Amitriptyline HCL (Elavil)

Tricyclic Behavior Modifier; Anti-Pruritic; Neuropathic Pain Modifier

Highlights Of Prescribing Information

Tricyclic “antidepressant” used primarily for behavior disorders & neuropathic pain/pruritus in small animals

May reduce seizure thresholds in epileptic animals

Sedation & anticholinergic effects most likely adverse effects

Overdoses can be very serious in both animals & humans

What Is Amitriptyline HCL Used For?

Amitriptyline has been used for behavioral conditions such as separation anxiety or generalized anxiety in dogs, and excessive grooming, spraying and anxiety in cats. Amitriptyline may be useful for adjunctive treatment of pruritus, or chronic pain of neuropathic origin in dogs and cats. In cats, it potentially could be useful for adjunctive treatment of lower urinary tract disease. Amitriptyline has been tried to reduce feather plucking in birds.

Pharmacology / Actions

Amitriptyline (and its active metabolite, nortriptyline) has a complicated pharmacologic profile. From a slightly oversimplified viewpoint, it has 3 main characteristics: blockage of the amine pump, thereby increasing neurotransmitter levels (principally serotonin, but also norepinephrine), sedation, and central and peripheral anticholinergic activity. Other pharmacologic effects include stabilizing mast cells via H-l receptor antagonism, and antagonism of glutamate receptors and sodium channels. In animals, tricyclic antidepressants are similar to the actions of phenothiazines in altering avoidance behaviors.


Amitriptyline is rapidly absorbed from both the GI tract and from parenteral injection sites. Peak levels occur within 2-12 hours. Amitriptyline is highly bound to plasma proteins, enters the CNS, and enters maternal milk in levels at, or greater than those found in maternal serum. The drug is metabolized in the liver to several metabolites, including nortriptyline, which is active. In humans, the terminal half-life is approximately 30 hours. Half-life in dogs has been reported to be 6-8 hours.

Before you take Amitriptyline HCL

Contraindications / Precautions / Warnings

These agents are contraindicated if prior sensitivity has been noted with any other tricyclic. Concomitant use with monoamine oxidase inhibitors is generally contraindicated. Use with extreme caution in patients with seizure disorders as tricyclic agents may reduce seizure thresholds. Use with caution in patients with thyroid disorders, hepatic disorders, KCS, glaucoma, cardiac rhythm disorders, diabetes, or adrenal tumors.

Adverse Effects

The most predominant adverse effects seen with the tricyclics are related to their sedating and anticholinergic (constipation, urinary retention) properties. Occasionally, dogs exhibit hyperexcitability and, rarely, develop seizures. However, adverse effects can run the entire gamut of systems, including cardiac (dysrhythmias), hematologic (bone marrow suppression), GI (diarrhea, vomiting), endocrine, etc. Cats may demonstrate the following adverse effects: sedation, hypersalivation, urinary retention, anorexia, thrombocytopenia, neutropenia, unkempt hair coat, vomiting, ataxia, dis-orientation and cardiac conductivity disturbances.

Reproductive / Nursing Safety

Isolated reports of limb reduction abnormalities have been noted; restrict use to pregnant animals only when the benefits clearly outweigh the risks. In humans, the FDA categorizes this drug as category D for use during pregnancy (There is evidence of human fetal risk, hut the potential benefits from the use of the drug in pregnant women may he acceptable despite its potential risks.)

Overdosage / Acute Toxicity

Overdosage with tricyclics can be life-threatening (arrhythmias, cardiorespiratory collapse). Because the toxicities and therapies for treatment are complicated and controversial, it is recommended to contact a poison control center for further information in any potential overdose situation.

There were 25 exposures to amitriptyline reported to the ASPCA Animal Poison Control Center (APCC; during 2005-2006. In these cases, 21 were cats with 5 showing clinical signs. Common findings recorded in decreasing frequency included: anorexia, mydriasis and adipsia. The remaining 4 cases were dogs with no reported clinical signs.

How to use Amitriptyline HCL

Amitriptyline HCL dosage for dogs:

For adjunctive treatment of pruritus:

a) 1-2 mg/kg PO q12h ()

b) For acral pruritic dermatitis: 2.2 mg/kg PO twice daily; only occasionally effective. A 2-4 week trial is recommended ()

For behavior disorders amenable to tricyclics:

a) For separation anxiety or generalized anxiety: 1-2 mg/kg PO q12h; with behavior modification ()

b) 1-4 mg/kg PO q12h. Begin at 1-2 mg/kg PO q12h for 2 weeks, increase by 1 mg/kg up to maximum dosage (4 mg/ kg) as necessary. If no clinical response, decrease by 1 mg/kg PO q12h for 2 weeks until at initial dosage. ()

c) 2.2-4.4 mg/kg PO q12h ()

d) 0.25-1.5 mg/kg PO every 12-24h ()

For neuropathic pain:

a) 1-2 mg/kg PO ql2-24h ()

b) For adjunctive treatment of pain associated with appendicular osteosarcoma: 1-2 mg/kg PO ql2-24h ()

Amitriptyline HCL dosage for cats:

For adjunctive treatment of behavior disorders amenable to tricyclics:

a) 5-10 mgper cat PO once daily ()

b) 0.5-2 mg/kg PO ql2-24h; start at 0.5 mg/kg PO q12h ()

c) 0.5-1 mg/kg PO ql2-24h ()

d) 0.5-1 mg/kg PO ql2-24h. Allow 3-4 weeks for initial trial. ()

For self-mutilation behaviors associated with anxiety:

a) 5-10 mg per cat PO once to twice daily; with behavior modification ()

b) 1-2 mg/kg PO q12h ()

For pruritus (after other more conventional therapies have failed):

a) 5-10 mg per cat PO once daily or 2.5-7.5 mg/cat once to twice daily. When discontinuing, taper dose over 1-3 weeks. ()

For symptomatic therapy of idiopathic feline lower urinary tract disease:

a) 2.5-12.5 mg (total dose) PO once daily at night ()

b) 5-10 mg (total dose) PO once daily at night; the drug is in popular use at present and further studies are needed ()

c) Reserved for cases with severe, recurrent signs; 2.5-12.5 mg (total dose) PO at the time the owner retires for the night. Dosage is adjusted to produce a barely perceptible calming effect on the cat. If no improvement is seen within 2 months, the medication may be gradually tapered and then stopped. ()

For neuropathic pain:

a) 2.5-12.5 mg/cat PO once daily ()

b) 0.5-2 mg/kg PO once daily; may be a useful addition to NSAIDs for chronic pain. ()

Amitriptyline HCL dosage for birds:

For adjunctive treatment of feather plucking:

a) 1-2 mg/kg PO ql2-24 hours. Anecdotal reports indicate some usefulness. Barring side effects, may be worth a more prolonged course of therapy to determine efficacy. ()


■ Efficacy

■ Adverse effects; it is recommended to perform a cardiac evaluation, CBC and serum chemistry panel prior to therapy

■ For cats, some clinicians recommend that liver enzymes be measured prior to therapy, one month after initial therapy, and yearly, thereafter

Client Information

■ All tricyclics should be dispensed in child-resistant packaging and kept well away from children or pets.

■ Several weeks may be required before efficacy is noted and to continue dosing as prescribed. Do not abruptly stop giving medication without veterinarian’s advice.

Chemistry / Synonyms

A tricyclic dibenzocycloheptene-derivative antidepressant, amitriptyline HCL occurs as a white or practically white, odorless or practically odorless crystalline powder that is freely soluble in water or alcohol. It has a bitter, burning taste and a pKa of 9.4.

Amitriptyline may also be known as amitriptylini hydrochloridum; many trade names are available.

Storage / Stability

Amitriptyline tablets should be stored at room temperature. The injection should be kept from freezing and protected from light.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products: None

The ARCI (Racing Commissioners International) has designated this drug as a class 2 substance. See the appendix for more information.

Human-Labeled Products:

Amitriptyline HCL Tablets: 10,25, 50, 75,100,150 mg; generic; (Rx)

There are also fixed dose oral combination products containing amitriptyline and chlordiazepoxide, and amitriptyline and perphenazine.


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.


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).


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. ()


■ 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)


Amikacin Sulfate (Amikin, Amiglyde-V)

Aminoglycoside Antibiotic

Highlights Of Prescribing Information

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

Adverse Effects: Nephrotoxicity, ototoxicity, neuromuscu-lar blockade

Cats may be more sensitive to toxic effects

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

Now usually dosed once daily when used systemically

What Is Amikacin Sulfate Used For?

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

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


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

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

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

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


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

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

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

Before you take Amikacin Sulfate

Contraindications / Precautions / Warnings

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

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

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

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

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

Adverse Effects

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

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

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

Reproductive / Nursing Safety

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

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

Overdosage / Acute Toxicity

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

How to use Amikacin Sulfate

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

Amikacin Sulfate dosage for dogs:

For susceptible infections:

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

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

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

Amikacin Sulfate dosage for cats:

For susceptible infections:

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

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

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

Amikacin Sulfate dosage for ferrets:

For susceptible infections:

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

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

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

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

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

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

Amikacin Sulfate dosage for cattle:

For susceptible infections:

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

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

Amikacin Sulfate dosage for horses:

For susceptible infections:

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

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

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

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

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

For uterine infusion:

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

b) 1-2 grams IU ()

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

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

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

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

Amikacin Sulfate dosage for birds:

For susceptible infections:

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

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

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

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

Amikacin Sulfate dosage for reptiles:

For susceptible infections:

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

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

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

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

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

Amikacin Sulfate dosage for fish:

For susceptible infections:

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


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

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

■ Gross monitoring of vestibular or auditory toxicity is recommended.

Client Information

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

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

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

Chemistry / Synonyms

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

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

Storage / Stability/Compatibility

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

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

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

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

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

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

Dosage Forms / Regulatory Status

Veterinary-Labeled Products:

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

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

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

Human-Labeled Products:

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


Acepromazine Maleate (PromAce, Aceproject)

Phenothiazine Sedative / Tranquilizer

Highlights Of Prescribing Information

Negligible analgesic effects

Dosage may need to be reduced in debilitated or geriatric animals, those with hepatic or cardiac disease, or when combined with other agents

Inject IV slowly; do not inject into arteries

Certain dog breeds (e.g., giant breeds, sight hounds) may be overly sensitive to effects

May cause significant hypotension, cardiac rate abnormalities, hypo- or hyperthermia

May cause penis protrusion in large animals (esp. horses)

What Is Acepromazine Used For?

Acepromazine is approved for use in dogs, cats, and horses. Labeled indications for dogs and cats include: “… as an aid in controlling intractable animals… alleviate itching as a result of skin irritation; as an antiemetic to control vomiting associated with motion sickness” and as a preanesthetic agent. The use of acepromazine as a sedative/tranquilizer in the treatment of adverse behaviors in dogs or cats has largely been supplanted by newer, effective agents that have fewer adverse effects. Its use for sedation during travel is controversial and many no longer recommend drug therapy for this purpose.

In horses, acepromazine is labeled “… as an aid in controlling fractious animals,” and in conjunction with local anesthesia for various procedures and treatments. It is also commonly used in horses as a pre-anesthetic agent at very small doses to help control behavior.

Although not approved, it is used as a tranquilizer (see doses) in other species such as swine, cattle, rabbits, sheep and goats. Acepromazine has also been shown to reduce the incidence of halothane-induced malignant hyperthermia in susceptible pigs.

Before you take Acepromazine

Contraindications / Precautions / Warnings

Animals may require lower dosages of general anesthetics following acepromazine. Use cautiously and in smaller doses in animals with hepatic dysfunction, cardiac disease, or general debilitation. Because of its hypotensive effects, acepromazine is relatively contraindicated in patients with hypovolemia or shock. Phenothiazines are relatively contraindicated in patients with tetanus or strychnine intoxication due to effects on the extrapyramidal system.

Intravenous injections should be made slowly. Do not administer intraarterially in horses since it may cause severe CNS excitement/depression, seizures and death. Because of its effects on thermoregulation, use cautiously in very young or debilitated animals.

Acepromazine has no analgesic effects; treat animals with appropriate analgesics to control pain. The tranquilization effects of acepromazine can be overridden and it cannot always be counted upon when used as a restraining agent. Do not administer to racing animals within 4 days of a race.

In dogs, acepromazine’s effects may be individually variable and breed dependent. Dogs with MDR1 mutations (many Collies, Australian shepherds, etc.) may develop a more pronounced sedation that persists longer than normal. It may be prudent to reduce initial doses by 25% to determine the reaction of a patient identified or suspected of having this mutation.

Acepromazine should be used very cautiously as a restraining agent in aggressive dogs as it may make the animal more prone to startle and react to noises or other sensory inputs. In geriatric patients, very low doses have been associated with prolonged effects of the drug. Giant breeds and greyhounds may be extremely sensitive to the drug while terrier breeds are somewhat resistant to its effects. Atropine may be used with acepromazine to help negate its bradycardic effects.

In addition to the legal aspects (not approved) of using acepromazine in cattle, the drug may cause regurgitation of ruminal contents when inducing general anesthesia.

Adverse Effects

Acepromazine’s effect on blood pressure (hypotension) is well described and an important consideration in therapy. This effect is thought to be mediated by both central mechanisms and through the alpha-adrenergic actions of the drug. Cardiovascular collapse (secondary to bradycardia and hypotension) has been described in all major species. Dogs may be more sensitive to these effects than other animals.

In male large animals acepromazine may cause protrusion of the penis; in horses, this effect may last 2 hours. Stallions should be given acepromazine with caution as injury to the penis can occur with resultant swelling and permanent paralysis of the penis retractor muscle. Other clinical signs that have been reported in horses include excitement, restlessness, sweating, trembling, tachypnea, tachycardia and, rarely, seizures and recumbency.

Its effects of causing penis extension in horses, and prolapse of the membrana nictitans in horses and dogs, may make its use unsuitable for show animals. There are also ethical considerations regarding the use of tranquilizers prior to showing an animal or having the animal examined before sale.

Occasionally an animal may develop the contradictory clinical signs of aggressiveness and generalized CNS stimulation after receiving acepromazine. IM injections may cause transient pain at the injection site.

Overdosage / Acute Toxicity

The LD50 in mice is 61 mg/kg after IV dosage and 257 mg/kg after oral dose. Dogs receiving 20-40 mg/kg over 6 weeks apparently demonstrated no adverse effects. Dogs gradually receiving up to 220 mg/kg orally exhibited signs of pulmonary edema and hyperemia of internal organs, but no fatalities were noted.

There were 128 exposures to acepromazine maleate reported to the ASPCA Animal Poison Control Center (APCC; during 2005-2006. In these cases, 89 were dogs with 37 showing clinical signs and the remaining 39 reported cases were cats with 12 cats showing clinical signs. Common findings in dogs recorded in decreasing frequency included ataxia, lethargy, sedation, depression, and recumbency. Common findings in cats recorded in decreasing frequency included lethargy, hypothermia, ataxia, protrusion of the third eyelid, and anorexia.

Because of the apparent relatively low toxicity of acepromazine, most overdoses can be handled by monitoring the animal and treating clinical signs as they occur; massive oral overdoses should definitely be treated by emptying the gut if possible. Hypotension should not be treated with epinephrine; use either phenylephrine or norepinephrine (levarterenol). Seizures may be controlled with barbiturates or diazepam. Doxapram has been suggested as an antagonist to the CNS depressant effects of acepromazine.

How to use Acepromazine

Note: The manufacturer’s dose of 0.5-2.2 mg/kg for dogs and cats is considered by many clinicians to be 10 times greater than is necessary for most indications. Give IV doses slowly; allow at least 15 minutes for onset of action.

Acepromazine dosage for dogs:

a) Premedication: 0.03-0.05 mg/kg IM or 1-3 mg/kg PO at least one hour prior to surgery (not as reliable) ()

b) Restraint/sedation: 0.025-0.2 mg/kg IV; maximum of 3 mg or 0.1-0.25 mg/kg IM; Preanesthetic: 0.1-0.2 mg/kg IV or IM; maximum of 3 mg; 0.05-1 mg/kg IV, IM or SC ()

c) To reduce anxiety in the painful patient (not a substitute for analgesia): 0.05 mg/kg IM, IV or SC; do not exceed 1 mg total dose ()

d) 0.55-2.2 mg/kg PO or 0.55-1.1 mg/kg IV, IM or SC (Package Insert; PromAce — Fort Dodge)

e) As a premedicant with morphine: acepromazine 0.05 mg/kg IM; morphine 0.5 mg/kg IM ()

Acepromazine dosage for cats:

a) Restraint/sedation: 0.05-0.1 mg/kg IV, maximum of 1 mg ()

b) To reduce anxiety in the painful patient (not a substitute for analgesia): 0.05 mg/kg IM, IV or SC; do not exceed 1 mg total dose ()

c) 1.1-2.2 mg/kg PO, IV, IM or SC (Package Insert; PromAce — Fort Dodge)

d) 0.11 mg/kg with atropine (0.045-0.067 mg/kg) 15-20 minutes prior to ketamine (22 mg/kg IM). ()

Acepromazine dosage for ferrets:

a) As a tranquilizer: 0.25-0.75 mg/kg IM or SC; has been used safely in pregnant jills, use with caution in dehydrated animals. ()

b) 0.1-0.25 mg/kg IM or SC; may cause hypotension/hypothermia ()

Acepromazine dosage for rabbits, rodents, and small mammals:

a) Rabbits: As a tranquilizer: 1 mg/kg IM, effect should begin in 10 minutes and last for 1-2 hours ()

b) Rabbits: As a premed: 0.1-0.5 mg/kg SC; 0.25-2 mg/kg IV, IM, SC 15 minutes prior to induction. No analgesia; may cause hypotension/hypothermia. ()

c) Mice, Rats, Hamsters, Guinea pigs, Chinchillas: 0.5 mg/kg IM. Do not use in Gerbils. ()

Acepromazine dosage for cattle:

a) Sedation: 0.01-0.02 mg/kg IV or 0.03-0.1 mg/kg IM ()

b) 0.05 -0.1 mg/kg IV, IM or SC ()

c) Sedative one hour prior to local anesthesia: 0.1 mg/kg IM ()

Acepromazine dosage for horses:

(Note: ARCI UCGFS Class 3 Acepromazine)

a) For mild sedation: 0.01-0.05 mg/kg IV or IM. Onset of action is about 15 minutes for IV; 30 minutes for IM ()

b) 0.044-0.088 mg/kg (2-4 mg/100 lbs. body weight) IV, IM or SC (Package Insert; PromAce — Fort Dodge)

c) 0.02-0.05 mg/kg IM or IV as a preanesthetic ()

d) Neuroleptanalgesia: 0.02 mg/kg given with buprenorphine (0.004 mg/kg IV) or xylazine (0.6 mg/kg IV) ()

e) For adjunctive treatment of laminitis (developmental phase): 0.066-0.1 mg/kg 4-6 times per day ()

Acepromazine dosage for swine:

a) 0.1-0.2 mg/kg IV, IM, or SC ()

b) 0.03-0.1 mg/kg ()

c) For brief periods of immobilization: acepromazine 0.5 mg/ kg IM followed in 30 minutes by ketamine 15 mg/kg IM. Atropine (0.044 mg/kg IM) will reduce salivation and bronchial secretions. ()

Acepromazine dosage for sheep and goats:

a) 0.05-0.1 mg/kg IM ()


■ Cardiac rate/rhythm/blood pressure if indicated and possible to measure

■ Degree of tranquilization

■ Male horses should be checked to make sure penis retracts and is not injured

■ Body temperature (especially if ambient temperature is very hot or cold)

Client Information

■ May discolor the urine to a pink or red-brown color; this is not abnormal

■ Acepromazine is approved for use in dogs, cats, and horses not intended for food

Chemistry / Synonyms

Acepromazine maleate (formerly acetylpromazine) is a phenothiazine derivative that occurs as a yellow, odorless, bitter tasting powder. One gram is soluble in 27 mL of water, 13 mL of alcohol, and 3 mL of chloroform.

Acepromazine Maleate may also be known as: acetylpromazine maleate, “ACE”, ACP, Aceproject, Aceprotabs, PromAce, Plegicil, Notensil, and Atravet.

Storage / Stability/Compatibility

Store protected from light. Tablets should be stored in tight containers. Acepromazine injection should be kept from freezing.

Although controlled studies have not documented the compatibility of these combinations, acepromazine has been mixed with atropine, buprenorphine, chloral hydrate, ketamine, meperidine, oxymorphone, and xylazine. Both glycopyrrolate and diazepam have been reported to be physically incompatible with phenothiazines, however, glycopyrrolate has been demonstrated to be compatible with promazine HC1 for injection.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products:

Acepromazine Maleate for Injection: 10 mg/mL for injection in 50 mL vials; Aceproject (Butler), PromAce (Fort Dodge); generic; (Rx). Approved forms available for use in dogs, cats and horses not intended for food.

Acepromazine Maleate Tablets: 5, 10 & 25 mg in bottles of 100 and 500 tablets; PromAce (Fort Dodge); Aceprotabs (Butler) generic; (Rx). Approved forms available for use in dogs, cats and horses not intended for food.

When used in an extra-label manner in food animals, it is recommended to use the withdrawal periods used in Canada: Meat: 7 days; Milk: 48 hours. Contact FARAD (see appendix) for further guidance.

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

Human-Labeled Products: None




Animal Studies

In animals, amantadine hydrochloride caused several pharmacologic effects at relatively high doses. Signs of motor activity stimulation (increased spontaneous motor activity and antagonism of tetrabenazine- induced sedation) occurred in mice at oral doses of 35-40 mg/kg and above. A transient vasodepressor effect, cardiac arrhythmias and a weak ganglionic-blocking effect in dogs were observed following intravenous doses of 13.5 mg/kg or above. EEG activation has been reported in the rat and rabbit with high parenteral doses.

In addition, the observations summarized in the table below have afforded evidence that amantadine HCl causes norepinephrine release and blockade of norepinephrine re-uptake at peripheral autonomic neuron storage sites.


Response Species Dose (mg/kg) Route
Blockade by reserpine pre-treatment of amantadine-induced transient increase in myocardial contractile force. dog 1 to 3 intravenous
Potentiation of norepine-phrine vasopressor response. dog 40.5 intravenous
Block of phenethylamine vasopressor response. dog >13.5 intravenous
Block of norepinephrine uptake into the heart. mouse >31 intraperitoneal

Amantadine hydrochloride is well absorbed by the oral route in all species studied; the rate of excretion of the drug is first order. The metabolism of amantadine hydrochloride in the monkey and mouse is somewhat similar to that in man. The monkey and mouse metabolize the drug less than the rat, dog and rabbit. The urine appears to be the major route of elimination. The dog has been shown to convert a portion of the administered drug to its N-methyl derivative which is excreted in the urine. No other metabolites have been identified.


The results of acute oral, intraperitoneal and intravenous toxicity studies in several species of laboratory animals are shown in Table Acute Toxicity Of Amantadine Hydrochloride LD50 (95% confidence limits). Oral LD50 values for dogs and rhesus monkeys could not be obtained because the animals vomited. One dog, which did not vomit, died at 93 mg/kg following signs of central nervous system stimulation, including clonic convulsions. In monkeys at doses of 200-500 mg/kg, emesis always occurred and convulsions appeared irregularly. At levels near the LD50, signs of central nervous system stimulation followed by tremors and brief clonic convulsions were common to the three rodent species by all routes of administration. All deaths occurred promptly, usually within a few minutes, or at the most within a few hours after compound administration.

Table Acute Toxicity Of Amantadine Hydrochloride LD50 (95% confidence limits)

Species Sex Oral
Mouse F 700 (621,779) 205 (194,216) 97 (88,106)
Rat F 890(761,1019) 223 (167,279)
Rat M 1275 (1095,1455)
Rat, neonatal M,F 150 (111,189)
Guinea pig F 360 (316,404)
Dog M,F >372*
Monkey, M >500* >37
* Emesis occurred

Chronic oral toxicity experiments were carried out with rats (88-94 weeks), dogs (2 years) and monkeys (6 months). The amantadine hydrochloride dose levels were 16, 80 and 100-160 mg/kg; 8, 40 and 40-80 mg/kg; and 10, 40 and 100 mg/kg, respectively, administered daily (5 days per week). In rats, at the high dose only, a statistically significant decrease in body weight and excess mortality was seen; signs of central nervous system stimulation after each dosing, reduced food intake, and susceptibility to infection were noted. In dogs, tremors, hyperexcitability and emesis were seen at the middle and high levels, and food intake was reduced. One dog in the middle, and three dogs in the high-level group died. In an additional dog experiment, 30 mg/kg of amantadine hydrochloride divided into two doses six hours apart, was given seven days per week for six months. No drug-related effects were seen. In the monkey experiment, stimulation was continuously evident in the high level and was seen sporadically in the middle-level group. No other effects were noted. In none of these experiments with rats, dogs and monkeys were any amantadine hydrochloride-related pathological or histomorpho-logical changes seen.

Effects on Reproduction

In rats, a 3-litter reproduction study was performed. Amantadine hydrochloride 10 mg/kg in the diet, resulted in no observed abnormality. When the dose was raised to 32 mg/kg, fertility and lactation indices were somewhat depressed. No fetal abnormalities were noted in this experiment.

In a different study virgin rats were dosed orally with amantadine hydrochloride (50 or 100 mg/kg) from 5 days prior to mating until day 6 of pregnancy. Autopsy performed on day 14 of gestation showed significant decreases in the number of implantations and number of resorptions at 100 mg/kg. Teratology studies were performed in rats by administering the drug (37, 50 or 100 mg/kg) orally on days 7-14 of gestation. Autopsy just before parturition showed increases in resorption and decreases in the number of pups per litter at 50 and 100 mg/kg. Malformation of pups occurred with a frequency of 0% at the 37 mg/kg, 4.7% at the 50 mg/kg and 17% at the 100 mg/kg level. The majority of changes were skeletal (mainly spinal column and rib deficits), but some visceral changes (edema, undescended ovaries and testes) were also mentioned.

In a teratology study carried out in Japan, pregnant rats received amantadine hydrochloride (40 or 120 mg/kg) orally on days 9 to 14 of gestation. At the higher dose the dams had a slightly decreased rate of increase in body weight, the mortality rate of the fetus was increased and the surviving pups showed decreased body weight. This difference, however, disappeared after the end of the first postnatal week. There were no malformations or skeletal abnormalities.

In a teratogenetic study mice received amantadine hydrochloride 10 or 40 mg/kg, p.o., from the 7th to the 12th day of pregnancy. The most important findings include, at the high dose level, increased fetus mortality and reduced body weight of the dams as well as of the surviving offspring. One case of exencephalia was found in the high-level group which, in the opinion of the investigators, was not drug-related.

Rabbits were mated and dosed six days later with 8 or 32 mg/kg through day 16 and sacrificed on day 28. A separate study was reported in which rabbits received amantadine hydrochloride orally, 100 mg/kg, on days 7 to 14 of gestation. No teratogenic or other adverse effects were seen in these rabbit experiments.


Heart Failure: Treatment Strategies

Management of Acute Decompensated Congestive Heart Failure

Dogs with dilated cardiomyopathy or mitral regurgitation often present with acute onset of coughing, dyspnea, restlessness, orthopnea, and weakness subsequent to the development of severe pulmonary edema and/or low cardiac output. The immediate priorities in these patients are resolution of the pulmonary edema, maintenance of adequate tissue perfusion pressure, and adequate delivery of blood flow to vital tissues. These goals must be achieved quickly, therefore it is important that the practitioner use drugs with proven hemodynamic benefits and a rapid onset of action.

Oxygen Supplementation

As left atrial and pulmonary capillary pressures increase and the lymphatics’ capacity to remove fluid is overwhelmed, the interstitial space and alveoli become flooded. Because these flooded alveoli lack ventilation and represent areas of functional shunting, oxygen administration must be combined with agents that effectively lower pulmonary venous pressure. Oxygen can easily be administered to compromised patients by provision of an oxygen-enriched environment (i.e., oxygen cage) or by use of nasal insufflation, achieving maximal inspired oxygen concentrations of 40% to 90%, respectively.

Reduction of Pulmonary Venous Pressure

Rapid reduction of pulmonary venous pressure is most readily achieved through use of a combination of intravenous (IV) drugs that lower the circulating plasma volume and redistribute the intravascular volume. Intravenous furosemide (2 to 8 mg/kg) should be administered to dogs with severe pulmonary edema to promote natriuresis and diuresis quickly. These large doses may be repeated (initially every 1 to 2 hours) until the respiratory rate and dyspnea start to decline. After stabilization, the dose should be reduced (2 to 4 mg/kg every 8 to 12 hours), because excessive administration may lead to profound dehydration, electrolyte depletion, renal failure, low cardiac output, and circulatory collapse.

Drugs that decrease preload (to combat congestion) and afterload (to decrease myocardial work) are administered concurrently with furosemide. Intravenous sodium nitroprusside is a potent, ultrarapid, balanced vasodilator that seems to reduce pulmonary venous pressure quickly and effectively. When used in animals with congestive heart failure, nitroprusside decreases right atrial and pulmonary capillary wedge pressures and systemic vascular resistance and increases cardiac output. Although hypotension and tachycardia are reported side effects, the reduction in systemic vascular resistance (SVR) is theoretically associated with an increase in cardiac output (CO) that serves to maintain systemic arterial blood pressure (BP = SVR. x CO). Nausea, vomiting, and cyanide toxicity during prolonged administration are other reported side effects. Because of its short half-life, nitroprusside, mixed with 5% dextrose, must be administered by constant-rate infusion (CRI). After institution of an initial dose of 1 µg/kg/min, the rate is slowly titrated upward while the blood pressure is monitored. An infusion rate of 2 to 5 µg/kg/min usually is sufficient to decrease afterload, although rarely doses as high as 10 µg/kg/min may be required. If significant hypotension is encountered after administration of nitroprusside, slowing the infusion rate generally is effective at raising the blood pressure to acceptable levels.

Sodium nitroprusside Nitroprusside is an intravenous preparation with potent arteriolar and venous vasodilative properties mediated by the formation of nitric oxide and subsequently the second messenger cyclic guanosine monophosphate (cGMP). To some degree, the combination of nitroprusside and dobutamine can be considered short-term “cardiac life support,” used primarily during an attempt to rescue dogs with severe, life-threatening pulmonary edema subsequent to dilated cardiomyopathy. This drug combination’s ability to reduce afterload quickly appears to be beneficial also in patients with chronic degenerative valvular disease and pulmonary edema, although management of these cases often can be accomplished less intensively.

Unfortunately, the beneficial hemodynamic profile of nitroprusside is accompanied by a difficult administration protocol that requires intensive monitoring. Because nitroprusside produces an almost immediate and often profound reduction in systemic vascular resistance, continuous blood pressure monitoring throughout administration is recommended. The drug is light sensitive, is given by constant-rate infusion (typically 2 to 5 µg/kg/min), and should not be infused with another agent, which necessitates placement of a second intravenous catheter for administration of dobutamine. These stringent requirements may provide cause for more frequent use of intravenous bipyridines to combat life-threatening heart failure, at least until studies are able to elucidate whether either method produces better results.

If nitroprusside is unavailable, balanced vasodilatation may be attempted through administration of an arterial vasodilator (hydralazine, 0.5 to 2 mg/kg given orally) in combination with a venodilator (nitroglycerin ointment, ¼ to ¾ -inch applied cutaneously every 8 to 12 hours; or isosorbide dinitrate, 0.5 to 2 mg/kg given orally every 8 hours). Although easier to administer, this therapy seems to be less effective at quickly reducing pulmonary venous pressure compared with nitroprusside.

Potent afterload reduction in patients with severe mitral insufficiency and large regurgitant volumes serves to decrease the left ventricular to left atrial pressure gradient and hence the volume of insufficiency. Nitroprusside, or possibly hydralazine, can effectively decrease the volume of mitral regurgitation and lower left atrial pressure in cases of severe congestive heart failure subsequent to rupture of the chordae tendineae or the onset of atrial fibrillation. Despite this obvious theoretical advantage, a recent human study showed that mitral regurgitation worsened in four of nine patients with mitral valve prolapse during nitroprusside infusion. This finding highlights the point that adjustments in the therapeutic regimen may be required and should be based on patient response rather than physiologic principles.

Augmentation of Systolic Performance

Preload reducing agents, such as furosemide, cannot enhance systolic function and in fact at high doses serve only to decrease cardiac output. Therefore the use of a rapid-acting, intravenous inotropic agent is vital to the management of acute decompensated congestive heart failure in dogs with dilated cardiomyopathy. Although there is debate over whether dogs with mitral valve insufficiency have systolic dysfunction, acutely positive inotropic agents may serve to decrease the regurgitant orifice area and hence the volume of insufficiency.

The short-acting, positive inotropic agents most commonly used to manage decompensated heart failure increase cyclic adenosine monophosphate (cAMP). Dobutamine and dopamine are sympathomimetic agents that bind to beta, receptors, thereby stimulating adenylyl cyclase activity and production of cAMP. The bipyridines amrinone and milrinone increase cyclic adenosine monophosphate by preventing its degradation by phosphodiesterase. Both drug classes are capable of rapidly augmenting systolic function during constant-rate intravenous infusions. By increasing cytosolic cAMP, these agents enhance (1) calcium entry into the cell, promoting ventricular contraction; (2) diastolic calcium uptake by the sarcoplasmic reticulum, promoting ventricular relaxation; and (3) peripheral vasodilatation, reducing after-load. It should be remembered that the sympathomimetics also have alpha-agonistic properties that promote vasoconstriction. Unfortunately, both the sympathomimetics and the bipyridines may promote tachycardia and undesirable ventricular arrhythmias. Therefore careful electrocardiographs (ECG) monitoring is required during administration of these drugs, and significant or worsening ventricular arrhythmias may warrant discontinuation of the infusion and institution of antiarrhythmic therapy.

Sympathomimetics The sympathomimetics enhance cardiac contractility by complexing with myocardial beta receptors. After substrate binding to an unoccupied beta receptor, a coupled G-protein stimulates the enzyme cyclase to produce cAMP. This second-messenger “effector” system acts by means of protein kinase A to phosphorylate intracellular proteins, including the L-type calcium channel, phospholamban, and troponin I, thereby enhancing ventricular contraction and relaxation. Despite the sympathomimetics’ ability to increase cardiac contractility approximately 100% above baseline, not all drugs in this class are suitable for the management of heart failure. The specificity for beta receptor binding depends on the specific agent and dose administered. Sympathomimetics inappropriate for the management of heart failure include the pure beta agonist isoproterenol and the naturally occurring catecholamines norepinephrine and epinephrine. These agents tend to promote tachycardia, arrhythmias, and untoward alterations in systemic vascular resistance

Dobutamine and dopamine are more appropriate sympathomimetics for the management of heart failure. Although both drugs can enhance cardiac contractility, several drawbacks discourage long-term use: (1) they must be given intravenously, because successful oral administration is precluded by extensive first-pass hepatic metabolism; (2) because of their extremely short half-lives (approximately 1 to 2 minutes), they must be administered by constant-rate infusion; (3) almost any positive inotropic response tends to increase myocardial work and thus the propensity for ventricular arrhythmias; and (4) after 24 to 48 hours of constant-rate infusion, their positive inotropic response is limited by beta receptor downregulation and uncoupling. The tendency for long-term sympathomimetic administration to increase mortality, as documented in humans, appears to relegate these agents to short-term management of acute, life-threatening heart failure.

Dobutamine Dobutamine is a synthetic analog of dopamine that displays predominately betaj receptor binding (beta1 > beta2 > alpha). Dobutamine is able to increase cardiac contractility and thus cardiac output without causing a profound, concomitant increase in the heart rate. The mechanism underlying the lack of a positive chronotropic response is not well understood, but this characteristic tends to make dobutamine the most appropriate agent for short-term treatment of heart failure. It appears that complexing with vasodilative beta receptors and vasoconstrictive alpha receptors, combined with an increase in cardiac output, maintains arterial blood pressure at near baseline values. If the systolic blood pressure is normal to elevated, dobutamine infusion (slow titration up to 5 to 15 µg/kg/min in 5% dextrose) can be combined with the potent vasodilator nitroprusside in an attempt to decrease internal cardiac work and further enhance forward blood flow. Continuous ECG and blood pressure monitoring is recommended during this treatment regimen, and exacerbation of tachycardia or ventricular arrhythmias may necessitate discontinuation of dobutamine.

Dopamine A precursor of norepinephrine, dopamine can bind myocardial beta receptors in addition to peripherally located dopaminergic, beta2, and alpha receptors. Within the renal, mesenteric, coronary, and cerebral vascular beds, these dopaminergic DA2 receptors are able to promote vasodilata-tion at low infusion rates of dopamine (1 to 2 µg/kg/min). However, at higher infusion rates (10 to 20 µg/kg/min), these vasodilative properties are over-ridden by an undesirable, alpha-mediated vasoconstrictive response. Also, high doses are accompanied by increases in the heart rate, the likelihood of arrhythmogenesis, the release of norepinephrine, and the myocardial oxygen demand. Dopamine (slow titration up to 1 to 10 µg/kg/min) may be used in situations similar to those in which dobutamine is appropriate (e.g., profound myocardial failure) and may further enhance renal blood flow. For the authors, an increased propensity for the development of tachycardia relegates dopamine to the role of second-choice drug. As with dobutamine, careful ECG and blood pressure monitoring is indicated during dopamine administration.

Bipyridines Similar to the sympathomimetics, the bipyridines promote an increase in cardiac contractility by increasing cytosolic cyclic adenosine monophosphate levels. However, rather than directly enhancing the production of cAMP, they increase circulating levels by inhibiting phosphodiesterase III, the enzyme responsible for cyclic adenosine monophosphate inactivation. Unlike the sympathomimetics, the bipyridines do not rely on beta-adrenergic receptors and therefore are less affected by downregulation and uncoupling. Furthermore, because phosphodiesterase inhibitors increase vascular smooth muscle cyclic adenosine monophosphate without displaying affinity for alpha receptors, they are also vasodilators. Because of the bipyridines’ combination of positive inotropic and vasodilative properties, the term inodilators has come into use for these agents. Because they increase cytosolic calcium and myocardial work, they inherently carry the caveats of tachycardia and ventricular arrhythmias. In fact, the 28% increase in all-cause mortality identified in humans randomized to oral milrinone versus placebo has severely limited further attempts to evaluate agents that act via cAMP-dependent mechanisms.

Milrinone The phosphodiesterase inhibitor milrinone is substantially more potent than amrinone and is available in an intravenous preparation. Because of its combined positive inotropic and vasodilative properties, milrinone may be used as a substitute for the dobutamine/nitroprusside combination in the management of acute life-threatening heart failure. Despite milrinone’s ability to increase measures of fractional shortening after oral administration in dogs, this formulation is no longer available for prescription.”

There are no published reports regarding the hemodynamic effects of intravenous milrinone administered to dogs with acute myocardial failure. When administered to normal dogs at an infusion rate of 1 to 10 µg/kg/min, milrinone increased cardiac contractility 50% to 140%. Whether similar doses are efficacious in dogs with heart failure is uncertain, and dosing recommendations currently are difficult to propose. Because CRI milrinone requires 10 to 30 minutes to reach maximal peak effects in normal dogs, it may be prudent to administer a loading dose, followed by constant-rate infusion. Theoretical administration guidelines after the bolus would be to titrate the infusion rate upward slowly while monitoring the systemic blood pressure and a continuous electrocardiogram. Efficacy may be monitored clinically (e.g., reduction in the respiratory rate, alleviation of orthopnea) or echocardiographically with periodic measures of systolic function.

Amrinone The effects of amrinone are almost identical to those of milrinone except that it does not appear to be as potent. Although there are no reports of its large-scale use in the management of acute decompensated congestive heart failure, treatment recommendations have been extrapolated from studies of normal dogs. Constant-rate infusions of 10 to 100 µg/kg/min appear to be capable of increasing cardiac contractility by 10% to 80% in awake, normal dogs. Anesthetized dogs showed a 15% increase in the heart rate at an infusion rate of 30 µg/kg/min and a 20% increase at 100 µg/kg/min. This tachycardia may have been induced either directly, through cyclic adenosine monophosphate stimulation, or indirecdy, in response to a decrease in blood pressure. The 30 µg/kg/min infusion rate was associated with a 10% decrease in blood pressure, whereas the 100 µg/kg/min rate reduced blood pressure by 30%.I After institution of a CRI, amrinone requires approximately 45 minutes to reach peak effect. Therefore, similar to milrinone, it appears most appropriate to administer a slow IV bolus of 1 to 3 mg/kg, followed by a slowly up-titrated CRI of 10 to 100 µg/kg/min. Continuous ECG monitoring should be instituted to allow evaluation for excessive tachycardia or arrhythmogenesis, and the systemic blood pressure should be monitored to avoid hypotension.

Management of Acute Heart Failure Secondary to Diastolic Dysfunction

Cats with hypertrophic cardiomyopathy (HCM) often present with signs of respiratory distress subsequent to the development of pulmonary edema or pleural effusion. Impaired ventricular relaxation produces elevated atrial and venous pressures, with eventual fluid exudation into the alveoli or pleural space. The treatment goals for cats with HCM and heart failure focus on relieving congestion through preload reduction rather than augmenting systolic function or decreasing afterload.


Progression Of Heart Failure

Traditionally heart failure has been perceived as a hemodynamic disorder that promotes weakness, the development of debilitating congestive signs, deterioration of cardiac function, and ultimately death. Although the initial cardiac insult varies, it was historically rationalized that ventricular remodeling and disease progression occur as consequences of the compensatory mechanisms that promote vasoconstriction and fluid retention. It was recognized that diseased hearts operate on a depressed and flattened Frank-Starling curve, such that volume retention and vasoconstriction, rather than promoting cardiac output, merely exacerbated congestive heart failure. The symptoms of heart failure developed as venous pressures breached the lymphatics’ ability to remove edema or as blood flow to exercising muscles was severely limited.

If disease progression were solely mediated by hemodynamic alterations, it was hypothesized, drugs capable of “unloading” the heart (e.g., vasodilators and positive inotropes) would retard this progression and improve survival. In the first Veterans Affairs Heart Failure Trial (V-HeFT) completed in 1985, prazosin or a combination of hydralazine and isosorbide dinitrate was used to decrease preload and afterload. Although prazosin was more effective at reducing blood pressure, only the hydralazine/isosorbide dinitrate combination reduced mortality compared with placebo. The discordance between the hemodynamic and prognostic findings could not be explained by the traditional perception of heart failure. Support for the hemodynamic hypothesis was further undermined by the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial completed in December of 1994, which found that administration of amlodipine to patients with severe chronic heart failure had no significant effect on mortality.

Similar to the use of vasodilators to decrease ventricular wall stress and increase cardiac output, potent inotropic drugs capable of increasing cyclic adenosine monophosphate levels were developed with the intent to improve survival. If poor pump performance were responsible for the progressive nature of heart failure, it was hypothesized, these positive inotropes should alter the natural course of cardiovascular disease. The phosphodiesterase inhibitor milrinone, which has potent inotropic and vasodilative properties, in fact was found to alter the course of heart failure but in a fashion opposite that expected. In October of 1990, the Prospective Randomized Milrinone Survival Evaluation (PROMISE) trial was stopped 5 months prior to its scheduled completion date because administration of oral milrinone was found to increase all-cause mortality by 28%. Patients with the severest symptoms (i.e., New York Heart Association (NYHA] class IV), who therefore would be the most likely to receive additional medical therapy, showed a 53% increase in mortality. Administration of the partial beta-agonist xamoterol also failed to improve survival in a study of 516 patients.

These drug trial failures were accompanied in the late 1980s and early 1990s by an evolution in the understanding of the traditional hemodynamic model of heart failure. It still was recognized that hemodynamic alterations accounted for the symptomatic manifestations of cardiac disease, but a new understanding of the condition resulted in the conclusion that the body’s compensatory neurohormonal mechanisms contributed to the dilemma of disease progression. Activation of the sympathetic nervous system (SNS) and the renin-angiotensin system (RAS) was found to promote both adverse hemodynamic consequences and direct toxic effects on the myocardium. Cultured mammalian cardiomyocytes exposed to norepinephrine displayed a concentration-dependent decrease in viability that was attenuated significandy by beta-receptor blockade. In addition, norepinephrine was implicated in the provocation of ventricular arrhythmias and the impairment of sodium excretion by the kidneys. Pathophysiologic levels of angiotensin II were found to promote myocytolysis with subsequent fibroblast proliferation, and aldosterone was implicated in the process of myocardial extracellular matrix remodeling. These findings established a connection between hemodynamic mechanisms and neurohormonal consequences, which mutually promote a cycle of disease progression. The initial cardiac insult is followed by activation of neurohormonal compensatory mechanisms that produce further hemodynamic alterations and myocardial fibrosis. Cardiac output continues to decline, the compensatory mechanisms continue to be activated, and the disease process proceeds unabated.

This more complete understanding of the neurohormonal systems led to the development and use of drugs designed to antagonize the RAS. A breakthrough in the management of cardiovascular disease came with the utilization of angiotensin-converting enzyme (ACE) inhibitors in the mid to late 1980’s. Angiotensin-converting enzyme is capable of degrading vasodilative bradykinin and is responsible for cleaving relatively inactive angiotensin I to the potent vasoconstrictor angiotensin II (AT II). Indirectly angiotensin-converting enzyme is responsible for aldosterone production, because AT II is a primary stimulus for adrenal gland production of mineralocorticoids. Given angiotensin-converting enzyme’s critical position in the RAS, it was proposed that angiotensin-converting enzyme inhibition may promote beneficial hemodynamic and neurohormonal antagonistic and antifibrotic actions.

The angiotensin-converting enzyme inhibitor enalapril has been extensively studied in humans with varying stages of heart failure. In three studies, compared with placebo or the combination of hydralazine and isosorbide dinitrate, enalapril reduced all-cause mortality in humans with a reduced ejection fraction and heart failure.

In another study, compared with placebo, enalapril did not reduce the mortality rate in asymptomatic patients with reduced ejection fraction, although it delayed the onset of heart failure. Because angiotensin-converting enzyme inhibitors have been shown to alleviate symptoms, improve patients’ clinical status, and decrease mortality, the current recommendation is that all humans with heart failure due to left ventricular systolic dysfunction receive an angiotensin-converting enzyme inhibitor. The mortality reductions associated with administration of angiotensin-converting enzyme inhibitors lends support to the theory that disease progression is mediated by factors other than hemodynamics alone.

Management of Stable Compensated Congestive Heart Failure

Deficiencies of the Triple Drug Regimen

Potential therapeutic strategies

Management of Refractory Congestive Heart Failure

Management of Heart Failure Secondary to Diastolic Dysfunction

Maintenance Therapy

After stabilization, furosemide is switched to oral administration and the dose is decreased (6.25 mg given twice daily) to prevent excessive preload reduction, dehydration, and hypokalemia. In cases of hypertrophic cardiomyopathy, additional drugs may be instituted to reduce the heart rate and improve diastolic filling. Drugs frequently used in the management of HCM include the beta blocker atenolol and the calcium channel blocker diltiazem. Calcium channel Mockers theoretically can exert a beneficial effect in the management of HCM by modestly reducing the heart rate and contractility, thereby diminishing myocardial oxygen demand. Diltiazem may promote a direct positive lusitropic effect, and verapamil may partially reduce coronary endothelial dysfunction compared with propranolol. Atenolol (6.25 to 12.5 mg given orally every 12 to 24 hours) appears to exert better rate control and more consistently alleviates left ventricular outflow tract obstruction compared with diltiazem. Beta-adrenergic blockade may also prevent myocardial fibrosis by inhibiting catecholamine-induced cardiotoxicity and » may combat ventricular arrhythmias by decreasing myocardial oxygen consumption. One theoretical disadvantage of the use of beta blockers in the management of diastolic dysfunction is that phospholamban is an inhibitory protein that controls the rate of diastolic calcium uptake into the sarcoplasmic reticulum. Beta-adrenergic stimulation phosphorylates phospholamban and removes this inhibitory effect. Beta blockade may prevent this phosphorylation (and therefore decrease diastolic calcium uptake) and further impair the active process of ventricular relaxation.

Similar to beta blockers, with their proposed neurohormonal benefits, angiotensin-converting enzyme inhibitors likely are beneficial in the management of feline HCM. The authors have seen cats with symptomatic cardiomyopathy show marked neurohormonal activation. With this finding, and with the frequent requirement for furosemide to control pulmonary edema, it appears prudent to use enalapril (1.25 to 2.5 mg given orally every 12 to 24 hours) in the management of diastolic dysfunction. Although there is concern that afterload reduction may precipitate dynamic left ventricular outflow tract obstruction, recent data suggest that angiotensin-converting enzyme inhibitors can be used safely in cats with systolic anterior motion of the mitral valve.


Potential therapeutic strategies

Aldosterone antagonists The neurohormonal hypothesis of heart failure gains further support from the fact that the aldosterone antagonist spironolactone has proved efficacious in the management of severe heart failure in humans. Studies have recognized that small concentrations of aldosterone can stimulate cardiac fibroblast expression of type 1 and type III collagen, thereby promoting myocardial fibrosis. Although angiotensin-converting enzyme Inhibitors are considered effective at reducing aldosterone levels by inhibiting the formation of aldosterone’s primary secretagogue, angiotensin II, there is mounting evidence of a phenomenon called aldosterone escape. Increased potassium levels induced by angiotensin-converting enzyme inhibitors and decreased hepatic clearance may contribute to this RAS-independent increase in aldosterone. It also has become apparent that local tissue pathways for the production of aldosterone exist in extra-adrenal sites, although the importance of these tissue pathways has not been clarified. Because aldosterone impairs normal vasodilative responses, promotes myocardial fibrosis, potentiates the sympathetic nervous system, and influences electrolyte transport, a recent strategy to target heart failure has been the administration of aldosterone antagonists.

Addition of the aldosterone antagonist spironolactone to the baseline therapy of patients with severe heart failure produced a 30% reduction in mortality and a 35% reduction in the frequency of hospitalization for worsening heart failure. Although identification of the mechanism by which spironolactone exerts its beneficial effects was not the aim of the Randomized Aldactone Evaluation Study (RALES) group, a small substudy of 261 participants suggests that limitation of aldosterone-stimulated collagen synthesis is the major contributor. In a recent model of experimental heart failure created in dogs, the aldosterone antagonist eplerenone was able to attenuate the development of interstitial fibrosis and cardiomyocyte hypertrophy while increasing capillary density. Although the frequency and likelihood of aldosterone escape are unknown in dogs treated with angiotensin-converting enzyme inhibitors, it seems prudent to consider spironolactone administration for natients treated with enalapril. Currently the optimal dosing scheme for dogs is unknown; however, the authors combine spironolactone (2 mg/kg given orally twice daily) with their standard therapy (furosemide and enalapril with or without digoxin) to further combat the detrimental consequences of aldosterone. Whether this is the optimal regimen or whether spironolactone promotes symptomatic or survival benefit in dogs with heart failure is unknown at this time.

Beta-blockers Similar to what happens in humans, in dogs with congestive heart failure the body activates the sympathetic nervous system and renin-angiotensin-aldosterone system in an effort to maintain homeostasis. Unfortunately these short-term compensatory mechanisms promote adverse hemodynamic and biochemical alterations that ultimately contribute to weakness, debilitating congestive signs, deterioration of cardiac function, and ultimately death. The IMPROVE and COVE investigators identified the short-term utility of enalapril in combating dilated cardiomyopathy, and since then angiotensin-converting enzyme inhibition has become routine therapy. Although it has not been evaluated in controlled clinical trials, the loop diuretic furosemide appears to have a potent effect in alleviating the congestive clinical signs that frequently accompany heart failure. The efficacy, safety, and affordability of furosemide have made it a mainstay in the management of heart failure. Because systolic dysfunction is the primary phenotypic manifestation of dilated cardiomyopathy, the authors’ ideal therapy would further use an agent that augments systolic performance without promoting adverse events. In humans, long-term administration of beta agonists and phosphodiesterase inhibitors is marred by the resultant increase in mortality and in hospitalizations for heart failure. Whether these findings would also be reflected in large-scale canine trials is unknown, but the historical adverse events have caused pharmaceutical companies to abandon their marketing in the United States. Thus digoxin is the primary positive inotrope available to improve systolic function. Although it has been reported to produce echocardiographically identifiable improvements in fractional shortening in some dogs, it remains a relatively weak positive inotrope.

Just when some investigators had given up on the search for a safe positive inotropic agent, new investigations have identified a drug class that increased measures of systolic performance while decreasing mortality and hospitalizations. Surprisingly, this class of drugs is the beta blockers.

Agents that antagonize beta receptors act by interfering with the endogenous neurohormonal system. The primary integrator of the neurohormonal response to arterial underfilling appears to be the sympathetic nervous system. Excessive catecholamine levels promote a daunting number of detrimental effects: peripheral vasoconstriction, impaired sodium excretion by the kidneys, myocardial hypertrophy with impaired coronary flow, provocation of arrhythmias, apoptosis, and myocytolysis. Some researchers suggested that blockade of this primary integrator may retard the unrelenting nature of heart failure, whereas others were reluctant to blunt the effects (e.g., positive inotropic and chronotropic) of this potentially beneficial system. The proponents of beta blockade contended that these potential benefits are already self-limited by internalization and degradation of beta receptors in response to elevated circulating levels of norepinephrine. To settle the controversy, large-scale, placebo-controlled trials were conducted to identify the potential benefits of antiadrenergic therapy. In these studies, the second-generation beta blockers bisoprolol and metoprolol and the third-generation beta blocker carvedilol were shown to reduce mortality substantially in patients with a reduced ejection fraction. Because the study protocols included stringent observation, slow upward drug titration, and recruitment of patients with stable rather than decompensated heart failure, most of the patients enrolled in these trials were able to tolerate the short-term negative inotropic effects associated with beta blocker administration. With long-term administration, at 4 to 12 months of treatment beta blockers were found to induce a time-dependent process of reverse remodeling in which systolic function improved as myocardial hypertrophy regressed and the ventricular geometry normalized. Among the medications used to treat heart failure, this improvement in intrinsic systolic function appears to be unique to beta blockers. Based on these results, beta blocker administration currently is recommended for humans with stable heart failure secondary to systolic dysfunction.

The primary types of beta blockers evaluated thus far have been those that selectively inhibit the beta! receptor (metopro-lol and bisoprolol) and that antagonize beta1, beta2, and alpha1-adrenergic receptors (carvedilol). Although carvedilol blocks peripheral vasodilative beta2 receptors, it concurrently blocks vasoconstrictive alpha 1-adrenergic receptors, thereby enhancing its tolerance in patients afflicted with systolic dysfunction. In patients with mild to moderate heart failure, the reported tolerance for beta1-selective antagonists ranges from 79% to 100%, whereas carvedilol is tolerated by approximately 92% of patients. The most recent carvedilol study was performed in patients with stable NYHA class IV heart failure and an ejection fraction of less than 25%. Despite the severity of their disease, at 4 months 65% of patients assigned to carvedilol were receiving the target dose of their assigned medication.

The safety and efficacy of beta blockers in the management of heart failure have been more critically evaluated in controlled drug trials than has any other class of drugs. A meta-analysis of 18 published double-blind, placebo-controlled trials involving primarily NYHA class II and class III heart failure that were conducted through 1998 revealed persuasive positive effects on mortality, hospitalization, and the ejection fraction. Beta blockers reduced the risk of death by 32% and the risk of hospitalization for heart failure by 41% while increasing the ejection fraction by 29%.a Patients assigned to beta blockers were 32% more likely to show improvement in their heart failure class and 30% less likely to experience worsening heart failure. Large-scale trials of bisoprolol, metoprolol, and carvedilol have been reported since 1998, in which mortality reductions of 34%, 34%, and 35%, respectively, were identified. These impressive findings have led to small-scale investigations into the management of canine heart failure with carvedilol. While the results of those trials are awaited, new treatment strategies for the management of canine dilated cardiomyopathy and degenerative mitral valve disease can be hypothesized.

Beta-blockers for the management of dilated cardiomyopathy The management of canine dilated cardiomyopathy is often frustrating and unrewarding. Two retrospective analyses have shown median survival times of 65 days and 27 days, and 1-year survival probabilities of 37.5% and 17.5% have been reported. The prognosis for Doberman pinschers appears even worse, with a reported median survival time of 6.5 weeks and a 1-year survival probability of 3%. Survival times may since have improved with more robust use of angiotensin-converting enzyme inhibitors, but dilated cardiomyopathy seems to progress much more rapidly in dogs than in humans. Approximately 25% of human patients referred to major medical centers with newly diagnosed dilated cardiomyopathy die within 1 year, and the 5-year survival rate is 50%.

This discrepancy between humans and dogs in the rate of disease progression poses a problem for the management of dilated cardiomyopathy in dogs. As previously described, beta blockers have proved to be one of the most effective agents for combating heart failure, because their antiadrenergic properties offset the toxic and hemodynamic derangements induced by norepinephrine. Unfortunately, therapy for 1 to 3 months appears to be necessary before any improvement in systolic function is recognized, and administration for up to 18 months is needed for reversal of maladaptive remodeling with reduction in left ventricular volumes. It therefore seems that many dogs with dilated cardiomyopathy would not live long enough to reap the beneficial effects of beta blockers. The percentage of dogs that would tolerate the short-term negative inotropic effects induced by beta blockade also is uncertain.

A potential remedy for this situation may be concurrent, low-dose administration of a positive inotropic agent during the uptitration and early target phases of beta blocker therapy. The phosphodiesterase inhibitor and calcium sensitizer pimobendan may satisfactorily fulfill this role. A study evaluating the effectiveness of carvedilol therapy compared with a combination of carvedilol and pimobendan found that withdrawal of therapy because of worsening of heart failure occurred less often in the combination group.

Similar to amrinone and milrinone, pimobendan is able to improve cardiac contractility, promote ventricular relaxation, and induce vasodilatation by increasing cyclic adenosine monophosphate levels. However, pimobendan also has calcium-sensitizing properties that increase contractility by enhancing the interaction between troponin C and the prevailing cytosolic calcium level. Compared with agents that increase cAMP, a calcium sensitizer has several benefits: (1) it lowers the risk of induction of arrhythmias; (2) it reduces cell injury and death caused by calcium overload; (3) it exerts its effects without increasing energy demands; and (4) it has the potential to reverse systolic dysfunction in the face of acidosis and myocardial stunning. In a study of humans with heart failure, pimobendan was able to increase exercise capacity significantly without increasing oxygen consumption. Proarrhythmic effects were not identified during 24-hour electrocardiography, but a trend toward increased mortality was seen in the patients assigned to pimobendan. Enrollment criteria excluded any patients treated with beta blockers, therefore whether combination therapy may have reduced the trend toward increased mortality is speculative. Nonetheless, the concept of combining a novel positive inotropic agent with a slowly titrated beta blocker may very well deserve attention. Unfortunately, pimobendan currently is not available in the United States, and the use of beta blockers in the management of dilated cardiomyopathy should be considered purely investigational.

Beta-blockers for the management of chronic degenerative valve disease The authors currently manage CDVD with furosemide, an angiotensin-converting enzyme inhibitor, and digoxin, with the addition of spironolactone in moderate to severe cases. This combination directly targets excessive plasma volume and the renin-angiotensin system while indirecdy combating activation of the sympathetic nervous system. A new concept may include the addition of a beta blocker to antagonize directly the detrimental consequences of adrenergic activation. A recent study evaluated the hemodynamic effects of the angiotensin-converting enzyme inhibitor lisinopril versus a combination of lisinopril and the beta blocker atenolol in the treatment of experimental mitral regurgitation. Lisinopril was found to reduce significandy left ventricular end-diastolic pressure, pulmonary capillary wedge pressure, and end-diastolic stress, but it had no marked effect on forward stroke volume or left ventricular contractility. Three months after the addition of atenolol to this regimen, forward stroke volume and left ventricular contractility had returned to normal. Whether this effect occurred subsequent to an additional 3 months of angiotensin-converting enzyme inhibition or was mediated by the beta blockade is uncertain. Regardless, this study suggests that direct adrenergic antagonism may prove beneficial in the management of CDVD, and further studies may be warranted.


Angiotensin-Converting Enzyme Inhibitors

ACE Inhibitors

Despite their symptomatic benefits, diuretics should not be used as monotherapy in the management of congestive heart failure because they further activate the renin-angiotensin system. Drugs designed to inhibit angiotensin-converting enzyme block the formation of AT II, promote an increase in the circulating levels of bradykinin, and may temporarily reduce circulating aldosterone levels. Although angiotensin-converting enzyme inhibitors are frequendy categorized as balanced vasodilators, it appears likely that their beneficial effect on mortality is not mediated purely by hemodynamic alterations. They are relatively weak vasodilators compared with direct-acting arterial vasodilators such as hydralazine, and their ability to promote diuresis is much overshadowed by the less expensive loop diuretics. Rather, it is believed that angiotensin-converting enzyme inhibitors reduce mortality through their ability to blunt the detrimental consequences associated with long-standing activation of the RAS. Their early success has helped spearhead the current pharmacologic trend toward neurohormonal antagonism.

Activation of the neurohormonal cascade often begins with detection of arterial underfilling by mechanoreceptors in the carotid sinus and kidney. Regardless of whether this relative “hypotension” occurs secondary to low-output heart failure, severe mitral insufficiency, or profound hypovolemia, the common end-point is activation of the sympathetic nervous system and RAS. Additional activators of the renin-angiotensin-aldosterone system are reduced sodium delivery to the macula densa and sympathetic stimulation. Release of the protease renin from the juxtaglomerular apparatus promotes conversion of angiotensinogen to angiotensin I. Angiotensin-converting enzyme cleaves the C-terminal dipeptide from angiotensin I, thereby forming the octapeptide angiotensin II. In addition to being a potent vasoconstrictor, AT II has several other properties: (1) it is a primary secretagogue for aldosterone; (2) it potentiates presynaptic norepinephrine release; (3) it stimulates the release of antidiuretic hormone (vasopressin); (4) it promotes renal tubular sodium resorption; and (5) it has been linked to cardiomyocyte necrosis, apoptosis, and progression of ventricular fibrosis. Angiotensin-converting enzyme is also capable of cleaving the C-terminal dipeptide from bradykinin, therefore it appears to be a regulator of vasoconstrictive/ sodium retentive and vasodilative/natriuretic mechanisms. Although tissue angiotensin-converting enzyme and additional enzymatic pathways (e.g., chymase, cathepsin G, tonin, and tissue plasminogen activator) capable of producing AT II have been identified, their significance is unknown at this time.

ACE-inhibiting compounds are numerous and vary in their chemical structure, potency, bioavailability, and route of elimination. Most angiotensin-converting enzyme inhibitors, excluding captopril and lisinopril, are administered in the form of prodrugs that require conversion to their active form by hepatic metabolism. Enalapril requires conversion to enalaprilat, and benazepril is metabolized to benazeprilat. Although claims have been made that some formulations produce more profound angiotensin-converting enzyme inhibition, prolonged periods of efficacy, or superior tissue angiotensin-converting enzyme inhibition, the importance of these characteristics is unclear in naturally occurring heart failure.

The degree of angiotensin-converting enzyme inhibition and the duration of action of several agents, including benazepril, captopril, enalapril, lisinopril, and ramipril, have been evaluated in normal dogs. Hamlin and Nakayama documented that benazepril, enalapril, lisinopril, and ramipril were able to achieve similar degrees of angiotensin-converting enzyme inhibition after drug administration (about 75% inhibition at 1.5 hours and about 50% inhibition through 12 hours). Enalapril, lisinopril, and ramipril continued to display significant activity (about 25% inhibition) beyond 24 hours. These researchers also found that captopril was unable to reduce angiotensin-converting enzyme activity substantially, compared with control, beyond the 1 -5-hour sample. Whether captopril’s inability to suppress angiotensin-converting enzyme activity was a consequence of sample handling or merely an inability to suppress circulating versus tissue angiotensin-converting enzyme is uncertain. Evaluations of enalapril and benazepril in normal cats have identified maxima] angiotensin-converting enzyme inhibition of 48% and 98%, respectively, after single-dose administration. Benazepril was reported to show greater than 90% angiotensin-converting enzyme inhibition beyond 24 hours.

Excretion of the angiotensin-converting enzyme inhibitors is primarily via the kidneys, although benazepril appears to undergo significant biliary excretion in companion animals (about 50% in dogs and about 85% in cats). When angiotensin-converting enzyme inhibitors have been prescribed for patients with mild renal insufficiency, the recommendation historically has been to reduce both the dosage and frequency interval by approximately 50%. Administration of enalapril to dogs with experimental mild renal insufficiency is associated with a significant increase in the area under the curve (AUC) for the active metabolite enalaprilat. After benazepril was administered to the same dogs, no significant increase was seen in the AUC for benazeprilat. Whether concurrent cardiac disease, with its relatively depressed cardiac output, would be associated with impaired benazeprilat excretion is unclear. Current trends using “standard” doses of enalapril to treat glomerulonephritis and renal insufficiency are difficult to extrapolate to patients with heart failure and renal insufficiency because of their limited ability to increase cardiac output in the face of a reduced rate of glomerular filtration. In summary, the merits and limitations of the different formulations are unknown, and only the angiotensin-converting enzyme inhibitor enalapril has been specifically approved in the United States for the treatment of heart failure in dogs. The hypothesized improved safety of using benazepril rather than enalapril in patients with renal insufficiency has not been clinically evaluated in companion animals with cardiac disease.

Enalapril Enalapril is one of the few drugs that has been closely evaluated in dogs with naturally occurring congestive heart failure. The first reported placebo-controlled studies in dogs were short-term investigations, the Invasive Multicenter Prospective Veterinary Evaluation of Enalapril study (IMPROVE; 21 days) and the Cooperative Veterinary Enalapril study (COVE; 28 days), both published in 1995. These studies enrolled dogs with mitral valve insufficiency or dilated cardiomyopathy (DCM) to evaluate the hemodynamic (IMPROVE) and clinical (COVE) benefits of enalapril. The drug decreased pulmonary capillary wedge pressures in dogs with dilated cardiomyopathy and improved the heart failure class, pulmonary edema scores, and overall evaluation for both groups of dogs with heart failure. The benefits of these short-term studies were more pronounced for dogs with dilated cardiomyopathy than for those with mitral valve insufficiency. The COVE investigators found that twice daily oral administration of enalapril (0.5 mg/kg) appeared to promote more significant improvements than once daily therapy. The LIVE study group followed a subpopulation of dogs from the two short-term studies to evaluate the long-term effects of enalapril administration. These researchers found that dogs treated with enalapril were able to continue the study for longer than those receiving placebo (157.5 versus 77 days, P = 0.006). In contrast to the results of the short-term studies, the beneficial effect was more prominent in dogs with mitral valve insufficiency (P = 0.041) than in those with dilated cardiomyopathy (P = 0.06). An additional study supporting the benefits of angiotensin-converting enzyme inhibitor administration to dogs with heart failure found that enalapril significandy increased the exercise tolerance of dogs with experimentally created mitral insufficiency.

Despite these symptomatic benefits, the hope that early institution of angiotensin-converting enzyme inhibition will delay the onset of heart failure may go unfulfilled. To date, enalapril has been unable to delay the onset of heart failure in asymptomatic cases of mitral insufficiency. Whether angiotensin-converting enzyme inhibitors can reduce mortality in dogs or cats with heart failure has yet to be determined; even so, preliminary evidence reported in 2003 looks supportive, although not conclusive, for cats with diastolic dysfunction.

Benazepril Similar to enalapril, benazepril is a prodrug that must undergo hepatic metabolism to produce the active compound, benazeprilat. Oral administration of benazepril has produced variable and conflicting degrees of angiotensin-converting enzyme inhibition. An initial study reported that peak plasma benazeprilat concentrations were achieved 2 hours after oral administration. The percentage of angiotensin-converting enzyme inhibition after a single dose of 0.5 mg/kg of benazepril administered to normal dogs was 99.7% after 2 hours, 95.2% after 12 hours, and 87.3% after 24 hours. Similar results were found for the same intervals at doses of 0.25 mg/kg (97.8%, 89.2%, and 75.7%) and 1 mg/kg (99.1%, 94.0%, and 83.1%). Maximal angiotensin-converting enzyme inhibition after 15 doses was attained in dogs receiving 0.25 mg/kg of benazepril once daily (96.9% at 2 hours, 92.5% at 12 hours, and 83.6% at 24 hours). A second study, which also evaluated a single dose of 0.5 mg/kg of benazepril in normal dogs, showed angiotensin-converting enzyme inhibition of 81% at 1.5 hours, 37% at 12 hours, and 10.3% at 24 hours. Prolonged administration of benazepril was not evaluated. A final study, in which 0.5 mg/kg of benazepril was administered orally once daily to dogs with mitral insufficiency, showed angiotensin-converting enzyme inhibition to be 33.3% at 1 week, 28% at 2 weeks, and 42.7% at 4 weeks.

Based on these conflicting results, the current dosing recommendations are broad (0.25 to 0.5 mg/kg given orally once or twice daily). Whether benazepril is clinically more effective or safer than enalapril for dogs and cats with congestive heart failure remains unclear.

Adverse effects The mechanism by which angiotensin-converting enzyme inhibitors exert their beneficial properties (e.g., inhibition of angiotensin II production) also lends to the potential for adverse consequences. Although infrequendy encountered, complications may include systemic hypotension, azotemia, and hyperkalemia.

ACE inhibitors reduce systemic vascular resistance by decreasing circulating levels of angiotensin II and increasing circulating levels of bradykinin. In patients with severe heart failure in which an increase in cardiac output is unable to sustain systemic blood pressure, symptomatic hypotension may develop. Although this complication is infrequent, its likelihood increases with concomitant overzealous use of diuretics. Unfortunately, the clinical signs associated with severe low-output heart failure and systemic hypotension are very similar (e.g., weakness, exercise intolerance, and possibly stupor), a fact that lends emphasis to an important point: if a patient appears refractory to medical management, the blood pressure should be evaluated before more aggressive measures to combat heart failure are instituted.

A second adverse effect attributed to angiotensin-converting enzyme inhibitors’ unique ability to decrease angiotensin II production is a reduction in the glomerular filtration rate (GFR) and the development of azotemia. The glomerular filtration rate is determined by the glomerular capillary pressure (GCP). Based on the knowledge that pressure is equal to the product of flow and resistance (P = Q x R), it can be ascertained that the glomerular filtration rate ultimately is determined by renal plasma flow and the degree of efferent arteriolar vasoconstric-tion. In cases of heart failure in which renal plasma flow is diminished, the glomerular filtration rate is supported by the ability of ATII to constrict the efferent renal arte-riole. angiotensin-converting enzyme inhibitors’ ability to depress production of AT II promotes efferent renal arteriolar vasodilatation and hence a reduction in the GFR. The failing heart cannot further increase cardiac output, and an acute bout of azotemia may subsequendy develop. A recent study evaluating early institution of enalapril therapy in dogs with compensated mitral valve insufficiency found that dogs allocated to an angiotensin-converting enzyme inhibitor were not at a more significant risk of developing azotemia compared with dogs receiving placebo. In the authors’ experience, mild increases in blood urea nitrogen (BUN) and creatinine occur frequendy after institution of therapy with an angiotensin-converting enzyme inhibitor and furosemide. However, the development of severe azotemia, necessitating discontinuation of the angiotensin-converting enzyme inhibitor or a reduction in its dosage, occurs infrequently. This complication seems to occur most often in patients with severe heart failure that require aggressive diuretic administration to control congestive signs. Prior to institution of enalapril therapy, the authors evaluate the baseline biochemical parameters and perform a second measurement of the BUN, creatinine, and electrolytes 5 to 7 days after the start of treatment. If patients become anorectic or develop gastrointestinal signs during this time, we instruct the owners to discontinue all drugs and immediately present the animal for veterinary attention.

Hyperkalemia may be encountered during therapy with angiotensin-converting enzyme inhibitors as the result of a reduction in the glomerular filtration rate and a decline in circulating aldosterone levels. In the absence of aldosterone, sodium loss is favored and potassium levels rise. This complication appears to occur infrequently, presumably because most of the potent diuretics have potassium-wasting properties and tend to prevent the development of hyperkalemia. The authors have rarely encountered an increase in potassium that necessitated a dosage reduction for or discontinuation of an angiotensin-converting enzyme inhibitor. There is concern that the addition of spironolactone may potentiate hyperkalemia, therefore periodic electrolyte monitoring is prudent in patients receiving an angiotensin-converting enzyme inhibitor and a potassium-sparing diuretic.

Drug interactions Because aspirin inhibits cyclooxygenase and decreases prostaglandin formation, some have questioned whether administration of aspirin may negate some of the beneficial vasodilative properties exerted by angiotensin-converting enzyme inhibitors. An additional concern is that aspirin’s ability to reduce renal prostaglandin formation may worsen the angiotensin-converting enzyme inhibitor-induced reduction in the GFR. A recent retrospective analysis of six long-term, randomized trials of angiotensin-converting enzyme inhibitors found that aspirin did not significantly alter the beneficial effects of angiotensin-converting enzyme inhibitors in CHE Whether other commonly prescribed, non-steroidal anti-inflammatory agents blunt the potentially beneficial vasodilative properties of angiotensin-converting enzyme inhibitors is uncertain.


Future Prospects Currently Under Investigation

Medical Therapy

Search for a Safe Positive Inotropic Agent

A class of drugs currently receiving attention in the management of congestive heart failure is the calcium sensitizers. These agents can augment systolic performance by enhancing calcium binding to troponin C or by affecting the cross-bridge turnover kinetics without increasing cytosolic calcium levels. A potential drawback to clinical use of pure calcium sensitizers would be the enhanced reactivity of troponin C with diastolic cytosolic calcium levels, which would slow the process of myocardial relaxation. In an attempt to avoid this potential diastolic dysfunction, most of the agents under investigation today use a combination of phosphodiesterase (PDE) inhibition and calcium sensitization. Because these drugs produce both calcium sensitization and phosphodiesterase inhibition, it becomes difficult to determine whether the positive inotropic action stems from enhanced reactivity of troponin C and Ca2+ or cAMP-mediated phosphorylation of phospho-proteins, or a combination of the two.

In an effort to elucidate the mechanisms of the positive inotropic effects of pimobendan, EMD 53998, levosimendan, and OR-1896, a group of investigators sought to determine whether these drugs were capable of increasing left ventricular contractility (+dP/dt) without altering the myoplasmic Ca2+ transient. Each agent was administered at variable concentrations, and subsequently +dP/dt, myocardial calcium transients, phosphorylation of key intracellular phosphoproteins, and myocardial cyclic adenosine monophosphate levels were measured. The investigators found that low concentrations of levosimendan and OR-1896 were capable of increasing left ventricular contractility without affecting Ca2+ transients or myocardial cyclic adenosine monophosphate levels and without promoting significant phosphorylation of troponin I and C proteins. Administration of low concentrations of pimobendan or EMD 53998 produced more pronounced increases in Ca2+ transients compared with increases in left ventricular contractility. As the administration dose increased, all of the agents caused an increase in +dP/dt that was associated with further increases in myocardial cyclic adenosine monophosphate levels and phosphorylation of intracellular phosphoproteins. The investigators therefore concluded that pimobendan, EMD 53998, and higher doses of levosimendan and OR-1896 exerted positive inotropic properties through phosphodiesterase inhibition-mediated responses rather than through calcium sensitization. These researchers felt that their results lent support to the premise that low-dose levosimendan and OR-1896 were capable of augmenting left ventricular contractility by increasing the response of the myofilaments to the prevailing calcium concentrations.

It should be noted that these conclusions are far from universally accepted. Other investigators, including Endoh, have found that pimobendan can elicit a positive inotropic effect even in the presence of carbachol, a muscarinic receptor agonist that is useful for differentiating cAMP-mediated effects from those classified as calcium sensitization. Endoh’s report found that although levosimendan appears to have calcium-sensitizing properties, it must rely on simultaneous activation of cAMP-mediated signaling processes.

The varying results of these studies show that the precise mechanisms by which the calcium sensitizers exert a positive inotropic effect is uncertain and that long-term controlled studies are required to evaluate the effects of these drugs on the heart rate, arrhythmogenesis, and sudden death.

Pimobendan Despite its questionable calcium-sensitizing properties, pimobendan currendy is the most investigated agent in this drug class. Similar to other agents in this class, pimobendan combines calcium sensitization and phosphodiesterase inhibition to circumvent any diastolic dysfunction. However, this same property carries the potential for cAMP-dependent increases in arrhythmogenesis. Despite its predominandy cAMP-mediated inotropic effect, pimobendan can increase cardiac contractility to a degree similar to that of dobutamine but at a lower oxygen cost for contractility. Although pimobendan appears to lower myocardial oxygen consumption, the stigma associated with positive inotropic agents, especially those that increase cyclic adenosine monophosphate concentrations, may have doused early enthusiasm for pimobendan in the United States. Although not available in the United States, pimobendan currendy is available in Canada, Europe, and Japan and has undergone several small to medium-sized investigations in humans and dogs.

Multiple pimobendan trials have been completed in humans with heart failure. The results of these trials have been variable, pointing out both apparent beneficial effects and questionable, undesirable side effects.

A recent placebo-controlled study has been published that evaluated pimobendan therapy (0.3 to 0.6 mg/kg/day) in a small number of Doberman pinschers and cocker spaniels with dilated cardiomyopathy. The addition of pimobendan to standard therapy with digoxin, enalapril, and furosemide was associated with a significant improvement in the heart failure class. The cocker spaniels allocated to placebo and to pimobendan showed statistically similar median survival times (537 days versus 1037 days, P = 0.77), whereas the Doberman pinschers allocated to placebo had significandy shorter median survival times than those given pimobendan (50 days versus 329 days, P < 0.02).

This small study highlighted several findings. The first interesting finding is that cocker spaniels with dilated cardiomyopathy appear to have the potential for long-term survival. At the conclusion of the 4-year study, six of the 10 cocker spaniels were still alive (two in the pimobendan group and four in the placebo group). Three of the four dogs that had died (one in the placebo group and two in the pimobendan group) were euthanized for noncardiac disease; the fourth dog, allocated to pimobendan, died suddenly within 1 month of diagnosis. The study was too small to allow assessment of the propensity of pimobendan to exacerbate arrhythmias, but the drug may have contributed to the cocker spaniel’s sudden death.

Another interesting aspect of this study is that although positive inotropic therapy may prolong survival in Doberman pinschers with DCM, it may be prudent to randomize patients with atrial fibrillation (AF) separately from those without this condition. Historically Doberman pinschers with atrial fibrillation have had an abysmal 2.9-week median survival time. The pimobendan randomization happened to allocate three Doberman pinschers with AF into the placebo group and only one into the pimobendan group. This may have negatively affected survival in the placebo group, but it should be noted that the Doberman with atrial fibrillation that was treated with pimobendan survived for 37 weeks.

The observed reduction in heart failure class associated with pimobendan therapy likely will prompt further investigations into this agent. Whether pimobendan administration to dogs produces a trend toward increased mortality, as identified in the Pimobendan in Congestive Heart Failure (PICO) trial, is uncertain. Whether the combination of low-dose pimobendan and a beta blocker would have synergistic properties in dogs with dilated cardiomyopathy is uncertain but is an interesting concept. The study by Mallery et al. continues to pose the question of whether a small but significandy increased incidence of sudden death in dogs should preclude the availability of an agent with the potential to enhance their quality of life.

Angiotensin II Receptor Antagonists

The beneficial effects of angiotensin-converting enzyme inhibitors have largely been attributed to these drugs’ ability to decrease the formation of angiotensin II and increase circulating levels of bradykinin. However, alternative, ACE-independent pathways for the production of angiotensin II, including tissue plasminogen activator, cathepsin G, tonin, and chymase, may enable AT II “escape” even with administration of angiotensin-converting enzyme inhibitors. A study of patients treated with a variety of angiotensin-converting enzyme inhibitors identified angiotensin II “reactivation” in 15% of patients. This process occurred in the face of both high and low levels of angiotensin-converting enzyme activity, which suggests that alternate pathways were responsible for the production of angiotensin II. As a potential strategy for offsetting these alternate angiotensin II-generating pathways, agents capable of directly antagonizing the AT II receptors were developed. Two subtypes of angiotensin II receptors have been identified in humans: angiotensin II type 1 (AT1) and angiotensin II type 2 (AT2). Although these receptors belong to the same family, some researchers have suggested that their biologic activities differ markedly. AT, receptors are found primarily in the adrenal glands, vascular smooth muscle cells, kidney, and heart, where they mediate almost exclusively all the known actions of angiotensin II on blood pressure and osmoregulation. AT2 receptors are expressed in high density during fetal development; in adults they are found less abundandy in the adrenal medulla, uterus, ovary, and vascular endothelium and in areas of the brain. AT2 receptors appear to mediate biologic processes that counteract the trophic, AT|-mediated responses. Agents capable of blocking the AT, receptor subtype were developed with the aim of achieving more complete angiotensin II antagonism than is obtained with angiotensin-converting enzyme inhibitors. Also, selectively targeting the AT, receptor subtype would still allow for the potentially beneficial actions mediated by the AT2 receptors and avoid common side effects, predominandy coughing, associated with angiotensin-converting enzyme inhibitor therapy in humans. It is believed that the increased circulating levels of bradykinin promoted by angiotensin-converting enzyme inhibitors contribute to these drugs’ side effects, but it must be noted that this same property, which is lacking in AT II receptor antagonists, may contribute to the angiotensin-converting enzyme inhibitors’ success in the management of heart failure.

Efforts to determine whether angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists were superior or noninferior quickly followed the development of the latter agents. An early study, the Evaluation of Losartan in the Elderly (ELITE) trial, lent support to the premise that ATII receptor blockade may yield mortality benefits compared with angiotensin-converting enzyme inhibitors. Other studies that examined various subgroups followed. Mortality and morbidity end-points were examined to determine whether AT II inhibitors are preferable to angiotensin-converting enzyme inhibitors.

The results of ELITE II and the Valsartan Heart Failure Trial (Val-HeFT) suggest better tolerability of AT II inhibitors compared with angiotensin-converting enzyme inhibitors, but these studies provide no data to support the superiority of AT II inhibitors in the management of heart failure subsequent to systolic dysfunction. The proposed significant benefit behind combination therapy with AT II inhibitors and angiotensin-converting enzyme inhibitors identified in Val-HeFT is limited after the angiotensin-converting enzyme inhibitor-naive subgroup is removed from the analysis. Of additional concern was the fact that valsartan, compared to placebo, had an adverse effect on mortality (P = 0.009) in patients previously treated with angiotensin-converting enzyme inhibitors and beta blockers. Although these results cannot be extrapolated to veterinary medicine and because clinical trials have not been performed in dogs or cats with naturally occurring heart failure, the current utility of angiotensin II receptor antagonists appears limited.

Neutral Endopeptidase Inhibitors

With the success of the angiotensin-converting enzyme inhibitors established, research interests quickly shifted to additional, potentially beneficial neurohormonal pathways. Based on the recognition that atrial natriuretic peptide can promote natriuresis and diuresis and can directly inhibit the release of renin and aldosterone, new agents were developed in an effort to increase ANP’s circulating concentration. Neutral endopeptidase (NEP) is an enzyme that inactivates several substrates, including natriuretic peptides, angiotensins, and bradykinins. It was hypothesized that drugs capable of inhibiting NEP may prove beneficial in the management of congestive heart failure as single agents or in combination therapy. Early studies of the NEP inhibitor ecadotril given to dogs with pacing-induced heart failure showed increased urine output, sodium clearance, and renal sodium excretion compared with dogs given placebo. Another short-term study of ecadotril identified a dose- and time-dependent reduction in left ventricular end-diastolic pressures in dogs with experimental heart failure produced by repeated coronary embolization. Long-term administration of ecadotril (3 months) in dogs with left ventricular dysfunction produced by sequential intracoronary microembolizations was recendy reported to attenuate left ventricular remodeling and progressive left ventricular dysfunction compared with dogs receiving placebo.

Despite these findings, NEP inhibitors administered as single agents appear to have fallen out of the research arena. A communication on behalf of the International Ecadotril Multi-Centre Dose-Ranging Study reported findings from a study of 279 patients with chronic heart failure randomized to placebo or one of four doses of ecadotril. The study’s primary aim was to evaluate the safety and tolerability of ecadotril at doses of 50-400 mg twice daily. Two patients randomized to the highest dose of ecadotril developed pancytopenia at 47 and 53 days, and died rapidly of sepsis. The presence of a thioester group within the compound suggested an idiosyncratic ecadotril-induced aplastic anemia that was potentially dose related. Lower doses of ecadotril were not associated with adverse reactions. Although the study was not powered to exclude symptomatic benefit, patient-reported symptoms and quality of life-scores were unable to reveal any overall symptomatic benefit during the administration of ecadotril. A similar, smaller pilot study from the United States evaluating 50 patients randomized to placebo or ecadotril, 50 to 400 mg twice daily, did not identify any adverse sequela but again there were no changes identified in signs and symptoms of heart failure, NYHA class, or patient self-assessment of symptoms.

Vasopeptidase Inhibitors

Although it is difficult to determine the reasons for the relative lack of efficacy seen in the small pilot studies of ecadotril, the problem may have been that the drug increased not only natriuretic peptide levels but also the levels of circulating angiotensin II. More recently a group of drugs that can inhibit NEP and ACE, the so-called vasopeptidase inhibitors, has been developed. Omapatrilat has been the most rigorously evaluated vasopeptidase inhibitor in several trials for the management of congestive heart failure No significant difference was seen in the primary end-point of combined risk of death or hospitalization for heart failure requiring intravenous treatment (P = 0.187) between omapatrilat and angiotensin-converting enzyme inhibitors. To date, the inability of vasopeptidase inhibitors to provide substantial benefit compared with the proven efficacy of angiotensin-converting enzyme inhibitors may limit their clinical utility.

Endothelin Antagonists

Endothelin, a peptide released from endothelial cells, has powerful vasoconstrictive activity. Currently three peptides, endothelin-1, endothelin-2, and endothelin-3, and two receptor subtypes, ETA and ETB, have been identified. In principle, endothelin-1 promotes vasoconstriction by complexing with the ETA receptor and vasodilatation by binding to the ETB receptor, but this is somewhat species dependent. In addition to its vasodilative properties, the ETB receptor may promote vasoconstriction in some regional blood vessels, including the mesenteric and coronary vasculature.

Although endothelin’s name suggests that it is produced only in vascular endothelial cells, the genes that encode the three peptides have been identified in varying patterns in vascular smooth muscle cells, cardiac myocytes, renal tubular epithelial cells, bronchia] epithelial cells, glial cells, pituitary cells, macrophages, and mast cells. Therefore the importance of endothelin may extend well beyond simple vasoconstriction and include additional pleiotropic effects on many nonvascular tissues. Although endothelin is suspected of being linked to systemic hypertension, pulmonary hypertension, vascular remodeling, and acute renal failure, the emphasis of this discussion is on potential applications of endothelin to the progression of heart failure

Heart failure, through increased filling pressures and decreased peripheral perfusion, promotes activation of numerous neurohormonal reflexes to maintain cardiac output and circulatory homeostasis. Activation of the renin-angiotensin-aldosterone system and SNS and the release of arginine vasopressin are recognized to increase the concentration of circulating vasoconstrictors (i.e., angiotensin II, norepinephrine, and vasopressin) and to promote maladaptive remodeling. Furthermore, it has been shown that these compensatory mechanisms enhance the production of endothelin. Increased endothelin binding to the ETA receptors promotes vasoconstriction and smooth muscle cell proliferation, thereby further diminishing cardiac performance through afterload mismatch. Studies have also shown that the ETB receptors become upregulated and can promote vasoconstriction and cardiac fibrosis in the presence of heart failure. These findings have raised the possibility of administration of ETA receptor antagonists or a combination of ETA/ETB receptor antagonists to combat heart failure.

Chronic administration of endothelin antagonists to laboratory animals with experimental heart failure and acute administration to humans with heart failure resulted in beneficial hemodynamic profiles. In rats with heart failure induced by coronary artery ligation, the combination of an angiotensin-converting enzyme inhibitor and an endothelin (ETA) antagonist lowered the systolic blood pressure and the left ventricular end-systolic and left ventricular end-diastolic pressures significantly more than the angiotensin-converting enzyme inhibitor or endothelin antagonist alone. However, the drug combination did not significantly improve survival or reduce left ventricular weight and collagen density compared with rats randomized to an angiotensin-converting enzyme inhibitor alone. Endothelin antagonism without the benefit of angiotensin-converting enzyme inhibition did not result in a survival benefit compared with untreated rats with heart failure.

Despite these promising hemodynamic profiles, early evidence suggests that chronic nonselective and ETA-selective antagonism of endothelin receptors is of limited benefit in patients with severe heart failure. The Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure (ENABLE) trial evaluated the nonselective endothelin antagonist bosentan, which has proved beneficial in pulmonary hypertension, for the management of humans with NYHA class IIIb-IV heart failure and an ejection fraction of less than 35%. The patients randomized to Bosentan appeared to have an increased early risk of worsening heart failure requiring hospitalization.

These studies appear to highlight the fact that hemodynamic benefit may not equate with clinical benefit. Whether lower doses of the endothelin antagonists and slow uptitration might prove beneficial is unresolved at this time; however, the results of studies to date may have curtailed the momentum for the use of endothelin antagonists in the management of chronic heart failure.

Interventional Therapy

Passive Ventricular Constraint

In the early 1990s an experimental “ventricular assist” technique was developed in which a patient’s native skeletal muscle was wrapped around the failing ventricles to provide cardiac support. The latissimus dorsi, connected to a synchronizable burst stimulator, was used in an effort to increase cardiac contractility and hence functional status. The utility of dynamic cardiomyoplasty held promise because it alleviated the need for cardiac bypass, donor organs, and immunosuppression, which are required for cardiac transplantation. The feasibility of dynamic cardiomyoplasty in dogs was subsequendy documented, and researchers found a potential for improved contractile function even during contractions that were not assisted by myostimulation of the latissimus dorsi.

Although dynamic cardiomyoplasty has failed to gain prominence in the management of heart failure, the potential for limiting ventricular dilatation by means of passive constraint has prompted further study. The premise is that passive ventricular constraint may significandy slow or stabilize the remodeling process that accompanies heart failure. Because the constraint is passive and does not require myostimulation, a synthetic wrap could be used, simplifying the surgical procedure.

Despite the potential benefit of passive ventricular constraint in these models, the fact remains that veterinary patients tend to be presented for evaluation after severe cardiac dysfunction has already developed. New diagnostic modalities may allow for earlier detection of occult cardiac disease, but the variable nature of disease progression could still complicate the determination of which patients should be fitted with a cardiac support device. At this time, further studies are required to evaluate the efficacy of passive ventricular constraint in severe cardiac dysfunction, and diagnostic tests allowing early detection of cardiac disease must be developed.

Ventricular Resynchronization

Although systolic dysfunction classically is believed to be a myocardial phenomenon, the important role the cardiac conduction system plays in maintaining optimal cardiac performance is often forgotten. The normal conduction pathway modulates the contraction rate, the mechanical efficacy of atrial systole, and the co-ordination of the ventricular chambers. In humans the presence of an intraventricular conduction delay, typically in a left bundle branch block pattern, promotes disco-ordinate contraction, with early activation of the septal wall followed by delayed iateral contraction at higher stress. The presence of this conduction defect has been associated with a 60% to 70% higher risk of all-cause mortality and has remained an independent risk factor after adjustment for age, underlying cardiac disease, severity of heart failure, and treatment with angiotensin-converting enzyme inhibitors or beta blockers. The problem of ventricular discordance has long been recognized in patients with artificial ventricular pacemakers, and efforts to approximate the ventricular activation sequence more closely (i.e., by pacing the right ventricular outflow tract rather than the apex) have been shown to increase cardiac output.

Recendy a similar approach, called cardiac resynchronization therapy (CRT), has been used in patients with congestive heart failure and intraventricular conduction delay. Biventricular pacing or univentricular pacing of the left ventricular free wall has improved the contractile index +dP/dTmax and arterial pulse pressure within a single beat of commencement of pacing. The proposed benefits of CRT include a reduction in end-systolic and end-diastolic volumes and the ability to promote reverse remodeling. Ventricular resynchronization has been associated with increased systolic function despite a decline in myocardial oxygen consumption. This contrasts with traditional cAMP-dependent inotropic therapy and may explain the ability of biventricular pacing to improve functional patient status while promoting mortality benefits. Unfortunately, the ability of CRT to improve heart failure class and reduce mortality in veterinary medicine may be limited by the low prevalence of intraventricular conduction disturbances in dogs with dilated cardiomyopathy.

Stem Cells and Cellular Transplantation

Historically it has been recognized that cardiac and neural tissues lack the large postnatal regenerative capacity seen in the epithelial layers of the skin, intestinal and pulmonary mucosal linings, and connective tissues. Therefore the ability to repopulate areas of ischemic myocardium with cells capable of promoting angiogenesis or areas of fibrosis with cells that contribute to contractile function could prove curative.

Numerous cell types have been identified that may serve as potential sources for tissue grafting, including skeletal myoblasts, fetal cardiomyocytes, smooth muscle cells, embryonic stem cells and bone marrow-derived stromal and hematopoietic stem cells. Because of the complex electrophysiologic, structural, and contractile properties of myocardial cells, cardiomyocytes appear to be the ideal donor cells. The difficulty lies in harvesting and transplanting enough cells to mitigate the degree of cardiac dysfunction. The isolation of pluripotent stem cells from mouse blastocysts in 1981 may have provided the key to an endless vault of viable, transplantable cardiomyocytes.

The promise of stem cells lies in their capacity for prolonged self-renewal and their potential to differentiate into one or more cell types. Embryonic stem (ES) cells display wide-ranging plasticity, which allows them to form derivatives of all three germ layers. Their ability to undergo near endless cell doublings while retaining the capacity to differentiate into various cell types further advances their therapeutic potential. However, beyond the ethical considerations involved in the use of human embryonic stem cells (which veterinary practitioners may not face), many other hurdles must be overcome. One of the most important obstacles is defining a methodology to generate reproducible, spontaneous cardiomyocyte-differentiating stem cells with sufficient purity for clinical purposes. Emerging evidence suggests that an unknown combination of growth factors, transcription factors, feeder layers, and physical properties is involved in early cardiomyocyte differentiation. Delivery systems such as intracoronary catheterization techniques, intramyocardial injection, transendocardial delivery by means of catheter-based systems, and intravenous administration are currently being evaluated and refined to optimize the long-term survival of the grafted cells, to ensure the delivery of a critical mass of viable cells, and to promote the appropriate alignment with the host cells. These steps are vital to the functional and structural integration of stem cells in the host tissue. The immunogenicity of embryonic stem cells poses yet another challenge.

Stem cells are not confined to embryos; rather, small numbers of stem cells can be harvested from adult bone marrow. These adult mesenchymal stem (MS) cells maintain an undifferentiated phenotype in culture and appear to have the capacity for multilineage differentiation. The potential benefits of autologous adult mesenchymal stem cells, including ease of attainability, lack of immunogenicity, and absence of ethical objections, have prompted widespread research into their use in the management of cardiovascular disease. It remains to be seen whether repopulation of the myocardium with these cells is feasible in veterinary medicine and whether a sufficient number of viable cells to enhance systolic function can be delivered.