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INTRODUCTION

Nearly half (44%) of all households in the United States own at least one of the country’s 77.8 million pet dogs.¹ Although dogs may suffer from many of the same diseases and conditions that humans do, therapies can vary significantly regarding drugs, doses, frequencies, and routes of administration.

This activity is designed to impart a working knowledge of the canine disease states that are most likely to prompt a dog owner to have a prescription filled at a community pharmacy. It is intended as a primer for pharmacists, pharmacy technicians, and veterinary technicians to begin to consider the significant species-specific variations in medical therapy for dogs vs humans and to learn important techniques for due diligence for prescription review, caregiver counseling, and practice tips for caring for dogs.

A general decision framework for evaluating and dispensing prescriptions for canine patients is outlined in Figure 1.

Figure 1. Canine Prescription Due Diligence Decision Tree

CANINE HYPOTHYROIDISM

Canine hypothyroidism is one of the most common canine endocrine diseases. It results from impaired production and secretion of thyroid hormone. Almost all (95%) of cases are due to destruction of the thyroid gland itself (primary hypothyroidism), not hypothalamic or hypophyseal disease. Although vaccination and thyroid infection have been cited as etiologies for lymphocytic thyroiditis, neither is a proven cause.

Secondary hypothyroidism (< 5% of cases) denotes an impaired ability of the pituitary gland to secrete thyroid stimulating hormone (TSH), resulting in secondary thyroid follicular atrophy. Causes of secondary hypothyroidism include pituitary tumors, pituitary malformation, and isolated TSH deficiency.

Genetic predisposition likely plays a role in the development of hypothyroidism. Strong genetic predisposition is noted in certain breeds: Pointer, English Setter, Irish Setter, English Pointer, Skye Terrier, German Wirehaired Pointer, Old English Sheepdog, Boxer, Maltese, Kuvasz, American Staffordshire Terrier, Beagle, Golden Retriever, and Doberman. Spayed, middle-aged female dogs (4-10 years of age) have the highest risk.

Clinical signs of hypothyroidism in dogs include lethargy, mental dullness, inactivity, weight gain, cold intolerance, poor hair coat with symmetrical alopecia, and chronic ear infections. Some dogs may have ocular manifestations, including lipid deposits and ulceration in the cornea. Hypothyroidism may become severe enough to cause multi-organ system failure and result in myxedema. Myxedema is a life-threatening medical emergency; dogs experiencing decompensated hypothyroidism should be treated immediately with intravenous levothyroxine and other supportive care.

For primary hypothyroidism with treatment, the prognosis is excellent and life expectancy is normal. For secondary hypothyroidism, the prognosis is excellent if pituitary dysfunction is iatrogenic (eg, glucocorticoids) but guarded if dysfunction is caused by neoplasia.

Treatment Options

Oral administration of levothyroxine is the therapy of choice, with the goal of achieving a serum thyroxine (T4) concentration in the normal reference range (1.5-4.5 μg/dL). Normalization of an elevated TSH concentration also may be a goal of therapy.

At the time this module was finalized, Thyro-Tabs^® Canine (levothyroxine sodium tablets) was the only FDA-approved drug for the treatment of hypothyroidism in dogs.² The scored tablets are available in 9 strengths, ranging from 0.1 mg to 1.0 mg (in 0.1-mg increments). The initial daily dosage is 0.1 mg/10 lb body weight (0.01 mg/lb or 0.022 mg/kg) administered as a single dose every 24 hours or as a divided dose every 12 hours.³

Although most veterinarians dispense levothyroxine to patients from their clinics, some pet owners bring prescriptions to community pharmacies for filling. It is very important for pharmacists to recognize that significantly larger doses of levothyroxine are used in dogs, and doses usually administered twice daily instead of once daily. Factors that contribute to larger doses of levothyroxine in dogs include:⁴

• Higher glomerular filtration rate
• Lower oral bioavailability due to a shorter gastrointestinal (GI) tract (jejunum, ileum, and colon)
• Significantly higher fasting gastric pH (> 6)

Human dosage forms of levothyroxine typically are not suitable for use in large dogs because of the need for multiple tablets to achieve required doses (which can be prohibitively expensive).

Administration of levothyroxine sodium with food reduces oral bioavailability.³ The tablets may be administered with or without food; however, to help minimize day-to-day variations in serum total thyroxine (TT4) concentrations, dog owners should take one approach consistently (ie, administer all doses either with food or without food).

Bioavailability also varies among formulations of levothyroxine. Thyro-Tabs^® Canine was approved in January 2016; it is possible that some dogs still are being switched from previously available products, which now are considered to be unapproved drugs.⁵ Serum TT4 concentrations and clinical response should be monitored when dogs are switched from any other levothyroxine sodium formulation to Thyro-Tabs^® Canine.³

Many drugs alter serum T4 or TSH levels (Table 1). Dog owners should seek a veterinarian’s advice prior to using these drugs once a diagnosis of hypothyroidism has been established.

Monitoring and Follow-Up

Response to therapy is evaluated by monitoring clinical response and measuring the serum TT4 concentration (plus TSH concentration if indicated) every 4 to 8 weeks. Testing should be performed 4 to 6 hours after tablet administration (the time of peak serum TT4 concentration). Dose reduction is advised if the serum TT4 concentration is > 5 μg/dL; the dose should be increased if serum TT4 is < 1.5 μg/dL.

Adverse effects of levothyroxine typically occur when therapy is initiated, indicating that the dose is too high (thyrotoxicosis). Dog owners should contact their veterinarian if the treated dog exhibits increased thirst, excessive hunger, increased urination, excessive panting, rapid heart rate, nervousness, or excitement.

CANINE HYPERADRENOCORTICISM (CUSHING’S DISEASE)

Canine hyperadrenocorticism, or Cushing’s disease, is a common endocrine disease of dogs. It is classified as pituitary-dependent hyperadrenocorticism (PDH), adrenal-dependent hyperadrenocorticism (ADH), or iatrogenic hyperadrenocorticism.

PDH is the most common presentation, accounting for 85% of all cases of canine hyperadrenocorticism. More than 80% of PDH cases are caused by a pituitary tumor. Approximately 15% of dogs develop an adrenocortical tumor that causes ADH. Iatrogenic hyperadrenocorticism usually results from administration of excessive amounts of glucocorticoids to control allergic or immune-mediated disorders.

Both sexes of middle-aged dogs have a higher risk for hyperadrenocorticism. Certain breeds are overrepresented, including Poodle breeds, Dachshunds, Terrier breeds, German Shepherds, Beagles, Labrador Retrievers, Boston Terriers, and Boxers.

Classic clinical signs of canine hyperadrenocorticism include polyphagia, polydipsia, and polyuria with muscle wasting and a potbellied appearance. Excessive panting also is observed. Alopecia and skin hyperpigmentation are commonly seen.

Treatment Options

The goals of therapy for canine hyperadrenocorticism are to suppress or block cortisol secretion by the adrenal glands. Trilostane and mitotane are the preferred pharmacologic treatment options (Table 2). Ketoconazole and L-deprenyl (selegiline) have been used to treat canine hyperadrenocorticism, but neither is considered to be as effective as trilostane or mitotane.

Trilostane
Trilostane blocks cortisol synthesis through competitive inhibition of 3-β-hydroxysteroid dehydrogenase. It is the drug of choice for PDH. Trilostane also may be used in dogs with (1) adrenal tumors that do not respond to mitotane or (2) metastatic tumors. Trilostane sometimes is used to restore metabolic function before surgical adrenalectomy.

Trilostane is FDA-approved for use in dogs (Vetoryl^®). The usual starting dosage is 2–10 mg/kg administered by mouth once daily. Doses should be administered with food. Although once-daily administration is recommended, twice-daily dosing may be needed if clinical signs are not controlled for a full 24 hours.

Trilostane sometimes is compounded into an oral suspension according to USP <795> standards for nonsterile compounds. The commercially available capsules—not bulk drug substance—should be used as the source of active ingredient for compounded formulations.⁶ The dosage form should not be changed from solid to liquid without first consulting the veterinarian.

The following drugs may increase the effects of trilostane: aminoglutethimide, ketoconazole, and mitotane.

Mitotane
Mitotane is a cytotoxic agent that selectively lyses cells of the adrenal cortex, where cortisol synthesis occurs. It is an effective treatment for PDH and a viable alternative to surgical adrenalectomy for dogs with adrenal tumors.

Mitotane approved for humans is used off-label to treat dogs with canine Cushing’s disease. The absorption of mitotane is increased significantly in the presence of lipid; doses should be administered with food, preferably a high-fat food such as cheese or peanut butter. Ideally, each dose of mitotane should be administered with the same type of food to avoid fluctuations in blood levels.

There are two protocols for mitotane therapy: traditional therapy and medical adrenalectomy. These protocols have very different treatment goals.

Traditional Therapy. In traditional therapy, mitotane is administered to induce adrenal cytotoxicity at a level that controls the hyperproductive adrenal gland without inducing signs of hypoadrenocorticism. Traditional therapy consists of a high-dose induction phase (typically 5-7 days) followed by a lower-dose maintenance phase, with the dose based on induction response.

The usual dosage for induction therapy is 25 mg/kg administered by mouth every 12 hours. Dogs must be monitored closely during the induction phase: some dogs respond as soon as 5 days, while others may not respond for as long as 30 days. Dogs are considered to be “induced” when appetite returns to normal and water consumption is < 80 mL/kg/d. Caregivers should be taught how to calibrate the dog’s drinking bowl to assess intake, and they should take care to prevent access to unintended water sources during induction (eg, keep toilet lids down, cover fish tanks).

The usual maintenance dosage is 50 mg/kg/wk, divided into 2 or 3 doses over the week (eg, on Monday, Wednesday, and Friday).

Phenobarbital may lower blood levels of mitotane.

Medical Adrenalectomy. In medical adrenalectomy, mitotane is administered to destroy the adrenal cortex. Medical adrenalectomy is an option for dogs that are not good surgical candidates.

When used for medical adrenalectomy, mitotane is administered by mouth at a dosage of 75-100 mg/kg/d for 25 days. The total daily dose usually is divided and administered as 4 equal doses throughout the day (as close to every 6 hours as possible) to facilitate complete GI absorption and avoid neurological complications (ataxia, stupor, circling, blindness). Many veterinarians prescribe a supply of prednisone to be administered orally at a dosage of 0.1-0.5 mg/kg every 12 hours to counteract hypoadrenocorticism during periods of stress (see discussion in Canine Hypoadrenocorticism section).

Monitoring and Follow-Up

All treatments for hyperadrenocorticism can cause hypoadrenocorticism. Signs of hypoadrenocorticism include lethargy, weakness, vomiting, stumbling, and behavior change; electrolyte shifts also may occur. Dogs that exhibit any of these signs should be evaluated by a veterinarian immediately.

Dosage adjustments for both trilostane and mitotane are based on the results of physical examination and laboratory tests. The adrenocorticotropic hormone (ACTH) stimulation test for measuring serum cortisol levels is performed 4 to 6 hours after dosing. Serum biochemistry tests should include measurement of electrolytes.

Dogs treated with trilostane usually have a recheck physical examination at 2 weeks. Laboratory tests usually are performed at 2 weeks only if signs of hypoadrenocorticism are present. Otherwise, laboratory tests are performed 4 weeks after treatment is initiated.

For dogs treated with mitotane, follow-up occurs according to treatment phase. For the induction phase, dogs should undergo physical examination and laboratory tests 5 to 7 days after therapy is initiated, or when the dog’s water consumption drops below 80 mL/kg/d. Caregivers should contact the veterinarian immediately once the dog appears to be induced, even if it is before the scheduled recheck appointment.

During the maintenance phase of mitotane therapy, the ACTH stimulation test is repeated every 3 to 6 months, as well as 3 to 4 weeks after any dosage change or onset of clinical signs.

Dogs with treated PDH have a good prognosis, with an average survival time after diagnosis of 30 months. One small study found no significant difference in survival times for dogs with PDH treated with trilostane or mitotane.⁷ Dogs with adrenal tumors receiving medical treatment with trilostane or mitotane survive about 1 year, compared with 1.5 to 3 years for dogs that undergo surgical adrenalectomy.^7,8

Safety Considerations for Caregivers

Trilostane may cause spontaneous miscarriage during pregnancy. It should not be handled by women who are pregnant or trying to become pregnant.

Mitotane is a chemotherapy agent. It should not be handled by women who are pregnant or trying to become pregnant. Non-pregnant caregivers should handle mitotane with gloves and wash their hands thoroughly after handling. Mitotane is eliminated in the dog’s feces, so gloves should be worn and hands washed after disposing of feces.

CANINE HYPOADRENOCORTICISM (ADDISON’S DISEASE)

Hypoadrenocorticism (Addison’s disease) is a deficiency of mineralocorticoids, glucocorticoids, or both. It is caused by either destruction of the adrenal cortex (primary hypoadrenocorticism) or a lack of ACTH release from the pituitary gland (secondary hypoadrenocorticism).

Primary hypoadrenocorticism may result from immune-mediated destruction of the adrenal cortex. Clinical signs are apparent when 90% of the cortex no longer is functional.

Secondary hypoadrenocorticism may result from destructive lesions in the pituitary gland or hypothalamus. Alternatively, it may be the result of negative feedback from chronic administration of exogenous corticosteroids.

Young to middle-aged female dogs are at highest risk of hypoadrenocorticism. The condition predominates in certain breeds: Portuguese Water Dog, Standard Poodle, Nova Scotia Duck Tolling Retriever, Bearded Collie, Leonberger, Great Dane, Rottweiler, West Highland White Terrier, and Soft Coated Wheaten Terrier.

Animals deficient in glucocorticoids experience vomiting, diarrhea, lethargy, and weight loss, all of which are exacerbated by stressful situations (eg, boarding, travel, house guests, new animals in the household). Mineralocorticoids are critical to electrolyte balance; dogs with mineralocorticoid deficiency progressively develop hypovolemia, hypotension, reduced cardiac output, and decreased perfusion of the kidneys and other organs. Hyperkalemia that results from electrolyte imbalance causes decreased myocardial conduction and arrhythmias.

The prognosis for dogs with Addison’s disease is excellent with treatment. Client dedication to adherence and recheck appointments is critical.

Treatment Options

Treatment of acute Addisonian crisis occurs in the veterinary office, but maintenance therapy is conducted on an outpatient basis. Goals of therapy are to replace mineralocorticoids and glucocorticoids and restore electrolyte balance and stress response.

Desoxycorticosterone pivalate (DOCP), fludrocortisone acetate, and prednisone are the primary drug therapies for canine hypoadrenocorticism (Table 3).

Desoxycorticosterone Pivalate
DOCP is FDA-approved for the treatment of canine hypoadrenocorticism (Percorten-V™, Zycortal^®), and it is the mineralocorticoid of choice. DOCP is administered by subcutaneous or intramuscular injection approximately every 25 days. The usual dose is 2.2 mg/kg.

Once the frequency of DOCP administration is determined (see Monitoring and Follow-Up below), many pet owners can perform subcutaneous injections at home. DOCP is provided as an extended-release injectable suspension. The suspension is viscous; the vial should be shaken vigorously for 2 to 3 minutes before withdrawing the dose into the syringe. Because of the viscosity, DOCP suspension is best administered with a 20–22 gauge needle. After the needle is inserted into the skin, it is important to draw back on the plunger to ensure that the needle is not in a blood vessel (indicated by the presence of blood in the syringe). Some irritation may occur at the injection site.

DOCP replaces only the mineralocorticoid hormones. Small daily doses of glucocorticoid hormones (eg, prednisone) must be given for glucocorticoid replacement in most cases, or treatment failure will ensue.

Fludrocortisone Acetate
DOCP is relatively expensive. Therapy with desoxycorticosterone pivalate may be even more expensive if the owner cannot manage to give injections at home and must make monthly visits to the veterinarian. Oral fludrocortisone acetate is an alternative to DOCP in these cases.

Fludrocortisone acetate approved for humans (0.1 mg tablets) is used off-label for the treatment of canine hypoadrenocorticism. Most veterinarians prefer to provide prescriptions for fludrocortisone instead of maintaining inventories for dispensing.

Treatment is initiated at a dosage of 0.01 mg/kg by mouth every 12 hours and adjusted based on serum electrolyte concentrations. Large dogs may require multiple tablets per dose. Administration can be facilitated by wrapping the tablets in a slice of bread or cheese to ensure that all tablets are given at once.

Fludrocortisone has some glucocorticoid activity. Only about 50% of dogs treated with fludrocortisone require supplemental glucocorticoid (prednisone) administration. Because fludrocortisone has glucocorticoid activity, it may cause polydipsia, polyuria, and incontinence.

Tolerance to the effects of fludrocortisone may develop over time. This sometimes necessitates a switch to DOCP.

Prednisone
When prednisone is administered as chronic concurrent therapy for glucocorticoid replacement, treatment usually is initiated at a dosage of 0.1-0.22 mg/kg by mouth every 12 hours. That dose is tapered to the smallest amount that controls clinical signs.

Dogs may require supplemental prednisone during times of stress. Failure to provide adequate glucocorticoid support during times of stress can worsen lethargy, inappetence, and vomiting. Owners should know the situations that cause stress for their dog and be prepared to give prednisone on those days. If the dog already receives prednisone on a daily basis, the dose should be increased during stressful periods as prescribed by the veterinarian.

Monitoring and Follow-Up

Monitoring and follow-up are dictated by the specific treatment and recurrence of clinical signs.

For dogs treated with DOCP, serum electrolyte concentrations should be measured on days 12 and 25 after each injection for the first 2 to 3 months. The veterinarian will adjust the dose or dosing interval based on these results.

For dogs treated with fludrocortisone, serum electrolyte concentrations should be measured every 1 to 2 weeks for the first 6 to 18 months of therapy. Doses typically are increased during this time.

The electrolyte imbalances caused by canine hypoadrenocorticism can be life-threatening. Owners should watch for signs of vomiting, weakness, slow heartbeat (< 60 bpm), shivering, or collapse and seek veterinary care immediately if any of these occur.

CANINE DIABETES MELLITUS

Canine diabetes mellitus is estimated to occur in 1 in every 570 dogs in the United States.⁹ The vast majority of dogs have insulin-dependent (Type 1) diabetes; once they are diabetic, they are likely to remain diabetic for life.

Genetic predisposition increases the risk of diabetes in certain breeds, including Australian Terrier, Schnauzers, Bichon Frise, Spitz, Fox Terrier, Miniature Poodle, Samoyed, Cairn Terrier, Keeshond, Maltese, Toy Poodle, Lhasa Apso, Yorkshire Terrier, and Pugs. Middle-aged and older females have an increased risk of developing diabetes. Diabetes also may be precipitated by infection, drug therapy, obesity, immune-mediated destruction, and pancreatitis—all of which can cause irreversible destruction of β cells.

Signs of diabetes mellitus in dogs are similar to symptoms in humans. They include polydipsia, polyuria, weight loss in spite of polyphagia, dehydration, electrolyte imbalance, metabolic acidosis, frequent urinary tract infections, osmotic diuresis, lameness from peripheral neuropathy, and vision loss from diabetic cataracts.

The mean survival time in dogs following diagnosis is 3 years. However, the length of survival is highly dependent on owner commitment to adherence, and it is affected by concurrent disease.

Treatment Options

The goals of therapy in dogs with diabetes mellitus are to:

• Maintain blood glucose levels between 100 mg/dL and 250 mg/dL
• Minimize clinical signs of polyuria and polydipsia
• Avoid complications such as ketoacidosis and hypoglycemia (blood glucose < 80 mg/dL)
• Avoid sequelae such as cataracts

Dogs with diabetes are not controlled as tightly as humans with diabetes because of the risk of hypoglycemia. Feeding a consistent diet—type of food, quantity of food, and timing of meals— is critical to the success of therapy.

Oral hypoglycemic agents are not effective in dogs because of the absence of functional β cells. Dogs with diabetes must be treated with insulin. Individual response to insulin is erratic; the insulins employed most successfully in dogs are porcine zinc suspension (lente) and neutral protamine Hagedorn (NPH) (Table 4). Insulin detemir is not ideal for home use (at least initially) because of challenges associated with establishing effective dosing. Insulin glargine is not predictably effective in dogs, so it typically is reserved for use in dogs that do not respond well to porcine insulin zinc suspension or NPH insulin. Regular insulin and insulin lispro are used primarily at the veterinary clinic; they are administered by continuous intravenous infusion to treat diabetic ketoacidosis or severe hyperkalemia (regular insulin).

Although dogs generally have good glycemic control after insulin therapy is started, they often require dosage adjustment within just a few months as destruction of pancreatic β cells continues to worsen.

Porcine Insulin Zinc Suspension
A formulation of porcine insulin zinc suspension (Vetsulin^®) is FDA-approved for use in dogs (and cats). The aqueous suspension (40 U/mL) is available in 10-mL vials as well as in 2.7-mL cartridges for use with the VetPen^® insulin pen. Both the vials and the cartridges must be shaken well before use until a homogeneous, uniformly milky suspension is obtained.

It is possible to use insulin cartridges or prefilled pens as multidose vials, especially for cases in which the 10-mL vial would expire before the contents could be used. Doses can be withdrawn through the septum using an insulin syringe. Alternatively, the contents of the cartridge could be repackaged aseptically into an empty sterile vial according to USP <797> sterile compounding standards.

Therapy with porcine insulin zinc suspension usually is initiated at a dosage of 0.25 U/kg by subcutaneous injection every 12 hours. If doses are withdrawn from a vial, the dose should be administered using a U-40 insulin syringe. If U-40 syringes are not available, the dose should be multiplied by 2.5 to determine the correct dose volume for a U-100 syringe.

The duration of action of porcine insulin zinc suspension (10-14 hours) may be too long for twice-daily (every 12 hours) dosing in many dogs. Because the glucose nadir can be unpredictable, dogs should be observed closely for signs of hypoglycemia (see Monitoring and Follow-Up below).

NPH Insulin
NPH insulin suspension (100 U/mL) approved for humans is used off-label in dogs with diabetes. Therapy usually is initiated at a dosage of 0.25 U/kg by subcutaneous injection every 12 hours. Vials should be rolled gently between the palms of the hands (not shaken) at least 10 times before a dose is withdrawn.

The duration of action of NPH suspension (6-12 hours) may be too short for twice-daily (every 12 hours) dosing in some dogs.

NPH insulin is available from multiple manufacturers. Dogs should be monitored closely for glycemic control when switching from one brand of NPH insulin to another.

Insulin Detemir
Insulin detemir solution (100 U/mL) approved for humans sometimes is used off-label in dogs with diabetes. Therapy usually is initiated at a dosage of 0.1-0.2 U/kg by subcutaneous injection every 12 to 24 hours, starting at the low end of the dosing range. However, therapy should be initiated at a veterinary clinic with a blood glucose curve to determine duration of effect and glucose nadir. The duration of action of insulin detemir (10-16 hours) may be too long for use in some dogs.

Monitoring and Follow-Up

When insulin therapy is initiated, veterinarians often will keep the dog hospitalized for the first 24 or 48 hours to verify that the starting dose does not cause hypoglycemia. Blood glucose is measured at 3, 6, and 9 hours after the initial dose of insulin; the dosage is adjusted as necessary to avoid hypoglycemia and maintain glycemic control (glucose < 250 mg/dL). Owners then begin administering that dosage at home. In households with multiple caregivers, the caregivers should be encouraged to develop a system for documenting insulin doses administered, to avoid double-dosing in particular.

Owners may be instructed to monitor the dog’s water consumption, food consumption, and blood or urine glucose. Owners who monitor blood glucose should obtain blood samples from hairless areas (eg, marginal ear vein, paw pads, elbow callus, inner lip). The sampling sites should be cleaned thoroughly to avoid infection.

At 1 month after insulin therapy is initiated, dogs should receive a complete physical examination and weight check along with laboratory tests (complete blood count, serum chemistries, serum fructosamine). Fructosamine reference ranges for glycemic control are similar to those for humans:

• < 250 uMol/L = prolonged hypoglycemia
• 300-350 uMol/L = excellent
• 350-400 uMol/L = good
• 400-450 uMol/L = fair
• > 450 uMol/L = poor

Physical examination and laboratory tests are repeated every 3 to 6 months, depending on patient response.

It is important that owners watch for signs of hypoglycemia. Dogs with low blood glucose may exhibit lethargy, weakness, disorientation, unusual behavior, anxiety or depression, tremors, collapse, unresponsiveness, and sometimes seizures. Although humans suffering from hypoglycemia often experience diaphoresis, dogs are unable to sweat.

Owners should contact their veterinarian immediately if a dog exhibits signs of hypoglycemia. As soon as possible, they should administer glucose solution or corn syrup (1 g/kg body weight, which is approximately 0.6 mL/10 lb of body weight) orally or on the gums, or sublingually if the animal is not conscious enough to swallow. After successful emergency administration of oral glucose, small amounts of food should be offered to the dog at intervals of 1 to 2 hours until blood glucose returns to normal.

CANINE IDIOPATHIC EPILEPSY

Idiopathic epilepsy is the most common cause of seizures in dogs. There usually is no obvious cause for the seizures (eg, fever, neoplasia, trauma). The seizure threshold is simply decreased.

A genetic predisposition is known or suspected in German Shepherds, Belgian Tervurens, Keeshonds, Beagles, Dachshunds, Labrador Retrievers, Golden Retrievers, Border Collies, Shetland Sheepdogs, Irish Wolfhounds, Vizlas, Bernese Mountain Dogs, and English Springer Spaniels. Onset typically occurs between 6 months and 3 years of age but may appear as late as 5 years of age; the younger the onset, the more refractory epilepsy is to therapy.

Idiopathic epilepsy is characterized by generalized onset, tonic-clonic seizures that last for 1 to 2 minutes and recur at relatively regular intervals, varying from weeks to months. During a seizure, the dog may lie on one side and exhibit increased extensor muscle tone, rhythmic muscle contractions (manifested as paddling of all 4 limbs and chomping of the mandible), loss of consciousness (although the eyes may remain open), loss of bladder and bowel control, and vocalization. The seizure is followed by a period of confusion and disorientation during recovery. Dogs with epilepsy may be completely normal between seizures.

The prognosis is good in treated dogs that have less than 1 seizure every 12 to 16 weeks. Treatment of epilepsy requires commitment of both time and money by owners. Perfect control of epilepsy is unlikely, and owners should be counseled accordingly. Seizures may cluster or occur more frequently as dogs age, especially large breed dogs.

Treatment Options

Anticonvulsant therapy is initiated when any of the following occur in dogs:

• Seizures increase in frequency or severity
• The seizure-free interval is less than 12 to 16 weeks
• Seizures begin to cluster
• The dog experiences at least 1 episode of status epilepticus (a series of seizures or a continuous seizure lasting 5 minutes or longer, with no periods of intervening consciousness)

Although the principles of therapy and pharmacologic options are similar to those employed for humans, significant differences exist.

Phenobarbital, potassium bromide, zonisamide, levetiracetam, and gabapentin are used most commonly for the treatment of canine idiopathic epilepsy (Table 5).

Phenobarbital
Phenobarbital is the drug of choice for canine idiopathic epilepsy and may be used as monotherapy. Tablets approved for humans are used off-label in dogs. An oral elixir formulation also is available, but the high alcohol content prohibits use in dogs.

Phenobarbital therapy is initiated at a dosage of 2-3 mg/kg by mouth every 12 hours, with a target therapeutic range (trough) of 25-35 μg/mL. The trough level should be measured after 2 weeks of therapy, and the phenobarbital dosage should be adjusted in increments of 25% over 2-week intervals until the therapeutic range is achieved. Autoinduction of microsomal enzymes may necessitate increasing the dose over time.

Dogs may experience transient sedation and ataxia for 7 to 10 days after phenobarbital therapy is started. Common adverse effects include polyphagia, polydipsia, and polyuria. Approximately 40% of dogs experience a transient idiosyncratic hyperexcitability. Phenobarbital also can cause reversible neutropenia or thrombocytopenia.

Phenobarbital is a potent inducer of hepatic enzymes. This can result in large increases in ALT; hepatotoxicity is reversible if the drug is discontinued early. Phenobarbital is involved in numerous drug interactions.

Potassium Bromide
Potassium bromide is the drug of choice for add-on therapy in dogs treated with phenobarbital. The mechanism of action is competitive displacement of chloride from the neuronal membrane. Potassium bromide also competes with chloride for renal reabsorption. High chloride intake (eg, from sodium chloride) increases the renal excretion of bromide; this can decrease serum concentrations and lead to breakthrough seizures.

As discussed in greater detail in Module 6 (“Top 30 Veterinary-Only Prescription Drugs, Part 2: Hormonal Drugs and Selected Individual Agents”), potassium bromide had been approved for use in humans but was withdrawn from marketing in 1975 for safety reasons (bromide toxicity, also known as bromism). There currently are no FDA-approved commercial products for humans or animals, including the widely marketed K·BroVet^® tablets, which are not FDA-approved. USP has developed a validated compounded preparation monograph for potassium bromide oral solution 250 mg/mL.

When potassium bromide is used as add-on therapy, treatment is initiated at a dosage of 15-30 mg/kg by mouth every 24 hours, with a target therapeutic range (trough) of 1-2 mg/mL. Potassium bromide sometimes also is used as monotherapy at a dosage of 30-35 mg/kg by mouth every 24 hours, with a target therapeutic range (trough) of 2.5-3 mg/mL. Because potassium bromide has a mean half-life of 26 days, therapy may be initiated with a high loading dose for several days.

Adverse effects of potassium bromide include transient sedation, GI upset, polyphagia, polyuria, and polydipsia. Dogs treated with potassium bromide should be monitored for signs of bromism: stupor, coma, ataxia, and tetraparesis. Because of the risk of bromism in humans, caregivers should be counseled to wear gloves and wash hands thoroughly when handling potassium bromide.

Zonisamide
Zonisamide capsules approved for use in humans sometimes are used off-label for the treatment of canine idiopathic epilepsy, either as monotherapy or add-on therapy in dogs treated with phenobarbital. USP has developed a validated compounded preparation monograph for zonisamide oral suspension.

As monotherapy, zonisamide is initiated at a dosage of 5 mg/kg by mouth every 12 hours. When used as add-on therapy, the initial dosage of zonisamide is 10 mg/kg by mouth every 12 hours. The target therapeutic range is 10-40 μg/mL.

Common adverse effects of zonisamide therapy include transient ataxia, sedation, vomiting, and loss of appetite. Zonisamide has been associated with a severe idiosyncratic hepatotoxicity in dogs;¹⁰ hepatic enzymes should be monitored closely.

Zonisamide is a sulfonamide. Human caregivers with sulfa allergies should avoid contact with zonisamide.

Levetiracetam
Levetiracetam approved for use in humans sometimes is used off-label for the treatment of canine idiopathic epilepsy. It is available as standard-release tablets, extended-release tablets, oral solution, and solution for injection.

The dosage of levetiracetam depends on the dosage form and indication. Therapy with regular-release tablets is initiated at a dosage of 20 mg/kg by mouth every 8 hours. Therapy with extended-release tablets is initiated at a dosage of 30 mg/kg by mouth every 12 hours. When the injectable solution is used for the treatment of status epilepticus, it is administered as an intravenous infusion of 30-60 mg/kg over 5 minutes.

Levetiracetam has a wide margin of safety. Common adverse effects include transient sedation, ataxia, vomiting, and inappetence.

Gabapentin
Gabapentin approved for use in humans sometimes is used off-label for the treatment of canine idiopathic epilepsy. It is available as tablets, capsules, and an oral solution that contains xylitol 300 mg/mL as a sweetener. Xylitol-containing solutions are contraindicated in dogs because of the risk of xylitol toxicity. USP has developed a validated compounded preparation monograph for xylitol-free gabapentin suspension 50 mg/mL.

Gabapentin therapy is initiated at a dosage of 10-20 mg/kg by mouth every 8 hours. Dosages up to 80 mg/kg every 8 hours have been used safely. Gabapentin may be used as add-on therapy in dogs treated with potassium bromide or as a third add-on drug for dogs treated with phenobarbital and potassium bromide. The target therapeutic range is thought to be 4-16 mg/mL, but it rarely is measured in clinical practice.

Common adverse effects of gabapentin therapy include transient sedation and ataxia.

Other Therapies
Felbamate is considered to be a second-line or third-line drug for the treatment of canine idiopathic epilepsy. When it is used, therapy is initiated at a dosage of 15 mg/kg by mouth every 8 hours. Adverse reactions in dogs include keratoconjunctivitis sicca, induction of liver enzymes, tremor, limb rigidity, salivation, restlessness, and agitation (at high doses). Approximately 30% of dogs treated with felbamate as an add-on to phenobarbital therapy will develop hepatotoxicity. Although aplastic anemias and fatal hepatopathies reported in humans have not been observed in dogs, limited usage of felbamate in dogs may mask the true incidence.

Diazepam is not a good choice for chronic oral management of epilepsy in dogs. It has a short half-life and tolerance develops rapidly.

Treatment of Status Epilepticus and Cluster Seizures

Both diazepam injectable solution 5 mg/mL and midazolam injectable solution 5 mg/mL are used for the treatment of status epilepticus or cluster seizures in dogs. Owners may need to administer these drugs at home if a dog has a seizure or a cluster of seizures lasting longer than 5 minutes. Owners may benefit from the use of special dispensing pins that enable removal of doses from vials quickly without the need for a needle and syringe.

Diazepam solution is administered rectally at a dosage of 2 mg/kg every 10 minutes, not to exceed 3 doses in 24 hours. The patient-specific dose should be drawn up at the onset of the seizure and administered directly into the dog’s rectum. Doses should not be pre-drawn into plastic syringes because of significant diazepam sorption.

Compared with diazepam, midazolam has a faster onset of action but shorter duration of action. It is administered intranasally as single dose of 0.2-0.5 mg/kg; the dose may be repeated twice if the seizures continue. The patient-specific dose should be drawn up at the onset of seizure and inserted directly into the dog’s nares. Doses should not be pre-drawn into plastic syringes because of significant drug sorption. Ideally, the dose is divided between the two nostrils; this can be difficult to accomplish during a seizure. Mucosal atomization devices may provide for greater bioavailability of intranasally administered midazolam. Dogs treated with midazolam should be observed for respiratory depression.

Monitoring and Follow-Up

Routine follow-up for dogs with epilepsy consists of physical examination and serum chemistries every 6 months. Owners are advised to keep a seizure diary and record all events associated with a seizure for objective assessment of response to therapy.

Therapy-specific recommendations for monitoring and follow-up include the following:

• For phenobarbital, measure blood levels every 6 months once the therapeutic range is achieved
• For potassium bromide, measure bromide blood levels 1 month after therapy is initiated and then 8 to 12 weeks later
• For zonisamide, perform routine physical examination and serum chemistries within 2 weeks of initiation therapy because of the risk of idiosyncratic hepatotoxicity

CANINE URINARY INCONTINENCE

Urinary incontinence is the loss of control of voluntary micturition, manifesting as dribbling of urine involuntarily while at rest or during sleep. Urinary incontinence may be caused by functional, neurologic, or congenital defects. The most common cause is urethral sphincter mechanism incompetence (USMI), in which the outlet mechanism in the urethra is weak. Acquired incompetent urethral sphincters are thought to be related to early spay and insufficient estrogen to ensure urethral competence. A recent investigation of spayed female dogs with USMI revealed that the risk for the condition decreased with every 3 months of delay in neutering during the first year of life.¹¹

Treatment Options

Treatment of urinary continence in female dogs relies heavily on estrogen replacement. The synthetic estrogens estriol and diethylstilbestrol (DES) increase the responsiveness of urethral smooth muscle to nervous (norepinephrine) control, thereby increasing muscle tone in the bladder neck and urethra.

The sympathomimetic amine phenylpropanolamine is used for males as well as for females refractory to estrogen treatment. Phenylpropanolamine is believed to stimulate norepinephrine release by acting indirectly on both α-adrenergic and β-adrenergic receptors of smooth muscle, resulting in increased tone of the urethra, bladder neck, and internal urethral sphincter.

Dosing information for the drugs used to treat canine urinary incontinence is summarized in Table 6. Pharmacists may recall that two of these drugs (DES and phenylpropanolamine) were withdrawn from the human market for safety reasons. Caregivers should exercise caution when handling these medications.

Dogs with incontinence may suffer urine scalding of the skin until drug therapy takes effect. The perineal area and inner thighs should be kept clean and dry to prevent urine scald. Owners should be warned not to use diaper rash products without first consulting a veterinarian; many products (eg, vitamin A & D ointment, zinc oxide, ointments containing menthol or camphor) contain ingredients that can be toxic if ingested.

Estriol
Estriol is FDA-approved for use in dogs (Incurin^®). It should not be used in male dogs or pregnant female dogs.

Estriol is available as 1-mg tablets. The starting dosage for all dogs is 2 mg (2 tablets) orally once daily for a minimum of 14 days. After urinary incontinence is controlled, the lowest effective daily dose should be determined. This is accomplished by decreasing the dose in a stepwise manner—from 2 mg (2 tablets) once daily to 1 mg (1 tablet) once daily, then to 0.5 mg (½ tablet) once daily—depending on the response of the individual dog. A minimum of 7 days should elapse between each dose adjustment. After the lowest effective daily dose is identified, the dose may be decreased further by administering estriol once every 2 days.

Dogs should not receive more than 2 mg (2 tablets) of estriol per day. If the dog does not respond to a dosage of 2 mg per day, the diagnosis should be reassessed.

The most common adverse effects of estriol therapy are lack of appetite, vomiting, increased thirst, and swollen vulva. Estrogens (including estriol) may induce heat cycles in intact female dogs. Although estrogens carry a risk of myelosuppression in dogs, the risk appears to be low with estriol because of its short duration of action. Nonetheless, owners should contact a veterinarian immediately if the dog becomes lethargic, shows bruising, or has a fever > 104°F. Estriol should be used with caution in dogs with hepatic disease. If administered concomitantly with a corticosteroid, estriol may inhibit metabolism of the steroid or displace it from plasma proteins, necessitating adjustment of corticosteroid dosing.

Diethylstilbestrol
DES had been approved for use in humans, but it was withdrawn from marketing in 1975 after it was linked to cancers and birth defects in treated women and their offspring. No dosage forms are commercially available for use in humans or animals; DES typically is compounded in patient-specific gelatin capsules for veterinary use. DES should not be used in male dogs or pregnant female dogs.

DES therapy is initiated with an induction dosage of 0.5-1 mg (0.02 mg/kg) daily for 3 to 5 days. The daily dose should not exceed 1 mg. After the induction period, the dosing frequency is decreased to every other day, and the dose is decreased to the lowest effective dose that maintains continence. Some dogs benefit from combination therapy with phenylpropanolamine.

Estrogens may induce heat cycles in intact female dogs. Estrogens carry a risk of myelosuppression in dogs, especially at higher doses; owners should contact a veterinarian immediately if the dog becomes lethargic, shows bruising, or has a fever > 104°F. Because of the risks in humans, caregivers who are pregnant or trying to become pregnant should avoid contact with DES. Estriol may be a better choice for dogs in these households.

Phenylpropranolamine
Phenylpropanolamine is FDA-approved for use in dogs (Proin^®). It is available as liver-flavored chewable tablets. Although phenylpropanolamine was approved for use in humans as an anorectic and decongestant, it has not been available since 2005, when it was shown to be an independent risk factor for hemorrhagic stroke.

The usual dosage of phenylpropanolamine in dogs with urinary incontinence is 2 mg/kg by mouth every 12 hours. Some dogs require administration every 8 hours; others are well-controlled with once-daily administration.

Common adverse effects of phenylpropanolamine therapy include transient dose-related vomiting, anorexia, restlessness, anxiety, irritability, urine retention, tachycardia, and hypertension. Phenylpropanolamine should be used with caution in dogs with glaucoma, prostatic hypertrophy, hyperthyroidism, diabetes mellitus, cardiovascular disorders, kidney insufficiency, or hypertension.

Monitoring and Follow-Up

Dogs treated with estrogens should be monitored for signs of bone marrow suppression (bleeding, bruising, fever, infection) within the first few weeks of therapy and after dosage increases. Veterinarians recommend routine blood pressure monitoring for dogs treated with phenylpropanolamine.

CANINE CARDIOVASCULAR DISEASE

The most important canine cardiovascular disease is chronic mitral valvular disease, also known as canine chronic valvular heart disease (CCVHD). It affects 85% of dogs 13 years of age or older and accounts for 75% of canine heart disease.¹² CCVHD sometimes is referred to as endocardiosis, myxomatous valve degeneration, or mitral regurgitation.

CCVHD commonly affects the mitral valve (left atrioventricular valve), although some cases also involve the tricuspid valve. The specific etiology is unclear. Mechanical valve stress causes mitral valve deterioration; chemical and hormonal signaling causes normal valve interstitial cells to morph into myofibroblast-type cells that produce degenerative changes in the valve. Early lesions manifest as nodules on the free margins of the valve. Redundant tissue forms, resulting in prolapse toward the atrium. Valves slowly begin to leak, and the process eventually culminates in mitral regurgitation.

Males of smaller breeds have a higher risk than large breeds. Breeds at particular risk include Poodles, Yorkshire Terriers, Pugs, Pomeranians, Miniature Schnauzers, Chihuahuas, Fox Terriers, Cocker Spaniels, Boston Terriers, Miniature Pinschers, Lhasas, and Cavalier King Charles Spaniels. Prevalence is greatest among middle-aged and older dogs; disease severity increases with age.

Many dogs with CCVHD remain asymptomatic for years. When clinical signs appear, they include decreased exercise tolerance, pulmonary congestion, edema, and cough. Syncope and collapse may occur in advanced disease.

Prognosis depends on early diagnosis and owner commitment to adherence and monitoring. A reasonable quality of life can be achieved with drug therapy and dietary management.

Treatment Options

The American College of Veterinary Internal Medicine (ACVIM) convened a panel in 2009 to develop consensus guidelines for CCVHD.¹² Treatment of CCVHD historically has been controversial; to help gain agreement on treatment guidelines, the ACVIM consensus group developed a classification of heart disease and heart failure for dogs (Table 7). The classification is based on similar classification systems for human disease from the New York Heart Association (NYHA) and the American College of Cardiology. Complete consensus could not be reached for treatment of all stages of heart disease and failure in dogs. Nevertheless, it is important for pharmacists to appreciate the classification systems used by veterinary cardiologists and understand the rationale for the recommended drug therapies.

Dogs in Stages A and B1 are monitored for changes in heart size or appearance of symptoms, but they generally do not receive drug therapy. Treatment of dogs in Stage B2 is controversial: some veterinarians believe that pharmacologic therapy will slow progression of the disease, while others do not. Dogs in Stage C receive drug therapy to increase the efficiency of the damaged heart, based on the severity of heart failure. Therapy may include diuretics, inotropes, ACE inhibitors, vasodilators, antiarrhythmics, and potentially spironolactone or digoxin. Dogs in Stage D remain on Stage C therapies at optimized (usually increased) doses and dosing intervals. Dogs in Stage D also may receive sildenafil for pulmonary hypertension, as well as bronchodilators and cough suppressants to manage intractable coughing associated with end-stage heart failure.

Pimobendan is a positive inotrope unique to veterinary medicine. In one study involving dogs suffering from congestive heart failure secondary to CCVHD, treatment with pimobendan conferred increased time before therapy was intensified and resulted in smaller heart size, higher body temperature, and less retention of free water.¹³

Dosing information for the drugs used to treat CCVHD is summarized in Table 8. The interested reader is encouraged to consult the ACVIM guidelines for specific stage-based dosing.

Furosemide
Furosemide tablets are FDA-approved for use in dogs and available from several manufacturers. An injectable solution (50 mg/mL) also is FDA-approved for use in dogs (Salix^®); some veterinarians prescribe subcutaneous administration of the injectable solution. Use of an appropriately buffered injectable product as described below is recommended to avoid pain on injection.

The usual dosage of furosemide in dogs is 2 mg/kg by mouth every 12 hours. Because the dosage is titrated to maintain patient comfort, the actual dosage may be as low as 1 mg/kg every 48 hours or as high as 4-6 mg/kg every 8 hours. The need for a dosage > 6 mg/kg every 8 hours indicates a transition to Stage D.

The dose of furosemide usually is titrated upward, with attention to effects on renal function and electrolyte status. High doses may cause hearing loss in dogs.

Formulations of furosemide injection for veterinary use have pH values in the range of 3.5 to 9. If furosemide will be administered by subcutaneous injection, a solution with a pH close to neutral (pH ~7) should be used to avoid discomfort and irritation at the injection site.

Owners should provide plenty of fresh drinking water for dogs treated with furosemide.

Enalapril
Enalapril tablets are FDA-approved for use in dogs but no longer manufactured in the United States. (Owners may be able to obtain tablets in Canada or from Internet pharmacies.) USP has developed a validated compounded preparation monograph for enalapril 10 mg/mL oral suspension for veterinary use.

The usual dosage of enalapril in dogs is 0.5 mg/kg by mouth every 12 hours. Dogs may experience transient vomiting and inappetence when therapy is initiated.

Serum creatinine and electrolyte concentrations should be measured 3 to 7 days after therapy is initiated to assess effects on glomerular filtration rate.

Pimobendan
Pimobendan chewable tablets are FDA-approved for use in dogs (Vetmedin^®). The usual dosage for the treatment of congestive heart failure is 0.25-0.3 mg/kg by mouth every 12 hours.

Adverse effects of pimobendan therapy are transient and mostly GI in nature. Vomiting, diarrhea, and inappetence are seen most commonly.

Spironolactone
Spironolactone approved for humans is used off-label for the treatment of dogs with CCVHD. The usual dosage is 0.25-2 mg/kg by mouth every 12 to 24 hours for aldosterone antagonism (not diuresis).

Adverse effects of spironolactone therapy are transient and include vomiting, diarrhea, and inappetence. Spironolactone should not be used in dogs with hyperkalemia or Addison’s disease.

Digoxin
Digoxin approved for humans is used off-label for the treatment of dogs with CCVHD. An oral elixir (0.05 mg/mL) that had been approved for use in dogs is no longer commercially available.

The use of digoxin in dogs currently is limited to controlling heart rate in atrial fibrillation or as an inotrope in dogs with congestive heart failure when financial constraints exist. The usual dosage is 2.5-5 μg/kg by mouth every 12 hours, with a target therapeutic range of 0.8-1.5 ng/mL 8 hours after the last dose.

Adverse effects of digoxin therapy are transient and include vomiting, diarrhea, and inappetence. Return of these signs after initial resolution may indicate drug toxicity.

Diltiazem
Diltiazem approved for humans is used off-label to control atrial fibrillation in dogs with CCVHD. Any of the currently available formulations—regular release, controlled delivery, and extended release—may be prescribed for dogs. It is critical that the correct dosage form and release profile be confirmed with the prescriber.

The usual dosage of diltiazem regular-release tablets in dogs is 0.5-1.5 mg/kg by mouth every 8 hours. The usual dosage of controlled-delivery and extended-release formulations is 3-5 mg/kg by mouth every 12 hours. Extended-release capsules may be opened to reveal individual 60-mg, extended-release tablets within; caregivers are instructed to open the capsule and administer tablets or fractions of tablets to achieve the required dose.

Bradycardia is the most common adverse effect of diltiazem therapy in dogs.

Sildenafil
Sildenafil approved for humans is used off-label to control pulmonary hypertension in dogs with CCVHD. The usual dosage is 1-2 mg/kg by mouth every 8 to 12 hours.

Adverse effects of sildenafil therapy are transient and include cutaneous flushing and GI upset. Sildenafil should not be used concomitantly with nitrates (nitroprusside or nitroglycerin).

Hydrocodone Bitartrate
Hydrocodone bitartrate approved for humans is used off-label for cough suppression in dogs with CCVHD. The usual dosage is 0.2-0.5 mg/kg by mouth every 6 to 12 hours; dosages as high as 1 mg/kg by mouth every 6 hours have been used. The goal of therapy is to suppress cough without causing excessive sedation.

Dogs in Stage C or D with cough can have an improved quality of life with antitussive therapy. However, hydrocodone bitartrate is a Schedule II controlled substance. Pharmacists may become concerned about frequent and early refills as the dosage increases. Pharmacists are encouraged to consult with prescribers to verify legitimate use.

Butorphanol Tartrate
Butorphanol tartrate tablets and injection are FDA-approved for use as an antitussive in dogs (Torbutrol^®). The usual dosage is 0.5 mg/kg by mouth every 6 to 12 hours. The goal of therapy is to suppress cough without causing excessive sedation. Dogs with ABCB1 (MDR1) mutations may experience profound sedation; the dosage of butorphanol tartrate should be reduced by 25% in dogs heterozygous for the MDR1 mutation and 30% to 50% in dogs homozygous (mutant/mutant) for the mutation.

Butorphanol tartrate is a Schedule IV controlled substance. It is possible that the easier refill process (compared with hydrocodone bitartrate) may encourage and facilitate owner adherence to drug administration.

Monitoring and Follow-Up

Monitoring and follow-up for dogs with CCVHD depends on disease stage, clinical signs, and specific drug therapy. In general, owners are instructed to monitor the dog’s resting heart rate (goal < 200 bpm) and respiratory rate (goal < 40 breaths/min) at home.

Dogs treated with digoxin need to have serum digoxin concentrations monitored to ensure they are within the target therapeutic range.

REFERENCES

1. American Pet Products Association. Pet industry market size & ownership statistics. https://americanpetproducts.org/press_industrytrends.asp. Accessed November 5, 2019.
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3. Thyro-Tabs Canine [package insert]. Shenandoah, IA: Lloyd, Inc; 2016. http://www.lloydinc.com/media/filer_private/2016/02/16/tt_1000_ct_insert_web_021116b_2.pdf. Accessed November 5, 2019.
4. Kuna S. The pH of gastric juice in the normal resting stomach. Arch Intern Pharmacodyn Ther. 1964;152:79-97.
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10. Schwartz M, Muñana KR, Olby NJ. Possible drug-induced hepatopathy in a dog receiving zonisamide monotherapy for treatment of cryptogenic epilepsy. J Vet Med Sci. 2011;73(11):1505-1508.
11. Byron J, Taylor K, Phillips G, Stahl M. Signalment and diagnosis of 205 neutered female dogs with urinary incontinence in the United States. In: Proceedings from the 2015 American College of Veterinary Internal Medicine Forum; June 3-6, 2015; Indianapolis, IN.
12. Atkins C, Bonagura J, Ettinger S, et al. Guidelines for the diagnosis and treatment of canine chronic valvular heart disease. J Vet Intern Med. 2009;23(6):1142-1150.
13. Häggström J, Boswood A, O’Grady M, et al. Longitudinal analysis of quality of life, clinical, radiographic, echocardiographic, and laboratory variables in dogs with myxomatous mitral valve disease receiving pimobendan or benazepril: the QUEST study. J Vet Intern Med. 2013;27(6):1441-1451.

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