Categories
Drugs

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

Antifungal

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.

Pharmacokinetics

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)

Categories
Drugs

Ammonium Chloride (Uroeze)

Acidifying Agent

Highlights Of Prescribing Information

Urinary acidifier; treatment of metabolic alkalosis

Contraindicated in patients with hepatic failure or uremia

Potential adverse effects are primarily GI distress; IV use may lead to metabolic acidosis

May increase excretion of quinidine; decrease efficacy of erythromycin or aminoglycosides in urine

What Is Ammonium Chloride Used For?

The veterinary indications for ammonium chloride are as a urinary acidifying agent to help prevent and dissolve certain types of uroliths (e.g., struvite), to enhance renal excretion of some types of toxins (e.g., strontium, strychnine) or drugs (e.g., quinidine), or to enhance the efficacy of certain antimicrobials (e.g., chlortetracycline, methenamine mandelate, nitrofurantoin, oxytetracycline, penicillin G or tetracycline) when treating urinary tract infections. Ammonium chloride has also been used intravenously for the rapid correction of metabolic alkalosis.

Because of changes in feline diets to restrict struvite and as struvite therapeutic diets (e.g., s/d) cause aciduria, ammonium chloride is not commonly recommended for struvite uroliths in cats.

Pharmacology / Actions

The acidification properties of ammonium chloride are caused by its dissociation into chloride and ammonium ions in vivo. The ammonium cation is converted by the liver to urea with the release of a hydrogen ion. This ion combines with bicarbonate to form water and carbon dioxide. In the extracellular fluid, chloride ions combine with fixed bases and decrease the alkaline reserves in the body. The net effects are decreased serum bicarbonate levels and a decrease in blood and urine pH.

Excess chloride ions presented to the kidney are not completely reabsorbed by the tubules and are excreted with cations (principally sodium) and water. This diuretic effect is usually compensated for in the kidneys after a few days of therapy.

Pharmacokinetics

No information was located on the pharmacokinetics of this agent in veterinary species. In humans, ammonium chloride is rapidly absorbed from the GL

Before you take Ammonium Chloride

Contraindications / Precautions / Warnings

Ammonium chloride is contraindicated in patients with severe hepatic disease as ammonia may accumulate and cause toxicity. In general, ammonium chloride should not be administered to uremic patients since it can intensify the metabolic acidosis already existing in some of these patients. As sodium depletion can occur, ammonium chloride should not be used alone in patients with severe renal insufficiency and metabolic alkalosis secondary to vomiting hydrochloric acid. In these cases, sodium chloride repletion with or without ammonium chloride administration should be performed to correct both sodium and chloride deficits. Ammonium chloride is contraindicated in patients with urate calculi or respiratory acidosis and high total CO2 and buffer base. Ammonium chloride alone cannot correct hypochloremia with secondary metabolic alkalosis due to intracellular potassium chloride depletion; potassium chloride must be administered to these patients.

Do not administer subcutaneously, rectally or intraperitoneally Use ammonium chloride with caution in patients with pulmonary insufficiency or cardiac edema.

Adverse Effects

Development of metabolic acidosis (sometimes severe) can occur unless adequate monitoring is performed. When used intravenously, pain at the injection site can develop; slow administration lessens this effect. Gastric irritation, nausea and vomiting may be associated with oral dosing of the drug. Urinary acidification is associated with an increased risk for calcium oxalate urolith formation in cats.

Overdosage / Acute Toxicity

Clinical signs of overdosage may include: nausea, vomiting, excessive thirst, hyperventilation, bradycardias or other arrhythmias, and progressive CNS depression. Profound acidosis and hypokalemia maybe noted on laboratory results.

Treatment should consist of correcting the acidosis by administering sodium bicarbonate or sodium acetate intravenously. Hypokalemia should be treated by using a suitable oral (if possible) potassium product. Intense acid-base and electrolyte monitoring should be performed on an ongoing basis until the patient is stable.

Reproductive / Nursing Safety

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 (), this drug is categorized as in class: B (Safe for use if used cautiously. Studies in laboratory animals may have uncovered some risk, hut these drugs appear to he safe in dogs and cats or these drugs are safe if they are not administered when the animal is near term.)

How to use Ammonium Chloride

Ammonium Chloride dosage for dogs:

For urine acidification:

a) As adjunctive therapy for struvite uroliths: 20 mg/kg PO three times daily ()

b) To enhance the renal elimination of certain toxins/drugs: 200 mg/kg/day divided four times daily ()

c) To enhance elimination of strontium: 0.2-0.5 grams PO 3-4 times a day (used with calcium salts) ()

For ATT (ammonia tolerance testing):

a) 2 mL/kg of a 5% solution of ammonium chloride deep in the rectum, blood sampled at 20 minutes and 40 minutes; or oral challenge with ammonium chloride 100 mg/kg (maximum dose = 3 grams) either in solution: dissolved in 20-50 mL warm water or in gelatin capsules, blood sampled at 30 and 60 minutes. Test may also be done by comparing fasting and 6-hour postprandial samples without giving exogenous ammonium chloride. (Center 2004)

Ammonium Chloride dosage for cats:

For urine acidification:

a) In struvite dissolution therapy if diet and antimicrobials do not result in acid urine or to help prevent idiopathic FUS in a non-obstructed cat: 20 mg/kg PO twice daily ()

b) As adjunctive therapy for struvite uroliths: 20 mg/kg PO twice daily ()

c) 800 mg per day given in the food once daily (if diet and antimicrobials do not reduce pH) ()

Ammonium Chloride dosage for horses:

a) 4-15 grams PO ()

b) Ammonium chloride as a urinary acidifier: 60-520 mg/kg PO daily. Ammonium salts are unpalatable and will have to be dosed via stomach tube or dosing syringe. Alternatively, ammonium sulfate at 165 mg/kg PO per day is more palatable and may be accepted when mixed with grain or hay. ()

c) As a urinary acidifier to enhance renal excretion of strychnine: 132 mg/kg PO ()

Ammonium Chloride dosage for cattle:

For urolithiasis prevention:

a) 200 mg/kg PO ()

b) 15-30 grams PO ()

Ammonium Chloride dosage for sheep and goats:

For urolithiasis prevention:

a) 200 mg/kg PO ()

b) 1-2 grams PO ()

Client Information

■ Contact veterinarian if animal exhibits signs of nausea, vomiting, excessive thirst, hyperventilation or progressive lethargy

■ Powders may have a bitter taste and patients may not accept their food after mixing

Chemistry / Synonyms

An acid-forming salt, ammonium chloride occurs as colorless crystals or as white, fine or course, crystalline powder. It is somewhat hygroscopic, and has a cool, saline taste. When dissolved in water, the temperature of the solution is decreased. One gram is soluble in approximately 3 mL of water at room temperature; 1.4 mL at 100°C. One gram is soluble in approximately 100 mL of alcohol.

One gram of ammonium chloride contains 18.7 mEq of ammonium and chloride ions. The commercially available concentrate for injection (26.75%) contains 5 mEq of each ion per mL and contains disodium edetate as a stabilizing agent. The pH of the concentrate for injection is approximately 5.

Ammonium chloride may also be known as muriate of ammonia and sal ammoniac.

Storage / Stability / Compatibility

Ammonium chloride for injection should be stored at room temperature; avoid freezing. At low temperatures, crystallization may occur; it may be resolubolized by warming to room temperature in a water bath.

Ammonium chloride should not be titrated with strong oxidizing agents etc. potassium chlorate) as explosive compounds may result.

Ammonium chloride is reported to be physically compatible with all commonly used IV replacement fluids and potassium chloride. It is incompatible with codeine phosphate, dimenhydrinate, methadone HCL, nitrofurantoin sodium, sulfisoxazole diolamine, and warfarin sodium. It is also reportedly incompatible with alkalis and their hydroxides.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products:

Ammonium Chloride Tablets: 200 mg, 400 mg; UriKare 200, 400 Tablets (Neogen); (Rx). Approved for use in cats and dogs.

Ammonium Chloride Granules: 200 mg per V4 teaspoonful powder; Uroeze200 (Virbac), UriKare 200 (Neogen); (Rx) Approved for cats and dogs.

Ammonium Chloride Granules: 400 mg per V4 teaspoonful powder; Uroeze (Virbac), UriKare 400 (Neogen); (Rx) Approved for cats and dogs.

Ammonium chloride is also found in some veterinary labeled cough preparations e.g., Spect-Aid Expectorant Granules (7% guaifenesin, 75% ammonium chloride, potassium iodide 2%) and in some cough syrups (also containing guaifenesin, pyrilamine and phenylephrine).

When used in large animals, feed grade ammonium chloride can be obtained from feed mills.

Human-Labeled Products:

Ammonium Chloride Injection: 26.75% (5 mEq/mL) in 20 mL (100 mEq) vials. Must be diluted before infusion; generic; (Rx). Preparation of solution for IV administration: Dilute 1 or 2 vials (100-200 mEq) in either 500 or 1000 mL of sodium chloride 0.9% for injection. Do not administer at a rate greater than 5 mL/min (human adult).

Categories
Drugs

Aminophylline Theophylline

Phosphodiesterase Inhibitor Bronchodilator

Highlights Of Prescribing Information

Bronchodilator drug with diuretic activity; used for bronchospasm & cardiogenic pulmonary edema

Narrow therapeutic index in humans, but dogs appear to be less susceptible to toxic effects at higher plasma levels

Therapeutic drug monitoring recommended

Many drug interactions

What Is Aminophylline Theophylline Used For?

The theophyllines are used primarily for their broncho dilatory effects, often in patients with myocardial failure and/or pulmonary edema. While they are still routinely used, the methylxanthines must be used cautiously due to their adverse effects and toxicity.

Pharmacology/Actions

The theophyllines competitively inhibit phosphodiesterase thereby increasing amounts of cyclic AMP which then increase the release of endogenous epinephrine. The elevated levels of cAMP may also inhibit the release of histamine and slow reacting substance of anaphylaxis (SRS-A). The myocardial and neuromuscular transmission effects that the theophyllines possess maybe a result of translocating intracellular ionized calcium.

The theophyllines directly relax smooth muscles in the bronchi and pulmonary vasculature, induce diuresis, increase gastric acid secretion and inhibit uterine contractions. They have weak chronotropic and inotropic action, stimulate the CNS and can cause respiratory stimulation (centrally-mediated).

Pharmacokinetics

The pharmacokinetics of theophylline have been studied in several domestic species. After oral administration, the rate of absorption of the theophyllines is limited primarily by the dissolution of the dosage form in the gut. In studies in cats, dogs, and horses, bioavail-abilities after oral administration are nearly 100% when non-sustained release products are used. One study in dogs that compared various sustained-release products (), found bioavailabilities ranging from approximately 30-76% depending on the product used.

Theophylline is distributed throughout the extracellular fluids and body tissues. It crosses the placenta and is distributed into milk (70% of serum levels). In dogs, at therapeutic serum levels only about 7-14% is bound to plasma proteins. The volume of distribution of theophylline for dogs has been reported to be 0.82 L/kg. The volume of distribution in cats is reported to be 0.46 L/kg, and in horses, 0.85-1.02 L/kg. Because of the low volumes of distribution and theophylline’s low lipid solubility, obese patients should be dosed on a lean body weight basis.

Theophylline is metabolized primarily in the liver (in humans) to 3-methylxanthine which has weakbronchodilitory activity. Renal clearance contributes only about 10% to the overall plasma clearance of theophylline. The reported elimination half-lives (mean values) in various species are: dogs = 5.7 hours; cats = 7.8 hours, pigs = 11 hours; and horses = 11.9 to 17 hours. In humans, there are very wide interpatient variations in serum half-lives and resultant serum levels. It could be expected that similar variability exists in veterinary patients, particularly those with concurrent illnesses.

Before you take Aminophylline Theophylline

Contraindications / Precautions / Warnings

The theophyllines are contraindicated in patients who are hypersensitive to any of the xanthines, including theobromine or caffeine. Patients who are hypersensitive to ethylenediamine should not take aminophylline.

The theophyllines should be administered with caution in patients with severe cardiac disease, seizure disorders, gastric ulcers, hyperthyroidism, renal or hepatic disease, severe hypoxia, or severe hypertension. Because it may cause or worsen preexisting arrhythmias, patients with cardiac arrhythmias should receive theophylline only with caution and enhanced monitoring. Neonatal and geriatric patients may have decreased clearances of theophylline and be more sensitive to its toxic effects. Patients with CHF may have prolonged serum half-lives of theophylline.

Adverse Effects

The theophyllines can produce CNS stimulation and gastrointestinal irritation after administration by any route. Most adverse effects are related to the serum level of the drug and may be symptomatic of toxic blood levels; dogs appear to tolerate levels that may be very toxic to humans. Some mild CNS excitement and GI disturbances are not uncommon when starting therapy and generally resolve with chronic administration in conjunction with monitoring and dosage adjustments.

Dogs and cats can exhibit clinical signs of nausea and vomiting, insomnia, increased gastric acid secretion, diarrhea, polyphagia, polydipsia, and polyuria. Side effects in horses are generally dose related and may include: nervousness, excitability (auditory, tactile, and visual), tremors, diaphoresis, tachycardia, and ataxia. Seizures or cardiac dysrhythmias may occur in severe intoxications.

Reproductive / Nursing Safety

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.)

Overdosage / Acute Toxicity

Clinical signs of toxicity (see above) are usually associated with levels greater than 20 mcg/mL in humans and become more severe as the serum level exceeds that value. Tachycardias, arrhythmias, and CNS effects (seizures, hyperthermia) are considered the most life-threatening aspects of toxicity. Dogs appear to tolerate serum levels higher than 20 mcg/mL.

Treatment of theophylline toxicity is supportive. After an oral ingestion, the gut should be emptied, charcoal and a cathartic administered using the standardized methods and cautions associated with these practices. Patients suffering from seizures should have an adequate airway maintained and treated with IV diazepam. The patient should be constantly monitored for cardiac arrhythmias and tachycardia. Fluid and electrolytes should be monitored and corrected as necessary. Hyperthermia may be treated with phenothiazines and tachycardia treated with propranolol if either condition is considered life threatening.

How to use Aminophylline Theophylline

Note: Theophyllines have a low therapeutic index; determine dosage carefully. Because of aminophylline/theophylline’s pharmacokinet-ic characteristics, it should be dosed on a lean body weight basis in obese patients. Dosage conversions between aminophylline and theophylline can be easily performed using the information found in the Chemistry section below. Aminophylline causes intense local pain when administered IM and is rarely used or recommended via this route.

Aminophylline Theophylline dosage for dogs:

a) Using Theochron Extended-Release Tablets or Theo-Cap Extended-Release Capsules: Give 10 mg/kg PO every 12 hours initially, if no adverse effects are observed and the desired clinical effect is not achieved, give 15 mg/kg PO q12h while monitoring for adverse effects. ()

b) For adjunctive medical therapy for mild clinical signs associated with tracheal collapse (<50% collapse): aminophylline: 11 mg/kg PO, IM or IV three times daily. ()

c) For adjunctive therapy of severe, acute pulmonary edema and bronchoconstriction: Aminophylline 4-8 mg/kg IV or IM, or 6-10 mg/kg PO every 8 hours. Long-term use is not recommended. ()

d) For cough: Aminophylline: 10 mg/kg PO, IV three times daily ()

e) As a broncho dilator tor collapsing trachea: 11 mg/kg PO or IV q6- 12h ()

Aminophylline Theophylline dosage for cats:

a) Using Theo-Dur 20 mg/kg PO once daily in the PM; using Slo-Bid 25 mg/kg PO once daily in the PM (Johnson 2000) [Note: The products Theo-Dur and Slo-Bid mentioned in this reference are no longer available in the USA. Although hard data is not presently available to support their use in cats, a reasonable alternative would be to cautiously use the dog dose and products mentioned above in the reference by Bach et al — Plumb]

b) Using aminophylline tablets: 6.6. mg/kg PO twice daily; using sustained release tablets (Theo-Dur): 25-50 mg (total dose) per cat PO in the evening ()

c) For adjunctive medical therapy for mild clinical signs associated with tracheal collapse (<50% collapse): aminophylline: 5 mg/kg PO, two times daily. ()

d) For adjunctive therapy for bronchoconstriction associated with fulminant CHF: Aminophylline 4-8 mg/kg SC, IM, IV q8-12h. ()

e) For cough: Aminophylline: 5 mg/kg PO twice daily ()

Aminophylline Theophylline dosage for ferrets:

a) 4.25 mg/kg PO 2-3 times a day ()

Aminophylline Theophylline dosage for horses:

(Note: ARCI UCGFS Class 3 Aminophylline Theophylline)

NOTE: Intravenous aminophylline should be diluted in at least 100 mL of D5W or normal saline and administered slowly (not >25 mg/min). For adjunctive treatment of pulmonary edema:

a) Aminophylline 2-7 mg/kg IV q6- 12h; Theophylline 5-15 mg/kg PO q12h ()

b) 11 mg/kg PO or IV q8-12h. To “load” may either double the initial dose or give both the oral and IV dose at the same time. IV infusion should be in approximately 1 liter of IV fluids and given over 20-60 minutes. Recommend monitoring serum levels. ()

For adjunctive treatment for heaves (RAO):

a) Aminophylline: 5-10 mg/kg PO or IV twice daily. ()

b) Aminophylline: 4-6 mg/kg PO three times a day. ()

Monitoring

■ Therapeutic efficacy and clinical signs of toxicity

■ Serum levels at steady state. The therapeutic serum levels of theophylline in humans are generally described to be between 10-20 micrograms/mL. In small animals, one recommendation for monitoring serum levels is to measure trough concentration; level should be at least above 8-10 mcg/mL (Note: Some recommend not exceeding 15 micrograms/mL in horses).

Client Information

■ Give dosage as prescribed by veterinarian to maximize the drug’s benefit

Chemistry / Synonyms

Xanthine derivatives, aminophylline and theophylline are considered to be respiratory smooth muscle relaxants but, they also have other pharmacologic actions. Aminophylline differs from theophylline only by the addition of ethylenediamine to its structure and may have different amounts of molecules of water of hydration. 100 mg of aminophylline (hydrous) contains approximately 79 mg of theophylline (anhydrous); 100 mg of aminophylline (anhydrous) contains approximately 86 mg theophylline (anhydrous). Conversely, 100 mg of theophylline (anhydrous) is equivalent to 116 mg of aminophylline (anhydrous) and 127 mg aminophylline (hydrous).

Aminophylline occurs as bitter-tasting, white or slightly yellow granules or powder with a slight ammoniacal odor and a pKa of 5. Aminophylline is soluble in water and insoluble in alcohol.

Theophylline occurs as bitter-tasting, odorless, white, crystalline powder with a melting point between 270-274°C. It is sparingly soluble in alcohol and only slightly soluble in water at a pH of 7, but solubility increases with increasing pH.

Aminophylline may also be known as: aminofilina, aminophyllinum, euphyllinum, metaphyllin, theophyllaminum, theophylline and ethylenediamine, theophylline ethylenediamine compound, or theophyllinum ethylenediaminum; many trade names are available.

Theophylline may also be known as: anhydrous theophylline, teofillina, or theophyllinum; many trade names are available.

Storage / Stability/Compatibility

Unless otherwise specified by the manufacturer, store aminophylline and theophylline oral products in tight, light-resistant containers at room temperature. Do not crush or split sustained-release oral products unless label states it is permissible.

Aminophylline for injection should be stored in single-use containers in which carbon dioxide has been removed. It should also be stored at temperatures below 30°C and protected from freezing and light. Upon exposure to air (carbon dioxide), aminophylline will absorb carbon dioxide, lose ethylenediamine and liberate free theophylline that can precipitate out of solution. Do not inject aminophylline solutions that contain either a precipitate or visible crystals.

Aminophylline for injection is reportedly compatible when mixed with all commonly used IV solutions, but may be incompatible with 10% fructose or invert sugar solutions.

Aminophylline is reportedly compatible when mixed with the following drugs: amobarbital sodium, bretylium tosylate, calcium gluconate, chloramphenicol sodium succinate, dexamethasone sodium phosphate, dopamine HCL, erythromycin lactobionate, heparin sodium, hydro cortisone sodium succinate, lidocaine HCL, mephentermine sulfate, methicillin sodium, methyldopate HCL, metronidazole with sodium bicarbonate, pentobarbital sodium, phenobarbital sodium, potassium chloride, secobarbital sodium, sodium bicarbonate, sodium iodide, terbutaline sulfate, thiopental sodium, and verapamil HCL

Aminophylline is reportedly incompatible (or data conflicts) with the following drugs: amikacin sulfate, ascorbic acid injection, bleomycin sulfate, cephalothin sodium, cephapirin sodium, clindamycin phosphate, codeine phosphate, corticotropin, dimenhydrinate, dobutamine HCL, doxorubicin HCL, epinephrine HCL, erythromycin gluceptate, hydralazine HCL, hydroxyzine HCL, insulin (regular), isoproterenol HCL, levorphanol bitartrate, meperidine HCL, methadone HCL, methylprednisolone sodium succinate, morphine sulfate, nafcillin sodium, norepinephrine bitartrate, oxytetracycline, penicillin G potassium, pentazocine lactate, procaine HCL, prochlorperazine edisylate or mesylate, promazine HCL, promethazine HCL, sulfisoxazole diolamine, tetracycline HCL, vancomycin HCL, and vitamin B complex with C. Compatibility is dependent upon factors such as pH, concentration, temperature, and diluent used and it is suggested to consult specialized references for more specific information.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products: None

The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information.

Human-Labeled Products:

The listing below is a sampling of products and sizes available; consult specialized references for a more complete listing.

Aminophylline Tablets: 100 mg (79 mg theophylline) & 200 mg (158 mg theophylline); generic; (Rx)

Aminophylline Injection: 250 mg (equiv. to 197 mg theophylline) mL in 10 mL & 20 mL vials, amps and syringes; generic; (Rx)

Theophylline Time Released Capsules and Tablets: 100 mg, 125 mg 200 mg, 300 mg, 400 mg, 450 mg, & 600 mg. (Note: Different products have different claimed release rates which may or may not correspond to actual times in veterinary patients; Theophylline Extended-Release (Dey); Theo-24 (UCB Pharma); Theophylline SR (various); Theochron (Forest, various); Theophylline (Able); Theocron (Inwood); Uniphyl (Purdue Frederick); generic; (Rx)

Theophylline Tablets and Capsules: 100 mg, 200 mg, & 300 mg; Bronkodyl (Winthrop); Elixophyllin (Forest); generic; (Rx)

Theophylline Elixir: 80 mg/15 mL (26.7 mg/5 mL) in pt, gal, UD 15 and 30 mL, Asmalix (Century); Elixophyllin (Forest); Lanophyllin (Lannett); generic; (Rx)

Theophylline & Dextrose Injection: 200 mg/container in 50 mL (4 mg/mL) & 100 mL (2 mg/mL); 400 mg/container in 100 mL (4 mg/ mL), 250 mL (1.6 mg/mL), 500 mL (0.8 mg/mL) & 1000 mL (0.4 mg/mL); 800 mg/container in 250 mL (3.2 mg/mL), 500 mL (1.6 mg/mL) & 1000 mL (0.8 mg/mL); Theophylline & 5% Dextrose (Abbott & Baxter); (Rx)

Categories
Diseases

Canine Heartworm Disease: Complications And Specific Syndromes

Asymptomatic Heartworm Infection

Most dogs with heartworm infection are asymptomatic, even though many of these have heartworm disease (radiographic and pathologic lesions). Treatment is as described previously, using melarsomine in the split-dose regimen, along with a macrolide preventative.

Asymptomatic dogs may, however, become symptomatic af’er adulticidal therapy due to postadulticidal thromboembolization and lung injury (as “described elsewhere). The risk of postadulticidal thromboembolization can be imperfectly predicted by semiquantitation of the worm burden, using certain antigen tests, and by the severity of radiographic lesions. Clearly a dog with severe radiographic lesions will not tolerate thromboembolic complications well, but not all dogs with radiographic signs have heavy worm burdens. For example, a dog with moderate to severe radiographic lesions and high antigenemia may not be at high risk for postadulticidal PTE, because it is quite possible that the worms have died, explaining both the antigenemia (release from dead worms) and radio-graphic abnormalities (chronic HWD).This conclusion might also be valid in the dogs with severe radiographic lesions and negative or low antigenemia (assumes most or all worms have died, and antigen has been cleared). Alternatively, antigenic evidence of a heavy worm burden in a dog with minimal radiographic signs might still portend a severe reaction after melarsomine, because the findings suggest large worm numbers but without natural worm attrition (i.e., a relatively young infection with minimal disease). Of course, low worm burden and minimal radiographic lesions would suggest the least risk of an adverse reaction to adulticide.

It bears emphasis that with each scenario, guesswork is involved and precautions should be taken. When the risk is greatest, aspirin (5 to 7 mg/kg daily — begun 3 weeks prior to and continued until 3 weeks after adulticide) or even heparin may be used, and cage confinement is most important. The owners should be educated as to the risk, the suggestive signs, and the importance of prompt veterinary assistance in case of an adverse reaction.

Glomerulonephritis

The majority of dogs suffering from chronic HWI have glomerulonephritis, which can be severe. Therefore when a dog demonstrates glomerular disease, heartworm infection should be considered as a differential diagnosis. Although it is generally felt that the glomerular lesions produced by heartworm infection are unlikely to produce renal failure, a therapeutic dilemma results when one is found in a dog with proteinuria, azotemia, and HWI. Logic suggests that adulticidal therapy is indicated because heartworm infection contributes to glomerular disease, but it likewise carries risks. The approach embraced by this author is to hospitalize the patient and to administer intravenous fluids (lactated Ringer’s solution at 2 to 3 mL/kg/hr) for 48 hours (beginning 12 hours prior to the first melarsomine dose). The patient is then released, and a recheck appointment for blood urea nitrogen (BUN) and creatinine determination after 48 hours is advised. The second and third injections are tentatively scheduled for 1 to 3 months, with the treatment decision based on renal function and the overall response to initial adulticidal therapy.

Allergic Pneumonitis

Allergic pneumonitis, which is reported to affect 14% of dogs with HWD, is a relatively early development in the disease course. In fact, the pathogenesis probably involves immunologic reaction to dying microfilariae in the pulmonary capillaries. Clinical signs include cough and sometimes dyspnea and other typical signs of HWD, such as weight loss and exercise intolerance. Specific physical examination findings may be absent or may include dyspnea and audible crackles in more severe cases. Radiographic findings include those typical of heartworm disease but with an infiltrate, usually interstitial, but occasionally with an alveolar component, often worse in the caudal lung lobes. Eosinophils and basophils may be found in excess in peripheral blood and in airway samples. Corticosteroid therapy (prednisone or prednisolone at 1 to 2 mg/kg per day) results in rapid attenuation of clinical signs, with radiographic clearing in less than a week. The dose can then be stopped in 3 to 5 days if clinical signs subside. Although microfilaricidal therapy is typically not indicated because infections are often occult, macrolide prophylaxis is indicated to avoid further infection. Adulticidal therapy can be used after clinical improvement.

Eosinophilic Granulomatosis

A more serious, but rare, manifestation, pulmonary eosinophilic granulomatosis, responds less favorably. This syndrome is characterized by a more organized, nodular inflammatory process, associated with bronchial lymphadenopathy and, occasionally, pleural effusion. With pulmonary granulomatosis, cough, wheezes, and pulmonary crackles are often audible; when very severe, lung sounds may be muffled and associated with dyspnea and cyanosis. Treatment with prednisone at twice the dose for allergic pneumonitis is reported to induce partial or complete remission in 1 to 2 weeks. The prognosis remains guarded because recurrence within several weeks is common. Prednisone may be combined with cyclophosphamide or azathioprine in an effort to heighten the immunosuppressive effect. The latter combination appears to be the most effective Adulticide therapy should be delayed until remission is attained. As the prognosis for medical success is guarded; surgical excision of lobar lesions has been advocated.

Pulmonary Embolization

Spontaneous thrombosis or postadulticidal thromboembolization associated with dead and dying worms — the most important heartworm complication — may precipitate or worsen clinical signs, producing or aggravating PHT, right heart failure or, in rare instances, hemoptysis and pulmonary infarction. Acute fatalities may result from fulminant respiratory failure, exsanguination, DIC, or may be unexplained and sudden (arrhythmia or massive pulmonary embolism). The most common presentation, however, is a sudden onset of lethargy, anorexia, and cough 7 to 10 days after adulticidal therapy — often after failure to restrict exercise. Dyspnea, fever, mucous membrane pallor, and adventitial lung sounds (crackles) may be noted on physical examination. Thoracic radiographs reveal significant pulmonary infiltrates, most severe in the caudal lung lobes.

The degree of worsening, as compared with pretreatment radiographs, is typically dramatic. The infiltrate, typically alveolar, is most severe in the caudal lobes, and occasionally areas of consolidation are noted. Laboratory abnormalities vary with the severity of signs but may include leukocytosis, left shift, monocytosis, eosinophilia, and thrombocytopenia. The degree thrombocytopenia may provide prognostic information.

Medical management of thromboembolic lung disease is largely empiric and somewhat controversial. It is generally agreed that strict cage confinement, oxygen administration via oxygen cage or nasal insufflation (50 to 100 mL/kg), and prednisone (1 mg/kg/day for 3 to 7 days) are indicated in the most severe cases. KMW Some advocate careful fluid therapy (see recommendations for CS), measuring CVP to avoid precipitation of heart failure, to maximize tissue perfusion and combat dehydration. The use of heparin (75 IU/kg subcutaneously three times a day until platelet count has normalized [5 to 7 days]) and aspirin (5 to 7 mg/kg/day) has been advocated y some but remains controversial.

Other therapeutic strategies might include cough suppressants, antibiotics (if fever is unresponsive), and, although speculative at this time, vasodilators (amlodipine, hydralazine, diltiazem). If vasodilatory therapy is used, one must monitor blood pressure because hypotension is a potential side effect. Clinical improvement may be rapid and release from the hospital considered after several days’ treatment. For less severely affected dogs, careful confinement and prednisone at home are often adequate.

Congestive Heart Failure

Right heart failure results from increased right ventricular afterload (secondary to chronic pulmonary arterial disease and thromboemboli with resultant PHT). When severe and chronic, pulmonary hypertension may be complicated by secondary tricuspid regur-gitation and right heart failure. Congestive signs (ascites) are worsened in the face of hypoproteinemia. Calvert suggests that up to 50% of dogs with severe pulmonary vascular complication to heartworm disease will develop heart failure. Clinical signs variably include weight loss, exercise intolerance, ashen mucous membranes with prolonged capillary refill time, ascites, dyspnea, jugular venous distension and pulsation, arrhythmias with pulse deficits, and adventitial lung sounds (crackles and possibly wheezes). Dyspnea may be due to pulmonary infiltrates (PIE or PTE, but not cardiogenic pulmonary edema), abdominal distension, or pleural effusion.

Treatment aims include reduction of signs of congestion, reducing PHT, and increasing cardiac output. This involves dietary, pharmacologic, and procedural interventions. Moderate salt restriction is logical and probably useful in diminishing diuretic needs. This author chooses a diet designed for senior patients or early heart disease, because salt restriction should only be moderate. Diuretics may be useful in preventing recurrence of ascites but are typically not able to mobilize large fluid accumulations effectively. This then requires periodic abdominal or thoracic paracentesis (or both) when discomfort is apparent. Furosemide is typically used at 1 to 4 mg/kg daily, depending on severity and patient response Additional diuretics, which provide a supplemental effect by using differing parts of the nephron, include spironolactone (1 to 2 mg/kg orally twice a day) and chlorothiazide (2 mg/kg orally daily to every other day). The ACE-inhibitors (eg., enalapril, benazepril, lisino-pril, ramipril), by their effect on the renin-angiotensin-aldosterone system, may be of use as mixed vasodilators, in blunting pathologic cardiac remodeling, and in reducing fluid retention, particularly cases of refractory ascites. Adulticide therapy is delayed until clinical improvement is noted. No evidence indicates that digoxin improves survival in HWD. Because of the risk of toxicity and pulmonary vasoconstriction associated with its use, it is not routinely used by is author in the management of HWD-induced heart failure However, digoxin may be beneficial in the presence of supraventricular tachycardia or refractory heart failure Aspirin, theoretically useful because of its ability to ameliorate some pulmonary vascular lesions and vasoconstriction, may be used 5 mg/kg/day orally.

The arterial vasodilator, hydralazine, has been shown by Lombard to improve cardiac output in a small number of dogs with heartworm disease and heart failure. It has also been demonstrated to reduce pulmonary artery pressure and vascular resistance right ventricular work, and aortic pressure without changing cardiac output or heart rate in dogs with experimental heartworm disease (but without heart failure). Clinical experience has shown perceived improvement with the vasodilators diltiazem and amlodipine as well. Research and clinical experience suggest that hydralazine, amlodipine, and diltiazem might have a role in this setting, but further studies are necessary to define their role, if any. In heart failure the author uses hydralazine at 0.5 to 2 mg/kg orally twice a day, diltiazem at 0.5 to 1.5 mg/kg orally three times a day, or amlodipine at 0.1 to 0.25 mg/kg/day orally. The risk of hypotension with these therapies must be realized and blood pressure monitored.

Often heart failure follows adulticidal therapy, but if it is present prior to adulticidal therapy, the difficult question arises as when (or whether) to administer melarsomine. If clinical response to heart failure management is good, adulticidal therapy may be offered in 4 to 12 weeks, as conditions allow. Melarsomine is generally avoided if heart failure is refractory. Antiarrhythmic therapy is seldom necessary, although slowing the ventricular response to atrial fibrillation with digoxin, Diltiazem, or both () may be necessary in some cases.

Caval Syndrome

Heartworm CS is a relatively uncommon but severe variant or complication of HWD. Most studies have shown a marked sex predilection, with 75% to 90% of CS dogs being male. It is characterized by heavy worm burden (usually >60, with the majority of the worms residing in the right atrium and venae cavae) and a poor prognosis.

Studies performed in the author’s laboratory indicate that retrograde migration of adult heartworms to the cavae and right atrium, from 5 to 17 months after infection, produces partial inflow obstruction to the right heart and, by interfering with the valve apparatus, tricuspid insufficiency (with resultant systolic murmur, jugular pulse, and CVP increase). Affected dogs also exhibit pre-existent heartworm-induced PHT, which markedly increases the adverse hemodynamic effects of tricuspid regurgitation. These combined effects substantially reduce left ventricular preload and hence cardiac output. Cardiac arrhythmias may further compromise cardiac function.

This constellation of events precipitates a sudden onset of clinical signs, including hemolytic anemia caused by trauma to red blood cells (RBCs) as they pass through a sieve of heart-worms occupying the right atrium and venae cavae, as well as through fibrin strands in capillaries if disseminated intravascular coagulation has developed. Intravascular hemolysis, metabolic acidosis, and diminished hepatic function with impaired removal of circulating pro-coagulants contribute to the development of DIC. The effect of this traumatic insult to the erythron is magnified by increased RBC fragility, due to alterations in the RBC membrane in dogs with HWD. Hemoglobinemia, hemoglobinuria, and hepatic and renal dysfunction also are observed in many dogs. The cause of hepatorenal dysfunction is not clear, but it probably results from the combined effects of passive congestion, diminished perfusion, and the deleterious effects of the products of hemolysis. Without treatment, death frequently ensues within 24 to 72 hours due to cardiogenic shock, complicated by anemia, metabolic acidosis, and DIC.

A sudden onset of anorexia, depression, weakness, and occasionally coughing are accompanied in most dogs by dyspnea and hemoglobinuria. Hemoglobinuria has been considered pathognomonic for this syndrome. Physical examination reveals mucous membrane pallor, prolonged capillary refill time, weak pulses, jugular distension and pulsation, hepatosplenomegaly, and dyspnea. Thoracic auscultation may disclose adventitial lung sounds; a systolic heart murmur of tricuspid insufficiency (87% of cases); loud, split S2 (67%); and cardiac gallop (20%). Other reported findings include ascites (29%), jaundice (19%), and hemoptysis (6%). Body temperature varies from subnormal to mildly elevated.

Hemoglobinemia and microfilaremia are present in 85% of dogs suffering from CS. Moderate (mean PCV, 28%) regenerative anemia characterized by the presence of reticulocytes, nucleated RBC, and increased mean corpuscular volume (MCV) is seen in the majority of cases. This normochromic, macrocytic anemia has been associated with the presence of target cells, schistocytes, spur cells, and spherocytes. Leukocytosis (mean white blood cell (WBC] count, approximately 20,000 cells/cm) with neutrophilia, eosinophilia, and left shift has been described. Dogs affected with disseminated intravascular coagulation are characterized by the presence of thrombocytopenia and hypofibrinoginemia, as well as prolonged one stage prothrombin time (PT), partial thromboplastin time (PTT), activated coagulation time (ACT), and high fibrin degradation product concentrations. Serum chemistry analysis reveals increases in liver enzymes, bilirubin, and indices of renal function. Urine analysis reveals high bilirubin and protein concentrations in 50% of cases and more frequently, hemoglobinuria.

CVP is high in 80% to 90% of cases (mean, 11.4 cm H20). Electrocardiographic abnormalities include sinus tachycardia in 33% of cases and atrial and ventricular premature complexes in 28% and 6%, respectively. The mean electrical axis tends to rotate rightward (mean, +129 degrees), with an S1,2,3 pattern evident in 38% of cases. The S wave depth in CV6LU (V<) is the most reliable indicator of right ventricular enlargement (>0.8 mv) in 56% of cases. Thoracic radiography reveals signs of severe heartworm disease with cardiomegaly, main pulmonary arterial enlargement, increased pulmonary vascularity, and pulmonary arterial tortuousity recognized in descending order of frequency (). Massive worm inhabitation of the right atrium with movement into the right ventricle during diastole is evident echocardiographically. This finding on M-mode and two-dimensional echocardiograms is nearly pathognomonic for CS in the appropriate clinical setting. The right ventricular lumen is enlarged and the left diminished in size, suggesting pulmonary hypertension accompanied by reduced left ventricular loading. Paradoxical septal motion, caused by high right ventricular pressure, is commonly observed. No echocardiographic evidence of left ventricular dysfunction exists. Cardiac catheterization documents pulmonary, right atrial, and right ventricular hypertension and reduced cardiac output.

Prognosis is poor unless the cause of the crisis — the right atrial and caval heartworms — is removed. Even with this treatment, mortality can approximate 40%.

Fluid therapy is needed to improve cardiac output and tissue perfusion, to prevent or help to reverse DIC, to prevent hemoglobin nephropathy, and to aid in the correction of metabolic acidosis. Overexuberant fluid therapy, however, may worsen or precipitate signs of congestive heart failure. In the author’s clinic, a left jugular catheter is placed and intravenous fluid therapy instituted with 5% dextrose in water or one-half strength saline and 2.5% dextrose. The catheter should not enter the anterior vena cava because it will interfere with worm embolectomy. A cephalic catheter may be substituted for the somewhat inconvenient jugular catheter, but this does not allow monitoring of CVP. The intravenous infusion rate for fluids is dependent on the condition of the animal. A useful guideline is to infuse as rapidly as possible (up to 1 cardiovascular volume during the first hour) without raising the CVP or without raising it above 10 cm H20 if it was normal or near normal at the outset. Initial therapy should be aggressive (10 to 20 mL/kg/hr for the first hour) if shock is accompanied by a normal CVP (<5 cm HzO), and it should be curtailed to approximately 1 to 2 mL/kg/hr if CVP is 10 to 20 cm HzO. Whole blood transfusion is not indicated in most cases because anemia usually is not severe, and transfused coagulation factors may worsen DIG Sodium bicarbonate is not indicated unless metabolic acidosis is severe (pH, 7.15 to 7.20). Broad-spectrum antibiotics and aspirin (5 mg/kg daily) should be administered. Treatment for disseminated intravascular coagulation is described elsewhere in this text.

The technique for surgical removal of caval and atria] heartworms was developed by Jackson and colleagues. This procedure should be undertaken as early in the course of therapy as is practical. Often, sedation is unnecessary, and the procedure can be accomplished with only local anesthesia. The dog is restrained in left lateral recumbency after surgical clipping and preparation. The jugular vein is isolated distally. A ligature is placed loosely around the cranial aspect of the vein until it is incised, after which the ligature is tied. Alligator forceps (20 to 40 cm, preferably of small diameter) are guided gently down the vein while being held loosely between the thumb and forefinger. The jugular vein can be temporarily occluded with umbilical tape. If difficulty is encountered in passage of the forceps, gentle manipulation of the dog by assistants to further extend the neck will assist in passage of the forceps past the thoracic inlet; medial direction of the forceps may be necessary at the base of the heart. Once the forceps have been placed, the jaws are opened, the forceps are advanced slightly, the jaws are closed, and the worms are removed. One to four worms are usually removed with each pass. This process is repeated until five to six successive attempts are unsuccessful. An effort should be made to remove 35 to 50 worms. Care should be taken not to fracture heartworm during extraction. After worm removal, the jugular vein is ligated distally, and subcutaneous and skin sutures are placed routinely. Other catheters, such as urethral stone basket catheters, horsehair brushes, snares and flexible alligator forceps have also been used. Fluoroscopic guidance, when available, is useful in this procedure.

Successful worm retrieval is associated with a reduction in the intensity of the cardiac murmur and jugular pulsations, rapid clearing of hemoglobinemia and hemoglobinuria, and normalization of serum enzymatic aberrations. Immediate and latent improvement in cardiac function occurs over the next 24 hours. It is important to realize that removal of worms does nothing to reduce right ventricular afterload (PHT), and hence fluid therapy must be monitored carefully before and after surgery to avoid precipitation or worsening of right heart failure. Cage rest should be enforced for a period of time suitable for individual care.

Worm embolectomy through a jugular venotomy is frequently successful in stabilizing the animal, allowing adulticide therapy to be instituted to destroy remaining heartworms in a minimum of 1 month. Careful scrutiny of BUN and serum liver enzyme concentrations should precede the latter treatment. Aspirin therapy is continued for 3 to 4 weeks after adulticide therapy. Substantial improvement in anemia should not be expected for 2 to 4 weeks after worm embolectomy. Macrolide preventative therapy, as described previously, is administered at the time of release from the hospital.

Aberrant Migration

Although heartworms in the dog typically inhabit the pulmonary arteries of the caudal lung lobes, they may find their way to the right ventricle, and rarely (see Caval Syndrome) the right atria and venae cavae. Much less frequently, immature L5 may aberrantly migrate to other sites, including the brain, spinal cord, epidural space, anterior chamber of the eye, the vitreous, the subcutis, and the peritoneal cavity. In addition, the worms may inhabit the systemic circulation, producing systemic thromboembolic disease. Treatment of aberrantly migrating heartworms requires either nothing (e.g., peritoneal cavity), surgical excision of the offending parasite, adulticidal therapy, or symptomatic treatment (e.g., seizure control with brain migration). The method for surgical removal from internal iliac and femoral arteries has been described.

Categories
Drugs

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.

Pharmacology/Actions

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.

Pharmacokinetics

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. ()

Monitoring

■ 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)

Categories
Drugs

Allopurinol (Zyloprim)

Xanthine Oxidase Inhibitor; Purine Analog

Highlights Of Prescribing Information

Used as a uric acid reducer in dogs, cats, reptiles & birds & as an alternative treatment Leishmaniasis &Trypanosomiasis in dogs

Use with caution (dosage adjustment may be required) in patients with renal or hepatic dysfunction

Contraindicated in red-tailed hawks & should be used with caution, if at all, in other raptors

Diet may need to be adjusted to lower purine

GI effects are most likely adverse effects, but hypersensitivity, hepatic & renal effects can occur

Many potential drug interactions

What Is Allopurinol Used For?

The principle veterinary uses for allopurinol are for the prophylactic treatment of recurrent uric acid uroliths and hyperuricosuric calcium oxalate uroliths in small animals. It has also been used in an attempt to treat gout in pet birds and reptiles.

Allopurinol has been recommended as an alternative treatment for canine Leishmaniasis. Although it appears to have clinical efficacy, it does not apparently clear the parasite in most dogs at usual dosages. Allopurinol may also be useful for American Trypanosomiasis.

Pharmacology/Actions

Allopurinol and its metabolite, oxypurinol, inhibit the enzyme xanthine oxidase. Xanthine oxidase is responsible for the conversion of oxypurines (e.g., hypoxanthine, xanthine) to uric acid. Hepatic microsomal enzymes may also be inhibited by allopurinol. It does not increase the renal excretion of uric acid nor does it possess any antiinflammatory or analgesic activity.

Allopurinol is metabolized by Leishmania into an inactive form of inosine that is incorporated into the organism’s RNA leading to faulty protein and RNA synthesis.

Allopurinol, by inhibiting xanthine oxidase, can inhibit the formation of superoxide anion radicals, thereby providing protection against hemorrhagic shock and myocardial ischemia in laboratory conditions. The clinical use of the drug for these indications requires further study.

Pharmacokinetics

In Dalmatians, absorption rates were variable between subjects. Peak levels occur within 1-3 hours after oral dosing. Elimination half-life is about 2.7 hours. In dogs (not necessarily Dalmatians), the serum half-life of allopurinol is approximately 2 hours and for oxipurinol, 4 hours. Food does not appear to alter the absorption of allopurinol in dogs.

In horses, oral bioavailability of allopurinol is low (approximately 15%). Allopurinol is rapidly converted to oxypurinol in the horse as the elimination half-life of allopurinol is approximately 5 – 6 minutes. Oxypurinol has an elimination half-life of about 1.1 hours in the horse.

In humans, allopurinol is approximately 90% absorbed from the GI tract after oral dosing. Peak levels after oral allopurinol administration occur 1.5 and 4.5 hours later, for allopurinol and oxypurinol, respectively.

Allopurinol is distributed in total body tissue water but levels in the CNS are only about 50% of those found elsewhere. Neither allopurinol nor oxypurinol are bound to plasma proteins, but both drugs are excreted into milk.

Xanthine oxidase metabolizes allopurinol to oxypurinol. In humans, the serum half-life for allopurinol is 1-3 hours and for oxypurinol, 18-30 hours. Half-lives are increased in patients with diminished renal function. Both allopurinol and oxypurinol are dia-lyzable.

Before you take Allopurinol

Contraindications / Precautions / Warnings

Allopurinol is contraindicated in patients who are hypersensitive to it or have previously developed a severe reaction to it. It should be used cautiously and with intensified monitoring in patients with impaired hepatic or renal function. When used in patients with renal insufficiency, dosage reductions and increased monitoring are usually warranted.

Red-tailed hawks appear to be sensitive to the effects of allopurinol. Doses at 50 mg/kg PO once daily caused clinical signs of vomiting and hyperuricemia with renal dysfunction. Doses of 25 mg/kg PO once daily were safe but not effective in reducing plasma uric acid.

Adverse Effects

Adverse effects in dogs are apparently uncommon with allopurinol when fed low purine diets. There has been one report of a dog developing hemolytic anemia and trigeminal neuropathy while receiving allopurinol. Xanthine coatings have formed around ammonium urate uroliths in dogs that have been fed diets containing purine. If the drug is required for chronic therapy, reduction of purine precursors in the diet with dosage reduction should be considered.

Several adverse effects have been reported in humans including GI distress, bone marrow suppression, skin rashes, hepatitis, and vasculitis. Human patients with renal dysfunction are at risk for further decreases in renal function and other severe adverse effects unless dosages are reduced. Until further studies are performed in dogs with decreased renal function, the drug should be used with caution and at reduced dosages.

Reproductive / Nursing Safety

While the safe use of allopurinol during pregnancy has not been established, dosages of up to 20 times normal in rodents have not demonstrated decreases in fertility. Infertility in males (humans) has been reported with the drug, but a causal effect has not been firmly established. 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.)

Allopurinol and oxypurinol may be excreted into milk; use caution when allopurinol is administered to a nursing dam.

Overdosage / Acute Toxicity

Vomiting is common in dogs at doses >100 mg/kg per the APCC database. A human ingesting 22.5 grams did not develop serious toxicity. The oral LD50 in mice is 78 mg/kg.

There were 27 exposures to allopurinol reported to the ASPCA Animal Poison Control Center (APCC; www.apcc.aspca.org) during 2005-2006. In these cases 25 were dogs with 2 showing clinical signs; the remaining 2 reported cases were cats that showed no clinical signs. Common findings recorded in decreasing frequency included vomiting and tachycardia.

How to use Allopurinol

Allopurinol dosage for dogs:

For urate uroliths:

a) 7-10 mg/kg PO three times daily for both dissolution and prevention. Goal is to reduce urine uratexreatinine ratio by 50%. ()

b) For dissolution: 15 mg/kg PO q12h; only in conjunction with low purine foods.

For prevention: 10-20 mg/kg/day; because prolonged high doses of allopurinol may result in xanthine uroliths, it may be preferable to minimize recurrence with dietary therapy, with the option of treating infrequent episodes of urate urolith formation with dissolution protocols. ()

c) Alkalinize urine to a pH of 6.5-7 (see sodium bicarbonate monograph), give low purine diet and eliminate any UTI. Allopurinol at 10 mg/kg three times daily for the first month, then 10 mg/kg once daily thereafter. Reduce dose in patients with renal failure. ()

For Leishmaniasis:

a) 15 mg/kg PO twice daily for months ()

b) If possible use with meglumine antimoniate, if not, use allopurinol alone at 10 mg/kg PO twice daily. If animal has renal insufficiency, use at 5 mg/kg PO twice daily. ()

c) Meglumine antimoniate (100 mg/kg/day SQ) until resolution, with allopurinol at 20 mg/kg PO q12h for 9 months.

An alternate protocol using allopurinol alone: allopurinol 10 mg/kg PO q8h or 10-20 mg/kg PO q12h for 1-4 months. ()

Allopurinol dosage for cats:

For urate uroliths:

a) 9 mg/kg PO per day ()

Allopurinol dosage for birds:

For gout:

a) In budgies and cockatiels: Crush one 100 mg tablet into 10 mL of water. Add 20 drops of this solution to one ounce of drinking water. ()

b) For parakeets: Crush one 100 mg tablet into 10 mL of water. Add 20 drops of this solution to one ounce of drinking water or give 1 drop 4 times daily. ()

Allopurinol dosage for reptiles:

a) For elevated uric acid levels in renal disease in lizards: 20 mg/ kg PO once daily ()

b) For gout: 20 mg/kg PO once daily. Suggested dosage based upon human data as dose is not established for reptiles. ()

Monitoring

■ Urine uric acid (for urolithiasis)

■ Adverse effects

■ Periodic CBC, liver and renal function tests (e.g., BUN, Creatinine, liver enzymes); especially early in therapy

Client Information

■ Unless otherwise directed, administer after meals (usually 1 hour or so). Notify veterinarian if animal develops a rash, becomes lethargic or ill.

Chemistry / Synonyms

A xanthine oxidase inhibitor, allopurinol occurs as a tasteless, fluffy white to off-white powder with a slight odor. It melts above 300° with decomposition and has an apparent pKa of 9.4. Oxypurinol (aka oxipurinol, alloxanthine), its active metabolite, has a pKa of 7.7. Allopurinol is only very slightly soluble in both water and alcohol.

Allopurinol may also be known as: allopurinolum, BW-56-158, HPP, or NSC-1390; many trade names are available.

Storage / Stability/Compatibility

Allopurinol tablets should be stored at room temperature in well-closed containers. The drug is stated to be stable in both light and air. The powder for injection should be stored at 25°C; may be exposed to 15-30°C. Once diluted to a concentration < 6 mg/mL, store at room temperature and use within 10 hours; do not refrigerate. Compatible IV solutions include D5W and normal saline.

An extemporaneously prepared suspension containing 20 mg/ mL allopurinol for oral use can be prepared from the commercially available tablets. Tablets are crushed and mixed with an amount of Cologel suspending agent equal to V3 the final volume. A mixture of simple syrup and wild cherry syrup at a ratio of 2:1 is added to produce the final volume. This preparation has been reported to be stable for at least 14 days when stored in an amber bottle at either room temperature or when refrigerated.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products: None

Human-Labeled Products:

Allopurinol Tablets: 100 mg & 300 mg; Zyloprim (GlaxoWell-come); generic; (Rx)

Allopurinol Powder for Injection: 500 mg preservative-free in 30 mL vials; Aloprim (Nabi); Allopurinol Sodium (Bedford Labs); (Rx)

Categories
Diseases

Treatment of Systemic Arterial Thromboembolism

Euthanasia In cats that are in acute pain that have a poor prognosis due to severe cardiomyopathy, euthanasia is a humane means of dealing with the problem. Systemic throm-boembolism is often a horrible complication of cardiomyopathy, the treatment options are all relatively poor, and rethrombosis is common. Consequently, although one should not automatically give up on a patient, one should not give false hope either.

Pain Control Cats that present in pain must be treated appropriately for their pain. Appropriate drugs include a fentanyl patch, oxymorphone (intramuscularly, intravenously, or subcutaneously) and butorphanol tartrate (subcutaneously). Aspirin does not produce adequate pain control. Oxymorphone may produce excitement in some cats. The analgesic properties of butorphanol are five times that of morphine, and it remains a nonscheduled drug by the Food and Drug Administration. Its respiratory depressant effects equal that of morphine. Consequently, one must be careful when administering this drug to a patient with dyspnea. Acepromazine may be administered intravenously in addition as an anxiolytic agent to cats that still appear distressed after the administration of the analgesic or to cats that become agitated after oxymorphone administration. The pain abates with time (usually hours) as sensory nerves undergo necrosis.

Palliative Therapy Beyond pain control, many cats with systemic arterial thromboembolism receive only supportive care or the administration of drugs with no proven benefit. The primary outcome of arterial occlusion depends upon the extent of occlusion and the time to spontaneous reperfusion. Poor prognostic factors for short-term survival include worsening azotemia, moderate to severe pulmonary edema or pleural effusion, malignant arrhythmias, severe hypothermia, disseminated intravascular coagulation, and evidence of multiorgan embolization. Long-term, cats may lose an affected leg because of ischemic necrosis, die of toxemia, remain paralyzed from peripheral nerve damage, or regain full or partial function of their legs. About 50% of cats that are not treated definitively will regain all or most caudal limb motor function within 1 to 6 weeks. Return of function presumably is due to the cat’s own thrombolytic system (e.g., plasmin) disrupting the thromboembolus. The degree and rapidity of the dissolution depend on the activity of a particular cat’s thrombolytic system and the size and quality of the thromboembolus. Usually, cats that have some evidence of caudal limb flow recover more rapidly than do cats with no evidence of flow. Presumably this is because the size of the thromboembolus in cats with some flow is smaller. With total occlusion, some cats recanalize within days (others never recanalize).This extreme variability makes it very difficult to render a prognosis for a particular patient at presentation.

Palliative therapy may be only cage rest and pain control or can include administering drugs such as heparin, aspirin, or arteriolar dilators along with the cage rest. No drugs administered for palliation have any proven benefit over cage rest alone.

Heparin is commonly administered in the hopes of preventing new thrombus formation on top of the existing thromboembolus or in the hope of preventing a new thrombus from forming in the left atrium. However, no evidence indicates that heparin is of benefit in cats with STE. Heparin does not aid in thrombolysis. Heparin can be administered at an initial dose of 100 U/lb intravenously followed by a maintenance dose of 30 to 100 U/lb subcutaneously every 6 hours. The dose should be tailored to each individual cat to increase the activated partial thromboplastin time (aPTT) to at least 1.5 times baseline.

Indomethacin is effective at preventing vasoconstriction distal to the thromboembolus when administered to experimental cats prior to creating an aortic thrombus. Theoretically aspirin could do the same thing. However, no evidence indicates that it improves collateral blood flow.

The administration of drugs that dilate systemic arterioles (e.g., hydralazine, acepromazine) has been advocated. These drugs act by relaxing the smooth muscle in systemic arterioles. The exact anatomy of collateral vessels is not well described, but they are probably larger vessels than arterioles. They contain smooth muscle, because they can open and close. The ability of arteriolar dilators to counteract serotonin and thromboxane A2-induced vasoconstriction is unknown.

Definitive Therapy Definitive treatments for systemic arterial thromboembolism in cats include administration of exogenous fibrinolytic agents, balloon embolectomy, rheolytic thrombectomy, and surgery. All definitive procedures are associated with high mortality and common recurrence of the thromboembolus days to months after the initial removal.

Surgery Surgical removal of systemic thromboemboli is generally thought to be associated with high mortality and is not frequently performed. Cats with systemic arterial thromboembolism commonly have underlying cardiac disease, and many are in heart failure. They are poor anesthetic risks, and reperfusion syndrome may be produced. In reperfusion syndrome the muscles of the legs prior to removal of the systemic arterial thromboembolism undergo necrosis, cellular breakdown, and the release of potassium and hydrogen ions from the cells into the interstitial spaces. Sudden reperfusion carries these ions into the systemic circulation, causing acute and often severe hyperkalemia and metabolic acidosis. Surgical intervention may be a viable option if careful monitoring and treatment for reperfusion syndrome with insulin and glucose, sodium bicarbonate, or calcium (or a combination of these therapies) can be initiated immediately if it occurs.

Balloon embolectomy The procedure of choice in human medicine is balloon embolectomy. The author has had limited experience with balloon embolectomy. In this procedure the femoral arteries are isolated and a small balloon embolec-tomy catheter is passed from one femoral artery into the aorta. The femoral arteries are not extremely difficult to isolate. The catheter is pushed past the thromboembolus, and the balloon is then inflated and the catheter withdrawn, along with throm-boembolic material. The catheter is passed sequentially, first in one artery and then in the other. Usually this sequence must be repeated several times. Reperfusion syndrome may occur with balloon embolectomy.

Thrombolytic therapy Thrombolytic therapy is a possible means of dealing with cats with systemic arterial thromboembolism using fibrinolytic agents. Thromboemboli in cats are composed of red cells, strands of fibrin, and possibly platelets. Fibrinolytic agents cleave plas-minogen to plasmin. Plasmin hydrolyzes fibrin, resulting in thrombolysis. Different agents vary in their ability to bind specifically to fibrin-bound plasminogen and in their half-lives. Efficacy and complication rates appear to be very similar in humans. Complications consist primarily of hemorrhage due to fibrinolysis and rethrombosis. Fibrinolytic agents can be very effective at lysing systemic thromboemboli. However, the author and colleagues currently treat few cats with systemic arterial thromboembolism with these agents because reperfusion syndrome and rethrombosis are common.

Tissue plasminogen activator (t-PA) and streptokinase have been used in cats. Tissue plasminogen activator is an intrinsic protein present in all mammals. Numerous reports exist of the use of t-PA for the lysis of thrombi as therapy for acute myocardial infarction, pulmonary thromboembolism, and peripheral vascular obstruction in humans and experimental animals. The activity of genetically engineered t-PA in feline plasma is 90% to 100% of that seen in human plasma. The half-life of t-PA is quite short. Heparin must be administered concomitandy to prevent acute rethrombosis but does not need to be administered with streptokinase because it has a longer half-life. A clinical trial with t-PA in cats with aortic thromboemboli has shown acute thrombolytic efficacy (shortened time to reperfusion and ambulation) associated with the administration of t-PA at a rate of 0.1 mg to 0.4 mg/lb/hr for a total dose of 0.4 to 4 mg/lb intravenously. Forty three percent of cats treated survived therapy and were walking within 48 hours of presentation. Post-t-PA angiograms demonstrated resolution of the primary vascular occlusion. Thus acutely, t-PA effectively decreases the time to reperfusion and return to function in cats with aortic thromboemboli. However, 50% of the cats died during therapy in this clinical trial, which raises extreme concerns regarding acute thrombolysis. Fatalities resulted from reperfusion syndrome (70%), congestive heart failure (15%), and sudden arrhythmic death, presumably the result of embolization of a small thrombus to a coronary artery (15%). Severe hemorrhage into the region distal to the systemic arterial thromboembolism causing anemia was also a common complication. The cats that successfully completed t-PA therapy exhibited signs of increasing neuromuscular function and ambulatory ability within 2 days of presentation. This contrasts with 1 to 6 weeks before seeing similar signs of improvement in most cats exhibiting spontaneous resolution.

Mortality due to reperfusion syndrome can be reduced if the patient can be observed continuously by an individual trained to identify clinical and electrocardiographic evidence of hyperkalemia, if intensive monitoring of electrolytes and blood pH can be performed, and if aggressive medical therapy for hyperkalemia and metabolic acidosis can be initiated very quickly. This means dedicated care 24 hours a day until the thromboembolus is lysed. Thrombolysis may occur within 3 hours or take as long as 48 hours.

If reperfusion syndrome was the only major complicating factor in cats treated with thrombolytic agents, continued use in selected patients might be warranted. However, 90% of the cats that were successfully treated in the aforementioned clinical trial

had another systemic arterial thromboembolism within 1 to 3 months. Rethromboembolism occurred despite aspirin, warfarin, or heparin administration. In addition, t-PA is expensive. Consequently, the author does not currently use t-PA for systemic arterial thromboembolism in cats.

Streptokinase has clinical efficacy very similar to t-PA in human patients with coronary artery thrombosis. Streptokinase is less expensive. No controlled clinical trials of streptokinase use for systemic arterial thromboembolism in cats are available, and the author’s clinical experience with the drug has been generally negative. There has been one small experimental study in which throm-bin was injected between two ligatures placed at the terminal aorta to create a soft thrombus, followed by removal of the ligatures. Streptokinase was administered as a loading dose at 90,000 III followed by 45,000 IU/hr for 3 hours. This dose produced evidence of systemic fibrinolysis in a separate group of normal cats but without evidence of severe fibrinolysis or bleeding. In most cats there was no angiographic change and no improvement in limb temperature. There was a tendency for the thrombus weight to be lower in the treated cats when compared with control cats at postmortem examination. However, lysis of a fresh thrombus created with thrombin is probably much different from trying to lyse an established thromboembolus. Streptokinase is usually unsuccessful, may hasten the death of some cats through bleeding complications, and should not be routinely used.

Rheolytic thrombectomy Rheolytic thrombectomy is an experimental catheter-based system used for the dissolution of the thromboembolus using a high-velocity water jet at the end of the catheter that breaks up the thromboembolus and sucks it back into the system using the Venturi effect. Anesthesia is required and blood transfusion is almost always needed. The catheter is passed from the carotid artery to the region of the thromboembolus. The author and colleagues have used it in six cats. The procedure successfully removed the thromboembolus in five cats but only three left the hospital. Time from onset of clinical signs to thrombectomy was several hours to 8 days. The cat that had the procedure 8 days after the event had residual neurologic deficits but was the longest survivor. Interestingly, reperfusion syndrome has not been a common complication.

Adjunctive therapy Cats with systemic arterial thromboembolism are commonly in heart failure at the time of presentation. Medical therapy with furosemide and an angiotensin-converting enzyme inhibitor is often indicated. Cats that are in pain usually do not eat or drink. Fluid therapy is warranted but must not aggravate or produce heart failure

Cats that take a long time to recover caudal limb function or that only attain partial function may develop regions of skin and muscle necrosis, especially on the distal limbs. These regions may need to be debrided surgically. Cats that lose the function of only one leg or that do not regain function of one leg benefit from amputating that leg. Cats that have perma-nendy lost muscle function distal to the hock may benefit from arthrodesis.

Prognosis The short-term prognosis for life is guarded in cats without heart failure. Cats with a rectal temperature lower than 98.9° F had a worse prognosis in one study. Ifi The long-term prognosis is highly variable and depends on the ability to control the heart failure and the events surrounding the STE. One of the most common causes of death within the first 24 hours is euthanasia. In one study, cats lived between 3 and 30 months after the initial episode. The average survival time was about 10 to 12 months. In another study, MST for cats that recovered and were discharged from the hospital was approximately 4 months but was only about 2.5 months in cats that were also being treated for heart failure. The long-term prognosis for limb function depends on the ability of the cat to lyse its own clot or on the success of intervention. Many biologic variables determine whether or not reperfusion will spontaneously occur. A significant percentage of cats will develop a new thromboembolus, days to months after recovery.

Prophylaxis Feline patients with myocardial disease, especially those with an enlarged left atrium, should be considered at risk for developing intracardiac thrombi and signs of peripheral arterial thromboembolism, although the incidence appears to be low. Preventing peripheral thrombosis is, in theory, one of the most important therapeutic objectives for the veterinarian managing cats with severe myocardial disease. The ideal means of preventing thrombosis is resolution of the underlying myocardial disease. This is usually only possible in a cat with dilated cardiomyopathy secondary to taurine deficiency.

At-present, the only option available is to manipulate the patient’s coagulation system in an attempt to alter the delicate balance between the pathways that promote clotting and those that inhibit thrombus formation to reduce the patient’s thrombogenic potential. At this time, antiplatclet and anticoagulant therapies are the only means of preventing thrombus formation in cats with myocardial disease. Unfortunately, they are often ineffective and, in the case of warfarin, can produce serious side effects. Experience is similar in human medicine.

Antiplatelet therapy Prostaglandins enhance platelet aggregation via activation of cyclic adenosine monophosphate (cAMP). Aspirin (acetylsalicylic acid) acetylates platelet cyclooxygenase, preventing the formation of thromboxane A2, a potent prostaglandin-like platelet aggregating substance. The inhibition of platelet cyclooxygenase is irreversible, and bleeding time is restored to normal only after the production of new platelets. The inhibition of endothelial cyclooxygenase is reversible. The dose of aspirin recommended in cats is 10 mg/lb every third day. Whether or not this dose allows endothelial cyclooxygenase to recover or not in cats is undetermined. At this dose, aspirin has a half-life of 45 hours in the cat. In humans, doses as low as 20 to 100 mg/day inhibit platelet cyclooxygenase; however, no evidence suggests that this low dose has any more benefit than conventional daily doses of 625 to 1250 mg. In one study in cats, no difference was seen in thromboembolus recurrence between cats on low dose (5 mg/cat every 72 hours) and high dose (greater than or equal to 40 mg/cat every 72 hours). No evidence indicates that any dose of aspirin is effective at preventing the formation of an intracardiac thrombus in cats with myocardial disease. Clinical impression of aspirin’s efficacy varies between clinicians. Cats that have already experienced one systemic arterial thromboembolism are the only appropriate population in which to study the efficacy of an agent meant to prevent STE. Aspirin does not prevent recurrence of peripheral thromboembolism in this population.

Glycoprotein IIb and IIIa, an integrin present on platelet surfaces, is a receptor for fibrinogen, fibronectin, and von Willebrand factor. It mediates aggregation, adhesion, and spreading of platelets. The binding of prothrombin to glycoprotein IIb and IIIa also enhances the conversion of prothrombin to thrombin. Glycoprotein IIb and IIIa antagonists have been developed, and one (abciximab) increased mucosal bleeding time and reduced thrombus area when combined with aspirin (when compared with aspirin and placebo).

Anticoagulant therapy Available anticoagulants include heparin, the low molecular weight heparins, and warfarin. Heparin binds to a lysine site on AT, producing a conformational change at the arginine-reactive site that converts AT from a slow, progressive thrombin inhibitor to a very rapid inhibitor of thrombin and factor Xa. AT binds covalently to the active serine centers of coagulation enzymes. Factor Xa bound to platelets and thrombin bound to fibrin are protected from activation by the heparin-antithrombin III complex. Heparin may be administered intravenously or subcutaneously. Repeated intramuscular injection is discouraged because local hemorrhage may result. Some owners can administer heparin subcutaneously at home but the method is not ideal. The author and colleagues have noted rethrombosis with heparin therapy in some cats with cardiac disease. The dose of heparin for preventing thrombosis in cats is unknown.

Low molecular weight heparins include nadroparin calcium, enoxaparin sodium, dalteparin, ardeparin, tinzaparin, reviparin, and danaparoid sodium. The low molecular weight heparins have fewer bleeding complications in experimental animals, improved pharmacokinetics over heparin, are administered subcutaneously, and do not require monitoring in most situations. Although heparin does not reduce red cell aggregation in slow-moving blood, heparin and low molecular weight heparins are effective at preventing deep vein thrombosis in humans. Consequently, they may be beneficial in preventing intracardiac thrombus formation in cats with cardiomyopathy. No controlled studies are available. The author empirically uses enoxaparin sodium at a dose of 2.2 mg/lb every 12 hours subcutaneously in cats that have recovered from an systemic arterial thromboembolism or that have a severely enlarged left atrium and SEC.

Warfarin sodium is an oral anticoagulant (). Warfarin exerts no anticoagulant effect in vitro. In vivo, inhibitory effects on synthesis of clotting factors begin immediately. However, clotting is unaffected until already existing clotting factors decline. Therefore a delay occurs between initial administration and effect on the prothrombin time (FT). Historically, oral warfarin therapy has been monitored with the PT.This test measures the activity of factors II, VII, and X. The factor depressed most quickly and profoundly (usually factor VII) determines the FT during the initial days of therapy. The FT is performed by measuring the clotting time of platelet-poor plasma after the addition of thromboplastin and calcium, a combination of tissue factor and phospholipid. Intra- and interlaboratory variation in the FT was a significant problem for laboratories in the past, when crude extracts of human placenta or rabbit brain were the only source of thromboplastin. The international normalized ratio (INR), developed by the WHO in the early 1980s, is designed to eliminate problems in oral anticoagulant therapy caused by variability in the sensitivity of different commercial sources and different lots of thromboplastin. The INR is used worldwide by most laboratories performing oral anticoagulation monitoring and is routinely incorporated into dose planning for human patients receiving warfarin. When the anticoagulant effect is excessive, it can be counteracted by administering vitamin K,. However, once synthesis of factors 11, VII, IX, and X is reinstituted, time must elapse before factors achieve concentrations in the plasma that will adequately reverse the bleeding tendency. If serious bleeding occurs during therapy with warfarin, it may be stopped immediately by administering fresh blood or plasma that contains the missing clotting factors. Other drugs can modify the anticoagulant actions of warfarin by altering the bioavailability of vitamin K by altering the absorption, distribution, or elimination of the coumarins; by affecting synthesis or degradation of clotting factors; or by altering protein binding of the warfarin. The maintenance dose should be evaluated daily during the initial titration (3 days), then every other day (twice), and then weekly until a safe and stable dose regimen is determined. The therapeutic effect should be reevaluated periodically (at least once per month). The recommended initial dose is 0.1 to 0.2 mg per cat every 24 hours orally to a 6 to 10 lb/cat. The dose may then be increased to maintain an INR of 2.0 to 3.0. It can take up to 1 week for new steady state conditions to be achieved. The efficacy of warfarin at preventing recurrent thrombosis in cats with cardiac disease has been reported. M-s In one report, out of 23 cats examined retrospectively, 10 experienced a new thromboembolic episode while being administered warfarin. Two of these cats had at least two new episodes. In the other report, eight of 18 cats on warfarin experienced a new thromboembolic episode. This may be some improvement over the 75% recurrence rate reported for aspirin alone after t-PA therapy, but these results are still disappointing.i:,h In the first report, four cases also died suddenly (which could have been caused by thromboembolLsm). Three of these cats did not have postmortem examinations. The one cat that did have a postmortem examination had a thrombus present in its left atrium. One cat also died of a renal infarct that produced renal failure. Four cats appeared to have bleeding complications. In the second report, one cat died of a hemoabdomen and one was suspected to have an acute intracranial hemorrhage resulting in death. Consequendy, it appears that warfarin therapy can produce fatal complications. However, it should be noted that these studies were performed without using the INR for monitoring.

Categories
Drugs

Acetylcysteine (N-acetylcysteine, Mucomyst, NAC)

Antidote; Mucolytic

Highlights Of Prescribing Information

Used primarily as a treatment for acetaminophen or phenol toxicity & for its mucolytic effect; used anecdotally for treating degenerative myelopathy

Also used as a topical ophthalmic ()

Has caused hypersensitivity & bronchospasm when used in pulmonary tree

Administer via gastric- or duodenal tube for acetaminophen poisoning in animals

What Is Acetylcysteine Used For?

Acetylcysteine is used in veterinary medicine as both a mucolytic agent in the pulmonary tree and as a treatment for acetaminophen or phenol toxicity in small animals. It has been used anecdotally with aminocaproic acid to treat degenerative myelopathy in dogs.

In horses with strangles, acetylcysteine instilled into the gutteral pouch has been used to help break up chondroids and avoid the need for surgical removal. Acetylcysteine enemas have been used in neonatal foals to break up meconium refractory to repeated enemas.

Before you take Acetylcysteine

Contraindications / Precautions / Warnings

Acetylcysteine is contraindicated (for pulmonary indications) in animals hypersensitive to it. There are no contraindications for its use as an antidote.

Because acetylcysteine may cause bronchospasm in some patients when used in the pulmonary system, animals with bronchospastic diseases should be monitored carefully when using this agent.

Adverse Effects

When given orally for acetaminophen toxicity, acetylcysteine can cause GI effects (nausea, vomiting) and rarely, urticaria. Because the taste of the solution is very bad, use of taste masking agents {e.g., colas, juices) have been used. Since oral dosing of these drugs may be very difficult in animals, gastric or duodenal tubes may be necessary.

Rare adverse effects reported when acetylcysteine is administered into the pulmonary tract, include: hypersensitivity, chest tightness, bronchoconstriction, and bronchial or tracheal irritation.

Overdosage / Acute Toxicity

The LD50 of acetylcysteine in dogs is 1 g/kg (PO) and 700 mg/kg (IV). It is believed that acetylcysteine is quite safe (with the exception of the adverse effects listed above) in most overdose situations.

How to use Acetylcysteine

Acetylcysteine dosage for dogs:

For acetaminophen toxicity:

a) A 2-3 hour wait between activated charcoal and PO administration of acetylcysteine (NAC) is necessary. Give NAC as an initial oral loading dose of 140 mg/kg (dilute to 5% in dextrose or sterile water), followed by 70 mg/kg PO four times daily (q6h) for 7 treatments. With ingestion of massive quantities, some authors suggest using a 280 mg/kg loading dose and continuing treatment for 12-17 doses. May also be given IV after diluting to 5% and given via slow IV over 15-20 minutes. Additional therapy may include IV fluids, blood or Oxyglobin, ascorbic acid and SAMe. ()

b) 150 mg/kg PO or IV initially, then 50 mg/kg q4h for 17 additional doses ()

c) Loading dose of 140 mg/kg PO, then 70 mg/kg PO every 6 hours for 7 treatments ()

For phenol toxicity:

a) 140 mg/kg PO or IV initially, then 50 mg/kg q4h for 3 days. May be partially effective to reduce hepatic and renal injury. Resultant methemoglobinemia should be treated with ascorbic acid or methylene blue. ()

For respiratory use:

a) 50 mL/hr for 30-60 minutes every 12 hours by nebulization ()

For degenerative myelopathy:

a) 25 mg/kg PO q8h for 2 weeks, then q8h every other day. The 20% solution should be diluted to 5% with chicken broth or suitable diluent. Used in conjunction with aminocaproic acid (500 mg per dog PO q8h indefinitely). Other treatments may include prednisone (0.25-0.5 mg/kg PO daily for 10 days then every other day), Vitamin C (1000 mg PO q12h) and Vitamin E (1000 Int. Units PO q12h). Note: No treatment has been shown to be effective in published trials. ()

Acetylcysteine dosage for cats:

For acetaminophen toxicity:

a) A 2-3 hour wait between activated charcoal and PO administration of acetylcysteine (NAC) is necessary. Give NAC as an initial oral loading dose of 140 mg/kg (dilute to 5% in dextrose or sterile water), followed by 70 mg/kg PO four times daily (q6h) for 7 treatments. With ingestion of massive quantities, some authors suggest using a 280 mg/kg loading dose and continuing treatment for 12-17 doses. May also be given IV after diluting to 5% and given via slow IV over 15-20 minutes. Additional therapy may include IV fluids, blood or Oxyglobin9, ascorbic acid and SAMe. ()

b) 150 mg/kg PO or IV initially, then 50 mg/kg q4h for 17 additional doses ()

For phenol toxicity:

a) 140 mg/kg PO or IV initially, then 50 mg/kg q4h for 3 days. May be partially effective to reduce hepatic and renal injury. Resultant methemoglobinemia should be treated with ascorbic acid or methylene blue. ()

For respiratory use:

a) 50 mL/hr for 30-60 minutes every 12 hours by nebulization ()

For adjunctive treatment of hepatic lipidosis (see also Carnitine):

a) Identify underlying cause of anorexia and provide a protein replete feline diet, give acetylcysteine (NAC) at 140 mg/kg IV over 20 minutes, then 70 mg/kg IV q12h; dilute 10% NAC with saline 1:4 and administer IV using a 0.25 micron filter; correct hypokalemia and hypophosphatemia, beware of electrolyte changes with re-feeding phenomenon ()

Acetylcysteine dosage for horses:

To help break up chondroids in the gutteral pouch:

a) Instill 20% solution ()

In neonatal foals to break up meconium refractory to repeated enemas:

a) 8 grams in 20 g sodium bicarbonate in 200 mL water (pH of 7.6), give as enema as needed to effect ()

b) With foal in lateral recumbency, insert a 30 french foley catheter with a 30 cc bulb for a retention enema. Using gravity flow, infuse slowly 100-200 mL of 4% acetylcysteine solution and retain for 30-45 minutes. IV fluids and pain medication should be considered. Monitor for possible bladder distention. ()

Monitoring

When used for acetaminophen poisoning:

■ Hepatic enzymes (particularly in dogs)

■ Acetaminophen level, if available (particularly in dogs)

■ Hemogram, with methemoglobin value (particularly in cats)

■ Serum electrolytes, hydration status

Client Information

■ This agent should be used in a clinically supervised setting only

Chemistry / Synonyms

The N-acetyl derivative of L-cysteine, acetylcysteine occurs as a white, crystalline powder with a slight acetic odor. It is freely soluble in water or alcohol.

Acetylcysteine may also be known as: N-acetylcysteine or N-acetyl-L-cysteine, NAC, 5052 acetylcysteinum, NSC-111180, Acetadote, Mucomyst or ACC.

Storage / Stability/Compatibility

When unopened, vials of sodium acetylcysteine should be stored at room temperature (15-30°C). After opening, vials should be kept refrigerated and used within 96 hours. The product labeled for IV use states to use within 24 hours.

Acetylcysteine is incompatible with oxidizing agents; solutions can become discolored and liberate hydrogen sulfide when exposed to rubber, copper, iron, and during autoclaving. It does not react to aluminum, stainless steel, glass or plastic. If the solution becomes light purple in color, potency is not appreciably affected, but it is best to use non-reactive materials when giving the drug via nebulization. Acetylcysteine solutions are incompatible with amphotericin B, ampicillin sodium, erythromycin lactobionate, tetracycline, oxytetracycline, iodized oil, hydrogen peroxide and trypsin.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products: None

Human-Labeled Products:

Acetylcysteine injection: 20% (200 mg/mL), (0.5 mg/mL EDTA in 30 mL single-dose vials, preservative free; Acetadote (Cumberland); (Rx)

Acetylcysteine Solution: 10% & 20% (as sodium) in 4 mL, 10 mL, 30 mL & 100 mL (20% only) vials; Mucomyst (Apothecon); (Rx) Note: If using this product for dilution and then intravenous dosing, it is preferable to use a 0.2 micron in-line filter.

Categories
Diseases

Tetralogy of Fallot

The defining anatomic features of tetralogy of Fallot include right ventricular outflow obstruction (pulmonic stenosis), secondary right ventricular hypertrophy, a subaortic ventricular septal defect, and a rightward-positioned aorta. Pulmonic stenosis that occurs in combination with an isolated ventricular septal defect produces similar findings, but the infundibular septum is not malaligned, the aorta is normal in size, and the infundibulum of the right ventricle is not narrowed. These distinctions are commonly ignored in veterinary patients because corrective surgery is rarely performed.

Pathogenesis

Tetralogy of Fallot has been extensively studied in keeshond breeding colonies, and a spectrum of lesions ranging from the subclinical to the clinically complicated has been identified. Patterson et al. graded the conotruncal defects as follows:

Grade 1: Subclinical malformations involving persistence of the conus septum fusion line, aneurysm of the ventricular septum, and absence of the papillary muscle of the conus.

Grade 2: Pulmonic stenosis or ventricular septal defect in addition to the grade 1 lesions.

Grade 3: Tetralogy of Fallot — pulmonic stenosis, ventricular septal defect, and dextropositioned aorta (with secondary right ventricular hypertrophy.

Additional abnormalities found in some dogs included a dilated and tortuous ascending aorta, pulmonary atresia, hypoplasia of the supraventricular crest, and anomalies of the aortic arch system. Based on extensive breeding studies and sophisticated genetic analysis, conotruncal defects have been shown to be an inherited autosomal recessive trait with variable expression.

Pathophysiology

The essential components of tetralogy of Fallot are severe right ventricular outflow tract obstruction and a ventricular septal defect. As a result of the outflow obstruction and elevated right ventricular pressure, desaturated blood shunts from the right heart through the septal defect to mix with oxygenated blood coming from the left ventricle. PulmonSry arterial blood flow and pulmonary venous return are scant, and the left atrium and left ventricle are small (underdeveloped). The addition ot unoxygenated blood from the right ventricle to the systemic side of the circulation causes arterial hypoxemia, decreased hemoglobin oxygen saturation, cyanosis, and secondary polycythemia. Systemic collateral circulation to the lung increases via the bronchial arterial system. These vessels supply blood to the capillaries of the pulmonary parenchyma either directly or via anastomosing connections with a larger pulmonary artery. A substantial portion of this blood can participate in pulmonary gas exchange. Other aspects of clinical pathophysiology have been previously described (see Clinical Evaluation of the Patient with Cyanotic Heart Disease, above).

Clinical Findings

Tetralogy of Fallot is common in the keeshond and English bulldog and in some families of other breeds. It has also been recognized in the cat. Presenting complaints and clinical signs are as previously described for cyanotic heart disease. In most cases, the murmur of tetralogy of Fallot is produced by blood flowing through the stenotic pulmonic valve. A right-sided murmur, resulting from blood (low through the VSD, may predominate when pulmonic stenosis is mild and left-to-right shunting occurs across a restrictive ventricular septal defect (i.e., an acyanotic defect). The absence of an obvious murmur suggests pulmonary atresia and/or polycythemia with hyperviscosity (which reduces blood flow turbulence) and ejection across a large, nonrestrictive ventral septal defect (VSD). Exercise or excitement may induce or enhance detection of peripheral cyanosis by accentuating right-to-left shunting by mechanisms previously described.

Radiography usually reveals a small or normal-sized heart with rounding of the right ventricular border. The main pulmonary artery is not always visibly enlarged, in contrast to the usual case of pulmonic stenosis with intact ventricular septum. The pulmonary vasculature is diminished, and the left auricle may be inconspicuous as a consequence of decreased venous return. The ECG typically exhibits criteria for right heart enlargement, including right axis deviation, although left or cranially directed vectors may be found in some cats. Echocardiographic findings include right ventricular hypertrophy, increased right ventricular chamber dimensions, reduced left atrial (LA) and LV dimensions, a large subaortic VSD, and right ventricular outflow obstruction. Doppler or contrast studies can be used to document right-to-left shunting at the ventricular outflow level.

Cardiac catheterization demonstrates equilibration of left and right ventricular systolic pressures, compatible with a large, nonrestrictive ventral septal defect (VSD). Oximetry samples reveal a step-down at the left ventricular outflow level, and the aortic blood is relatively desaturated. Angiocardiography reveals right ventricular hypertrophy, narrowing ol the right ventricular infundibulum, pulmonic stenosis with minimal poststenotic dilatation, varying degrees of pulmonary artery hypoplasia, a large subaortic VSD, a small, dorsally displaced left ventricle, an enlarged and right-ward-positioned aorta, and prominent bronchial circulation.. Bidirectional shunting across the ventricular septal defect is common in anesthetized animals. Anticoagulation therapy (e.g., heparin) should be considered to prevent cerebral emboliza-tion during and immediately after cardiac catheterization.

Clinical Management

The natural history and survival times of dogs and cats with tetralogy of Fallot are not well characterized. Like other cyanotic heart diseases, tetralogy of Fallot can be tolerated for years if pulmonary blood flow is maintained and hyperviscos-ity is controlled. Most affected animals have severely limited exercise capacity. In cases of pulmonary atresia, pulmonary blood flow must be derived from a patent ductus arteriosus, the bronchial artery, or an elaborate network of systemic collaterals. Sudden death is common due to the combined consequences of hypoxia, hyperviscosity, or cardiac arrhythmia. Unlike with pulmonic stenosis with intact ventricular septum, congestive heart failure is an unusual outcome.

Options for treating animals with tetralogy of Fallot include medical and surgical approaches. Definitive correction of the defect (i.e., closure of the ventricular septal defect and removal or bypass of the stenosis) can be done under cardiopulmonary bypass, but such surgery is rarely performed in animals. As a general rule, the stenosis should not be relieved if the ventricular septal defect cannot be closed because the loss of right ventricular pressure results in marked left-to-right shunting with subsequent left-sided congestive heart failure. As an alternative to definitive correction, surgical palliation through the creation of a systemic to pulmonary shunt can be quite rewarding. Subclavian to pulmonary artery (Blalock-Taussig), ascending aorta to pulmonary artery (Potts), and aorta to right pulmonary artery (Waterston-Cooley) connections have been made in dogs and cats. Creation of a left-to-right shunt distal to the cyanotic defect increases pulmonary perfusion and allows a greater contribution of oxygenated blood to the systemic circulation. The size of the accessory shunt must be controlled to prevent overloading of the diminutive left ventricle and subsequent pulmonary edema. The extent to which these shunts remain patent over long periods in veterinary patients has not been reported.

Periodic phlebotomy, performed to maintain the PCV between 62% and 68%, produces a satisfactory result in many cases. Excessive bleeding should be avoided, and the blood that is withdrawn is replaced with crystalloid fluids to maintain cardiac output and tissue oxygen delivery. Some children with tetralogy of Fallot benefit from beta blockade with propranolol; however, controlled studies of the clinical efficacy of this treatment in animals are lacking. Severe hypoxic spells should be treated with cage rest, oxygen, and sodium bicarbonate (if metabolic acidosis is evident). Treatment with vasoconstrictive agents such as phenylephrine can also help reduce the amount of right-to-left shunting. Drugs with marked systemic vasodilating properties should be avoided.

Categories
Veterinary Medicine

Hyperkalemia

10. What concentration of potassium results in a diagnosis of hyperkalemia?

The serum potassium concentration should be > 5.5 mEq / L to diagnose hyperkalemia.

11. What are the most common causes of hyperkalemia in dogs and cats?

1. Increased intake

• Most commonly due to excessive potassium chloride or inadequate mixing in intravenous fluids

• Transcellular shifts

  • Lack of insulin
  • Acute mineral acidosis (HC1, NH4C1)
  • Acute tumor lysis syndrome
  • Massive tissue injury
  • Digitalis toxicity
  • Reperfusion after thromboembolism

2. Decreased renal excretion

• Urethral obstruction

• Anuric or oliguric renal failure (requires significant reduction in glomerular filtration rate and urinary output)

• Adrenal insufficiency

• Drugs

  • Angiotensin-converting enzyme (ACE) inhibitors
  • Potassium-sparing diuretics
  • Nonsteroidal antiinflammatory drugs (NSAIDs)
  • Heparin

12. What are the clinical manifestations of hyperkalemia?

Weakness and neuromuscular paralysis (without CNS disturbances), suppression of renal ammoniogenesis (which may result in metabolic acidosis), and bradycardia commonly result from hyperkalemia.

13. What are the most common electrocardiographic (ECG) signs of hyperkalemia?

Decreased heart rate, decreased P-wave amplitude, and increased QRS duration are the most sensitive ECG indicators of hyperkalemia. The spiked T-wave, which is classically considered an electrocardiographic sign of hyperkalemia, is rarely recognized clinically.

14. What is pseudohyperkalemia?

Circulating blood cells, particularly platelets and white blood cells, release potassium when activated or destroyed. Potassium is normally released from platelets during the clotting process. In dogs with thrombocytosis, mild to moderate increases in serum potassium are observed. This in vitro event has no physiologic effect in the animal. Erythrocytes in dogs and cats contain little intracellular potassium. Thus, hemolysis does not increase serum potassium concentrations.

15. What are the goals in treating hyperkalemia?

• To reverse the toxic effects on the heart.

• To shift potassium from the extracellular fluid compartment into the ICF compartment.

• To lower total body potassium levels.

16. How is hyperkalemia managed?

• Discontinue potassium administration (e.g., intravenous fluids, salt substitutes, potassium chloride, potassium penicillin).

• Administer calcium gluconate (2-10 ml of 10% solution) (reverses toxic effects on the heart).

• Consider administering sodium bicarbonate (0.25-1 mEq / kg IV) or 25% dextrose (1 gm / kg IV) with regular insulin (0.5-1.0 U / kg IV) to shift potassium from the extracellular fluid into the ICF

• Administer bolus potassium-free intravenous crystalloids to dilute extracellular fluid potassium.