Amphotericin B Desoxycholate, Amphotericin B Lipid-Based (Abelcet, Fungizone)


Highlights Of Prescribing Information

Systemic antifungal used for serious mycotic infections

Must be administered IV

Nephrotoxicity is biggest concern, particularly with the deoxycholate form; newer lipid based products are less nephrotoxic & penetrate into tissues better, but are more expensive

Renal function monitoring essential

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based interactions

What Is Amphotericin B Desoxycholate, Amphotericin B Lipid-Based Used For?

Because the potential exists for severe toxicity associated with this drug, it should only be used for progressive, potentially fatal fungal infections. Veterinary use of amphotericin has been primarily in dogs, but other species have been treated successfully. For further information on fungal diseases treated, see the Pharmacology and Dosage sections.

The liposomal form of amphotericin B can be used to treat Leishmaniasis.

Pharmacology / Actions

Amphotericin B is usually fungistatic, but can be fungicidal against some organisms depending on drug concentration. It acts by binding to sterols (primarily ergosterol) in the cell membrane and alters the permeability of the membrane allowing intracellular potassium and other cellular constituents to “leak out.” Because bacteria and rickettsia do not contain sterols, amphotericin B has no activity against those organisms. Mammalian cell membranes do contain sterols (primarily cholesterol) and the drug’s toxicity may be a result of a similar mechanism of action, although amphotericin binds less strongly to cholesterol than ergosterol.

Amphotericin B has in vitro activity against a variety of fungal organisms, including Blastomyces, Aspergillus, Paracoccidioides, Coccidioides, Histoplasma, Cryptococcus, Mucor, and Sporothrix. Zygomycetes is reportedly variable in its response to amphotericin. Aspergillosis in dogs and cats does not tend to respond satisfactorily to amphotericin therapy. Additionally, amphotericin B has in vivo activity against some protozoa species, including Leishmania spp. and Naegleria spp.

It has been reported that amphotericin B has immunoadjuvant properties but further work is necessary to confirm the clinical significance of this effect.


Pharmacokinetic data on veterinary species is apparently unavailable. In humans (and presumably animals), amphotericin B is poorly absorbed from the GI tract and must be given parenterally to achieve sufficient concentrations to treat systemic fungal infections. After intravenous injection, the drug reportedly penetrates well into most tissues but does not penetrate well into the pancreas, muscle, bone, aqueous humor, or pleural, pericardial, synovial, and peritoneal fluids. The drug does enter the pleural cavity and joints when inflamed. CSF levels are approximately 3% of those found in the serum. Approximately 90-95% of amphotericin in the vascular compartment is bound to serum proteins. The newer “lipid” forms of amphotericin B have higher penetration into the lungs, liver and spleen than the conventional form.

The metabolic pathways of amphotericin are not known, but it exhibits biphasic elimination. An initial serum half-life of 24-48 hours, and a longer terminal half-life of about 15 days have been described. Seven weeks after therapy has stopped, amphotericin can still be detected in the urine. Approximately 2-5% of the drug is recovered in the urine in unchanged (biologically active) form.

Before you take Amphotericin B Desoxycholate, Amphotericin B Lipid-Based

Contraindications / Precautions / Warnings

Amphotericin is contraindicated in patients who are hypersensitive to it, unless the infection is life-threatening and no other alternative therapies are available.

Because of the serious nature of the diseases treated with systemic amphotericin, it is not contraindicated in patients with renal disease, but it should be used cautiously with adequate monitoring.

Adverse Effects

Amphotericin B is notorious for its nephrotoxic effects; most canine patients will show some degree of renal toxicity after receiving the drug. The proposed mechanism of nephrotoxicity is via renal vasoconstriction with a subsequent reduction in glomerular filtration rate. The drug may directly act as a toxin to renal epithelial cells. Renal damage may be more common, irreversible and severe in patients who receive higher individual doses or have preexisting renal disease. Usually, renal function will return to normal after treatment is halted, but may require several months to do so.

Newer forms of lipid-complexed and liposome-encapsulated amphotericin B significantly reduce the nephrotoxic qualities of the drug. Because higher dosages may be used, these forms may also have enhanced effectiveness. A study in dogs showed that amphotericin B lipid complex was 8-10 times less nephrotoxic than the conventional form.

The patient’s renal function should be aggressively monitored during therapy. A pre-treatment serum creatinine, BUN (serum urea nitrogen/SUN), serum electrolytes (including magnesium if possible), total plasma protein (TPP), packed cell volume (PCV), body weight, and urinalysis should be done prior to starting therapy. BUN, creatinine, PCV, TPP, and body weight are rechecked before each dose is administered. Electrolytes and urinalysis should be monitored at least weekly during the course of treatment. Several different recommendations regarding the stoppage of therapy when a certain BUN is reached have been made. Most clinicians recommend stopping, at least temporarily, amphotericin treatment if the BUN reaches 30-40 mg/dL, serum creatinine >3 mg/dL or if other clinical signs of systemic toxicity develop such as serious depression or vomiting.

At least two regimens have been used in the attempt to reduce nephrotoxicity in dogs treated with amphotericin desoxycholate. Mannitol (12.5 grams or 0.5-1 g/kg) given concurrently with amphotericin B (slow IV infusion) to dogs may reduce nephrotoxicity, but may also reduce the efficacy of the therapy, particularly in blasto-mycosis. Mannitol treatment also increases the total cost of therapy. Sodium loading prior to treating has garnered considerable support in recent years. A tubuloglomerular feedback mechanism that induces vasoconstriction and decreased GFR has been postulated for amphotericin B toxicity; increased sodium load at the glomerulus may help prevent that feedback. One clinician (Foil 1986), uses 5 mL/kg of normal saline given in two portions, before and after amphotericin B dosing and states that is has been “… helpful in averting renal insufficiency….”

Cats are apparently more sensitive to the nephrotoxic aspects of amphotericin B, and many clinicians recommend using reduced dosages in this species (see Dosage section).

Adverse effects reported in horses include: tachycardia, tachyp-nea, lethargy, fever, restlessness, anorexia, anemia, phlebitis, polyuria and collapse.

Other adverse effects that have been reported with amphotericin B include: anorexia, vomiting, hypokalemia, distal renal tubular aci-dosis, hypomagnesemia, phlebitis, cardiac arrhythmias, non-regenerative anemia and fever (may be reduced with pretreatment with NSAIDs or a low dosage of steroids). Calcinosis cutis has been reported in dogs treated with amphotericin B. Amphotericin B can increase creatine kinase levels.

Reproductive / Nursing Safety

The safety of amphotericin B during pregnancy has not been established, but there are apparently no reports of teratogenicity associated with the drug. The risks of therapy should be weighed against the potential benefits. In humans, the FDA categorizes this drug as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, hut there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, hut adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters.) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: A (Prohahly safe. Although specific studies may not have proved the safety of all drugs in dogs and cats, there are no reports of adverse effects in laboratory animals or women.)

Overdosage / Acute Toxicity

No case reports were located regarding acute intravenous overdose of amphotericin B. Because of the toxicity of the drug, dosage calculations and solution preparation procedures should be double-checked. If an accidental overdose is administered, renal toxicity maybe minimized by administering fluids and mannitol as outlined above in the Adverse Effects section.

How to use Amphotericin B Desoxycholate, Amphotericin B Lipid-Based

All dosages are for amphotericin B desoxycholate (regular amphotericin B) unless specifically noted for the lipid-based products.

Note: Some clinicians have recommended administering a 1 mg test dose (less in small dogs or cats) IV over anywhere from 20 minutes to 4 hours and monitoring pulse, respiration rates, temperature, and if possible, blood pressure. If a febrile reaction occurs some clinicians recommend adding a glucocorticoid to the IV infusion solution or using an antipyretic prior to treating, but these practices are controversial.

A published study () demonstrated less renal impairment and systemic adverse effects in dogs who received amphotericin BIV slowly over 5 hours in 1 L of D5W than in dogs who received the drug IV in 25 mL of D5W over 3 minutes.

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for dogs:

For treatment of susceptible systemic fungal infections:

a) Two regimens can be used; after diluting vial (as outlined below in preparation of solution section), either:

1) Rapid-Infusion Technique: Dilute quantity of stock solution to equal 0.25 mg/kg in 30 mL of 5% dextrose. Using butterfly catheter, flush with 10 mL of D5W. Infuse amphotericin B solution IV over 5 minutes. Flush catheter with 10 mL of D5W and remove catheter. Repeat above steps using 0.5 mg/kg 3 times a week until 9-12 mg/kg accumulated dosage is given.

2) Slow IV Infusion Technique: Dilute quantity of stock solution to equal 0.25 mg/kg in 250-500 mL of D5W. Place indwelling catheter in peripheral vein and give total volume over 4-6 hours. Flush catheter with 10 mL of D5W and remove catheter. Repeat above steps using 0.5 mg/kg 3 times a week until 9-12 mg/kg accumulated dosage is given. ()

b) In dehydrated, sodium-depleted animals, must rehydrate before administration. Dosage is 0.5 mg/kg diluted in D5W. In dogs with normal renal function, may dilute in 60-120 mL of D5W and give by slow IV over 15 minutes. In dogs with compromised renal function, dilute in 500 mL or 1 liter of D5W and give over slowly IV over 3-6 hours. Re-administer every other day if BUN remains below 50 mg/dl. If BUN exceeds 50 mg/dl, discontinue until BUN decreases to at least 35 mg/dl. Cumulative dose of 8 -10 mg/kg is required to cure blastomycosis or histoplasmosis. Coccidioidomycosis, aspergillosis and other fungal diseases require a greater cumulative dosage. ()

c) For treating systemic mycoses using the lipid-based products: AmBisome, Amphocil or Abelcet Give test dose of 0.5 mg/ kg; then 1-2.5 mg/kg IV q48h (or Monday, Wednesday, Friday) for 4 weeks or until the total cumulative dose is reached. Use 1 mg/kg dose for susceptible yeast and dimorphic fungi until a cumulative dose of 12 mg/kg is reached; for more resistant filamentous fungal infections (e.g., pythiosis) use the higher dose 2-2.5 mg/kg until a cumulative dose of 24-30 mg/kg is reached. ()

d) For treating systemic mycoses using the amphotericin B lipid complex (ABLC; Abelcet) product: 2-3 mg/kg IV three days per week for a total of 9-12 treatments (cumulative dose of 24-27 mg). Dilute to a concentration of 1 mg/mL in dextrose 5% (D5W) and infuse over 1-2 hours ()

e) For systemic mycoses using amphotericin B lipid complex (Abelcet): Dilute in 5% dextrose to a final concentration of 1 mg/mL and administer at a dosage of 2-3 mg/kg three times per week for 9-12 treatments or a cumulative dosage of 24-27 mg/kg ()

For blastomycosis (see general dosage guidelines above):

a) Amphotericin B 0.5 mg/kg 3 times weekly until a total dose of 6 mg/kg is given, with ketoconazole at 10-20 mg/kg (30 mg/kg for CNS, bone or eye involvement) divided for 3-6 months ()

b) Amphotericin B 0.15-0.5 mg/kg IV 3 times a week with ketoconazole 20 mg/day PO once daily or divided twice daily; 40 mg/kg divided twice daily for ocular or CNS involvement (for at least 2-3 months or until remission then start maintenance). When a total dose of amphotericin B reaches 4-6 mg/kg start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or ketoconazole at 2.5-5 mg/kg PO once daily. If CNS/ocular involvement use ketoconazole at 20-40 mg/kg PO divided twice daily ()

c) For severe cases, using amphotericin B lipid complex (Abelcet): 1-2 mg/kg IV three times a week (or every other day) to a cumulative dose of 12-24 mg/kg ()

For cryptococcosis (see general dosage guidelines above):

a) Amphotericin B 0.5 – 0.8 mg/kg SC 2 – 3 times per week. Dose is diluted in 0.45% NaCl with 2.5% dextrose (400 mL for cats, 500 mL for dogs less than 20 kg and 1000 mL for dogs greater than 20 kg). Concentrations greater than 20 mg/L result in local irritation and sterile abscess formation. May combine with flucytosine or the azole antifungals. ()

For histoplasmosis (see general dosage guidelines above):

a) Amphotericin B 0.15 – 0.5 mg/kg IV 3 times a week with ketoconazole 10-20 mg/day PO once daily or divided twice daily (for at least 2-3 months or until remission then start maintenance). When a total dose of amphotericin B reaches 2-4 mg/kg, start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or at 2.5-5 mg/kg PO once daily ()

b) As an alternative to ketoconazole treatment: 0.5 mg/kg IV given over 6-8 hours. If dose is tolerated, increase to 1 mg/ kg given on alternate days until total dose of 7.5-8.5 mg/kg cumulative dose is achieved ()

For Leishmaniasis:

a) Using the liposomal form of Amphotericin B: 3-3.3 mg/kg IV 3 times weekly for 3-5 treatments)

b) Using AmBisome (lipid-based product): Give initial test dose of 0.5 mg/kg, then 3-3.3 mg/kg IV every 72-96 hours until a cumulative dose of 15 mg/kg is reached. May be possible to give the same cumulative dose with a lower level every 48 hours. ()

For gastrointestinal pythiosis:

a) Resect lesions that are surgically removable to obtain 5 – 6 cm margins. Follow-up medical therapy using the amphotericin B lipid complex (ABLC; Abelcet) product: 1-2 mg/kg IV three times weekly for 4 weeks (cumulative dose 12-24 mg). May alternatively use itraconazole at 10 mg/kg PO once daily for 4-6 months. ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for cats:

For treatment of susceptible systemic fungal infections: a) Rapid-Infusion Technique: After diluting vial (as outlined below in preparation of solution section), dilute quantity of stock solution to equal 0.25 mg/kg in 30 mL of 5% dextrose. Using butterfly catheter, flush with 10 mL of D5W Infuse amphotericin B solution IV over 5 minutes. Flush catheter with 10 mL of D5W and remove catheter. Repeat above steps using 0.25 mg/kg 3 times a week until 9-12 mg/kg accumulated dosage is given. ()

For cryptococcosis (see general dosage guidelines above):

a) As an alternative therapy to ketoconazole: Amphotericin B: 0.25 mg/kg in 30 mL D5WIV over 15 minutes q48h with flucytosine at 200 mg/kg/day divided q6h PO. Continue therapy for 3-4 weeks after clinical signs have resolved or until BUN >50 mg/dl. (Legendre 1989)

b) Amphotericin B 0.15-0.4 mg/kg IV 3 times a week with flucytosine 125-250 mg/day PO divided two to four times a day. When a total dose of amphotericin B reaches 4-6 mg/ kg, start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month with flucytosine at dosage above or with ketoconazole at 10 mg/kg PO once daily or divided twice daily ()

c) Amphotericin B 0.5-0.8 mg/kg SC 2-3 times per week. Dose is diluted in 0.45% NaCl with 2.5% dextrose (400 mL for cats, 500 mL for dogs less than 20 kg and 1000 mL for dogs greater than 20 kg). Concentrations greater than 20 mg/L result in local irritation and sterile abscess formation. May combine with flucytosine or the azole antifungals. ()

d) For treating systemic mycoses using the amphotericin B lipid complex (ABLC; Abelcet) product: 1 mg/kg IV three days per week for a total of 12 treatments (cumulative dose of 12 mg). Dilute to a concentration of 1 mg/mL in dextrose 5% (D5W) and infuse over 1-2 hours ()

For histoplasmosis (see general dosage guidelines above):

a) Amphotericin B: 0.25 mg/kg in 30 mL D5WIV over 15 minutes q48h with ketoconazole at 10 mg/kg q12h PO. Continue therapy for 4-8 weeks or until BUN >50 mg/dl. If BUN increases greater than 50 mg/dl, continue ketoconazole alone. Ketoconazole is used long-term (at least 6 months of duration. ()

b) Amphotericin B 0.15-0.5 mg/kg IV 3 times a week with ketoconazole 10 mg/day PO once daily or divided twice daily (for at least 2-3 months or until remission, then start maintenance). When a total dose of amphotericin B reaches 2-4 mg/ kg, start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or at 2.5-5 mg/kg PO once daily ()

For blastomycosis (see general dosage guidelines above):

a) Amphotericin B: 0.25 mg/kg in 30 mL D5WIV over 15 minutes q48h with ketoconazole: 10 mg/kg q12h PO (for at least 60 days). Continue amphotericin B therapy until a cumulative dose of 4 mg/kg is given or until BUN >50 mg/dl. If renal toxicity does not develop, may increase dose to 0.5 mg/ kg of amphotericin B. ()

b) Amphotericin B 0.15-0.5 mg/kg IV 3 times a week with ketoconazole 10 mg/day PO once daily or divided twice daily (for at least 2-3 months or until remission then start maintenance). When a total dose of amphotericin B reaches 4-6 mg/ kg start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or ketoconazole at 2.5 – 5 mg/kg PO once daily. If CNS/ocular involvement, use ketoconazole at 20-40 mg/kg PO divided twice daily. ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for rabbits, rodents, and small mammals:

a) Rabbits: 1 mg/kg/day IV ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for horses:

For treatment of susceptible systemic fungal infections:

a) For fungal pneumonia: Day 1: 0.3 mg/kg IV; Day 2: 0.4 mg/kg IV; Day 3: 0.6 mg/kg IV; days 4-7: no treatment; then every other day until a total cumulative dose of 6.75 mg/kg has been administered ()

b) For phycomycoses and pulmonary mycoses: After reconstitution (see below) transfer appropriate amount of drug to 1L of D5W and administer using a 16 g needle IV at a rate of 1 L/ hr. Dosage schedule follows: Day 1: 0.3 mg/kg IV; Day 2: 0.45 mg/kg IV; Day 3: 0.6 mg/kg IV; then every other day for 3 days per week (MWF or TTHSa) until clinical signs of either improvement or toxicity occur. If toxicity occurs, a dose may be skipped, dosage reduced or dosage interval lengthened. Administration may extend from 10-80 days. ()

For intrauterine infusion: 200-250 mg. Little science is available for recommending doses, volume infused, frequency, diluents, etc. Most intrauterine treatments are commonly performed every day or every other day for 3-7 days. ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for Llamas:

For treatment of susceptible systemic fungal infections: a) A single case report. Llama received 1 mg test dose, then initially at 0.3 mg/kg IV over 4 hours, followed by 3 L of LRS with 1.5 mL of B-Complex and 20 mEq of KC1 added. Subsequent doses were increased by 10 mg and given every 48 hours until reaching 1 mg/kg q48h IV for 6 weeks. Animal tolerated therapy well, but treatment was ultimately unsuccessful (Coccidioidomycosis). ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for birds:

For treatment of susceptible systemic fungal infections:

a) For raptors and psittacines with aspergillosis: 1.5 mg/kg IV three times daily for 3 days with flucytosine or follow with flucytosine. May also use intratracheally at 1 mg/kg diluted in sterile water once to 3 times daily for 3 days in conjunction with flucytosine or nebulized (1 mg/mL of saline) for 15 minutes twice daily. Potentially nephrotoxic and may cause bone marrow suppression. ()

b) 1.5 mg/kg IV q12h for 3-5 days; topically in the trachea at 1 mg/kg q12h; 0.3-1 mg/mL nebulized for 15 minutes 2-4 times daily ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for reptiles:

For susceptible fungal respiratory infections: a) For most species: 1 mg/kg diluted in saline and given intratracheally once daily for 14-28 treatments ()

Client Information

■ Clients should be informed of the potential seriousness of toxic effects that can occur with amphotericin B therapy

■ The costs associated with therapy

Chemistry / Synonyms

A polyene macrolide antifungal agent produced by Streptomyces nodosus, amphotericin B occurs as a yellow to orange, odorless or practically odorless powder. It is insoluble in water and anhydrous alcohol. Amphotericin B is amphoteric and can form salts in acidic or basic media. These salts are more water soluble but possess less antifungal activity than the parent compound. Each mg of amphotericin B must contain not less than 750 micrograms of anhydrous drug. Amphotericin A may be found as a contaminant in concentrations not exceeding 5%. The commercially available powder for injection contains sodium desoxycholate as a solubilizing agent.

Newer lipid-based amphotericin B products are available that have less toxicity than the conventional desoxycholate form. These include amphotericin B cholesteryl sulfate complex (amphotericin B colloidal dispersion, ABCD, Amphotec), amphotericin B lipid complex (ABLC, Abelcet), and amphotericin B liposomal (ABL, L-AMB, Ambisome).

Amphotericin B may also be known as: amphotericin; amphotericin B cholesteryl sulfate complex, amphotericin B lipid complex, amphotericin B liposome, amphotericin B phospholipid complex, amphotericin B-Sodium cholesteryl sulfate complex, anfotericina B, or liposomal amphotericin B; many trade names are available.

Storage / Stability / Compatibility

Vials of amphotericin B powder for injection should be stored in the refrigerator (2-8°C), protected from light and moisture. Reconstitution of the powder must be done with sterile water for injection (no preservatives — see directions for preparation in the Dosage Form section below).

After reconstitution, if protected from light, the solution is stable for 24 hours at room temperature and for 1 week if kept refrigerated. After diluting with D5W (must have pH >4.3) for IV use, the manufacturer recommends continuing to protect the solution from light during administration. Additional studies however, have shown that potency remains largely unaffected if the solution is exposed to light for 8-24 hours.

Amphotericin B deoxycholate is reportedly compatible with the following solutions and drugs: D5W, D5W in sodium chloride 0.2%, heparin sodium, heparin sodium with hydrocortisone sodium phosphate, hydrocortisone sodium phosphate/succinate and sodium bicarbonate.

Amphotericin B deoxycholate is reportedly incompatible with the following solutions and drugs: normal saline, lactated Ringer’s, D5-normal saline, Ds-lactated Ringer’s, amino acids 4.25%-dextrose 25%, amikacin, calcium chloride/gluconate, carbenicillin disodium, chlorpromazine HCL, cimetidine HCL, diphenhydramine HCL, dopamine HCL, edetate calcium disodium (Ca EDTA), gentamicin sulfate, kanamycin sulfate, lidocaine HCL, metaraminol bitartrate, methyldopate HCL, nitrofurantoin sodium, oxytetracycline HCL, penicillin G potassium/sodium, polymyxin B sulfate, potassium chloride, prochlorperazine mesylate, streptomycin sulfate, tetracycline HCL, and verapamil HCL. Compatibility is dependent upon factors such as pH, concentration, temperature and diluent used; consult specialized references or a hospital pharmacist for more specific information.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products: None

Human-Labeled Products:

Amphotericin B Desoxycholate Powder for Injection: 50 mg in vials; Amphocin (Gensia Sicor); Fungizone Intravenous (Apothecon); generic (Pharma-Tek); (Rx)

Directions for reconstitution/administration: Using strict aseptic technique and a 20 gauge or larger needle, rapidly inject 10 mL of sterile water for injection (without a bacteriostatic agent) directly into the lyophilized cake; immediately shake well until solution is clear. A 5 mg/mL colloidal solution results. Further dilute (1:50) for administration to a concentration of 0.1 mg/mL with 5% dextrose in water (pH >4.2). An in-line filter may be used during administration, but must have a pore diameter >1 micron.

Amphotericin B Lipid-Based Suspension for Injection: 100 mg/20 mL (as lipid complex) in 10 mL & 20 mL vials with 5 micron filter needles: Abelcet (Enzon); (Rx)

Amphotericin B Lipid-Based Powder for Injection: 50 mg/vial (as cholesteryl) in 20 mL vials; 100 mg (as cholesteryl) in 50 mL vials; Amphotec (Sequus Pharmaceuticals); 50 mg (as liposomal) in single-dose vials with 5-micron filter; AmBisome (Fujisawa; (Rx)

Amphotericin B is also available in topical formulations: Fungizone (Apothecon); (Rx)


Amikacin Sulfate (Amikin, Amiglyde-V)

Aminoglycoside Antibiotic

Highlights Of Prescribing Information

Parenteral aminoglycoside antibiotic that has good activity against a variety of bacteria, predominantly gram-negative aerobic bacilli

Adverse Effects: Nephrotoxicity, ototoxicity, neuromuscu-lar blockade

Cats may be more sensitive to toxic effects

Risk factors for toxicity: Preexisting renal disease, age (both neonatal & geriatric), fever, sepsis & dehydration

Now usually dosed once daily when used systemically

What Is Amikacin Sulfate Used For?

While parenteral use is only approved in dogs, amikacin is used clinically to treat serious gram-negative infections in most species. It is often used in settings where gentamicin-resistant bacteria are a clinical problem. The inherent toxicity of the aminoglycosides limit their systemic use to serious infections when there is either a documented lack of susceptibility to other, less toxic antibiotics or when the clinical situation dictates immediate treatment of a presumed gram-negative infection before culture and susceptibility results are reported.

Amikacin is also approved for intrauterine infusion in mares. It is used with intra-articular injection in foals to treat gram-negative septic arthritis.


Amikacin, like the other aminoglycoside antibiotics, act on susceptible bacteria presumably by irreversibly binding to the 30S ribosomal subunit thereby inhibiting protein synthesis. It is considered a bactericidal concentration-dependent antibiotic.

Amikacin’s spectrum of activity includes: coverage against many aerobic gram-negative and some aerobic gram-positive bacteria, including most species of E. coli, Klebsiella, Proteus, Pseudomonas, Salmonella, Enterobacter, Serratia, and Shigella, Mycoplasma, and Staphylococcus. Several strains of Pseudomonas aeruginosa, Proteus, and Serratia that are resistant to gentamicin will still be killed by amikacin.

Antimicrobial activity of the aminoglycosides is enhanced in an alkaline environment.

The aminoglycoside antibiotics are inactive against fungi, viruses and most anaerobic bacteria.


Amikacin, like the other aminoglycosides is not appreciably absorbed after oral or intrauterine administration, but is absorbed from topical administration (not from skin or the urinary bladder) when used in irrigations during surgical procedures. Patients receiving oral aminoglycosides with hemorrhagic or necrotic enteritises may absorb appreciable quantities of the drug. After IM administration to dogs and cats, peak levels occur from ½1 hour later. Subcutaneous injection results in slightly delayed peak levels and with more variability than after IM injection. Bio availability from extravascular injection (IM or SC) is greater than 90%.

After absorption, aminoglycosides are distributed primarily in the extracellular fluid. They are found in ascitic, pleural, pericardial, peritoneal, synovial and abscess fluids; high levels are found in sputum, bronchial secretions and bile. Aminoglycosides are minimally protein bound (<20%, streptomycin 35%) to plasma proteins. Aminoglycosides do not readily cross the blood-brain barrier nor penetrate ocular tissue. CSF levels are unpredictable and range from 0-50% of those found in the serum. Therapeutic levels are found in bone, heart, gallbladder and lung tissues after parenteral dosing. Aminoglycosides tend to accumulate in certain tissues such as the inner ear and kidneys, which may help explain their toxicity. Volumes of distribution have been reported to be 0.15-0.3 L/kg in adult cats and dogs, and 0.26-0.58 L/kg in horses. Volumes of distribution may be significantly larger in neonates and juvenile animals due to their higher extracellular fluid fractions. Aminoglycosides cross the placenta; fetal concentrations range from 15-50% of those found in maternal serum.

Elimination of aminoglycosides after parenteral administration occurs almost entirely by glomerular filtration. The approximate elimination half-lives for amikacin have been reported to be 5 hours in foals, 1.14-2.3 hours in adult horses, 2.2-2.7 hours in calves, 1-3 hours in cows, 1.5 hours in sheep, and 0.5-2 hours in dogs and cats. Patients with decreased renal function can have significantly prolonged half-lives. In humans with normal renal function, elimination rates can be highly variable with the aminoglycoside antibiotics.

Before you take Amikacin Sulfate

Contraindications / Precautions / Warnings

Aminoglycosides are contraindicated in patients who are hypersensitive to them. Because these drugs are often the only effective agents in severe gram-negative infections, there are no other absolute contraindications to their use. However, they should be used with extreme caution in patients with preexisting renal disease with concomitant monitoring and dosage interval adjustments made. Other risk factors for the development of toxicity include age (both neonatal and geriatric patients), fever, sepsis and dehydration.

Because aminoglycosides can cause irreversible ototoxicity, they should be used with caution in “working” dogs (e.g., “seeing-eye,” herding, dogs for the hearing impaired, etc.).

Aminoglycosides should be used with caution in patients with neuromuscular disorders (e.g., myasthenia gravis) due to their neuromuscular blocking activity.

Because aminoglycosides are eliminated primarily through renal mechanisms, they should be used cautiously, preferably with serum monitoring and dosage adjustment in neonatal or geriatric animals.

Aminoglycosides are generally considered contraindicated in rabbits/hares as they adversely affect the GI flora balance in these animals.

Adverse Effects

The aminoglycosides are infamous for their nephrotoxic and ototox-ic effects. The nephrotoxic (tubular necrosis) mechanisms of these drugs are not completely understood, but are probably related to interference with phospholipid metabolism in the lysosomes of proximal renal tubular cells, resulting in leakage of proteolytic enzymes into the cytoplasm. Nephrotoxicity is usually manifested by: increases in BUN, creatinine, nonprotein nitrogen in the serum, and decreases in urine specific gravity and creatinine clearance. Proteinuria and cells or casts may be seen in the urine. Nephrotoxicity is usually reversible once the drug is discontinued. While gentamicin may be more nephrotoxic than the other aminoglycosides, the incidences of nephrotoxicity with all of these agents require equal caution and monitoring.

Ototoxicity (8th cranial nerve toxicity) of the aminoglycosides can manifest by either auditory and/or vestibular clinical signs and may be irreversible. Vestibular clinical signs are more frequent with streptomycin, gentamicin, or tobramycin. Auditory clinical signs are more frequent with amikacin, neomycin, or kanamycin, but either form can occur with any of these drugs. Cats are apparently very sensitive to the vestibular effects of the aminoglycosides.

The aminoglycosides can also cause neuromuscular blockade, facial edema, pain/inflammation at injection site, peripheral neuropathy and hypersensitivity reactions. Rarely, GI clinical signs, hematologic and hepatic effects have been reported.

Reproductive / Nursing Safety

Aminoglycosides can cross the placenta and while rare, may cause 8th cranial nerve toxicity or nephrotoxicity in fetuses. Because the drug should only be used in serious infections, the benefits of therapy may exceed the potential risks. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, hut there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans.) In a separate system evaluating the safety of drugs in canine and feline pregnancy (), this drug is categorized as in class: C (These drugs may have potential risks. Studies in people or laboratory animals have uncovered risks, and these drugs should he used cautiously as a last resort when the benefit of therapy clearly outweighs the risks.)

Aminoglycosides are excreted in milk. While potentially, amikacin ingested with milk could alter GI flora and cause diarrhea, amikacin in milk is unlikely to be of significant concern after the first few days of life (colostrum period).

Overdosage / Acute Toxicity

Should an inadvertent overdosage be administered, three treatments have been recommended. Hemodialysis is very effective in reducing serum levels of the drug but is not a viable option for most veterinary patients. Peritoneal dialysis also will reduce serum levels but is much less efficacious. Complexation of drug with either carbenicillin or ticarcillin (12-20 g/day in humans) is reportedly nearly as effective as hemodialysis. Since amikacin is less affected by this effect than either tobramycin or gentamicin, it is assumed that reduction in serum levels will also be minimized using this procedure.

How to use Amikacin Sulfate

Note: Most infectious disease clinicians now agree that aminoglycosides should be dosed once a day in most patients (mammals). This dosing regimen yields higher peak levels with resultant greater bacterial kill, and as aminoglycosides exhibit a “post-antibiotic effect”, surviving susceptible bacteria generally do not replicate as rapidly even when antibiotic concentrations are below MIC. Periods where levels are low may also decrease the “adaptive resistance” (bacteria take up less drug in the presence of continuous exposure) that can occur. Once daily dosing may decrease the toxicity of aminoglycosides as lower urinary concentrations may mean less uptake into renal tubular cells. However, patients who are neutropenic (or otherwise immunosuppressed) may benefit from more frequent dosing (q8h). Patients with significantly diminished renal function who must receive aminoglycosides may need to be dosed at longer intervals than once daily. Clinical drug monitoring is strongly suggested for these patients.

Amikacin Sulfate dosage for dogs:

For susceptible infections:

a) Sepsis: 20 mg/kg once daily IV ()

b) 15 mg/kg (route not specified) once daily (q24h). Neutropenic or immunocompromised patients may still need to be dosed q8h (dose divided). ()

c) 15-30 mg/kg IV, IM or SC once daily (q24h) ()

Amikacin Sulfate dosage for cats:

For susceptible infections:

a) Sepsis: 20 mg/kg once daily IV ()

b) 15 mg/kg (route not specified) once daily (q24h). Neutropenic or immunocompromised patients may still need to be dosed q8h (dose divided). ()

c) 10-15 mg/kg IV, IM or SC once daily (q24h) ()

Amikacin Sulfate dosage for ferrets:

For susceptible infections:

a) 8-16 mg/kg IM or IV once daily ()

b) 8-16 mg/kg/day SC, IM, IV divided q8-24h ()

Amikacin Sulfate dosage for rabbits, rodents, and small mammals:

a) Rabbits: 8-16 mg/kg daily dose (may divide into q8h-q24h) SC, IM or IV Increased efficacy and decreased toxicity if given once daily. If given IV, dilute into 4 mL/kg of saline and give over 20 minutes. ()

b) Rabbits: 5-10 mg/kg SC, IM, IV divided q8-24h Guinea pigs: 10-15 mg/kg SC, IM, IV divided q8-24h Chinchillas: 10-15 mg/kg SC, IM, IV divided q8-24h Hamster, rats, mice: 10 mg/kg SC, IM q12h Prairie Dogs: 5 mg/kg SC, IM q12h ()

c) Chinchillas: 2-5 mg/kg SC, IM q8- 12h ()

Amikacin Sulfate dosage for cattle:

For susceptible infections:

a) 10 mg/kg IM q8h or 25 mg/kg q12h ()

b) 22 mg/kg/day IM divided three times daily ()

Amikacin Sulfate dosage for horses:

For susceptible infections:

a) 21 mg/kg IV or IM once daily (q24h) ()

b) In neonatal foals: 21 mg/kg IV once daily ()

c) In neonatal foals: Initial dose of 25 mg/kg IV once daily; strongly recommend to individualize dosage based upon therapeutic drug monitoring. ()

d) Adults: 10 mg/kg IM or IV once daily (q24h)

Foals (<30 days old): 20-25 mg/kg IV or IM once daily (q24h).

For uterine infusion:

a) 2 grams mixed with 200 mL sterile normal saline (0.9% sodium chloride for injection) and aseptically infused into uterus daily for 3 consecutive days (Package insert; Amiglyde-V — Fort Dodge)

b) 1-2 grams IU ()

For intra-articular injection as adjunctive treatment of septic arthritis in foals:

a) If a single joint is involved, inject 250 mg daily or 500 mg every other day; frequency is dependent upon how often joint lavage is performed. Use cautiously in multiple joints as toxicity may result (particularly if systemic therapy is also given). ()

For regional intravenous limb perfusion (RILP) administration in standing horses:

a) Usual dosages range from 500 mg-2 grams; dosage must be greater than 250 mg when a cephalic vein is used for perfusion and careful placement of tourniquets must be performed. ()

Amikacin Sulfate dosage for birds:

For susceptible infections:

a) For sunken eyes/sinusitis in macaws caused by susceptible bacteria: 40 mg/kg IM once or twice daily. Must also flush sinuses with saline mixed with appropriate antibiotic (10-30 mL per nostril). May require 2 weeks of treatment. ()

b) 15 mg/kg IM or SC q12h ()

c) For gram-negative infections resistant to gentamicin: Dilute commercial solution and administer 15-20 mg/kg (0.015 mg/g) IM once a day or twice a day ()

d) Ratites: 7.6-11 mg/kg IM twice daily; air cell: 10-25 mg/egg; egg dip: 2000 mg/gallon of distilled water pH of 6 ()

Amikacin Sulfate dosage for reptiles:

For susceptible infections:

a) For snakes: 5 mg/kg IM (forebody) loading dose, then 2.5 mg/kg q72h for 7-9 treatments. Commonly used in respiratory infections. Use a lower dose for Python curtus. ()

b) Study done in gopher snakes: 5 mg/kg IM loading dose, then 2.5 mg/kg q72h. House snakes at high end of their preferred optimum ambient temperature. ()

c) For bacterial shell diseases in turtles: 10 mg/kg daily in water turtles, every other day in land turtles and tortoises for 7-10 days. Used commonly with a beta-lactam antibiotic. Recommended to begin therapy with 20 mL/kg fluid injection. Maintain hydration and monitor uric acid levels when possible. ()

d) For Crocodilians: 2.25 mg/kg IM q 72-96h ()

e) For gram-negative respiratory disease: 3.5 mg/kg IM, SC or via lung catheter every 3-10 days for 30 days. ()

Amikacin Sulfate dosage for fish:

For susceptible infections:

a) 5 mg/kg IM loading dose, then 2.5 mg/kg every 72 hours for 5 treatments. ()


■ Efficacy (cultures, clinical signs, WBC’s and clinical signs associated with infection). Therapeutic drug monitoring is highly recommended when using this drug systemically. Attempt to draw samples at 1,2, and 4 hours post dose. Peak level should be at least 40 mcg/mL and the 4-hour sample less than 10 mcg/mL.

■ Adverse effect monitoring is essential. Pre-therapy renal function tests and urinalysis (repeated during therapy) are recommended. Casts in the urine are often the initial sign of impending nephrotoxicity.

■ Gross monitoring of vestibular or auditory toxicity is recommended.

Client Information

■ With appropriate training, owners may give subcutaneous injections at home, but routine monitoring of therapy for efficacy and toxicity must still be done

■ Clients should also understand that the potential exists for severe toxicity (nephrotoxicity, ototoxicity) developing from this medication

■ Use in food producing animals is controversial as drug residues may persist for long periods

Chemistry / Synonyms

A semi-synthetic aminoglycoside derived from kanamycin, amikacin occurs as a white, crystalline powder that is sparingly soluble in water. The sulfate salt is formed during the manufacturing process. 1.3 grams of amikacin sulfate is equivalent to 1 gram of amikacin. Amikacin may also be expressed in terms of units. 50,600 Units are equal to 50.9 mg of base. The commercial injection is a clear to straw-colored solution and the pH is adjusted to 3.5-5.5 with sulfuric acid.

Amikacin sulfate may also be known as: amikacin sulphate, amikacini sulfas, or BB-K8; many trade names are available.

Storage / Stability/Compatibility

Amikacin sulfate for injection should be stored at room temperature (15 – 30°C); freezing or temperatures above 40°C should be avoided. Solutions may become very pale yellow with time but this does not indicate a loss of potency.

Amikacin is stable for at least 2 years at room temperature. Autoclaving commercially available solutions at 15 pounds of pressure at 120°C for 60 minutes did not result in any loss of potency.

Note: When given intravenously, amikacin should be diluted into suitable IV diluent etc. normal saline, D5W or LRS) and administered over at least 30 minutes.

Amikacin sulfate is reportedly compatible and stable in all commonly used intravenous solutions and with the following drugs: amobarbital sodium, ascorbic acid injection, bleomycin sulfate, calcium chloride/gluconate, cefoxitin sodium, chloramphenicol sodium succinate, chlorpheniramine maleate, cimetidine HCl, clindamycin phosphate, colistimethate sodium, dimenhydrinate, diphenhydramine HCl, epinephrine HCl, ergonovine maleate, hyaluronidase, hydrocortisone sodium phosphate/succinate, lincomycin HCl, metaraminol bitartrate, metronidazole (with or without sodium bicarbonate), norepinephrine bitartrate, pentobarbital sodium, phenobarbital sodium, phytonadione, polymyxin B sulfate, prochlorperazine edisylate, promethazine HCL, secobarbital sodium, sodium bicarbonate, succinylcholine chloride, vancomycin HCL and verapamil HCL.

The following drugs or solutions are reportedly incompatible or only compatible in specific situations with amikacin: aminophylline, amphotericin B, ampicillin sodium, carbenicillin disodium, cefazolin sodium, cephalothin sodium, cephapirin sodium, chlorothiazide sodium, dexamethasone sodium phosphate, erythromycin gluceptate, heparin sodium, methicillin sodium, nitrofurantoin sodium, oxacillin sodium, oxytetracycline HCL, penicillin G potassium, phenytoin sodium, potassium chloride (in dextran 6% in sodium chloride 0.9%; stable with potassium chloride in “standard” solutions), tetracycline HCL, thiopental sodium, vitamin B-complex with C and warfarin sodium. Compatibility is dependent upon factors such as pH, concentration, temperature and diluent used; consult specialized references or a hospital pharmacist for more specific information.

In vitro inactivation of aminoglycoside antibiotics by beta-lac-tam antibiotics is well documented. While amikacin is less susceptible to this effect, it is usually recommended to avoid mixing these compounds together in the same syringe or IV bag unless administration occurs promptly. See also the information in the Amikacin Sulfate Interaction and Amikacin Sulfate/Lab Interaction sections.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products:

Amikacin Sulfate Injection: 50 mg (of amikacin base) per mL in 50 mL vials; Amiglyde-V (Fort Dodge), AmijectD (Butler), Amikacin K-9 (RXV), Amikacin C (Phoenix), Amtech Amimax C (IVX), Caniglide (Vedco); generic (VetTek); (Rx); Approved for use in dogs.

Amikacin Sulfate Intrauterine Solution: 250 mg (of amikacin base) per mL in 48 mL vials; Amifuse E (Butler), Amiglyde-V (Fort Dodge), Amikacin E (Phoenix), Amikacin E (RXV), Amtech Amimax E (IVX), Equi-phar Equiglide (Vedco); (Rx); Approved for use in horses not intended for food.

WARNING: Amikacin is not approved for use in cattle or other food-producing animals in the USA. Amikacin Sulfate residues may persist for long periods, particularly in renal tissue. For guidance with determining use and withdrawal times, contact FARAD (see Phone Numbers & Websites in the appendix for contact information).

Human-Labeled Products:

Amikacin Injection: 50 mg/mL and 250 mg/mL in 2 mL and 4 mL vials and 2 mL syringes; Amikin (Apothecon); generic; (Rx)


Acetazolamide, Acetazolamide Sodium (Diamox, Dazamide)

Carbonic Anhydrase Inhibitor Diuretic; Antiglaucoma Agent

Highlights Of Prescribing Information

Used primarily for metabolic alkalosis or glaucoma in small animals; HYPP in horses

Contraindicated in patients with significant hepatic, renal, pulmonary or adrenocortical insufficiency, hyponatremia, hypokalemia, hyperchloremic acidosis or electrolyte imbalance

Give oral doses with food if GI upset occurs

Electrolytes & acid/base status should be monitored with chronic or high dose therapy

Monitor with tonometry if using for glaucoma

What Is Acetazolamide Used For?

Acetazolamide has been used principally in veterinary medicine for its effects on aqueous humor production in the treatment of glaucoma, metabolic alkalosis, and for its diuretic action. It may be useful as an adjunctive treatment for syringomyelia in dogs. Acetazolamide’s use in small animals is complicated by a relatively high occurrence of adverse effects.

In horses, acetazolamide is used as an adjunctive treatment for hyperkalemic periodic paralysis (HYPP).

In humans, the drug has been used as adjunctive therapy for epilepsy and for acute high-altitude sickness.

Before you take Acetazolamide

Contraindications / Precautions / Warnings

Carbonic anhydrase inhibitors are contraindicated in patients with significant hepatic disease (may precipitate hepatic coma), renal or adrenocortical insufficiency, hyponatremia, hypokalemia, hyperchloremic acidosis, or electrolyte imbalance. They should not be used in patients with severe pulmonary obstruction that are unable to increase alveolar ventilation or in those who are hypersensitive to them. Long-term use of carbonic anhydrase inhibitors is contraindicated in patients with chronic, noncongestive, angle-closure glaucoma as angle closure may occur and the drug may mask the condition by lowering intraocular pressures.

Acetazolamide should be used with caution in patients with severe respiratory acidosis or having preexisting hematologic abnormalities. Cross sensitivity between acetazolamide and antibacterial sulfonamides may occur.

Adverse Effects

Potential adverse effects that maybe encountered include: GI disturbances, CNS effects (sedation, depression, weakness, excitement, etc.), hematologic effects (bone marrow depression), renal effects (crystalluria, dysuria, renal colic, polyuria), hypokalemia, hypergly-cemia, hyponatremia, hyperuricemia, hepatic insufficiency, derma-tologic effects (rash, etc.), and hypersensitivity reactions.

At the dosages used for HYPP in horses adverse effects are reportedly uncommon.

Overdosage / Acute Toxicity

Information regarding overdosage of this drug was not located. Monitor serum electrolytes, blood gases, volume status, and CNS status during an acute overdose; treat symptomatically and supportively.

How to use Acetazolamide

Directions for reconstitution of injection: Reconstitute 500 mg vial with at least 5 mL of Sterile Water for Injection; use within 24 hours after reconstitution.

Acetazolamide dosage for dogs:

For adjunctive treatment of metabolic alkalosis:

a) 10 mg/kg four times daily (may aggravate volume contraction and hypokalemia) ()

For adjunctive therapy of glaucoma:

a) 10-25 mg/kg divided 2-3 times daily ()

b) 50-75 mg/kg PO 2-3 times a day ()

c) 50 mg/kg IV one time; 7 mg/kg, PO three times daily ()

For adjunctive therapy of hydrocephalus in pediatric patients:

a) 0.1 mg/kg PO q8h ()

Acetazolamide dosage for cats:

For adjunctive therapy of glaucoma:

a) 50 mg/kg IV once; 7 mg/kg, PO three times daily ()

Acetazolamide dosage for horses:

(Note: ARCI UCGFS Class 4 Acetazolamide)

For adjunctive therapy of hyperkalemic periodic paralysis (HYPP):

a) 2.2-4.4 mg/kg PO twice daily ()

b) 0.5-2.2 mg/kg PO twice daily ()

c) 3 mg/kg PO (dosing interval not specified) ()

■ Ruminants:

a) 6-8 mg/kg IV, IM, or SC ()

Acetazolamide dosage for swine:

a) 6-8 mg/kg IV, IM, or SC ()


■ Intraocular pressure tonometry (if used for glaucoma)

■ Blood gases if used for alkalosis

■ Serum electrolytes

■ Baseline CBC with differential and periodic retests if using chronically

■ Other adverse effects

Client Information

■ Give with food if using oral preparation and GI upset occurs

■ Notify veterinarian if abnormal bleeding or bruising occurs or if animal develops tremors or a rash

Chemistry / Synonyms

A carbonic anhydrase inhibitor, acetazolamide occurs as a white to faintly yellowish-white, odorless, crystalline powder with pKas of 7.4 and 9.1. It is very slightly soluble in water, sparingly soluble in hot water (90- 100°C) and alcohol. Acetazolamide sodium occurs as a white lyophilized solid and is freely soluble in water. The injection has a pH of 9.2 after reconstitution with Sterile Water for Injection. Acetazolamide may also known as: acetazolam, acetazolamidum, or sodium acetazolamide; many trade names are available.

Storage / Stability/Compatibility

Acetazolamide products should be stored at room temperature.

To prepare parenteral solution: reconstitute with at least 5 mL of Sterile Water for Injection. After reconstitution, the injection is stable for one week when refrigerated, but as it contains no preservatives, it should be used within 24 hours.

Acetazolamide sodium for injection is reportedly physically compatible with all commonly used IV solutions and cimetidine HC1 for injection.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products: None

The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information.

Human-Labeled Products:

Acetazolamide Tablets: 125 mg, 250 mg; generic; (Rx)

Acetazolamide Sustained-Release Capsules: 500 mg; Diamox Sequels (Barr); (Rx)

Acetazolamide Injection: 500 mg per vial; Diamox (Wyeth-Ayerst); (Rx)

Acetazolamide Powder for Injection (lyophilized): 500 mg for re-constitution; generic; (Rx)

Veterinary Medicine

Esophageal Disorders

1. What is the most common clinical sign of an esophageal disorder?


2. What is the difference between regurgitation and reflux?

Regurgitation refers to passive, retrograde movement of ingested material to a level proximal to the upper esophageal sphincter; usually this material has not reached the stomach. In most cases, regurgitation results from abnormal esophageal peristalsis, esophageal obstruction, or asynchronous function of the gastroesophageal junction.

Reflux refers to the movement of gastric and duodenal contents into the esophagus without associated eructation or vomiting.

3. List the causes of regurgitation.

1. Megaesophagus

• Idiopathic

• Secondary

  • Myasthenia gravis
  • Polyneuropathy
  • Systemic lupus erythematosus
  • Polymyositis
  • Toxicosis (lead, thallium)
  • Hypothyroidism
  • Hypoadrenocorticism

2. Esophageal foreign body

3. Esophageal stricture

• Intraluminal stricture

• Extraluminal stricture due to compression

  • Abscess
  • Cranial mediastinal mass
  • Thoracic hilar lymphadenopathy

4. Vascular ring anomaly

5. Neoplasia (primary or metastatic)

6. Granuloma (e.g., Spirocerca lupi)

7. Hiatal hernia

8. Esophageal diverticula

4. What is megaesophagus?

Megaesophagus is a specific syndrome characterized by a dilated, hypoperistaltic esophagus.

5. What is the most common complication of megaesophagus?

Aspiration pneumonitis.

6. Does esophageal dilatation on thoracic radiographs confirm an esophageal disorder?

No. The following conditions often produce transient dilatation of the esophagus:

• Aerophagia

• Anxiety

• Respiratory distress (dyspnea)

• Anesthesia

• Vomiting

7. How is esophageal motility evaluated?

Thoracic radiography initially evaluates for evidence of an esophageal foreign body, esophageal dilatation, or thoracic mass. Ideally a barium esophagogram with fluoroscopy should be performed. It is best to mix food with the barium to observe for decreased contractility.

8. What is myasthenia gravis?

Myasthenia gravis is an immune-mediated disorder, either acquired or congenital (familial), resulting from the action of autoantibodies against nicotinic acetylcholine receptors at the neuro-muscular junctions.

9. What are the most common clinical signs of myasthenia gravis?

• Premature fatigue with exercise

• Spastic pelvic limb gait

• Tetraparesis

• Collapse

• Tachypnea

• Respiratory distress

• Sialosis

• Regurgitation

• Dysphagia

• Weakness of facial muscles

• Decreased palpebral reflex

10. What is the test of choice for myasthenia gravis?

Acetylcholine receptor antibody titers (> 0/6 nM/L) in dogs. Antibodies are detectable in 80-90% of dogs with acquired disease.

11. What other tests can be used for myasthenia gravis?

• Edrophonium response test. Edrophonium (0.1-0.2 mg/kg IV) results in dramatic improvement in gait for 1-2 minutes in many but not all animals. Pretreatment with atropine (0.02 mg/kg IV) decreases salivation, defecation, urination, bronchosecretion, and bronchoconstriction. Oxygen and an endotracheal tube should be readily available.

• Ten percent or greater decremental response to the fourth or fifth compound action potential recorded from the interosseous muscle after repetitive stimulation of the tibia or ulnar nerve at 3 Hz.

• Increase in jitter on single-fiber electromyography.

• Intercostal muscle biopsy identifying acetylcholine receptor antibodies at the neuromuscular junction.

12. Describe the typical profile of a dog with myasthenia gravis.

• Breeds most commonly affected: golden retriever, German shepherd

• Bimodal age of onset: 2-4 years and 9-13 years

13. How is myasthenia gravis treated?

1. Anticholinesterase drugs — neostigmine

• Injectable (Prostigmin [Roche]): 0.02 mg/lb IM every 6 hr

• Oral (Mestinon [Roche]): 0.25-0.45 mg/lb every 8-12 hr

2. Corticosteroids

14. Describe the principles for management of megaesophagus.

1. Remove the cause if possible.

2. Minimize chances for aspiration of esophageal contents. (Feed the animal in an upright position so that the upper body is elevated to at least 45° above the lower body. Maintain this position for at least 10 minutes after eating and before bedtime.)

3. Maximize nutrient intake to the GI tract (if possible, feed 2-4 times/day).

15. What is an alternative means of feeding dogs with megaesophagus?

Gastrostomy tube.

16. What is the prognosis for a dog with megaesophagus?

Guarded to poor.

17. List causes of esophageal stricture in dogs.

• Esophagitis

• Reflux of gastric acid during general anesthesia (on a tilted operating table)

• Ingestion of a strong acid or alkali material

• Esophageal foreign bodies

• Thermal burns

• Hairballs (cats)

18. How is esophageal stricture diagnosed?

Esophageal stricture is diagnosed by barium esophagogram and esophageal endoscopy.

19. List the treatment options for esophageal stricture and the success rate for each.

• Surgery (esophagotomy, patch grafting, resection and anastomosis): < 50% success

• Esophageal bougienage: 50-70% success

• Balloon catheter dilatation: > 50-70% success (treatment of choice, ideally done under fluoroscopy)

20. What are the most common areas of the esophagus in which foreign bodies lodge?

• Thoracic inlet

• Hiatus of the diaphragm

• Base of the heart

21. How do you manage dogs with an esophageal foreign body?

Esophageal foreign bodies are considered an emergency. The following steps are recommended:

1. Endoscopic removal of the foreign body is usually successful. Either extract the foreign body or carefully push it into the stomach. If the foreign body is a bone, it is often best to push it into the stomach. Gastrostomy is not usually required for removal of the bone, but serial radiography should be done to ensure digestion or passage of the bone.

2. If esophagoscopy is unsuccessful, surgical removal is required.

3. Assess the esophageal mucosa for hemorrhage, erosions, lacerations, or perforations.

4. Withhold food and water for 24-48 hours, and give crystalloid fluids and parenteral antibiotics.

22. What treatments are available for esophageal reflux?

Metoclopramide (Reglan) increases gastroesophageal sphincter tone and decreases gastric reflux into the stomach.

H2 receptor-blocking agents (e.g., cimetidine or ranitidine) reduce the acidity of refluxed gastric contents.

Sucralfate suspension is an aluminum salt that selectively binds to injured gastroesophageal mucosa and acts as an effective barrier against the damaging actions of gastric acid, pepsin, and bile acids associated with reflux esophagitis.

Veterinary Drugs


Diltiazem Hydrochloride


A calcium channel blocker, diltiazem HCl occurs as a white to off-white crystalline powder having a bitter taste. It is soluble in water and alcohol. Potencies may be expressed in terms of base (active moiety) and the salt. Dosages are generally expressed in terms of the salt. Diltiazem is also known as latiazem HCl.

Storage – Stability – Compatibility

Diltiazem oral products should be stored at room temperature in tight, light resistant containers.

Diltiazem: Pharmacology

Diltiazem is a calcium-channel blocker similar in action to drugs such as vera-pamil or nifedipine. While the exact mechanism is unknown, diltiazem inhibits the transmembrane influx of extracellular calcium ions in myocardial cells and vascular smooth muscle, but does not alter serum calcium concentrations. The net effects of this action is to inhibit the cardiac and vascular smooth muscle contractility, thereby dilating main systemic and coronary arteries. Total peripheral resistance, blood pressure and cardiac afterload are all reduced.

Diltiazem also has effects on cardiac conduction. It slows AV node conduction and prolongs refractory times. Diltiazem rarely affects SA node conduction, but in patients with Sick Sinus Syndrome, resting heart rates may be reduced.

Although diltiazem can cause negative inotropic effects, it is rarely of clinical importance (unlike verapamil or nifedipine). Diltiazem apparently does not affect plasma renin or aldosterone concentrations nor affect blood glucose or insulin concentrations.

Diltiazem: Uses – Indications

Diltiazem may be useful in the treatment of atrial fibrillation, supraventricular tachycardias, and hypertrophic cardiomyopathy. For specific information, refer to the Dosages section.


After an oral dose, about 80% of the dose is absorbed rapidly from the gut, but because of a high first pass effect only about half of that absorbed reaches the systemic circulation. Approximately 75% of the drug is bound to serum proteins in humans. Diltiazem enters maternal milk in concentrations approximating those found in the plasma. Diltiazem is rapidly and almost completely metabolized in the liver. Serum half lives in humans range from 3.5 to 10 hours. Renal impairment may only slightly increase half lives.

Contraindications – Precautions – Reproductive Safety

Diltiazem is contraindicated in patients with severe hypotension (<90 mm Hg systolic), sick sinus syndrome or 2nd or 3rd degree AV block (unless a functioning pacemaker is in place), acute MI, radiographically documented pulmonary congestion, or if the patient is hypersensitive to it.

Diltiazem should be used with caution in geriatric patients or those with heart failure (particularly if also receiving beta blockers), or hepatic or renal impairment.

High doses in rodents have resulted in increased fetal deaths and skeletal abnormalities. Use during pregnancy only when the benefits outweigh the potential risks.

Diltiazem: Adverse Effects – Warnings

Experience in both dogs and cats is limited. At usual doses, brady-cardia is the most prominent side effect reported in dogs thus far. Specific adverse effects in cats are not well described. Potentially, GI distress, hypotension, heart block or other rhythm disturbances, CNS effects, rashes, or elevations in liver function tests could occur in either species.

Overdosage – Acute Toxicity

The oral LD50 in dogs has been reported as >50 mg/kg. Symptoms noted after overdosage may include heart block, bradycardia, hypotension, and heart failure. Treatment should consist of gut emptying protocols when warranted, and supportive and symptomatic treatment. Atropine may be used to treat bradycardias or 2nd or 3rd degree AV block. If these do not respond to vagal blockade, isoproterenol may be tried (with caution). Fixed block may require cardiac pacing. Inotropics (e.g., dobutamine, dopamine, isoproterenol) and pressors (e.g., dopamine, norepinephrine) may be required to treat heart failure and hypotension. A slow intravenous calcium infusion (1 ml/10 kg body weight of 10% calcium gluconate) may also be useful for severe acute toxicity.

Diltiazem: Drug Interactions

While data conflicts regarding whether diltiazem affects digoxin pharmacokinetics, diligent monitoring of digoxin serum concentrations should be performed. Diltiazem may increase the likelihood of bradycardia, AV block or CHF developing in patients also receiving beta blockers (including ophthalmic beta blockers). Additionally, diltiazem may substantially increase the bioavailability of propranolol. Cimetidine may increase plasma diltiazem concentrations; increased monitoring of diltiazem’s effects are warranted. Ranitidine may also affect diltiazem concentrations, but to a lesser extent. Diltiazem may affect cyclosporin or quinidine serum concentrations; increased monitoring and dosage adjustments may be required.

Diltiazem: Doses

Doses for dogs:

For treatment of supraventricular tachyarrhthymias:

a) 0.5 – 1 (up to 1.5) mg/kg PO q8h (PionZZZ

b) For atrial fibrillation with rapid ventricular response in dogs with dilated cardiomyopathy: 0.4 – 0.5 mg/kg PO tid; increase dosage gradually every 2-3 days while patient is observed for deterioration of cardiovascular function. Dosages above 1 mg/kg are not recommended.

c) Initially give a 0.25 mg/kg IV bolus over 2 minutes. Repeat 0.25 mg/kg IV bolus every 15 minutes until conversion occurs or total dosage of 0.75 mg/kg has been given.

For supraventricular arrhythmias, hypertrophic cardiomyopathy, hypertension:

a) 0.5 – 1.5 mg/kg PO q8h; titrate upwards to effect

Doses for cats:

For treatment of supraventricular tachyarrhythmias:

a) 0.5 – 1 (up to 1.5) mg/kg PO q8h

For treatment of hypertrophic cardiomyopathy:

a) 7.5 mg PO tid

b) 1.75 – 2.5 mg/kg PO tid

c) Initially 7.5 mg (l/4th of a 30 mg tablet) PO q8h; may be given as initial therapy in asymptomatic cats or added to therapy in cats responding poorly to furosemide or enalapril.

For supraventricular arrhythmias, hypertrophic cardiomyopathy, hypertension: a) 0.5 – 2.5 mg/kg PO q8h

Monitoring Parameters

1) ECG/Heart Rate; 2) Blood Pressure; 3) Adverse Effects

Client Information

Inform clients of potential adverse effects. Stress compliance.

Dosage Forms – Preparations – FDA Approval Status – Withholding Times

Veterinary-Approved Products:


Human-Approved Products:

Diltiazem Tablets 30 mg, 60 mg, 90 mg, and 120 mg; Cardizem® (Hoechst Marion Roussel) (Marion Merrell Dow, generic; (Rx)

Diltiazem Extended-Release Tablets: 120 mg, 180 mg, & 240 mg; Tiamate® (Hoechst Marion Roussel) (Rx)

Diltiazem Oral Capsules Extended Release 60 mg, 90 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg; Cardizem® SR (Hoechst Marion Roussel); (Rx);Cardizem CD® (Hoechst Marion Roussel) (Rx);Dilacor XR® (Rhone-Poulenc Rorer) (Rx);Tiazac® (Forest) (Rx); generic (Rx)

Diltiazem Injection 5 mg/ml in 5 ml & 10 ml vials; Cardizem® (Hoechst Marion Roussel); Diltiazem (Bedford Labs) (Rx)

Veterinary Medicine

Acute Pancreatitis

1. Compare acute and chronic pancreatitis.

Acute Chronic
Acute inflammatory condition Long-standing inflammation
No evidence of fibrosis Fibrosis and loss of acinar cell mass
Mild or severe Mild or severe
Reversible histopathologic changes Irreversible histopathologic changes


2. Describe the pathophysiology of severe pancreatitis.

Severe pancreatitis is characterized by extensive pancreatic necrosis and multiple organ involvement (perhaps even organ failure). The exocrine pancreas produces a number of digestive enzymes necessary for the degradation of proteins, fats, and polysaccharides. These enzymes are synthesized in inactive proenzyme forms that are activated only after they are secreted into the small intestine. In pancreatitis digestive enzymes are activated in the pancreas rather than the intestine because of damage to the gland or some stimulatory signal that results in pancreatic autodigestion. Systemic complications develop as activated pancreatic enzymes enter the bloodstream.

3. What is the most common cause of acute pancreatitis?

In most cases, the cause remains unknown. Causes that are often listed include nutrition (high fat meal), drugs (cholinesterase inhibitors and cholinergic agonists, thiazide diuretics, furosemide, estrogens, azathioprine, L-asparaginase, sulfonamides, tetracycline, metronidazole, cimetidine, ranitidine, acetaminophen, procainamide, and nitrofurantoin), organophosphates, trauma, hypoperfusion, hypercalcemia, hyperlipidemia (Schnauzers), and neoplastic infiltration by pancreatic adenocarcinoma. In cats, pancreatitis also is associated with concurrent hepatic lipidosis, infection with Toxoplasma gondii, and biliary tract inflammation.

4. Why is ingestion of a meal high in fat implicated as a cause of acute pancreatitis in dogs?

The pancreatic enzyme lipase metabolizes ingested triglycerides to free fatty acids in pancreatic capillaries. These fatty acids are directly injurious to the pancreas. The high incidence of pancreatitis in miniature Schnauzers also may be related to the high prevalence of familial hyperlipoproteinemia.

5. What are the primary presenting complaints and physical findings in dogs with pancreatitis?

Common clinical findings are vomiting, abdominal pain, dehydration, and fever. In dogs the duration of vomiting may be several days or, in acute hemorrhagic pancreatitis, only a few hours. Uncommon systemic complications include icterus, respiratory distress, and bleeding disorders.

6. Do cats present with the same symptoms as dogs?

Of interest, whereas vomiting is a common historical finding in dogs, most cats present with anorexia (97%), lethargy (100%), dehydration (92%), hypothermia (68%), vomiting (35%), abdominal pain (25%), a palpable abdominal mass (23%), respiratory distress (20%), ataxia (15%), and diarrhea (15%).

7. What are the radiographic signs of pancreatitis?

The most common radiographic finding is loss of visceral detail (ground-glass appearance) in the right cranial abdomen. Other radiographic signs include displacement of the descending duodenum to the right and of the stomach to the left, presence of a mass medial to the descending duodenum, and a gas-filled duodenum.

8. Describe the ultrasonic changes associated with pancreatitis.

Ultrasound changes include pancreatic swelling, increased echogenicity of the pancreas, and, less frequently, a mass effect in the area of the pancreas.

9. Are elevations in serum amylase and lipase activities definitive for the diagnosis of pancreatitis?

No. Neither enzyme is pancreas-specific; both are also produced by gastric and intestinal mucosal cells. Furthermore, because both enzymes are eliminated through the urine, a decrease in renal perfusion results in elevations of both enzymes. Finally, the administration of dexamethasone to dogs causes significant elevations in lipase without histologic evidence of pancreatitis.

10. Do normal lipase and amylase values eliminate the possibility of pancreatitis?

No. Many dogs and even more cats have confirmed pancreatitis with normal levels of both enzymes. Normal enzyme values in animals with pancreatitis may be due to impairment in pancreatic perfusion, depletion of stored enzymes, and / or disruption of the synthesis of new enzymes.

11. How is the diagnosis of pancreatitis confirmed?

Other than by histology, pancreatitis cannot be diagnosed on the basis of one test result. Common laboratory findings include leukocytosis, hyperglycemia, hypocalcemia, and elevations in amylase and lipase. Elevations in trypsin-like-immunoreactivity (TLI) correlate well with pancreatitis in both dogs and cats but also are affected by renal perfusion; furthermore, results generally take several days to return. Abdominal fluid analysis — in particular, lipase levels higher than serum lipase values — helps to make a case for pancreatitis. Ultrasound is useful for identifying an enlarged, inflamed pancreas. Diffuse or focal hypoechoic areas in the gland, along with compatible laboratory and physical findings, justify a high index of suspicion of pancreatitis.

12. How can the severity of acute pancreatitis be ascertained?

On admission it may not be easy to predict the severity or probable cause of acute pancreatitis. The clinician should be cognizant of concurrent laboratory abnormalities or clinical signs suggesting systemic complications. Examples include thrombocytopenia or clotting abnormalities, which may suggest disseminated intravascular coagulation (DIC); oliguria, which may indicate acute renal failure; hypotension and tachycardia, which may indicate systemic inflammatory response syndrome; and hypoglycemia, which may suggest sepsis.

13. What are the key components in treatment of pancreatitis?

The most important element of treatment is adequate fluid resuscitation. Decreased pancreatic perfusion due to hypovolemia, which may result from vomiting and third-space losses, may lead to progression of the disease if fluid therapy is inadequate. Recent studies suggest that colloid fluid resuscitation (plasma, hetastarch, and dextran 70) is an important component in the therapy of pancreatitis. In particular, fresh frozen plasma (10-20 ml / kg) is important in treatment of moderate-to-severe cases. Plasma as a colloid provides only small increases in oncotic properties but supplies clotting factors for management of disseminated intravascular coagulation and protease inhibitors that deactivate pancreatic enzymes in the systemic circulation. Prophylactic antibiotics, pain relief, antiemetics, and antacids are also important components of therapy. Studies in cats with experimentally induced acute hemorrhagic pancreatitis have shown that low-dose dopamine (5 mg / kg / min) reduces the severity of pancreatitis by reducing microvascular permeability. Dopamine as an adjunctive treatment awaits clinical evaluation.

14. How is fresh frozen plasma useful in the treatment of pancreatitis?

Studies in dogs suggest when alpha2-macroglobulin, one of the scavenger proteins for activated proteases in serum, is depleted, death rapidly ensues. Fresh frozen plasma (FFP) or fresh whole blood not only contains alpha2-macroglobulin but also albumin. Unfortunately, in a study of human pancreatitis patients, plasma failed to show any benefit. Incubating FFP with heparin may release antithrombin III and thus be useful in disseminated intravascular coagulation secondary to pancreatitis.

15. Is there evidence supporting the use of antibiotics or nonsteroidal antiinflammatory agents in pancreatitis?

No. Studies in humans have shown no benefit to antibiotics nor non-steroidal antiinflammatory agents. No data are available for the dog or cat.

16. What is the role of surgery in acute pancreatitis?

In most instances, pancreatitis is treated medically, and surgical intervention is not recommended. In patients that develop septic peritonitis or pancreatic abscess, however, surgery is the treatment of choice to remove necrotic tissue and to lavage the abdomen. Surgery also should be considered in patients who continue to deteriorate even with aggressive medical management.

17. What is done when the patient vomits every time food is offered?

Most patients with mild pancreatitis recover after avoidance of oral ingestion for 2 days, followed first by gradual introduction of water and then by small meals high in carbohydrates over the next few days. In patients that continue to vomit when offered food, one must first evaluate the case to ensure that no underlying disorder other than pancreatitis explains the persistent vomiting. In cases of smoldering pancreatitis, placement of a jejunostomy tube to provide nutrition with minimal stimulation of the pancreatitis should be strongly considered.

18. What are the long-term complications of pancreatitis?

Recurrent episodes of pancreatitis may result in progressive loss of pancreatic tissue and eventual development of diabetes mellitus and / or exocrine pancreatic insufficiency. Additional complications reported include acute fluid accumulation, infected necrosis, pancreatic pseudo-cyst formation, and pancreatic abscess.


19. Do corticosteroids cause severe pancreatitis?

Corticosteroids do not appear to cause pancreatitis, although they do increase serum lipase activity (but decrease serum amylase activity). Corticosteroid therapy is of no proven benefit in pancreatitis and may be harmful in severe pancreatitis.

20. Should food and water be withheld to allow the pancreas to rest and recover from the inflammatory episode?

Pancreatic rest has become the mainstay for treatment of acute pancreatitis, despite the absence of any clinical or experimental evidence to support this approach! Contrary to popular belief, pancreatic rest by avoiding pancreatic exocrine secretion has not made any impact on the clinical outcome of pancreatitis. Furthermore, no conclusive evidence to date indicates that medical treatment intended to decrease pancreatic exocrine secretion has any benefit, other than avoidance of pain, on the course of the disease. These observations are not surprising when one considers the fact that pancreatic exocrine secretion is severely impaired in an inflamed pancreas. If the pancreas is unable to respond to secretory stimuli, it makes perfect sense that therapeutic maneuvers to avoid pancreatic exocrine stimulation will have no bearing on the disease process.

21. Should total parenteral nutrition (TPN) be used in the treatment of pancreatitis?

In human patients, no difference in serum amylase activities between patients receiving total parenteral nutrition and controls is seen in the first 7 days after the diagnosis of acute pancreatitis. Although the total parenteral nutrition group achieved significantly greater nitrogen balance than controls, they also required significantly more days to first oral intake of clear liquids and full caloric intake. Most importantly, total parenteral nutrition patients experienced a significant prolongation of hospital stay (15 vs. 10 days in controls). No information is available in animals with pancreatitis.

22. Should total enteral nutrition (TEN) be used in the treatment of pancreatitis?

In human patients, total enteral nutrition moderates the acute-phase response and improves disease severity and clinical outcome despite unchanged pancreatic injury on computed tomography scan. Oxidant stress and systemic exposure to endotoxin also are reduced with total enteral nutrition. In humans, enteral feeding modulates the inflammatory and sepsis response in acute pancreatitis and is clinically beneficial. No information is available in animals with pancreatitis.



Constipation; Cause

The etiopathogenesis of idiopathic megacolon is still incompletely understood. Several reviews have emphasized the importance of considering an extensive list of differential diagnoses (e. g., neuromuscular, mechanical, inflammatory, metabolic and endocrine, pharmacologic, environmental, and behavioral causes) for the obstipated cat (Box Differential Diagnosis of Constipation in the Cat). A review of published cases suggests that 96% of cases of obstipation are accounted for by idiopathic megacolon (62%), pelvic canal stenosis (23%), nerve injury (6%), or Manx sacral spinal cord deformity (5%). A smaller number of cases are accounted for by complications of colopexy (1%) and colonic neoplasia (1%); colonic hypo- or aganglionosis was suspected, but not proved, in another 2% of cases. Inflammatory, pharmacologic, and environmental and behavioral causes were not cited as predisposing factors in any of the original case reports. Endocrine factors (e. g., obesity, hypothyroidism) were cited in several cases, but were not necessarily impugned as part of the pathogenesis of megacolon. It is important to consider an extensive list of differential diagnoses in an individual animal, but it should be kept in mind that most cases are idiopathic, orthopedic, or neurologic in origin. Behavioral (e. g., stress) or environmental (e. g., competition for the litter box) factors, or both, may play an important role in the development of this lesion, but they have not been very well characterized in retrospective or prospective studies.

Differential Diagnosis of Constipation in the Cat

Neuromuscular Dysfunction

Colonic smooth muscle: idiopathic megacolon, aging

Spinal cord disease: lumbosacral disease, cauda equine syndrome, sacral spinal cord deformities (Manx cat)

Hypogastric or pelvic nerve disorders: traumatic injury, malignancy, dysautonomia

Submucosal or myenteric plexus neuropathy: dysautonomia, aging

Mechanical Obstruction

Intraluminal: foreign material (bones, plant material, hair), neoplasia, rectal diverticula, perineal hernia, anorectal strictures

Intramural: neoplasia

Extraluminal: pelvic fractures, neoplasia


Perianal fistula, proctitis, anal sac abscess, anorectal foreign bodies, perianal bite wounds

Metabolic and Endocrine

Metabolic: dehydration, hypokalemia, hypercalcemia Endocrine: hypothyroidism, obesity, nutritional secondary hyperparathyroidism


Opioid agonists, cholinergic antagonists, diuretics, barium sulfate, phenothiazines

Environmental and Behavioral

Soiled litter box, inactivity, hospitalization, change in environment

Constipation: PaThophysiology

Megacolon develops through two pathologic mechanisms: (1) dilation and (2) hypertrophy. Dilated megacolon is the end stage of colonic dysfunction in idiopathic cases. Cats affected with idiopathic dilated megacolon have permanent loss of colonic structure and function. Medical therapy may be attempted in such cases, but most affected cats eventually require colectomy. Hypertrophic megacolon, on the other hand, develops as a consequence of obstructive lesions (e. g., malunion of pelvic fractures, tumors, foreign bodies).

Hypertrophic megacolon may be reversible with early pelvic osteotomy, or it may progress to irreversible dilated megacolon if appropriate therapy is not instituted.

Constipation and obstipation are earlier manifestations of the same problem. Constipation is defined as infrequent or difficult evacuation of feces but does not necessarily imply a permanent loss of function. Many cats suffer from one or two episodes of constipation without further progression. Intractible constipation that has become refractory to cure or control is referred to as obstipation. The term obstipation implies a permanent loss of function. A cat is assumed to be obstipated only after several consecutive treatment failures. Recurring episodes of constipation or obstipation may culminate in the syndrome of megacolon.

The pathogenesis of idiopathic dilated megacolon appears to involve functional disturbances in colonic smooth muscle. In vitro isometric stress measurements have been performed on colonic smooth muscle obtained from cats suffering from idiopathic dilated megacolon. Megacolonic smooth muscle develops less isometric stress in response to neurotransmitter (acetylcholine, substance P, cholecystokinin), membrane depolarization (potassium chloride), or electrical field stimulation, when compared with healthy controls. Differences have been observed in longitudinal and circular smooth muscle from the descending and ascending colon. No significant abnormalities of smooth muscle cells or of myenteric neurons were observed on histologic evaluation. These studies initially suggested that the disorder of feline idiopathic megacolon is a generalized dysfunction of colonic smooth muscle and that treatments aimed at stimulating colonic smooth muscle contraction might improve colonic motility. More recent studies suggest that the lesion may begin in the descending colon and progress to involve the ascending colon over time.

Clinical Examination

History Constipation, obstipation, and megacolon mav in observed in cats ol any age, sex, or breed; however, most cases are observed in middle-aged (mean: 5.8 vears) male cats (70% male, 30% female) of domestic shorthair (DSH) (46%), domestic longhair (15%), or Siamese (12%) breeding. Affected cats are usually presented for reduced, absent, or painful defecation for a period of time ranging from days to weeks or months. Some cats are observed making multiple, unproductive attempts to defecate in the litter box, whereas other cats may sit in the litter box for prolonged periods of time without assuming a defecation posture. Dry, hardened feces are observed inside and outside of the litter box. Occasionally, chronically constipated cats have intermittent episodes of hematochezia or diarrhea due to the mucosal irritant effect of fecal concretions. This may give the pet owner the erroneous impression that diarrhea is the primary problem. Prolonged inability to defecate may result in other systemic signs, including anorexia, lethargy, weight loss, and vomiting.

Physical examination

Colonic impaction is a consistent physical examination finding in affected cats. Other findings will depend upon the severity and pathogenesis of constipation. Dehydration, weight loss, debilitation, abdominal pain, and mild to moderate mesenteric lymphadenopathy may be observed in cats with severe idiopathic megacolon. Colonic impaction may be so severe in such cases as to render it difficult to differentiate impaction from colonic, mesenteric, or other abdominal neoplasia. Cats with constipation due to dysautonomia may have other signs of autonomic nervous system failure, such as urinary and fecal incontinence, regurgitation due to megaesophagus, mydriasis, decreased lacrimation, prolapse of the nictitating membrane, and bradycardia. Digital rectal examination should be carefully performed with sedation or anesthesia in all cats. Pelvic fracture malunion may be detected on rectal examination in cats with pelvic trauma. Rectal examination might also identify other unusual causes of constipation, such as foreign bodies, rectal diverticula, stricture, inflammation, or neoplasia. Chronic tenesmus may be associated with perineal herniation in some cases. A complete neurologic examination, with special emphasis on caudal spinal cord function, should be performed to identify neurologic causes of constipation (e. g., spinal cord injury, pelvic nerve trauma, Manx sacral spinal cord deformity).

Diagnosis of Constipation

Although most cases of obstipation and megacolon are unlikely to have significant changes in laboratory data (e. g., complete blood count, serum chemistry, urinalysis), these tests should nonetheless be performed in all cats presented for constipation. Metabolic causes of constipation, such as dehydration, hypokalemia, and hypercalcemia may be detected in some cases. Basal serum T4 concentration and other thyroid function tests should also be considered in cats with recurrent constipation and other signs consistent with hypothyroidism. Although hypothyroidism was documented in only one case of obstipation and megacolon, obstipation is a frequent clinical sign in kittens affected with congenital or juvenile-onset hypothyroidism. Constipation could also theoretically develop after successful treatment of feline hyperthyroidism.

Abdominal radiography should be performed in all constipated cats to characterize the severity of colonic impaction and to identify predisposing factors such as intraluminal radioopaque foreign material (e. g., bone chips), intraluminal or extraluminal mass lesions, pelvic fractures, and spinal cord abnormalities. The radiographic findings of colonic impaction cannot be used to distinguish between constipation, obstipation, and megacolon in idiopathic cases. First or second episodes of constipation in some cats may be severe and generalized but may still resolve with appropriate treatment.

Ancillary studies may be indicated in some cases. Extraluminal mass lesions may be further evaluated by abdominal uhrasonography and guided biopsy, whereas intraluminal mass lesions are best evaluated by endoscopy. Colonoscopy mav also be used to evaluate the colon and anorecuim for suspected inflammatory lesions, strictures, sacculations, and diverticula. Barium enema contrast radiography may be used if colonoscopy is not possible. Both colonoscopy and barium enema contrast radiography will require general anesthesia and evacuation of impacted feces. Cerebrospinal fluid analysis, CT or MRI, and electrophysiologic studies should be considered in animals with evidence of neurologic impairment. Finally, colonic biopsy or anorectal manometry will be necessary to diagnose suspected cases of aganglionic megacolon.

Treatment of Constipation

The specific therapeutic plan will depend upon the severity of constipation and the underlying cause (Table Drug Index — Constipation). Medical therapy may not be necessary with first episodes of constipation. First episodes are often transient and resolve without therapy. Mild to moderate or recurrent episodes of constipation, on the other hand, usually require some medical intervention. These cases may be managed, often on an outpatient basis, with dietary modification, water enemas, oral or suppository laxatives, colonic prokinetic agents, or a combination of these therapies. Severe cases of constipation usually require brief periods of hospitalization to correct metabolic abnormalities and to evacuate impacted feces using water enemas, manual extraction of retained feces, or both. Follow-up therapy in such cases is directed at correcting predisposing factors and preventing recurrence. Subtotal colectomy will become necessary in cats suffering from obstipation or idiopathic dilated megacolon. These cats, by definition, are unresponsive to medical therapy. Although pelvic osteotomy is described for cats with pelvic canal stenosis, subtotal colectomy is an effective treatment and is considered the standard of surgical care.

Drug Index — Constipation

Drug Classification And Example Dose
Rectal Suppositories
Dioctyl sodium sulfosuccinate (Colace, Mead Johnson) 1-2 pediatric suppositories
Glycerin 1-2 pediatric suppositories
Bisacodyl (Dulcolox; Boehringer Ingelheim) 1-2 pediatric suppositories
Warm tap water 5-10 mL / kg
Warm isotonic saline 5-10 mL / kg
Dioctyl sodium sulfosuccinate (Colace, Mead Johnson) 5-10 mL / cat
Dioctyl sodium sulfosuccinate (Disposaject, PittmanMoore) 250 mg (12 ml) given pre rectum
Mineral oil 5-10 mL / cat
Lactulose (Cephulac. Merrell Dow; Duphalac, Reid Rowell) 5-10 mL / cat
Oral Laxatives
Bulk laxatives
Psyllium (Metamucil, Searle) 1-4 tsp mixed with food, every 24 or 12 hours
Canned pumpkin 1-4 tsp mixed with food, every 24 hours
Coarse wheat bran 1-4 tblsp mixed with food, every 24 hours
Emollient laxatives
Dioctyl sodium sulfosuccinate (Colace, Mead Johnson) 50 mg orally, every 24 hours
Dioctyl calcium sulfosuccinate (Surfax, Hoechst) 50 mg orally, every 24 or 12 hours as needed
Lubricant laxatives
Mineral oil 10-25 ml orally, every 24 hours
Petrolatum (Laxatone, Evsco) 1-5 ml orally, every 24 hours
Hyperosmotic laxatives
Lactulose (Cephulac, Merrell Dow, Duphalac, Reid Rowell) 0.5 ml / kg orally, every 12 to 8 hours as needed
Stimulant laxatives
Bisacodyl (Dulcolax, Boehringer Ingelheim) 5 mg orally, every 24 hours
Prokinetic Agents
Cisapride (compounding pharmacies) 0.1-1.0 mg / kg orally every 12 to 8 hours
Tegaserod (Zelnorm, Novartis) – dogs 0.05-0.10 mg / kg orally, twice a day
Ranitidine (Zantac, Claxo SmithKline) 1.0-2.0 mg / kg orally, every 12 to 8 hours
Nizatidine (Axid, Eli Lilly) 2.5-5.0 mg / kg orally, every 24 hours


Removal of Impacted Feces

Removal of impacted feces may be accomplished through the use of rectal suppositories, enemas, or manual extraction.

Rectal suppositories

A number of pediatric rectal suppositories are available for the management of mild constipation. These include dioctyl sodium sulfosuccinate (emollient laxative), glycerin (lubricant laxative), and bisacodyl (stimulant laxative). The use of rectal suppositories requires a compliant pet and pet owner. Suppositories can be used alone or in conjunction with oral laxative therapy.


Mild to moderate or recurrent episodes of constipation may require administration of enemas, manual extraction of impacted feces, or both. Several types of enema solutions may be administered, such as warm tap water (5 to 10 mL / kg), warm isotonic saline (5 to 10 mL / kg), dioctyl sodium sulfosuccinate (5 to 10 mL / cat), mineral oil (5 to 10 mL / cat), or lactulose (5 to 10 mL / cat). Enema solutions should be administered slowly with a well-lubricated 10 to 12F rubber catheter or feeding tube. Enemas containing sodium phosphate are contraindicated in cats because of their propensity for inducing severe hypernatremia, hyperphos-phatemia, and hypocalcemia in this species.

Manual extraction

Cases unresponsive to enemas may require manual extraction of impacted feces. Cats should be adequately rchydrated and then anesthetized with an endotracheal tube in place to prevent aspiration should colonic manipulation induce vomiting. Water or saline is infused into the colon while the fecal mass is manually reduced by abdominal palpation. Sponge forceps may also be introduced rectally (with caution) to break down the fecal mass. It may be advisable to evacuate the fecal mass over a period of several days to reduce the risks of prolonged anesthesia and perforation of a devitalized colon. If this approach fails, colotomy may be necessary to remove the fecal mass. Laxative or prokinetic therapy (or both) may then be instituted once the fecal mass has been removed.

Laxative Therapy

Laxatives promote evacuation of the bowel through stimulation of fluid and electrolyte transport or increases in propulsive motility. They are classified as bulk-forming, emollient, lubricant, hyperosmotic, or stimulant laxatives according to their mechanism of action. Hundreds of products are available for the treatment of constipation. Table Drug IndexConstipation summarizes those products that have been used with some success in cats.

Bulk-forming laxatives

Most of the available bulk-forming laxatives are dietary fiber supplements of poorly digestible polysaccharides and celluloses derived principally from cereal grains, wheat bran, and psyllium. Some constipated cats will respond to supplementation of the diet with one of these products, but many require adjunctive therapy (e. g., other types of laxatives or colonic prokinetic agents). Dietary fiber is preferable because it is well tolerated, more effective, and more physiologic than other laxatives. Fiber is classified as a bulk-forming laxative, although it has many other properties. The beneficial effects of fiber in constipation include increased fecal water content, decreaseo intestinal transit time, and increased frequency of defecation. Fiber supplemented diets are available commercially, or the pet owner may wish to add psyllium (1 to 4 teaspoon per meal), wheat bran (1 to 2 tablespoon per meal), or pumpkin (1 to 4 tablespoon per meal) to canned cat food. Cats should be well hydrated before commencing fiber supplementation to maximize the therapeutic effect. Fiber supplementation is most beneficial in mildly constipated cats, prior to the development of obstipation and megacolon. In obstipated and megacolon cats, fiber may in fact be detrimental. Low-residue diets may be more beneficial in obstipated and megacolonic cats.

Emollient laxatives

Emollient laxatives are anionic detergents that increase the miscibility of water and lipid in digesta, thereby enhancing lipid absorption and impairing water absorption. Dioctyl sodium sulfosuccinate and dioctyl calcium sulfosuccinate are examples of emollient laxatives available in oral and enema form. Anecdotal experience suggests that dioctyl sodium sulfosuccinate therapy may be most useful in animals with acute but not chronic constipation. As with bulk-forming laxatives, animals should be well hydrated before emollient laxatives are administered. It should be noted that clincial efficacy has not been definitively established for the emollient laxatives. Dioctyl sodium sulfosuccinate, for example, inhibits water absorption in isolated colonic segments in vitro, but it may be impossible to achieve tissue concentrations great enough to inhibit colonic water absorption in vivo. Dioctyl sodium sulfosuccinate at a dose of 30 mg / kg / day had no effect on fecal consistency in beagle dogs. Further studies are required to determine the clinical efficacy and therapeutic role of dioctyl sodium sulfosuccinate in the management of the constipated cat.

Lubricant laxatives

Mineral oil and white petrolatum are the two major lubricant laxatives available for the treatment of constipation. The lubricating properties of these agents impede colonic water absorption and permit greater ease of fecal passage. These effects are usually moderate, however, and, in general, lubricants are beneficial only in mild cases of constipation. Mineral oil use should probably be limited to rectal administration because of the risk of aspiration pneumonia with oral administration, especially in depressed or debilitated cats.

Hyperosmotic laxatives

This group of laxatives consists of the poorly absorbed polysaccharides (e. g., lactose, lactulose), the magnesium salts (e. g., magnesium citrate, magnesium hydroxide, magnesium sulfate), and the polyethylene glycols. Lactose is not effective as a laxative agent in all cats. Lactulose is the most effective agent in this group. The organic acids produced from lactulose fermentation stimulate colonic fluid secretion and propulsive motility. Lactulose administered at a dose of 0.5 mL / kg body weight every 8 to 12 hours fairly consistently produces soft feces in the cat. Many cats with recurrent or chronic constipation have been well managed with this regimen of lactulose. The dose may have to be tapered in individual cases if flatulence and diarrhea become excessive. Magnesium salts are not currently recommended in the treatment of feline constipation and idiopathic megacolon. Some veterinarians have reported anecdotal successes with the polyethylene glycols.

Stimulant laxatives

The stimulant laxatives (bisacodyl, phenolphthalein, castor oil, cascara, senna) are a diverse group of agents that have been classified according to their ability to stimulate propulsive motility. Bisacodyl, for example, stimulates NO-mediated epithelial cell secretion and myenteric neuronal depolarization. Diarrhea results from the combined effect of increased mucosal secretion and colonic propulsion. Bisacodyl (at a dose of 5 mg orally, every 24 hours) is the most effective stimulant laxative in the cat. It may be given individually or in combination with fiber supplementation for long-term management of constipation. Daily administration of bisacodyl should probably be avoided, however, because of injury to myenteric neurons with chronic use.

Colonic Prokinetic Agents

Previous studies of feline colonic smooth muscle function have suggested that stimulation of colonic smooth muscle contraction might improve colonic motility in cats affected with idiopathic dilated megacolon. Unfortunately, many of the currently available gastrointestinal prokinetic agents have not proved useful in the therapy of feline constipation, either because of significant side effects (e. g., bethanechol) or because the prokinetic effect is limited to the proximal gastrointestinal tract (e. g., metoclopramide, domperidone, erythromycin). The 5-HT4 serotonergic agonists (e. g., cisapride, prucalopride, tegaserod, mosapride) appear to have the advantage of stimulating motility from the gastroesophageal sphincter to the descending colon with relatively few side effects. Cisapride, for example, increases gastroesophageal sphincter pressure, promotes gastric emptying, and enhances small intestinal and colonic propulsive motility. Cisapride enhances colonic propulsive motility through activation of colonic neuronal or smooth muscle 5-HT receptors in a number of animal species. In vitro studies have shown that cisapride stimulates feline colonic smooth muscle contraction, although it has not yet been conclusively shown that cisapride stimulates feline colonic propulsive motility in vivo. A large body of anecdotal experience suggests that cisapride is effective in stimulating colonic propulsive motility in cats affected with mild to moderate idiopathic constipation; cats with long-standing obstipation and megacolon are not likely to show much improvement with cisapride therapy. Cisapride was widely used in the management of canine and feline gastric emptying, intestinal transit, and colonic motility disorders throughout most of the 1990s. Cisapride was withdrawn from the American, Canadian, and certain Western European countries in July 2000 after reports of untoward cardiac side effects in human patients. Cisapride causes QT interval prolongation and slowing of cardiac repolarization via blockade of the rapid component of the delayed rectifier potassium channel (IKr). This effect may result in a fatal ventricular arrhythmia referred to as torsades de pointes. Similar effects have been characterized in canine cardiac Purkinje fibers, but in vivo effects have not yet been reported in dogs or cats. The withdrawal of cisapride has created a clear need for new gastrointestinal prokinetic agents, although cisapride continues to be available from compounding pharmacies throughout the United States. Two new prokinetic agents, tegaserod and prucalopride, are in differing stages of drug development and may prove useful in the therapy of gastrointestinal motility disorders of several animal species.

Tegaserod is a potent partial nonbenzamide agonist at 5-HT4 receptors and a weak agonist at 5-HT1D receptors. Tegaserod has definite prokinetic effects in the canine colon, but it has not yet been studied in the feline colon. Intravenous doses of tegaserod (0.03 to 0.3 mg / kg) accelerate colonic transit in dogs during the first hour after intravenous administration. Tegaserod at doses of 3 to 6 mg / kg orally has also been shown to normalize intestinal transit in opioid-induced bowel dysfunction in dogs, and it may prove useful in other disorders of intestinal ileus or pseudo-obstruction. Gastric effects of tegaserod have not been reported in the dog, so this drug may not prove as useful as cisapride in the treatment of delayed gastric emptying disorders. In vitro studies suggest that tegaserod does not prolong the QT interval or delay cardiac repolarization as has been occasionally reported with cisapride. Tegaserod was marketed under the trade name of Zelnorm in the United States in September 2002 for the treatment of constipation-predominant IBS in women. As with many other drugs in companion animal medicine, tegaserod has not been licensed for the treatment of canine or feline gastrointestinal motility disorders.

Prucalopride is a potent 5-HT4 receptor agonist that stimulates giant migrating contractions and defecation in the dog and cat. Prucalopride also appears to stimulate gastric emptying in the dog. In lidamidine-induced delayed gastric emptying in dogs, prucalopride (0.01 to 0.16 mg / kg) dose-dependendy accelerates gastric emptying of dextrose solutions. Prucalopride has not yet been marketed in the United States or elsewhere.

Misoprostol is a prostaglandin E, analogue that reduces the incidence of nonsteroidal anti-inflammatory drug (NSAID)-induced gastric injury. The main side effects of misoprostol therapy are abdominal discomfort, cramping, and diarrhea. Studies in dogs suggest that prostaglandins may initiate a giant migrating complex pattern and increase colonic propulsive activity. In vitro studies of misoprostol show that it stimulates feline and canine colonic smooth muscle contraction. Given its limited toxicity, misoprostol may be useful in cats (and dogs) with severe refractory constipation.

Ranitidine and nizatidine, classic histamine H2 receptor antagonists, may also stimulate canine and feline colonic motility. These drugs stimulate contraction apparently through inhibition of tissue acetylcholinesterase and accumulation of acetylcholine at the motor endplate. It is not yet clear how effective these drugs are in vivo, although both drugs stimulate feline colonic smooth muscle contraction in vitro. Cimetidine and famotidine, members of the same classification of drug, are without this effect.

Constipation; Surgery

Colectomy should be considered in cats that are refractory to medical therapy. Cats have a generally favorable prognosis for recovery after colectomy, although mild to moderate diarrhea may persist for weeks to months postoperatively in some cases. Although pathologic hypertrophy may be reversible with early pelvic osteotomy in some cases, subtotal colectomy is an effective treatment for this condition regardless of duration, and pelvic osteotomy is not required.

Prognosis of Constipation

Many cats have one or two episodes of constipation without further recurrence, although others may progress to complete colonic failure. Cats with mild to moderate constipation generally respond to conservative medical management (e. g., dietary modification, emollient or hyperosmotic laxatives, colonic prokinetic agents). Early use of colonic prokinetic agents (in addition to one or more laxative agents) is likely to prevent the progression of constipation to obstipation and dilated megacolon in these cats. Some cats may become refractory to these therapies, however, as they progress through moderate or recurrent constipation to obstipation and dilated megacolon. These cats eventually require colectomy. Cats have a generally favorable prognosis for recovery after colectomy, although mild to moderate diarrhea may persist for 4 to 6 weeks postoperatively in some cases.

Veterinary Medicine

Recovery And Analgesia

Recovery involves ventilation with 100% oxygen. The endotracheal tube is removed once the bird will no longer tolerate its presence. Regardless of the anesthetic used, practically all patients will appear disorientated and will attempt to flap their wings during recovery. Every attempt should be made to gently constrain them (without restricting respiration) to ensure that they do not damage their wings / feathers. This can be best achieved by lightly wrapping them in a towel. Usually with isoflurane anesthesia, recovery is over in 5-10 minutes, however if ketamine is used recovery may take much longer. During any recovery period the environmental temperature should be kept in the 25-30 °C range to prevent hypothermia developing. Keeping the recovery area quiet and dimly lit to ensure minimal adverse stimulation is advised.

The patient should be encouraged to take food as soon as it is able, again to minimise the deleterious effects of hypoglycaemia seen in these high metabolic rate species.


Analgesia has been shown to reduce the time taken for an avian patient to return to normal eating and preening behaviour, to reduce levels of anesthetic required if administered preoperatively, and to result in less wound breakdowns due to self-trauma (Table Commonly used analgesics in birds).

Table Commonly used analgesics in birds

Analgesic drug Dose rate Dosing interval
Butorphanol 1-4mg / kg subcutaneously, intramuscularly

0.02-0.04 mg / kg intravenously

Buprenorphine 0.02-0.06 mg / kg subcutaneously, intramuscularly q8-12h
Meloxicam 0.1-0.2 mg / kg subcutaneously, intramuscularly, peros q24h
Carprofen 2-4 mg / kg subcutaneously, peros q24h

(SC = subcutaneously; IM = intramuscularly; IV = intravenously; PO = peros; q6h = every 6 hours; q8h = every 8 hours; q12h = every 12 hours; q24h = every 24 hours)

Opioids such as butorphanol at 3-4mg / kg have been used in cockatoos and African grey parrots. Doses may need to be repeated three times daily due to its relatively short-acting properties. It does however have some respiratory suppression side effects and requires liver metabolism to be excreted. Other opioids used include buprenorphine at doses of 0.1 mg / kg intravenously or intramuscularly twice daily. Buprenorphine is a predominant μ opioid receptor partial agonist and studies in pigeons at least have suggested that birds’ central nervous system receptors are mainly K rather than p.. Butorphanol therefore may be the preferred opioid in many birds.

Non-steroidal anti-inflammatory drugs (NSAIDs), such as carprofen at 4-5 mg / kg once daily, have been used. Others include meloxicam at 0.2-0.3 mg / kg once daily. As these are all NSAIDs particular care should be taken in patients with gastrointestinal or renal disease; avian patients, due to their kidney structure, are more sensitive to some of these side effects than their mammalian counterparts. This is particularly so in some birds of prey such as the Indian white-necked vulture (Gyps bengalensis) which has been nearly wiped out by the NSAID diclofenic acid used in cattle, the fallen carcases of which formed a large part of its diet. The cause of death has been well reported as kidney damage. This author has found meloxicam to be generally safe in many species including many birds of prey such as vultures, however care should still be used in novel species. Concurrent fluid therapy is often advised when using NSAIDs, with or without gastrointestinal protectants such as sucralfate and cimetidine.



Gastric Erosion And Ulceration

Gastric erosions and ulcers are associated with a number of primary gastric and non-gastric disorders (Table Association of Gastric Ulceration and Erosion with Specific Diseases). Clinical signs range in duration and severity, from acute to chronic and mild to life threatening. The pathomechanisms underlying gastric damage can be broadly attributed to impairment of the gastric mucosal barrier (defined above) through direct injury, interference with gastroprotective prostaglandins (PGE2), mucous or bicarbonate, decreased blood flow, and hypersecretion or gastric acid.

Association of Gastric Ulceration and Erosion with Specific Diseases

Gastric Problem Related Diseases
Metabolic / Endocrine Hypoadrenocorticism, uremia, liver disease, mastocytosis, d. i. c.
Hypergastrinemia and other APUDomas
Inflammatory Gastritis
Neoplastic Leiomyoma, adenocarcinoma, lymphosarcoma
Drug-induced Nonsteroidal and steroidal anti-inflammatories
Hypotension Shock, sepsis
Idiopathic Stress, spinal surgery, exercise induced (sled dogs)


Perhaps the most predictable recipe for gastric erosion is the combination of a non-steroidal anti-inflammatory and a glucocorticoid, either alone, or in combination with interver-tebral disk disease.

Nonsteroidal anti-inflammatory drugs cause direct mucosal damage and interfere with prostaglandin synthesis. Flunixin mcglumine, aspirin, and ibuprofen have all been associated with erosions in healthy dogs. To circumvent toxicity caused by the inhibition of “friendly prostaglandins” (PGE2), drugs that preferentially block “inducible” cyclooxygenase (COX-2) have been developed. These COX-2 selective agents, such as carprofen, meloxicam, derccoxib, and potentially etodolac, are less ulcerogenic in normal dogs. However, even COX-2 selective drugs such as meloxicam are ulcerogenic in combination with dexamethasone, and their safety in sick animals remains to be determined.

High doses of glucocorticoids alone, such as dexamethasone and methylprednisolone, have also been associated with gastric erosions but the mechanisms by which they induce damage are not clear. Unlike NSAIDs, their effects are not ameliorated by PGE2 analogs.

Hypersecretion of gastric acid in response to histamine release from mast cell tumors, and gastrin from gastrinomas has also been clearly implicated as a cause of gastroduodenal ulceration and esophagitis in dogs and cats.

Renal failure, hepatic failure, hypoadrenocorticism, and hypotension are frequently proposed as risk factors for gastric erosion or ulceration, although few details have been published on the pathogenesis, frequency, or severity of gastric damage in these conditions. In a recent study of dogs with renal failure, ulceration was present in only 1 of 28 dogs. The predominant findings in these dogs were mucosal edema, vasculopathy, and mineralization that correlated to the degree of azotemia and calcium phosphorous product.

Sled dogs in the Iditarod are prone to develop gastric erosions and / or ulcers. This finding is similar to exercising humans and horses in whom the pathogensis is not understood hut is responsive to acid suppression.

Erosions and ulcers are aJso a sequela of gastric cancer and gastritis and are discussed elsewhere in this chapter.

Clinical Findings

Vomiting, hematemesis, and melena may be present in patients with gastric erosions or ulcers. Pale mucous membranes, abdominal pain, weakness, inappetance, hypcrsalivation (potentially associated with esophagitis as a consequence of gastric acid hypersecretion), and evidence of circulatory compromise are more variably present. Access to toxins and drugs, particularly NSAlDs, should be determined.

Clinicopathologic testing is directed at identifying diseases associated with gastric erosions and ulcers (see Table Association of Gastric Ulceration and Erosion with Specific Diseases) and the consequences of erosion / ulceration. The complete blood count may reveal anemia that is initially regenerative but can progress to become microcytic, hypochromic, and minimally regenerative. When accompanied by thromhocytosis and decreased iron saturation or low serum ferritin, these findings are characteristic of chronic bleeding and iron deficiency. Lack of a stress leukogram and eosiniphilia in dogs is supportive of hypoadrenocorticism. Eosinophilia could also be consistent with dietary allergy, eosinophilic gastroenteritis, mastocytosis, or a hyperseosinophilic syndrome. A neutrophilic leukocytosis and a left shift may indicate inflammation or possible gastric perforation. Examination of a buffy coat smear may help to detect mastocytosis.

Biochemistry and urinalysis may reveal findings consistent with dehydration (azotemia and hypersthcnuria), renal failure (e. g., azotemia and isosthenuria), hepatic disease (e. g., increased liver enzymes or bilirubin; decreased cholesterol, albumin, BUN], or hypoadrenocorticism (i. e., Na+:K+ ratio <27:1). It will also identify electrolyte and acid base abnormalities associated with vomiting and gastrointestinal ulceration. The presence of a metabolic alkalosis, hypochloremia, hypokalemia, and acid urine is consistent with upper gastrointestinal obstruction (physical or functional) or a hypersecretory state. Testing should be performed to detect abnormalities in primary and secondary hemostasis that may be associated with gastrointestinal bleeding. Serum gastrin and potentially histamine concentrations can be evaluated where acid hypersecretion is suspected as a cause of ulceration.


Diagnostic imaging

Plain radiographs are not usually helpful in diagnosing gastric erosions or ulcers but may help to rule out other causes of vomiting, such as foreign bodies, peritonitis, and gastric perforation. Contrast radiographs may reveal filling defects but do not allow detailed mucosal evaluation or sampling.

Ultrasonography can be performed to evaluate the gastric wall for thickening associated with ulcers and masses and also helps to rule out non-gastric causes of vomiting. The information provided by radiography and ultrasound is complementary to endoscopic evaluation, which is the diagnostic test of choice.

Endoscopy allows the direct evaluation of gastric damage and mucosal sampling. NSAID-associated ulcers tend to be found in the antxum and are not usually associated with marked mucosal thickening or irregular edges. This contrasts with ulcerated tumors that frequently have thickened edges and surrounding mucosa. Ulcers should be biopsied at the periphery to avoid perforation. Endoscopic biopsies are not ideal for diagnosing infiltrative gastric tumors and several biopsies from the same site are usually taken to enable sampling of deeper tissue. Endoscopic guided fine-needle aspirates, with use of a needle and tubing in the biopsy channel, can also be used to sample deep lesions. Even with this approach the diagnosis may be missed, and surgical biopsy required for a definitive diagnosis.

The combination of mucosal erosion or ulceration, antral mucosal hypertrophy, copious gastric juice, and esophagitis is highly suggestive of a gastric hypersecretory state. It is prudent to measure gastric pH and serum gastrin in patients with gastric erosion / ulceration that is not associated with drugs or gastric tumors. Dogs with mast cell tumors and hyperhistaminemia-induced acid hypersecretion have low serum gastrin concentrations. Finding a combination of gastric pH less than 3 and a high serum gastrin concentration prompts further investigation of gastrinoma by secretin stimulation test, ultrasonography (liver and pancreas), and pentertreotide scintigraphy.


Treatment of gastric erosions and ulcers is directed at the underlying cause, which ensures adequate hydration and perfusion, including blood transfusion if needed, and restoring electrolyte and acid base disturbances. Additional support is directed at shoring up the gastric mucosal barrier by enhancing mucosal protection and cytoprotection, and decreasing gastric acid secretion. Where vomiting is persistent, antiemetics may help to reduce fluid loss, discomfort, and the risk of esophagitis.

Fluid Therapy

The rate of fluid administration depends on the presence or absence of shock, the degree of dehydration, and the presence of diseases (e. g., cardiac or renal), which predispose to volume overload. Patients with a history of vomiting who are mildly dehydrated are usually responsive to crystalloids (e. g., LRS or 0.9% NaCl) at a rate that will provide maintenance and replace both deficits and ongoing losses over a 24-hour period. Potassium depletion is often a consequence of prolonged vomiting or anorexia, and most polyionic replacement fluids contain only small amounts of potassium. Therefore KC1 is added to parenteral fluids on the basis of serum levels.

Patients with signs of shock require more aggressive support. The volume deficit can be replaced with crystalloids at an initial rate of 60 to 90 mLAg / h, then tailored to maintain tissue perfusion and hydration. Colloid solutions can also be used to treat animals in shock to reduce the amount of crystalloid required (e. g., Hetastarch, hemaccel at 10 to 20 mL / kg IV over 4 to 6 hours). Plasma, colloids, packed cells, or whole blood is occasionally required to treat severe hypoproteinemia or anemia, which can develop in vomiting animals with severe ulceration or HGE.

Central venous pressure monitoring and evaluation of urine output are necessary in patients with severe gastrointestinal disease, particularly those complicated by third space losses of fluid into the gut or peritoneum.

The effect of vomiting on acid-base balance is hard to predict and therapeutic intenention to correct acid-base imbalances should be based on blood gas determination. Where severe metabolic acidosis is present (pH <7.1, HCO3- <10 mmol / L), sodium bicarbonate (l mmolAg) can be given under careful supervision for the development of worsening hypokalemia, and hypocalcemia, and CSF acidosis. Further bicarbonate supplementation is based on repeated blood gas analysis. Metabolic alkalosis usually responds to replacing volume deficit, chloride, and potassium with IV 0.9% NaCl + KG. Diagnostic investigations should initially center on ruling out upper gastrointestinal obstruction. The administration of antisecretory drugs such as H2 antagonists may help to limit Cl–efflux into gastric juice.

Reducing Acid Secretion and Providing Mucosal Protection

Pharmacologic inhibition of acid secretion can be effected by blocking H2 (cimeridine, ranitidine, famotidine), gastrin (proglumide), and acetylcholine (atropine, pirenzipine) receptors, and by inhibiting adenyl cyclase (PGE analogs) and H+/K+ ATPase (e. g., omeprazole). H Long-acting somatostatin analogs such as octreotide directly decrease the secretion of gastrin and gastric acid.

Decreasing gastric acid secretion with an H2 receptor antagonist has been shown to promote mucosal healing in dogs with a variety ot experimentally induced ulcers and erosions. Famotidine is an attractive choice as it does not inhibit P450 enzymes and can be given once daily. The additional prokinetic activity of ranitidine or nizatidine (mediated by anticholinesterase activity) may make them good choices in the face of delayed gastric emptying associated with defective propulsion. In patients with severe or persistent gastric ulceration that is refractory to H2 antagonists, more complete inhibition of gastric acid secretion can be achieved with a H+/K+-ATPase inhibitor such as omeprazole (0.2 to 0.7 mg / kg SID PO—dogs). Omeprazole is the initial drug of choice in patients with acid hypersecretion secondary to r. ast cell tumors and gastrinoma (Zollinger-Ellison syndrome). Omeprazole has been shown to have few long-term side effects in dogs, but it should be used with caution in patients with liver disease and reviewed for interactions with drugs such as cisapride.

In sled dogs with exercise-associated gastric hemorrhage treatment with omeprazole significantly reduced mean gastric severity score compared to placebo but also was associated with increased frequency of diarrhea (omeprazole 54%, placebo 21%). The authors recommended further investigation of diarrhea associated with omeprazole treatment hefore omeprazole can be recommended for routine prophylactic treatment in these athletes.

The combination of omeprazole and the long acting somatostatin analog Octreotide effectively reduced vomiting in a dog with gastrinoma (Octreotide 2 to 20 μg / kg SC TID). Octreotide can also be employed to rapidly decrease gastric acid secretion in patients discovered to have large ulcers at endoscopy and may also be useful for controlling gastric bleeding (see human studies).

Mucosal Protectants

The PGE2 analog, misoprostol, protects against NSA1D-induced erosions in dogs at doses that do not inhibit acid secretion (3 to 5 μg / kg PO TID in dogs) and may be given to dogs receiving chronic NSAIDs for arthritis. The main side effect of misoprostol is diarrhea and it should not be given to pregnant animals.

The mucosal protectant polyaluminum sucrose sulfate (sucralfate) binds to areas denuded of mucosal epithelium regardless of the underlying cause and is useful lor treating gastric erosions and ulcers and esophagitis. Sucralfate can be given to patients receiving injectable antacids, but it may compromise absorption of other oral medications and is probably best separated from these by 2 hours or so.

In contrast to the efficacy of misoprostol and H2 antagonists in preventing NSAID-induced erosions, the prophylactic administration of various combinations of misoprostol, cimetidine, and omeprazole has not been shown to prevent gastric erosions in dogs with or without intervertebral disk disease receiving high-dose glucocorticoids. However, these drugs may speed healing of gastric lesions in these patients. Sucralfate is probably the drug of choice for treating gastrointestinal ulceration in patients receiving high doses of corticosteroids because it is not dependent on the premise that acid is causing or delaying healing.

Mast cell tumors are also worth considering separately as gastric ulceration is a frequent and severe complication. Mast cell tumors are thought to cause vomiting via the central effects of histamine on the CRTZ and the peripheral effects of histamine on gastric acid secretion (with resultant hyperacidity and ulceration). Treatment of mastocyosis with H1 and H2 histamine antagonists (e. g., diphenhydramine and famotidine) should reduce the central and peripheral effects of histamine. Corticosteroids are used to decrease tumor burden. Where acid hypersecretion is present, or is suspected, it is likely best managed with proton pump inhibitors (e. g., omeprazole 0.2 to 0.7 mg / kg SID). Somatostatin analogs may also be useful for controlling refractory gastric acid hypersecretion (Octreotide 2 to 20 μg / kg SC TID).


Antiemetics can be used where vomiting is severe or compromising fluid and electrolyte balance, or causing discomfort. The initial agent used in dogs is usually metoclopramide, which antagonizes D2-dopaminergic and 5HT3-serotonergic receptors and has cholinergic effects on smooth muscle (1 mg / kg / 24h CRI IV). Phenothiazine derivatives such as chlorpromazine and prochlorperazine are antagons of alpha1 and alpha2-adrenergic, H1 -and H2-histaminergic, and D2-dopaminergic receptors in the vomiting center and CRTZ and are used if metoclopramide is ineffective and the patient is normotensive. Nonselective cholinergic receptor antagonists (other than the M1 specific antagonist- pirenzipine) such as atropine, scopolamine, aminopentamide, and isopropamide are generally avoided as they may cause ileus, delayed gastric emptying, and dry mouth.

Antibiotics and Analgesia

Prophylactic antibiotic cover (e. g., cephalosporins, ampicillin) may be warranted in animals with shock and major gastrointestinal barrier dysfunction. Leukopenia, neutrophilia, fever, and bloody stools are additional indications for prophylactic antibiotics in animals with vomiting or diarrhea. Initial choices in these situations include ampicillin or a cephalosporin (effective against gram-positive and some gram-negative and anaerobic bacteria), which can be combined with an aminoglycoside (effective against gram-negative aerobes) when sepsis is present and hydration status is adequate, Enrofloxacin is a suitable alternative to an aminoglycoside in skeletally mature patients at risk of nephrotoxicity from an aminoglycoside.

Analgesia can be provided using opioids like buprenor-phine (0.0075 to 0.01 mg / kg IM).

Surgery may be required when the cause of ulceration is unclear or to resect large non-healing ulcers or those about to perforate.

Veterinary Medicine

What is the best treatment for chemotherapy-induced renal failure?

The initial goals for treating drug- and tumor-related acute renal failure in dogs and cats are to discontinue all drugs that may be nephrotoxic, to document prerenal or postrenal abnormalities, and to initiate fluid therapy. The primary objectives of fluid therapy are to correct deficits such as dehydration and excesses such as volume overload, as seen in oliguric renal failure; to supply maintenance needs; and to supplement ongoing losses, such as those due to vomiting and diarrhea. Each patient must be assessed carefully, and a treatment plan must be based on hydration status, cardiovascular performance, and biochemical data. Maintenance requirements vary from 44-110 ml/kg body weight; smaller animals require the larger amount. A simpler formula is to use 66 ml/kg/day. The amount of fluid that is needed daily for maintenance must be supplemented by an amount equal to external losses due to vomiting and diarrhea. In patients with renal failure, 1.5-3 times this amount of fluid is administered daily to achieve diuresis. The success of diuresis can be monitored by documenting adequate urine output (> 2 ml/kg/hr). Fluid therapy should meet daily needs, replace excessive losses, and correct dehydration. The percentage of dehydration should be determined; approximately 75% of the fluids needed to correct dehydration should be administered during the first 24 hours. Fluid therapy should be altered to correct electrolyte and acid-base abnormalities. In acute renal failure, potassium-containing fluids generally are not ideal because systemic hyperkalemia is often present. Until more is known about the systemic effects of sepsis, lactate-containing fluids should be avoided because sepsis and cancer are associated with hyperlactatemia, which worsens with administration of lactate-containing fluids.

Fluid Therapy for a 10-kg Dog with 5% Dehydration and Diarrhea

1. Correct dehydration. 5% (0.05) x 10 kg body weight = 0.5 kg of water needed to correct dehydration.
1000 mk/kg of water x 0.5 kg = 500 ml of water needed to correct dehydration.
75% (0.75) x 500 ml = 375 ml of fluid should be adminstered to replace 75% of dehydration.
2. Administer fluids to meet daily needs. 66 ml/kg (daily requirement) x 10 kg body weight = 660 ml needed on daily basis. Other believe that daily requirements are best estimated as [30 (kg)+ 70].
3. Replace ongoing losses. Estimated losses through diarrhea = 200 ml.
4. Fluids needed, first 24 hr. 375 ml + 660 ml + 200 ml = 1235 ml; increase fluid therapy judiciously to increase urine output to sustain mild-to-moderate diuresis.

General Approach for a Dog in Renal Failure

Stop administration of nephrotoxins. Discontinue cisplatin, methotrexate, doxorubicin, and aminoglycosides; avoid anesthesia.
Assess patient status. Complete blood count, blood chemistry profile
Specifically determine:
% dehydration
Amount of ongoing losses (e.g., vomiting, diarrhea, blood loss)
Maintenance of fluid requirements
Electrolyte and biochemical abnormalities
Cardiovascular performance
Urine output
Select and administer specific fluids. Tailor therapy to needs of each patient.
Isotonic polyionic fluid initially, preferably potassium-free (e.g., NaCl).
Correct dehydration first over 6-8 hr to prevent further renal ischemia while watching carefully for pathologic oliguria and subsequent volume overload.
Meet maintenance requirements (approximately 66 ml/kg/day).
Meet ongoing losses (vomiting, diarrhea)
Induce mild-to-moderate diuresis.
Monitor urine output, ensure adequate output. Metabolism cage or indwelling catheter.
For inadequate output (< 0.5-2 ml/kg/hr):
Mannitol or dextrose, 0.5-1.0 gm/kg in slow IV bolus
Furosemide, 2-4 mg/kg IV every 1-3 hr as needed
Dopamine, 1-3 |ig/kg/min IV (50 mg dopamine in 500 ml of 5% dextrose = 100 |ig/ml solution)
Correct acid-base and electrolyte abnormalities. Rule out hypercalcemia of malignancy; treat specifically for that if identified.
Provide mild-to-moderate diuresis. Urine output: 2-5 ml/kg/hr; monitor body weight, heart and respiratory rate, and central venous pressure for signs of overhydration.
Consider peritoneal dialysis if not responsive. Temporary or chronic ambulatory peritoneal dialysis with specific dialysate solution may be helpful.
Initiate long-term plans. Continue diuresis until blood urea nitrogen and creatinine normalize or until values stop improving despite aggressive therapy and clinically stable patient; then gradually taper fluids.
Control hyperphosphatemia if indicated (e.g., aluminum hydroxide, 500 mg at each feeding).
Treat gastric hyperacidity if indicated (cimetidine, 5-10 mg/kg every 6hr IV or orally).

If oliguric renal failure is present, a diligent and aggressive approach should be made to increase urine output, first by increasing glomerular filtration rate and renal blood flow. In addition, osmotic diuresis can be used to increase urine flow. If urine output is less than 0.5-2 ml/kg/hr despite aggressive fluid therapy, furosemide should be administered every 1-3 hours. Furosemide increases glomerular filtration rate and enhances diuresis in many patients. If furosemide is not effective, mannitol or 50% dextrose may be used as an osmotic diuretic to enhance urine production. The advantage of dextrose over mannitol is that dextrose can be detected on a urine glucose test strip. If furosemide and osmotic diuretics are not effective, dopamine may be administered as a constant-rate infusion. Dopamine enhances renal blood flow and increases urine output secondarily.

Treatment for acute renal failure should be continued until the patient is substantially improved and until abnormal biochemical parameters have been corrected or at least stabilized. Therapy then should be tapered over several days and a home treatment plan developed, including avoidance of nephrotoxic drugs, high-quality, low-quantity protein diet, maintenance of a low stress environment, and provision of fresh, clean water at will.