN, creatinine, potassium, PCV/TP
    10. Cimetidine / ranitidine / famotidine
      1. CNS disturbances reported in elderly humans with decreased GFR when given H2 blockers without appropriate dose reductions
      2. Reduce dosage in renal failure
      3. Either decrease dose or extend dosing interval (either method used in people)
    11. Metoclopramide
      1. Standard CRI dosages (1-2 mg/kg/day) may cause tremor and ataxia in azotemic patients
      2. Consider 0.25-0.50 mg/kg/day and titrate to dose that controls emesis without tremor
      3. Or substitute maropitant as antiemetic (but this lacks prokinetic effects)
    12. Atenolol
      1. Renally cleared (unlike propranolol)
      2. Given at 25-50% of standard dosages in humans with moderate to severe renal insufficiency
    13. ACE inhibitors
      1. Benazepril is preferred over enalapril in azotemic patients
        1. Benazepril undergoes some hepatic clearance, and does not accumulate in azotemia
      2. All ACE inhibitors have potential adverse effects on GFR
        1. Efferent arteriolar dilation can drop GFR
        2. May lead to worsened azotemia, particularly with:
          1. Concurrent NSAIDs
          2. Concurrent furosemide
          3. High ACEi dosages
      3. Monitor BUN, creatinine, and electrolytes in patients on ACE inhibitors, especially those with pre-existing azotemia
    14. NSAID's
      1. Decreased renal clearance, decreased protein binding, and adverse effects on GFR
      2. Use alternatives to NSAIDs in azotemic patients with osteoarthritis:
        1. Tramadol, buprenorphine
        2. Acupuncture
        3. SAMe
          1. Some efficacy for osteoarthritis in humans
      3. If NSAID is required for pain control and quality of life, use conservative NSAID dosages, and monitor frequently for
        1. Dehydration, inappetance, or increases in BUN and creatinine
        2. Coxibs have same potential to adversely affect GFR
        3. COX-2 is constituitively expressed in the kidney
      4. Coxibs are not safer than classical NSAIDs in renal insufficiency
    IV. Neonates and pediatric patients

    A. Gastrointestinal tract
    1. Markedly increased intestinal permeability in the first 24 hours post partum
      1. Allows the absorption of immunoglobulins from colostrum.
      2. Oral drugs may have unexpectedly high bioavailability in this time frame.
      3. IV or intraosseous administration may give more reliable absorption of most drugs.
      4. Oral neomycin can reach high systemic plasma levels in premature infants, and should be avoided in newborn puppies and kittens.
    2. Relatively high gastric pH (> 3.0) though 5 weeks of age)
      1. Empirical use of pump blockers and H2 blockers is not indicated in this population.
      2. High gastric pH may decrease the bioavailability of:
        1. Ketoconazole, itraconazole
          1. Fluconazole may be better absorbed
        2. Oral iron supplements.
    3. Nursing puppies and kittens may absorb some oral drugs poorly due to drug binding by milk components, particularly calcium.
      1. Enrofloxacin oral bioavailability is low in nursing kittens.
      2. The same may be true for doxycycline, which is also bound by dietary calcium
    B. Factors affecting drug disposition
    1. Low body fat
      1. May lead to higher plasma (and CNS) concentrations of lipid soluble drugs, such as most anesthetics.
    2. Low plasma albumin
      1. Could lead to increased free fraction of highly protein bound drugs such as benzodiazepines, possibly leading to increased sedative effects following single doses.
      2. Albumin approaches adult levels by 16 weeks
    C. Hepatobiliary function
    1. Biliary function is not fully developed at birth, leading to a mild physiologic cholestasis
      1. Bile flow reaches normal adult levels by 4 to 6 weeks
    2. Cytochrome P450 content is low in newborn puppies but approaches adult levels by 4 to 6 weeks
      1. Lidocaine and theophylline
      2. Longer elimination half-lives in young puppies (<1- 2 weeks old).
    3. Glucuronidation is also incompletely developed in newborn dogs
      1. Reaches adult levels by 4 to 6 weeks of age
      2. Drugs that rely on glucuronidation for elimination, such as many NSAIDs, are likely to have markedly delayed clearance
    D. Renal function
    1. Immature renal tubular function prior to 8 weeks
      1. Relatively low numbers of capsular nephrons
      2. Inefficient tubular secretion of drugs
      3. Low GFR
    2. Renally cleared drugs with narrow margins of safety, such as NSAIDs, should be avoided
    3. Puppies less than 3 weeks old cannot excrete potassium efficiently
      1. Serum potassium should be monitored carefully in young puppies on IV potassium supplementation.
    4. Neonates also show immature proximal tubular reabsorption of glucose and amino acids
      1. Glucosuria and proteinuria can be seen in normal young puppies
      2. Will resolve with maturation, and does not require additional diagnostics or treatment
    E. Response to anesthetics
    1. Neonates are particularly susceptible to adverse effects from anesthetics:
      1. Immature drug elimination pathways
      2. Low body fat for drug re-distribution
      3. Low resting arterial blood pressures
    2. Neonates are predisposed to hypotension under anesthesia
      1. Poor cardiac compliance
      2. Immature baroreceptors
      3. Incomplete sympathetic innervation to the heart.
    3. Neonates are also prone to hypothermia
      1. Low body fat and high body surface area
      2. Cannot mediate effective vasoconstriction or shiver (shivering develops after the first week).
      3. Hypothermia leads to delayed elimination of anesthetics, hypotension, and ileus
      4. Hypothermia also places a large energy demand on the neonate to maintain body temperature.
      5. Heating pads are not as effective as warmed air or radiant heat.
        1. Heated incubators or Bair huggers (forced air warming units), prewarmed IV fluids, and heat lamps (e.g. during radiography) are helpful
    4. In very young puppies (< 4 days of age) hypoxia leads to bradycardia instead of a compensatory tachycardia
      1. In addition, puppies up to 2 weeks of age do not respond to atropine with an increase in heart rate
      2. For young puppies with bradycardia, treatment with oxygen and warming, rather than atropine, is recommended
    F. Susceptibility to drug toxicities
    1. Fluoroquinolones can lead to cartilage toxicity in growing puppies
      1. Dose dependent
      2. Weight bearing joints in large breed pups are particularly susceptible
      3. In growing kittens, cartilage lesions are not seen when fluoroquinolones are used at label doses
    2. Tetracycline causes a yellow discoloration of enamel in erupting teeth in humans, dogs, and cats.
      1. This is much less common with doxycycline, with only rare reports of tooth discoloration in doxycycline-treated children
    3. Aminoglycosides are nephrotoxic in neonatal dogs and cats as in adults.
      1. However, classic signs of nephrotoxicity, such as granular casts and a rise in serum creatinine, are not observed in neonatal pups, despite the development of renal lesions and impairment of GFR
      2. Aminoglycosides should be avoided whenever possible in very young patients
    Table 1: Conditions that may require drug dosage adjustment in dogs and cats

    Condition Drugs Dose adjustment Evidence
    Hepatic insufficiency Metronidazole


    Benzodiazepines


    Propranolol
    Use reduced (e.g. 25-50% of standard) dosages in significant hepatic failure Empirical recommendations in humans

    Pharmacokinetics of midazolam in cirrhotic humans

    Pharmacokinetics of beta blockers in cirrhotic humans
    (Note: PK of atenolol, which is renally cleared, was not affected)
    Ascites Beta lactam antibiotics
    Aminoglycosides
    Fluoroquinolones
    Dose based on total body weight, including ascites Studies in human patients
    Hypoalbuminemia NSAIDs

    Benzodiazepines
    Probably not necessary with maintenance dosing, due to increased renal clearance of extra free drug Pharmacokinetics of highly protein bound drugs in humans with nephrotic syndrome without azotemia
    Obesity Aminoglycosides
    Digoxin
    Dose on lean body weight Pharmacokinetics of gentamicin in obese cats

    Pharmacokinetics of digoxin in obese humans
    Renal failure or age-related renal dysfunction Benazepril No dosage adjustment necessary Studies in experimentally induced renal insufficiency in dogs and cats
    Aminoglycosides Avoid or prolong dosing interval based on trough serum drug concentrations Gentamicin pharmacokinetics in azotemic dogs
    Fluoroquinolones Prolong the dosing interval Based on modeling of ciprofloxacin in humans
    Famotidine Prolong dosing interval or reduce dose Studies in human patients
    Atenolol Prolong dosing interval or reduce dose Studies in human patients
    Metoclopramide Reduce CRI to 25%-50% of standard dosage Anecdotal experience
    Meloxicam Dose adjustments not necessary for short term use in humans Pharmacokinetics in humans
    Trimethoprimsulfadiazine Avoid use in dehydrated patients or with urinary acidifiers Numerous clinical reports in humans of obstructive crystalluria




  • © 2009 - Lauren A. Trepanier, DVM, PhD, Dip. ACVIM, Dip. ACVCP - All rights reserved