Categories
Drugs

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.

Pharmacokinetics

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; www.apcc.aspca.org) 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. ()

Monitoring

■ 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.

Categories
Drugs

Aminophylline Theophylline

Phosphodiesterase Inhibitor Bronchodilator

Highlights Of Prescribing Information

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

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

Therapeutic drug monitoring recommended

Many drug interactions

What Is Aminophylline Theophylline Used For?

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

Pharmacology/Actions

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

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

Pharmacokinetics

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

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

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

Before you take Aminophylline Theophylline

Contraindications / Precautions / Warnings

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

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

Adverse Effects

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

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

Reproductive / Nursing Safety

In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, hut there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans.)

Overdosage / Acute Toxicity

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

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

How to use Aminophylline Theophylline

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

Aminophylline Theophylline dosage for dogs:

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

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

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

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

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

Aminophylline Theophylline dosage for cats:

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

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

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

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

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

Aminophylline Theophylline dosage for ferrets:

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

Aminophylline Theophylline dosage for horses:

(Note: ARCI UCGFS Class 3 Aminophylline Theophylline)

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

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

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

For adjunctive treatment for heaves (RAO):

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

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

Monitoring

■ Therapeutic efficacy and clinical signs of toxicity

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

Client Information

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

Chemistry / Synonyms

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

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

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

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

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

Storage / Stability/Compatibility

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

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

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

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

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

Dosage Forms / Regulatory Status

Veterinary-Labeled Products: None

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

Human-Labeled Products:

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

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

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

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

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

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

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

Categories
Drugs

Aminopentamide Hydrogen Sulfate (Centrine)

Anticholinergic/Antispasmodic

Highlights Of Prescribing Information

Anticholinergic/antispasmodicfor GI indications in small animals

Typical adverse effect profile (“dry, hot, red”); potentially could cause tachycardia

Contraindicated in glaucoma; relatively contraindicated in tachycardias, heart disease, GI obstruction, etc.

What Is Aminopentamide Hydrogen Sulfate Used For?

The manufacturer states that the drug is indicated “in the treatment of acute abdominal visceral spasm, pylorospasm or hypertrophic gastritis and associated nausea, vomiting and/or diarrhea” for use in dogs and cats.

Pharmacology/Actions

Aminopentamide is an anticholinergic agent that when compared to atropine has been described as having a greater effect on reducing colonic contractions and less mydriatic and salivary effects. It reportedly may also reduce gastric acid secretion.

Pharmacokinetics

No information was located.

Before you take Aminopentamide Hydrogen Sulfate

Contraindications / Precautions / Warnings

The manufacturer lists glaucoma as an absolute contraindication to therapy and to use the drug cautiously, if at all, in patients with pyloric obstruction. Additionally, aminopentamide should not be used if the patient has a history of hypersensitivity to anticholinergic drugs, tachycardias secondary to thyrotoxicosis or cardiac insufficiency, myocardial ischemia, unstable cardiac status during acute hemorrhage, GI obstructive disease, paralytic ileus, severe ulcerative colitis, obstructive uropathy or myasthenia gravis (unless used to reverse adverse muscarinic effects secondary to therapy).

Antimuscarinic agents should be used with extreme caution in patients with known or suspected GI infections, or with autonomic neuropathy. Atropine or other antimuscarinic agents can decrease GI motility and prolong retention of the causative agent(s) or toxin(s) resulting in prolonged clinical signs.

Antimuscarinic agents should be used with caution in patients with hepatic disease, renal disease, hyperthyroidism, hypertension, CHF, tachyarrhythmias, prostatic hypertrophy, esophageal reflux, and in geriatric or pediatric patients.

Adverse Effects

Adverse effects resulting from aminopentamide therapy may include dry mouth, dry eyes, blurred vision, and urinary hesitancy. Urinary retention is a symptom of too high a dose and the drug should be withdrawn until resolved.

Overdosage / Acute Toxicity

No specific information was located regarding acute overdosage clinical signs or treatment for this agent. The following discussion is from the Atropine monograph that could be used as a guideline for treating overdoses:

If a recent oral ingestion, emptying of gut contents and administration of activated charcoal and saline cathartics may be warranted. Treat clinical signs supportively and symptomatically. Do not use phenothiazines as they may contribute to the anticholinergic effects. Fluid therapy and standard treatments for shock may be instituted.

The use of physostigmine is controversial and should probably be reserved for cases where the patient exhibits either extreme agitation and is at risk for injuring themselves or others, or for cases where supraventricular tachycardias and sinus tachycardias are severe or life threatening. The usual dose for physostigmine (human) is: 2 mg IV slowly (for average sized adult), if no response, may repeat every 20 minutes until reversal of toxic antimuscarinic effects or cholinergic effects takes place. The human pediatric dose is 0.02 mg/kg slow IV (repeat q10 minutes as above) and may be a reasonable choice for treatment of small animals. Physostigmine adverse effects (bronchoconstriction, bradycardia, seizures) may be treated with small doses of IV atropine.

How to use Aminopentamide Hydrogen Sulfate

Aminopentamide Hydrogen Sulfate dosage for dogs:

a) May be administered every 8-12 hours via IM, SC or oral routes. If the desired effect is not attained, the dosage maybe gradually increased up to 5 times those listed below: Animals weighing: 10 lbs or less: 0.1 mg; 11-20 lbs: 0.2 mg; 21-50 lbs: 0.3 mg; 51 -100 lbs: 0.4 mg; over 100 lbs: 0.5 mg (Package Insert; Centrine — Fort Dodge)

b) To decrease tenesmus in malabsorption/maldigestion syndromes: 0.1-0.4 mg SC, or IM twice daily-three times daily ()

c) As an antiemetic: 0.1-0.4 mg SC, or IM two to three times daily ()

Aminopentamide Hydrogen Sulfate dosage for cats:

a) As in “a” above in dogs

b) As an antiemetic: 0.1-0.4 mg SC, or IM two to three times daily ()

c) As second-line adjunctive therapy for refractory IBD: 0.1-0.4 mg/kg SC two to three times daily ()

Client Information

■ Contact veterinarian if animal has difficulty urinating or if animal is bothered by dry eyes or mouth

Chemistry / Synonyms

An antispasmodic, anticholinergic agent, aminopentamide hydrogen sulfate has a chemical name of 4-(dimethylamino)-2,2-diphenylvaleramide.

Aminopentamide hydrogen sulfate may also be known as dimevamid or Centrine.

Storage / Stability

Store aminopentamide tablets and injection at controlled room temperature (15-30°C; 59-86°F).

Dosage Forms / Regulatory Status

Veterinary-Labeled Products:

Aminopentamide Hydrogen Sulfate Tablets: 0.2 mg; Centrine (Fort Dodge); (Rx). Approved for use in dogs and cats only.

Aminopentamide Hydrogen Sulfate Injection: 0.5 mg/mL in 10 mL vials; Centrine (Fort Dodge); (Rx). Approved for use in dogs and cats only.

Human-Labeled Products: None

Categories
Drugs

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; www.apcc.aspca.org) 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 ()

Monitoring

■ 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

Categories
Horses

Hemolytic Anemia

Hemolytic anemia is a pathologic condition that results from accelerated erythrocyte removal and can be intravascular and extravascular. Intravascular hemolysis occurs when erythrocytes are destroyed within the vascular space. Clinical signs associated with intravascular hemolysis are typically acute in onset and classically include icterus and red- to port-wine-colored urine. Extravascular hemolysis results from accelerated erythrocyte removal by macrophages in the spleen or liver and is characterized by icterus without hemoglobinuria.

Diseases That Primarily Cause Intravascular Hemolysis

Oxidative Erythrocyte Damage

Oxidant damage to erythrocytes can develop following exposure to a variety of oxidizing agents such as phenothiazines, onions, or wilted red maple (Acer rubrum) leaves. The latter cause is by far the most common. The oxidizing agent causes hemoglobin to become denatured with subsequent disulfide bond formation. Oxidized hemoglobin forms precipitates referred to as Heinz bodies that are visible with Romanowsky’s-stained blood smears. These cell changes result in increased fragility of cells with subsequent intravascular hemolysis and enhanced removal by the mononuclear phagocytic system in the spleen and liver. In addition, oxidative damage causes increased permeability of the membrane, thereby altering ion transport mechanisms and osmotic gradients. Due to these changes, erythrocytes may rupture within the vascular lumen, thus resulting in intravascular hemolysis and microangiopathy. In contrast to oxidative damage that leads to erythrocyte destruction, altered oxygen carrying capacity results when hemoglobin is oxidized and forms methemoglobin. Methemoglobinemia occurs when more than 1.77% of the hemoglobin is oxidized from the ferrous (Fe2+) to the ferric (Fe3+) state by oxidizing agents.

Because A. rubrum is a common tree in the eastern United States, toxicity associated with red maple leaf ingestion is a fairly common clinical disease in that region. Although the specific toxic agent in the plant has not been identified, a seasonal trend appears to exist for the development of disease because more cases are associated with ingestion of wilted or dried leaves in the fall than for leaves ingested in the spring.

Clinical Signs and Diagnosis

In cases of red maple toxicity, a combination of intravascular and extravascular hemolysis develops over a variable period of 2 to 6 days. In severe cases, clinical signs of hemolytic anemia and tissue hypoxia secondary to methemoglobinemia may develop more rapidly. The prognosis for horses suffering from red maple toxicity is guarded; the approximate survival rate is 60% to 70%. Clinical signs result from the combined effects of tissue hypoxia and hemolysis that results in fever, tachycardia, tachypnea, lethargy, intense icterus, and hemoglobinuria, with characteristic brown coloration of skin, mucous membranes, and — if methemoglobinemia is present — blood. Hematologic abnormalities include anemia, increased mean corpuscular hemoglobin concentration and mean corpuscular hemoglobin, free plasma hemoglobin, anisocytosis, poikilocytosis, eccentrocytes, lysed erythrocytes that produce fragments or membrane ghosts, agglutination, increased red blood cell fragility, variable presence of Heinz bodies, and neutrophilia. Serum chemistry abnormalities include increased total and indirect bilirubin, serum creatinine, and serum urea nitrogen concentrations, reduced red blood cell glutathione and increased aspartate aminotransferase, sorbitol dehydrogenase, creatinine phosphokinase, and gamma-glutamyl transpeptidase activities.

Additional abnormalities may include hypercalcemia and hyperglycemia, with a variable degree of metabolic acidosis. Urinalysis findings could include any combination of the following: hemoglobinuria, methemoglobinuria, proteinuria, bilirubinuria, and urobilinogenuria. Methemoglobin can be quantified spectrophotometrically. Red maple leaf, wild onion, or phenothiazine toxicosis would be strongly suspected if a history of exposure or opportunity for exposure exists. Diagnosis is based on clinical signs of an acute onset primarily of intravascular hemolytic crisis supported by laboratory evidence of oxidative damage — that is, Heinz bodies or methemoglobinemia. Additional differential diagnoses for methemoglobinemia should include familial methemoglobinemia and nitrate toxicity, both of which are exceptionally rare in the horse.

Treatment

Treatment for oxidative injury involves reducing the fragility of erythrocytes, maximizing tissue oxygenation, maintaining renal perfusion, and providing supportive care. The horse needs to be removed from the environmental source of the toxin and treated with activated charcoal (8-24 mg/kg up to 2.2 kg PO) via nasogastric tube to reduce further absorption of red maple toxin. Dexamethasone (0.05-0.1 mg/kg IV ql2-24h) may be helpful to stabilize cellular membranes and reduce extravascular removal of erythrocytes by phagocytes. Ascorbic acid (10-20 g PO q24h) is often used to maintain cellular α-tocopherol in the reduced form and as a scavenger of free radicals. No data support the use of methylene blue as a reducing agent in horses; in fact, it may exacerbate oxida-tive damage. Oxygen insufflation may be required for horses that suffer from severe hypoxia. Whole blood transfusion from a compatible donor should be considered in those horses that demonstrate severe hemolytic disease. These signs include a severe reduction in venous oxygen tension (PVo2) and increased anion gap or packed cell volume (packed cell volume) 10% to 12% with evidence of cardiovascular and respiratory distress. In cases of severe hemolysis, pigmentary nephropathy — induced by the combination of excess filtration of hemoglobulin and hypoxemia — may be a complication. Renal function should therefore be monitored during the course of treatment. Intravenous fluids are administered as needed, but hemodilution in anemic patients should be avoided. If acute renal failure develops, diuretic agents such as dopamine, furosemide, or mannitol may be indicated. In high-risk patients, drug therapy should be designed to avoid additional potentially nephrotoxic agents such as aminoglycosides and non-steroidal antiinflammatory drug (NSAID) agents.

Prognosis

Complications are a major component of morbidity following severe hemolysis. Poor tissue oxygenation may lead to cerebral anoxia and altered mentation, renal failure, and myocarditis. Blood transfusion may result in colic secondary to reperfusion of hypoperfused bowel. Laminitis is always a concern in horses with severe illness and may be compounded by the use of corticosteroids. Disseminated intravascular coagulopathy may develop secondary to severe hemolysis.

In conclusion, horses should not be housed in areas with access to red maple trees or other potential oxi-dants. Good quality forage should be available at all times to reduce the likelihood of horses ingesting leaves as they fall or blow into pastures. Other maple varieties of trees should be considered potentially dangerous; reports have suggested clinical signs consistent with red maple toxicity when affected animals were exposed to red maple hybrids.

Additional Causes of Intravascular Hemolysis

Microangiopathic hemolysis may be associated with vessel thrombosis. Hemolysis is secondary to intravascular fibrin accumulation and may be characterized by the presence of schizocytes. This is a potential complication that is characteristic of chronic disseminated intravascular coagulation (DIC) in horses. Fulminant liver failure also carries the potential complication of hemolysis. Clinical evidence is consistent with intravascular hemolysis that includes icterus and hemoglobinuria. The severity of hemolysis contributes to mortality in most cases. Lesions at necropsy are consistent with DIC. It has been proposed that alterations in exchangeable red blood cell lipoprotein are affected by increased bile acids, thus contributing to altered metabolism of red cells resulting in hemolysis.

Toxin exposure may result in acute intravascular hemolysis. Snakebites that result in envenomation with potential hemolysis include: rattlesnakes (Crotalus spp.), pigmy rattlesnakes (Sistrurus spp.), copperhead (Agk-istrodon spp.), cottonmouth (Agkistrodon piscivorus), or water moccasins. Snake toxins comprise more than 90% proteins that include proteolytic and phospholipase enzymes. These toxins are well known to induce episodes of severe hemolysis and altered coagulation mechanisms. Bacterial exotoxins produced from Clostridium spp. and some staphylococcal pathogens carry the potential of inducing severe intravascular hemolysis, which is especially apparent in septic neonatal foals. Although rare in horses, infection by Leptospira pomona and Leptospira icterohaemorrhagiae serotypes have been reported to cause acute intravascular hemolysis in several large animal species. Intravenous iatrogenic administration of hypotonic fluids or undiluted dimethyl sulfoxide (DMSO) or excessive administration of water enemas to neonates may result in hemolysis. Although rare, heavy metal intoxication may also cause hemolysis.

Diseases That Primarily Cause Extravascular Hemolysis

Categories
Horses

Maternal And Foal Behavior And Problems

Normal Maternal-Foal Behavior

Key aspects of normal equine maternal behavior include (1) attending to the foal within seconds after delivery, including nuzzling, licking, and vocalization, (2) avoiding walking or lying on the neonate, (3) allowing and facilitating nursing of own, but not other foals, and (4) protecting the neonate from intruders by positioning herself between the neonate and intruders, and even attacking or driving away intruders. Interactive bonding behavior occurs between the neonate and dam beginning at parturition and continuing for the first day or two until the selective bond is established. The foal plays an active role in eliciting maternal behavior and bonding. Even before standing, the foal reaches the head and neck to nudge and nose the dam. The foal vocalizes and responds to the vocalizations of the dam, even before standing. After standing the foal seeks the udder. Once on its feet and nursing the foal actively lingers near and returns to the mare if separated.

Abnormal Maternal-Foal Behavior

Inadequate or abnormal mothering behavior and bonding of mares and foals is a relatively rare, yet very urgent problem. The etiology of such behavior and the most efficient course of intervention or therapy for the various types of problems continue to be subjects of controversy. In general, problems are more common among first-time mothers, and some types of problems may recur with subsequent foals. The abnormal behavior usually occurs immediately after parturition but in some cases may emerge after 1 or several days of normal behavior. The important task is to determine the specific nature of the problem while maintaining the safety and strength of the foal and the potential for maintaining the bond.

At least six distinct categories of inadequate or aberrant behavior have been identified in mares. The simplest type is ambivalence with a lack of attention and protection or bonding to the foal. This is most commonly found with sick, weak, or medicated mares and/or foals, or in mares and foals separated or overmanipulated during the periparturient period. Normal maternal-foal interaction may commence as the strength of one or the other returns. In cases in which a decision is made to try to revive the bond, it is best to keep the animals together with minimal disturbance necessary for the supportive health care.

Excessive aggression toward humans or other animals seems to be related to extreme protectiveness of the foal. Although strong maternal protectiveness in free-running conditions may be celebrated, in the domestic situation it actually can lead to injury of the foal. While rushing to interpose herself between the foal and perceived threat, the mare may trample or push the foal into human-made obstacles in confined conditions. The intensity of such protectiveness typically subsides within a few days but may persist through weaning in rare cases.

Management aimed at avoiding evoking protectiveness when the foal is in a position where it might be trampled, coupled with deliberate training of the mare to accept necessary intruders, usually are adequate solutions. Injuries to the young foal may be less likely when in a large stall or paddock than if in a small stall. Even when directly witnessed, protective behavior can be easily misinterpreted as attack of the foal. In open spaces, these mares rarely injure the foal, so moving the pair from a box stall to a large paddock may facilitate diagnosis. Overprotective mares tend to become even more so with subsequent foals. They often do best if allowed to foal under pasture conditions rather than in a confined foaling stall.

Some mares fear the foal as if it were an intruder. In such mares, normal bonding and protective behavior seem displaced by an urgency to escape from the foal, as they would in instances of fear of a pig or llama. Most of these can become tolerant with systematic desensitization (gradual introduction with reassurance and reward) as would be done for any feared novel object or situation.

Avoidance of the foal or aggression that is clearly limited to nursing typically, but not always, occurs with obvious udder edema and sensitivity to tactile stimulation. Positive bonding behavior and protectiveness may remain normal. For nursing avoidance or mild aggression, nursing supervision with physical restraint of the mare under halter and/or in a nursing chute in general seems to work better than tranquilization. Phenothiazine-based tranquilizers, reserpine (up to 4 mg), and benzodiazepine derivatives are possible treatments, but precautions must be taken to avoid adverse effects on the nursing foal.

Savage attack, a fifth type of maternal behavior problem is relatively rare but usually life threatening to the foal. The most common scenario is a sudden offensive attack, with lowered head and opened mouth biting or grasping the withers, neck, or back of the foal. The dam may lift, shake, and toss the foal against an object or stamp and hold it to the ground. In contrast to foals injured by overprotective mares, fearful mares, or mares resisting nursing, savagely attacked foals usually have bite wounds and serious multiple skeletal injuries. The only recommended practical long-term solution is permanent separation of the mare and foal. Savage attack often follows one or more days of apparently normal acceptance, bonding behavior, protection, and nursing of the foal, and it usually repeats if the mare and foal are not separated. It is for this reason that supervision, restraint, and tranquilization are rarely practical solutions to savage attack. Savage attack of foals usually repeats with subsequent foals. A nurse mare when available is the recommended best alternate rearing situation for foals. The window of opportunity for fostering varies among mares, but usually best results are obtained with both mare acceptance and foal bonding to the mare within 3 days of parturition. The hide, blanket, fetal membranes, or feces from the biologic foal can be used to mask the “foreign odor” of the foster foal.

In busy breeding areas, breeder networks connect orphans and rejected foals with potential nurse mares (mares that have lost a foal). Also some farms that specialize in preparing “professional” nurse mares for lease to farms with orphan foals. Hand-feeding in isolation from other foals or horses is not a generally successful strategy because behavioral maladjustments in the form of inadequate socialization with horses and overattachment to humans usually ensue. Tub-fed kindergartens of several foals housed together with minimal human contact generally have good physical and social development outcomes.

Adoption or stealing of the foals from other mares usually occurs during the thief mare’s periparturient period. Upon foaling of her own neonate, the thief mare may abandon the stolen foal, which may not be reaccepted by its original dam. This is probably the most rare type of maternal behavior problem in horses, most commonly seen under unusual management conditions, such as induction of parturition in a large number of closely confined mares.

Categories
Veterinary Drugs

Acepromazine

Acepromazine Maleate

(Promace)

Chemical Compound: 2-Acetyl-10-(3-dimethylaminopropyl) phenothiazine hydrogen maleate

DEA Classification: Not a controlled substance

Preparations: Generally available in 5-, 10-, 25-mg tablets and 10 mg/ml injectable forms

Clinical Pharmacology

Acepromazine is a low-potency phenothiazine neuroleptic agent that blocks postsynaptic dopamine receptors and increases the turnover rate of dopamine. Acepromazine has a depressant effect on the central nervous system (CNS) resulting in sedation, muscle relaxation, and a reduction in spontaneous activity. In addition, there are anti-cholinergic, antihistaminic, and alpha-adrenergic blocking effects.

Acepromazine, like other phenothiazine derivatives, is metabolized in the liver. Both conjugated and unconjugated metabolites are excreted in urine. Metabolites can be found in the urine of horses up to 96 hours after dosing. Horses should not be ridden within 36 hours of treatment.

Indications

Acepromazine is indicated as a preanesthetic agent, for control of intractable animals, as an antiemetic agent to control vomiting due to motion sickness in dogs and cats, and as a tranquilizer in horses.

Contraindications

Acepromazine can produce prolonged depression when given in excessive amounts or when given to animals that are sensitive to the drug. The effects of acepromazine may be additive when used in combination with other tranquilizers and will potentiate general anesthesia. Tranquilizers should be administered in smaller doses during general anesthesia and to animals that are debilitated, animals with cardiac disease, or animals with sympathetic blockage, hypovolemia, or shock. Phenothiazines should be used with caution during epidural anesthetic procedures because they may potentiate the hypotensive effects of local anesthetics. Phenothiazines should not be used prior to myelography.

Acepromazine should not be used in patients with a history of seizures and should be used with caution in young or debilitated animals, geriatric patients, pregnant females, giant breeds, greyhounds, and boxers. Studies in rodents have demonstrated the potential for embryotoxicity. Phenothiazines should not be used in patients with bone marrow depression.

Side Effects

Phenothiazines depress the reticular activating system and brain regions that control vasomotor tone, basal metabolic rate, and hormonal balance. They also affect extrapyramidal motor pathways and can produce muscle tremors and akathisia (restlessness, pacing, and agitation).

Cardiovascular side effects include hypotension, bradycardia, cardiovascular collapse, and reflex tachycardia. Hypertension is possible with chronic use. Syncope, collapse, apnea, and unconsciousness have been reported. Other side effects include hypothermia, ataxia, hyperglycemia, excessive sedation, and aggression. Paradoxical excitability has been reported in horses, cats, and dogs.

Hematological disorders have been reported in human patients taking phenothiazines, including agranulocytosis, eosinophilia, leukopenia, hemolytic anemia, thrombocytopenia, and pancytopenia.

There is anecdotal evidence that chronic use may result in exacerbation of noise-related phobias. Startle reactions to noise can increase with acepromazine use. Acepromazine is contraindicated in aggressive dogs, because it has been reported to facilitate acute aggressiveness in rare cases.

Priapism, or penile prolapse, may occur in male large animals. Acepromazine should be used with caution in stallions, as permanent paralysis of the retractor muscle is possible.

In a safety study, no adverse reactions to acepromazine occurred when it was administered to dogs at three times the upper limit of the recommended daily dosage (1.5 mg/lb). This dose caused mild depression that resolved within 24 hours after termination of dosing. The LD50 (the dose that kills half of the animals [mice] tested) is 61 mg/kg for intravenous administration and 257 mg/kg for oral administration.

Adverse Drug Interactions

Additive depressant effects can occur if acepromazine is used in combination with anesthetics, barbiturates, and narcotic agents. Concurrent use of propranolol can increase blood levels of both drugs. Concurrent use of thiazide diuretics may potentiate hypotension.

Overdose

Gradually increasing doses of up to 220 mg/kg PO were not fatal in dogs, but resulted in pulmonary edema. Hypotension can occur after rapid intravenous injection causing cardiovascular collapse. Epinephrine is contraindicated for the treatment of acute hypotension produced by phenothiazine tranquilizers because further depression of blood pressure can occur.

Overdosage of phenothiazine antipsychotics in human patients is characterized by severe CNS depression, coma, hypotension, extrapyramidal symptoms, agitation, convulsions, fever, dry mouth, ileus, and cardiac arrhythmias. Treatment is supportive and symptomatic, and it may include gastric lavage, airway support, and cardiovascular support.

Doses in Nonhuman Animals

Dosages should be individualized depending upon the degree of tranquilization required. Generally, as the weight of the animals increases, the dosage requirement in terms of milligram of medication per kilogram weight of the animal decreases. Doses that are 10 times lower than the manufacturer’s recommended dose may be effective. Arousal is most likely in the first 30 minutes after dosing. Maximal effects are generally reached in 15-60 minutes, and the duration of effect is approximately 3-7 hours. There may be large individual variation in response (Tables Doses for antipsychotics for dogs and cats and Doses of antipsychotics for horses).

Table Doses for antipsychotics for dogs and cats

Drug Canine Feline
Acepromazine 0.5-2.0 mg/kg PO q8h or prn 1.0-2.0 mg/kg PO prn
Chlorpromazine 0.8-3.3 mg/kg PO q6h 3.0-6.0 mg/kg PO
Promazine 2.0-6.0 mg/kg IM or IV q4-6h prn 2.0-4.5 mg/kg IM
Thioridizine 1.0-3.0 mg/kg PO ql2-24h
Haloperidol 0.05-2.0 mg/kg PO ql2h 0.1-1.0 mg/kg PO
Pimozide 0.03-0.3 mg/kg PO
Clozapine 1.0-7.0 mg/kg PO
Sulpiride 5.0-10.0 mg/kg PO

prn, according to need.

Table Doses of antipsychotics for horses

Drug Dose
Acepromazine 0.02-0.1 mg/kg IM
Promazine 0.4-1.0 mg/kg IV or 1.0-2.0 mg/kg PO q4-6h
Haloperidol decanoate 0.004 mg/kg IM

 

Effects Documented in Nonhuman Animals

Several incidences of idiosyncratic aggression in dogs and cats treated with acepromazine have been reported. In an incident report received by the United States Pharmacopeia Veterinary Practitioners’ Reporting Program, a German shepherd dog being treated with acepromazine following orthopedic surgery attacked and killed the other dog in the household, with no prior history of aggression. There were two incidences of aggression following acepromazine administration identified by the FDA Adverse Drug Experience Summary between 1987 and 1994. There are reports of aggressive behavior following oral and parenteral administration of acepromazine. While this is a rare side effect, the potential for serious injury should prompt practitioners to educate owners about this possibility and suggest appropriate precautions.

In horses, acepromazine can be detected in the urine for at least 25 hours after injection of 0.1 mg/kg.

Categories
Veterinary Drugs

Antipsychotics

Antipsychotics are used to treat most forms of psychosis, including schizophrenia, in humans. They do not have the same significance in animal behavior therapy and are usually most appropriately used on a short-term, intermittent basis. The first antipsychotic, chlorpromazine, was developed in 1950. Individual antipsychotic drugs show a wide range of physiological effects, resulting in tremendous variation in side effects. The most consistent pharmacological effect is an affinity for dopamine receptors. In humans, antipsychotics produce a state of relative indifference to stressful situations. In animals, antipsychotics reduce responsiveness to a variety of stimuli, exploratory behavior, and feeding behavior. Conditioned avoidance responses are lost in animals that are given antipsychotics.

Antipsychotic agents are divided into two groups based on side effect profiles (low-potency and high-potency drugs) or by structural classes (Table Classes of antipsychotic drugs). Low-potency antipsychotics have a lower affinity at D2 receptor sites, higher incidence of anticholinergic effects (sedation), stronger alpha-adrenergic blockade (cardiovascular side effects), and require larger doses (1-3 mg/kg), but have a lower incidence of extrapyramidal side effects. High-potency antipsychotics show a greater affinity for D2 receptor sites, fewer autonomic effects, less cardiac toxicity, a higher incidence of extrapyramidal signs, and are effective in smaller doses (0.5-1 mg/kg). The phenothiazine neuroleptics are antipsychotics that are commonly used in veterinary medicine for sedation and restraint.

Table Classes of antipsychotic drugs

Phenothiazine tranquilizers
High potency
Fluphenazine (Prolixin)
Low potency
Acepromazine (Promace)
Chlorpromazine (Thorazine)
Promazine (Sparine)
Thioridizine (Melleril)
Butyrophenones
Haloperidol (Haldol)
Droperidol (Innovar)
Azaperone (Stresnil, Suicalm)
Diphenylbutylpiperidines
Pimozide (Orap)
Dibenzoxazepines
Clozapine (Clozaril)
Atypical antipsychotics
Sulpiride (Sulpital)

 

Action

Antipsychotic agents block the action of dopamine, a catecholamine neurotransmitter that is synthesized from dietary tyrosine. Dopamine regulates motor activities and appetitive behaviors. Dopamine depletion is associated with behavioral quieting, depression, and extrapyramidal signs. Excess dopamine is associated with psychotic symptoms and the development of stereotypies. A large proportion of the brain’s dopamine is located in the corpus striatum and mediates the part of the extrapyramidal system concerned with coordinated motor activities. Dopaminergic neurons project to the basal ganglia and extrapyramidal neuronal system. Side effects associated with blockade of this system are called extrapyramidal responses. Dopamine is also high in some regions of the limbic system.

The nigrostriatal pathway consists of cell bodies originating in the substantia nigra and mediates motor activities. The mesolimbic pathway consists of neuronal cell bodies that originate in the ventral tegmental area, project to ventral striatum and limbic structures, and mediate appetitive behaviors. Dopamine is broken down by monoamine oxidase inside the presynaptic neuron or by catechol-O-methyltransferase outside the presynaptic neuron. There are five dopamine receptor subtypes. Traditional antipsychotics are D2 receptor antagonists and block 70-90% of D2 receptors at therapeutic doses.

Antipsychotics have a wide spectrum of physiological actions. Traditional antipsychotics have antihistaminic activity, dopamine receptor antagonism, alpha-adrenergic blockade, and muscarinic cholinergic blockade. Blockade of dopamine receptors in the basal ganglia and limbic system produces behavioral quieting, as well as depression of the reticular-activating system and brain regions that control thermoregulation, basal metabolic rate, emesis, vasomotor tone, and hormonal balance. Antipsychotics produce ataraxia: a state of decreased emotional arousal and relative indifference to stressful situations. They suppress spontaneous movements without affecting spinal and pain reflexes.

Overview of Indications

Antipsychotic agents are most often used in veterinary practice when chemical restraint is necessary. Antipsychotic agents are used for restraint or the temporary decrease of motor activity in cases of intense fear or stereotypic behavior. A complete behavioral and medical history is necessary to determine which pharmacological agents will be the most beneficial for any given case. A comprehensive treatment plan that includes behavior modification exercises and environmental modifications, along with drug therapy, has the best chance for success.

Antipsychotic agents have poor anxiolytic properties and should not be the sole treatment for any anxiety-related disorder. Therefore, while they can be useful in preventing self-injury or damage to the environment by an animal exhibiting a high-intensity fear response, they are not appropriate for long-term therapy and treatment of phobias.

Antipsychotic agents are indicated for the treatment of intense fear responses requiring heavy sedation to prevent self-injury or property damage. Sedation to the point of ataxia may be necessary to control frantic responses in storm-phobic dogs, but owners often report that their dogs still appear to be frightened.

Antipsychotic agents have also been used in game capture operations and to allow physical examination in intractable animals. Antipsychotics can also be used as antiemetics and for the treatment and prevention of motion sickness. When used as preanesthetic agents, antipsychotics may induce a state of indifference to a stressful situation.

Antipsychotic agents produce inconsistent results for the treatment of aggressive behavior, and in some cases have induced aggressive behavior in animals with no history of aggressiveness.

General Pharmacokinetics

Antipsychotic agents have a high hepatic extraction ratio. Metabolites are generally inactive compounds and excreted in the urine. Maximal effect occurs about 1 hour after administration. Duration of action ranges from 4 to 24 hours. Half-lives range from 10 to 30 hours in humans. These agents are highly lipid soluble and highly protein bound.

Contraindications, Side Effects, and Adverse Events

Significant side effects can occur with acute antipsychotic use because of decreased dopaminergic activity in the substantia nigra. Side effects may include motor deficits or Parkinsonian-like symptoms, such as difficulty initiating movements (akinesis), muscle spasms (dystonia), motor restlessness (akathisia), and increased muscle tone resulting in tremors or stiffness.

Behavior effects include indifference (ataraxia), decreased emotional reactivity, and decreased conditioned avoidance responses. Antipsychotic agents may also cause a suppression of spontaneous movements, a decrease in apomorphine-induced stereotypies, a decrease in social and exploratory behaviors, a decrease in operant responding, and a decrease in responses to non-nociceptive stimuli.

Tardive dyskinesia occurs as a result of upregulation of dopamine receptors with chronic antipsychotic use. An increase in postsynaptic receptor density due to dopamine blockade can result in the inability to control movements or torticollis, and hyperkinesis. The dopaminergic system is unique in that intermittent use of antipsychotic medications can result in up-regulation of postsynaptic receptors. Chronic side effects may occur after three months of treatment. At least 10-20% of human patients treated with antipsychotics for more than one year develop tardive dyskinesia, and the symptoms are potentially irreversible even after the medication is discontinued.

Bradycardia and transient hypotension due to alpha-adrenergic blocking effects can occur. Syncope has been reported, particularly in brachycephalic breeds. Hypertension is possible with chronic use.

Endocrine effects include an increase in serum prolactin, luteinizing hormone, follicle-stimulating hormone suppression, gynecomastia, gallactorhea, infertility, and weight gain. Parasympatholytic autonomic reactions are possible. Other side effects include lowered seizure threshold, hematological disorders (thrombocytopenia), hyperglycemia, and electrocardiographic changes. Priapism has been reported in stallions.

Antipsychotic agents should be used with caution, if at all, in patients with seizure disorders, hepatic dysfunction, renal impairment, or cardiac disease, and in young or debilitated animals, geriatric patients, pregnant females, giant breeds, greyhounds, and boxers.

Overdose

Neuroleptic malignant syndrome is a rare, but potentially fatal, complex of symptoms associated with antipsychotic use. It results in muscular rigidity, autonomic instability, hyperthermia, tachycardia, cardiac dysrhythmias, altered consciousness, coma, increased liver enzymes, creatine phosphokinase, and leukocytosis. Mortality reaches 20-30% in affected humans. Treatment includes discontinuation of the antipsychotic medication, symptomatic treatment, and medical monitoring.

Categories
Veterinary Medicine

Canine Parvovirus

1. What are the common clinical signs in dogs with canine parvovirus (CPV)?

• Lethargy

• Vomiting

• Inappetence

• Fever

• Acute-onset diarrhea

• Profound neutropenia (white blood cells < 1000/mm3)

Puppies between the ages of 6 weeks to 6 months are most commonly affected. In a Canadian study, sexually intact dogs had a 4-fold greater risk than spayed or neutered dogs, and the months of July, August, and September had a 3-fold increase in cases of canine parvovirus.

2. What systems other than the GI tract are involved with canine parvovirus?

In a study of dogs with the GI form of canine parvovirus, arrhythmia was diagnosed in 21 of 148 cases, including supraventricular arrhythmias and conduction disturbances. Some dogs developed significant enlargement of the cardiac silhouette and other radiographic cardiac abnormalities. CPV can replicate in bone marrow, heart, and endothelial cells; replication in endothelial cells of the brain produces neurologic disease.

3. What other infectious diseases may be mistaken for canine parvovirus infection?

Infection with Salmonella sp., Campylobacter sp., or Escherichia coli may mimic canine parvovirus symptoms and also cause the shift in white blood cells. CPV infection also may be confused with hemorrhagic gastroenteritis (HGE), although HGE is seen most commonly in smaller breeds and usually resolves in 24 hours. Coronavirus often presents with GI signs, but neutropenia tends to resolve more rapidly than with canine parvovirus infection. Clinical signs of infection with coronavirus are usually seen only in dogs also infected with parvovirus.

4. What is the primary mode of transmission of canine parvovirus?

The number of viral particles in the feces is quite high; the fecal-oral route is the most likely means of transmission. No studies of vomitus have been done, but it probably contains viral particles.

5. How does canine parvovirus infect the intestines?

Viral replication occurs in the oropharynx during the first 2 days of infection, spreading to other organ systems via the blood. By the third to fifth day a marked viremia develops. The virus reaches the intestinal mucosa from the blood rather than from the intestinal lumen. Clinical signs are seen 4-5 days after exposure, and the incubation period ranges from 3-8 days, with shedding of the virus on day 3.

6. Where does canine parvovirus replicate in the body?

The virus replicates in rapidly dividing cells, which include lymph nodes, spleen, bone marrow, and intestines. In the intestines, viral replication kills the germinal epithelium of the intestinal crypts, leading to epithelial loss, shortening of the intestinal villi, vomiting, and diarrhea. Lymphoid necrosis and destruction of myeloproliferative cells result in lymphopenia and, in severe cases, panleukopenia. Only about one-third of canine parvovirus cases have defined neutropenia or lymphopenia.

7. How has the clinical presentation of CPV infection changed since the 1970s?

There are several strains of canine parvovirus, including the original strain, CPV-1; the minute virus; and the most severe strain, CPV-2 (with subtypes 2a and 2b). CPV-2b is now the most common strain in the United States. CPV-1, which dominated in the 1970s, caused a milder disease associated with fever and a larger window for treatment. CPV-2b causes a more explosive acute syndrome that affects young dogs 6-12 weeks of age, making the window between the first signs of GI upset and treatment much narrower and more critical. There have been no major changes in presentation in the past 6 years; lethargy, listlessness, and bloody diarrhea are the most common presenting signs. Other diseases associated with or mistaken for canine parvovirus are canine distemper virus, coccidial or giardial infection, hookworms, roundworms, or a combination of these.

8. When and how does one diagnose canine parvovirus?

CPV is most easily diagnosed with a fecal enzyme-linked immunosorbent assay (ELIS A). If the test is negative but canine parvovirus is still suspected, isolate the animal and run the test again in 48 hours. The virus is not usually shed until day 3, and conscientious clients may bring the animal to the hospital at the first sign of illness. The period during which canine parvovirus is shed in the feces is brief, and the virus is not usually detectable until day 10-12 after infection. Usually the acute phase of illness has passed by this time. Modified live canine parvovirus vaccines shed in the feces may give a false-positive ELISA result 4-10 days after vaccination.

One also may use a combination of ELISA, complete blood count, and radiographs to diagnose canine parvovirus. Radiographs may help to rule out the possibility of an intestinal foreign body, and detection of generalized ileus with fluid-filled loops of intestines supports the diagnosis of canine parvovirus. Be sure to have enough antigen in the fecal sample when running the ELISA; watery stools may dilute the antigen and give a false-negative result.

Conclusive proof of canine parvovirus infection is made with electron microscope identification of the virus.

9. What are the recommendations for inpatient care of dogs with CPV?

1. Aggressive fluid therapy. Correct dehydration and provide intravenous maintenance fluid volumes of a balanced crystalloid solution. Make every attempt to replace continuing losses (vomitus and diarrhea) with equal volumes of crystalloid fluids. The easiest method is simply to estimate the volume lost and double your estimate. Continuing losses need to be replaced at the time that they occur. Use Normosol with at least 20 mEq/L of potassium chloride supplementation. Monitor glucose level. If necessary, add 2.5-5% dextrose to intravenous fluids. A 5% dextrose solution creates an osmotic diuresis, but it also allows assessment of progress in dealing with a septic case (glucose increases when the animal receives 5% dextrose if the sepsis is resolving). Low levels of magnesium chloride may be added to fluids to help correct unresponsive hypokalemia.

2. Antibiotic therapy. Broad-spectrum parenteral antibiotics are recommended because of disruption of the mucosal barrier and potential sepsis. Bacteremia is identified in 25% of dogs infected with parvovirus. A combination of ampicillin and gentamicin is recommended. Most veterinarians use only a first-generation cephalosporin in dogs without neutropenia or fever and reserve ampicillin and gentamicin or amikacin for dogs with signs of sepsis. One should be cautious about using an aminoglycoside because of renal toxicity.

3. Endotoxin-neutralizing products. Endotoxin-neutralizing products may be administered along with antibiotic therapy. The rationale for their use is based on the large population of gram-negative bacteria; by killing the bacteria, antibiotic therapy may shower the body with en-dotoxin, thus exacerbating the canine parvovirus condition. Studies have shown that endotoxin-neutralizing products decrease the incidence of septic shock. They may be diluted (4 ml/kg) with an equal volume of saline and administered intravenously over 30-60 minutes. Dogs who have recovered from parvovirus infections can be a good source for serum. Serum should be collected within 4 months of infection.

4. Antiemetics. Metoclopramide is the drug of choice. Phenothiazine derivatives should be used with caution and only after adequate volume replacement is initiated to avoid severe hypotension. Antiemetics are especially useful when continued vomiting makes it difficult to maintain hydration or electrolyte balance.

5. Motility modifiers. The use of motility modifiers is controversial. Anticholinergic anti-diarrheal medications may suppress segmental contractions and actually hasten transit time. Narcotic analgesics and synthetic opiates are better choices but should be reserved for severe or prolonged cases because slowing the flow through the intestine may increase toxin absorption.

6. Nothing per os (NPO). Begin a slow return to water 24 hours after the animal stops vomiting, and slowly progress to gruel made from a bland diet.

10. What is granulocyte colony-stimulating factor (GCSF)? What role does it have in treating dogs with CPV?

Granulocyte colony-stimulating factor selectively stimulates release of granulocytes form the bone marrow. Preliminary studies have shown that it reduces morbidity and mortality due to canine parvovirus. Unfortunately, it is available only as a human drug and is expensive, but when the positive benefits are considered, its use may be justified.

11. Does interferon benefit a dog with parvovirus infection?

Interferon given parenterally has been shown to be beneficial. The suggested dosage of human recombinant interferon is 1.3 million units/m2 subcutaneously 3 times/week.

12. How is a dog with canine parvovirus monitored?

Monitor respiration and central venous pressure (CVP) to prevent overhydration. With osmotic diarrhea the animal loses protein. If abdominal or extremity swelling is observed or if the total solids drop by 50% from admission values or go below 2.0 gm/dl, the animal should be supplemented with either 6% hetastarch or plasma to maintain colloid oncotic pressures. Blood glucose should be monitored at least 4 times/day on the first two days. Glucose level may drop precipitously and suddenly. Most importantly, weigh the dog at least twice each day. If adequate crystalloid replacement is provided, body weight does not decrease from initial values. Ideally body weight should increase at a rate comparable to the degree of dehydration originally assessed. Dogs that can hold down water for 12 hours may be offered a gruel made from bland foods. Most dogs force-fed by hand will vomit. This response may be physical or psychological (association of food with vomiting). Nasogastric tubes seem to help this problem. Metoclopramide speeds gastric emptying, acts as an antiemetic, and decreases gastric distention when added to the liquid diet. Dogs that are not vomiting should be offered food even if the diarrhea has not totally stopped. A low-fat, high-fiber diet is a good choice to stimulate intestinal motility.

13. How do you know when to send a dog home?

The dog should stay in the hospital for 12 hours after it has ingested solid food with no vomiting. Clients should report immediately any vomiting in the next 7 days or refusal to eat for 24 hours. A high-fiber diet is recommended for reducing diarrhea. A recheck appointment in 1 week with a stool sample helps the clinician to assess progress.

14. What recommendations do you offer to clients who have had a CPV-infected animal in their household and now want a new pet?

Prevention involves a proper vaccination regimen, limited exposure to other animals (especially in puppies less than 12 weeks of age), cleaning contaminated areas with bleach (allowing prolonged contact time), and vacuuming all surfaces with which the previous pet came into contact (rugs, carpet, walls, furniture). Newer higher-titer vaccines (some of which may be started as early as 4 weeks) are helpful. Generally, one should wait at least 1 month before bringing the new pet into the home. It is doubtful that the environment (especially outdoors) will ever be completely free of the virus. Canine parvovirus is a hardy and ubiquitous organism.

15. How long can a dog with CPV be expected to retain immunity?

A dog that has recovered from canine parvovirus can maintain life-long immunity.

16. What is the recommended vaccination schedule for dogs? Is it the same for every breed?

Some breeds are more susceptible to canine parvovirus than others. Rottweilers, American pitbull terriers, Doberman pinschers, and German shepherds are the most susceptible, whereas toy poodles and Cocker spaniels are less susceptible. The new higher-titer vaccines have a higher antigen level and a more virulent vaccine strain that can overcome maternal antibodies, unlike the older lower-titer vaccines. These vaccines narrow the window of infection, especially for susceptible breeds. The vaccination protocol for the new high-titer vaccines is 6, 9, and 12 weeks. Susceptible breeds should be vaccinated only with the high-titer canine parvovirus vaccine and then with a combination vaccine at 6-8, 12, and 16 weeks. For less susceptible breeds, the combination vaccines at 6-8, 12, and 16 weeks should be adequate. Some parvovirus vaccines are approved for use as early as 4 weeks of age.

17. How do you manage a sick puppy when the client is unwilling to pursue hospital treatment for CPV?

Canine parvovirus can be treated on an outpatient basis. A combination of dietary restriction, subcutaneous fluids, and, in some cases, GI medications may be used with a follow-up appointment in 1-3 days. Outpatient recommendations include the following:

• Small, frequent amounts of fluid

• Bland food

• Oral antibiotics

• Strong recommendation to have the pet reexamined and admitted for therapy if vomiting returns or anorexia persists

Nine of ten clients bring the dog back for inpatient care shortly after taking it home. Before treating an outpatient, remember that mildly depressed dogs may have a rectal temperature of 106° F and a blood glucose of 30 mg/dl in 12 hours or less.

18. Should a dog with suspected CPV be hospitalized and placed in isolation?

Undoubtedly hospitalization provides the best chance for survival. Isolation is more controversial. In most veterinary hospitals, isolation means that the animal is housed in a section of the hospital that is not staffed at all times. The adage “out of sight, out of mind” has led to the demise of many CPV-infected dogs. Experience with housing dogs with canine parvovirus in the critical care unit at the Veterinary Teaching Hospital of Colorado State University has shown that nosocomial infections can be avoided with a common-sense approach to patient management. The animal is placed in the least traveled area and has its own cleaning supplies; gowns and gloves are worn each time the animal is handled; and the animal’s cage is kept as clean as humanly possible. These procedures are no different from those in an isolation area. By being housed in an area where constant attention can be given, the animal receives adequate fluid replacement therapy and is monitored for changes, which occur rapidly.

19. How is nutrition provided for vomiting dogs?

Tough question! Dogs that have not eaten for 3-5 days are probably in a negative nitrogen balance, and certainly intestinal villi have undergone atrophy if not already destroyed by the canine parvovirus. The sooner patients begin receiving oral nutrition, the more rapidly they will recover. In addition, micronutrient therapy for the intestinal mucosa is required for maintenance of the mucosal barrier. Without this barrier, sepsis and bacteremia are more likely. Unfortunately, the only means to provide micronutrients is the oral route.

Glucose therapy does not provide nutritional support. It is best to think of dextrose as simply a source of water. One liter of 5% dextrose solution contains a mere 170 kcal. Increasing dextrose concentrations beyond 5% usually results in glycosuria and osmotic diuresis.

Patients that have not eaten for several days are primed for fat metabolism; thus, Intralipid (20%) may be added to fluids. It should be administered through a central IV catheter and requires strict aseptic management, which may be difficult if the patient is in an isolation area of the hospital.

For dogs that retain water without vomiting, glutamine may be added directly to the water bowl. Often placing electrolyte solutions in the water bowl is a good way to start the animal drinking. Placing dextrose in these fluids or even using commercial solutions such as Ensure-Plus in the bowl helps to provide intestinal nutrients.

20. Should parvovirus antibody levels be measured to check the immune status of the puppy?

Although antibodies to parvovirus can be measured, a negative titer does not necessarily mean that the dog is susceptible to canine parvovirus. Repeated revaccination of antibody-negative dogs usually does not result in significant titers.

Categories
Diseases

Constipation

Constipation; Cause

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

Differential Diagnosis of Constipation in the Cat

Neuromuscular Dysfunction

Colonic smooth muscle: idiopathic megacolon, aging

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

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

Submucosal or myenteric plexus neuropathy: dysautonomia, aging

Mechanical Obstruction

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

Intramural: neoplasia

Extraluminal: pelvic fractures, neoplasia

Inflammation

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

Metabolic and Endocrine

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

Pharmacological

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

Environmental and Behavioral

Soiled litter box, inactivity, hospitalization, change in environment

Constipation: PaThophysiology

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

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

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

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

Clinical Examination

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

Physical examination

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

Diagnosis of Constipation

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

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

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

Treatment of Constipation

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

Drug Index — Constipation

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

 

Removal of Impacted Feces

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

Rectal suppositories

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

Enemas

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

Manual extraction

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

Laxative Therapy

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

Bulk-forming laxatives

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

Emollient laxatives

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

Lubricant laxatives

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

Hyperosmotic laxatives

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

Stimulant laxatives

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

Colonic Prokinetic Agents

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

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

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

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

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

Constipation; Surgery

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

Prognosis of Constipation

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