Risa M. Roland, DVM, DACVIM (Cardiology); Sonya G. Gordon, DVM, DVSc, DACVIM (Cardiology)
Animals that develop significant heart disease often receive multiple classes of cardiovascular medications. This is especially true of animals are being treated for cardiovascular decompensation (forward and backward heart failure). Not only do cardiovascular drugs have their own list of side effects, these drugs often have significant interactions with each other. In addition, pre-existing co-morbidities may further complicate potential side effects and interactions. The goal of therapy is to help relieve clinical evidence of disease with minimal side effects. Knowledge of the possible side effects, drug interactions as well as the benefit of a drug's use may help with the risk-benefit ratio and help guide appropriate therapy. The following is a case-based discussion to illustrate three common classes of side-effects and interactions of common cardiovascular drugs used for hemodynamically significant heart disease.
Triple Diuretic Therapy
Signalment: 14-year-old, female spayed Shih Tzu, named Sheila. Sheila was diagnosed with severe chronic valvular disease with left-sided congestive heart failure 1½ years ago. Sheila has been maintained on enalapril 0.5 mg/kg PO BID, pimobendan 0.3 mg/kg PO BID, spironolactone 1 mg/kg PO BID and lasix. Initially, Sheila received 2 mg/kg PO BID but as her cough increased in frequency and severity, or she was found to have pulmonary venous congestion and/or mild edema on recheck visits, her lasix dose was increased. She also had one emergency trip to the hospital (5 months ago) where she had moderate pulmonary edema; her maintenance lasix dose was increased again at that time. Upon discharge during that visit, Sheila's owners were instructed to take nightly resting respiratory rates and to call if the rate was higher than her normal rate. Sheila presents to the hospital today for a recent exacerbation of cough and the owners have noticed that her resting respiratory rate is 44 breaths per minute (and since her last emergency visit, her respiratory rate has been 28 breaths per minute). She is currently receiving the above medications and her current dose of lasix is 4.5 mg/kg PO TID. Sheila is current on heartworm medication as well as flea and tick prevention, is up to date on vaccinations and eats a senior prescription diet. Physical examination revealed a BAR dog with a temperature of 101.2 degrees, a heart rate of 170 beats per minute, and a respiratory rate of 48 breaths per minute. Respiratory character was normal. She had a grade 5/6 left apical systolic murmur, strong, synchronous pulses, pink mucous membranes with a capillary refill time < 2 seconds, no abdominal distension or jugular venous distension or pulses. Lung auscultation revealed moderately increased bronchovesicular sounds over all lung fields. Diagnostic evaluation included thoracic radiographs, a blood pressure, PCV/TS, chemistry panel and electrolytes. Radiographs revealed cardiomegaly similar to previous studies (VHS= 12.4) with evidence of severe left atrial and left ventricular enlargement, mainstem bronchial compression, pulmonary venous congestion and mild pulmonary edema in the perihilar and caudo-dorsal lung fields. Blood pressure was 110 mm Hg and chemistry panel revealed a BUN of 38 with a creatinine of 1.2.
Given these results it is clear that Sheila requires additional diuretic therapy to maintain a euvolemic state and keep her free of signs of congestion and edema. One approach is to alter the delivery of the lasix (e.g., deliver it via the subcutaneous route at home as opposed to the oral route), if there is a possibility that the drug is not being absorbed appropriately, one recognized cause of diuretic resistance. Another method to improve diuresis is to employ sequential nephron blockade. Sequential nephron blockade involves the addition of diuretic agents of different classes to the original drug regimen to provide additional diuresis that the individual diuretic alone would not provide. In general, when a lasix dose of 4-5 mg/kg PO TID (Sheila's dose is in this range) is no longer sufficient to control signs of congestion and edema there is little use in increasing the oral dose any further. Additional diuresis may however be achieved through the addition of hydrochlorothiazide. The use of a thiazide diuretic as monotherapy does not typically provide significant diuresis, however the combination of the two drugs is potent, particularly following chronic monotherapy with lasix. (Note: for the purpose of this discussion spironolactone should not be considered a diuretic as its diuretic affects are minimal alone or in combination) With this added benefit of diuresis comes significant side effects and precautions must be taken to avoid clinically significant side effects/drug interactions.
Side effects of lasix alone include; hypovolemia, azotemia and electrolyte and acid base imbalances (in particular hypokalemia). Dogs like Sheila that receive lasix in addition to spironolactone (aldosterone antagonist), may have less of a risk of the development of clinically significant hypokalemia due to its potassium-sparing effects. However, spironolactone's potassium sparing effects are typically not sufficient to avoid the degree of hypokalemia that occurs when a thiazide diuretic is added to the combination chronic high dose lasix and spironolactone. Additionally, the relative risk of diuretic induced azotemia is potentiated by the addition of a thiazide diuretic. Hyponatremia and hypochloremia are also expected and no specific therapies are recommended as these changes are typically clinically insignificant. Thus in our clinic, when a thiazide diuretic is added to the drug regimen, the lasix dose is decreased by approximately 50% and potassium supplementation is initiated. Typically the lasix dose is reduced from 4-5 mg/kg PO TID to 3-3.5 mg/kg BID or 2-2.5 mg/kg TID, spironolactone is left at the same dose and hydrochlorothiazide is initiated at 2mg/kg BID. The risk of significant azotemia, hypokalemia and dehydration must be viewed in terms of the benefit of alleviated of edema that if not treated will be fatal and or is contributing to a poor quality of life.
Sheila was started on 2 mg/kg hydrochlorothiazide, her lasix dose was decreased to 2 mg/kg PO TID, she was started on Tumil K and all other medications were kept the same. Initiation of a severely restricted cardiovascular diet was not elected as it had already been previously tried and refused by Sheila. Sheila returned for a recheck 5 days later. The owners reported that she had a resting respiratory rate of 28 breaths per minute and she was eating and drinking well. Her cough returned to the frequency and duration that it had been prior to the visit 5 days previously. Physical exam was essentially unchanged except for a heart rate of 148 beats per minute and a respiratory rate of 40 breaths per minute SPACE with a normal respiratory character. A PCV/TS, chemistry panel and electrolytes as well as repeat thoracic radiographs were obtained. Thoracic radiographs revealed resolution of the mild pulmonary edema and normalization of the pulmonary venous size. PCV/TS were 47%/7.2 g/dL and BUN was 44 mg/dL with a creatinine of 1.4 mg/dL. Chloride was 98 mEq/L and sodium was 135 mEq/L. Potassium was 3.4 mEq/L.
Non-Steroidal Anti-Inflammatory Drugs (NSAIDS)
Signalment: 6-year-old MC Great Dane, named Charlie. Charlie was diagnosed with preclinical (asymptomatic) dilated cardiomyopathy 2 years ago and he was placed on enalapril 0.5 mg/kg PO BID and directed to continue his fish oil supplement, heartworm preventative and prescription senior. Six months ago, Charlie developed left-sided congestive heart failure and he was started on lasix 2 mg/kg PO BID, pimobendan 0.3 mg/kg PO BID and spironolactone 0.5 mg/kg PO BID. His bloodwork since the initiation of heart failure therapy has revealed mild azotemia (BUN 33 mg/dL; creatinine 1.9 mg/dL, UPC <1). On recheck evaluation for his heart disease, Charlie was found to be BAR, have a body condition score of 4/9, a Grade 2/6 left apical systolic murmur, strong pulses and pink mucous membranes with a capillary refill time < 2 seconds. No evidence of jugular distension or pulsation and no evidence of abdominal distension was noted. Lungs were clear in all fields. He was mildly lame on his right hind limb and orthopedic evaluation and radiographs revealed right-sided stifle pain with some evidence of degenerative joint disease on radiographs. The orthopedist suggested the initiation of an NSAID. As dogs with significant cardiovascular disease inherently have decreased cardiac output, they are at an increased risk of renal insufficiency regardless of the medication s that they are receiving. Angiotensin converting enzyme inhibition (ACEI) leads to a decrease in circulating angiotensin II. Angiotensin II is normally renoprotective through augmentation of auto regulation of glomerular filtration rate (GFR). Thus, ACEI can lead to azotemia. The combination of low cardiac output, ACEI and the addition of medications (such as diuretics) that serve to decrease blood volume all pose an important risk to the kidneys. Finally, older dogs may have chronic renal disease as co-morbidity, the volume state and drug interactions can lead to significant renal dysfunction leading to clinically significant azotemia. Despite these risks, the use of ACEI is generally well tolerated and has been shown to reduce morbidity and mortality in dogs with dilated cardiomyopathy and congestive heart failure and may reduce the progression of preclinical disease to clinical disease.1,2 Thus, clinically, the beneficial use of ACEI is accepted as outweighing the risks. The benefit may not outweigh the risks if an NSAID is added to the drug regimen. The kidneys are protected to an extent by prostaglandins as the prostaglandins aid in maintaining GFR by maintaining renal blood flow.3 The addition of a NSAID to the drug regimen may have significant renal consequences, including acute renal failure as the protective properties of the prostaglandins are eliminated by the NSAID.3,4 One options to help palliate Charlie's orthopedic pain includes the use of a different class of drugs such as opioids and or the use of complimentary therapy such as adequan injections, oral cosequin supplementation, acupressure or acupuncture. For palliation of neurologic pain gabapentin may be particularly useful and well tolerated. In the event Charlie was obese weight loss could also have been considered. Alternatively, a reduction in the ACEI dose may be initiated prior to the use of an NSAID. The best way to ensure a low dose of ACEI is to use benazepril as it is cleared predominantly through the liver in contrast to enalapril which is cleared renally make delivery of a low dose in the face of azotemia difficult or impossible. In Charlie's case we could have switched to benazepril and lowered the dose to 0.15 mg/kg SID. The dose of benazepril could then be increased overtime pending recheck of renal function. Additionally, if his azotemia was more significant and the need for a NSAID was required to maintain quality of life we could have discontinued the ACEI initiated the NSAID and recheck blood work and then considered reintroduction of benazepril at a low dose as outlined previously. Charlie was sent home with adequan injections and a prescription for tramadol and his orthopedic pain was palliated.
Signalment: 10-year-old MC Cavalier King Charles Spaniel, named Cecil. Cecil was diagnosed with chronic valvular disease at 5 years of age. He developed left-sided congestive heart failure at 8 years of age and is currently maintained on lasix 3 mg/kg PO TID, pimobendan 0.3 mg/kg PO BID, spironolactone 0.5 mg/kg PO BID, benazepril 0.5 mg/kg PO BID and theophylline 15 mg/kg PO BID (for mainstem bronchial compression). Cecil presented to the emergency clinic for lethargy and a possible fainting episode (the owner heard a crash, found him on his side, but by the time they reached him he has risen and was walking towards them). Physical examination revealed a QAR dog, with a grade 6/6 left apical systolic murmur, heart rate of 220 beats per minute with an irregular/chaotic rhythm. Pulses were weak and varied in intensity with frequent pulse deficits. Lungs were clear in all fields with a respiratory rate of 60 breaths per minute. Respiratory character was normal. No jugular pulsation or distension or abdominal distension was noted. Thoracic radiographs revealed severe generalized cardiomegaly (VHS= 14.4) which was similar to the last study. The pulmonary veins were not distended and there was no evidence of pulmonary edema. Blood pressure was variable and ranged from 80-100 mm Hg. An electrocardiogram revealed atrial fibrillation at a rate of 220-240 beats per minute. Blood work revealed a BUN of 28 mg/dL with a creatinine of 1.2 mg/dL. Electrolytes were within the normal range with the potassium at the lower end of normal. Digoxin was initiated at a dose of 0.20 mg/m2 PO BID. Cecil was sent home on this dose of digoxin and scheduled for a recheck in 3 days. At this visit, the owner reported that Cecil had lost his appetite and had developed diarrhea. On physical examination, the heart rate had decreased to 170-175 beats per minute and the rhythm was still irregular. Pulses were strong and synchronous with the heartbeat. Blood chemistry revealed mild hypokalemia as well as mild azotemia (BUN 42; creatinine 1.6). A digoxin level was obtained and, while awaiting the results, digoxin was discontinued for 2 doses and then restated at a reduced dose. Digoxin is a weak positive inotrope and an anti-arrhythmic and its current primary indications are for the treatment of supraventricular arrhythmias such as atrial fibrillation. It has a low therapeutic index and a high toxicity profile, which can cause significant side effects with only minimal changes in drug level; some dogs (particularity Dobermans) may even experience signs of toxicity when drug levels are in the normal range. Its side effects are numerous. It is pro-arrhythmic, and causes gastrointestinal upset such as; inappetence, anorexia, vomiting and diarrhea.5 Digoxin is predominately eliminated by the kidneys, thus it should be used cautiously in patients with renal insufficiency. Animals that are hypernatremic, hypokalemic, hypercalcemic, or have thyroid dysfunction may be more sensitive and may need smaller dosages. In addition, there are a number of potential drug-drug interactions with digoxin. Quinidine, amiodarone, diltiazem, cyclosporine, itraconazole, and spironolactone (which Cecil is currently taking) can lead to an increase in digoxin levels. The mechanism of this increase is thought to be due to inhibition of the P-glycoprotein digoxin transporter which is important for digoxin clearance. Cecil returned for a recheck evaluation 1 week later. The digoxin level from the previous visit revealed that the digoxin was above the therapeutic range. The owner reported that Cecil's appetite had improved, and the diarrhea had resolved, but he was still a bit lethargic. Physical examination revealed a heart rate of 175-180 beats per minute with decreased pulse quality. There were no pulse deficits noted. Amiodarone was added to the drug therapy regimen in an attempt to help control the heart rate with the existing dose of digoxin. Cecil returned for a recheck evaluation 2 weeks later. The owner reported that he was doing well, eating and drinking with no gastrointestinal upset. Physical examination revealed a heart rate of 140 beats per minute with an irregular rhythm and strong, synchronous pulses. Blood pressure was 110 mm Hg. A chemistry panel revealed a BUN of 32 mg/dL with a creatinine or 1.2 mg/dL. ALT was 567 U/L. Amiodarone is a Class III anti-arrhythmic that has use in the treatment of both ventricular and supraventricular arrhythmias. While the drug is very useful, it has multiple different side effects. Anorexia and vomiting are common side effects and are typically related to elevations in hepatic enzymes, most commonly elevations in ALT.6 The clinical signs and liver enzyme elevations typically resolve with time following discontinuation of the drug. Neutropenia has been reported with higher doses and decreased platelet numbers has been seen clinically as well.7 Platelet numbers reportedly normalize when the drug is withdrawn. In humans, its use can cause changes in thyroid status (both hypo and hyperthyroidism).6,7 In addition, in humans, the most significant side effect is the development of pulmonary fibrosis with high does chronic therapy, but to the best of the author's knowledge, this has not been reported in dogs. In addition, humans may develop a bluish color to the skin. This has not been reported in dogs. Due to the ALT elevations, the amiodarone was discontinued. Cecil was stared on 7.5 mg diltiazem in an effort to help control the ventricular response rate. He was sent home with instructions to watch for signs of gastrointestinal upset due to the interaction of diltiazem and digoxin. Cecil returned for a recheck evaluation 2 weeks later. The owner reported a normal appetite and no gastrointestinal upset. Physical examination revealed a heart rate of 130-140 with an irregular rhythm and strong, synchronous pulses. Blood work revealed a normalizing ALT, a BUN of 38 mg/dL and a creatine of 1.4 mg/dL. Complications are common with antiarrhythmic therapy and management of clinically significant arrhythmias such as atrial fibrillation typically require 2 or more antiarrhythmics compounding the potential for side effects and underlining the importance of re-evaluations.
The frequency of significant adverse drug side effects and drug interaction varies on an individual basis. As some of these side effects and drug interactions may cause clinical manifestation of disease, in an effort to minimize clinical adverse effects and to maximize positive effects, knowledge of drug side effects as well as drug-drug interactions is prudent. The clinician's job is to provide the best drug choice for the individual patient, while always maximizing the benefits and minimizing risks. Additionally, anticipation of unwanted side-effects and careful surveillance to note the presence of unwanted side effects is prudent in every case.
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2. Ettinger SJ, et al. J Am Vet Med Assoc 1998;213:1573-1577.
3. Trepanier LA, et al. J Vet Emerg Crit Care 2005; 15(4): 248-253.
4. Curry SL, et al. J Am Anim Hosp Assoc 2005;41:298-309.
5. Gordon SG, Kittleson MD in Small Animal Clinical Pharmacology 2nd edition. Saunders Elsevier, Edinburg 2008. pp. 380-457.
6. Bicer S, et al. J Vet Intern Med 2002;16:247-254.
7. Saunders AB, et al. J Vet Intern Med 2006;20:921-926.