Beginners guide to cardiac pharmacology

Until fairly recently, drugs used in cardiac medicine were limited to treating clinical signs of heart failure as they occurred, or for the management of arrhythmias. However, advances in canine drug therapy mean that patients with heart disease can now be treated before they develop symptoms, thereby prolonging survival time. Drugs used in the treatment of heart disease and failure can be split into three categories depending on their mode of action. They either remove excess fluid, promote cardiac contractility or inhibit the neurohormonal response activated in heart failure. Anti-arrhythmic drugs are divided into those that treat tachyarrhythmias and those that treat bradyarrhythmias. All drugs used in cardiac medicine can have deleterious effects and require routine monitoring; however, anti-arrhythmics have the potential to cause or worsen arrhythmias, and therefore need extra caution and careful observation.

What is heart disease and heart failure?

Heart disease is defined as any abnormality of cardiac structure or function. Heart failure is said to occur when clinical signs of increased tissue water and/or decreased tissue perfusion are present. The primary function of the heart is to maintain adequate blood pressure (see Figure 1). If for any reason cardiac output is compromised leading to a fall in blood pressure, two compensatory mechanisms are activated, in an attempt to normalise it (see Table 1). These compensatory mechanisms are the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS) (also known as the neurohormonal system). They act by increasing fluid retention, increasing vasoconstriction, and stimulate the heart to increase heart rate, all aimed at improving cardiac output. However, if arterial blood pressure cannot be normalised despite maximal activation of compensatory mechanisms, then low output heart failure will occur. Sometimes the fall in output is so acute that compensatory mechanisms have had insufficient time to activate, which may be seen with some arrhythmias or myocardial infarction. Although life saving in the short term, long-term stimulation of compensatory mechanisms causes progressive deterioration of cardiac function due to fatigue of the heart muscle. Patients can either present in acute life-threatening heart failure or with chronic heart failure. Figure 2 shows a cat open mouth breathing due to acute heart failure. For clinical signs of both, see Table 2.

Therapeutic management of heart disease and heart failure

The American College of Veterinary Medicine (ACVIM) published a consensus statement in 2009 (Atkins et al, 2009), which classified heart disease into different stages. Although this statement was designed to categorise chronic mitral valve disease (MVD), it can be applied to cardiac disease in general. This statement has been recently been updated to reflect recent advances in diagnosis and treatment of canine heart disease (Keene et al, 2019). Table 3 shows the stages of heart disease as identified by the consensus statement. Up until fairly recently, treatment was only indicated when dogs reached stage C, the point where conges tive heart failure (CHF) has developed. This is significant because statistics show that survival times when dogs reach stage C are poor. Dogs diagnosed with dilated cardiomyopathy (DCM) and CHF were reported to have an average survival time of 2–4 months (Martin et al, 2010), and dogs diagnosed with MVD and CHF had a mean survival time of less than 1 year (Häggström et al, 2008). However, in the last decade two studies have shown that the administration of pimobendan before CHF develops prolongs survival time. The PROTECT study (2012) showed that onset to CHF was prolonged by 9 months when pimobendan was administered to dogs with pre-clinical DCM (Summerfield et al, 2012). The EPIC trial (2016) showed that pimobendan prolonged survival time in dogs with MVD by 60% in the stage B2 class, resulting in an additional 462 days before developing heart failure (Boswood et al, 2016). There is no evidence that any drug is beneficial to cats before they develop heart failure (Kittleson, 2014).

Drugs effective in the treatment of heart failure fall into the following groups:

• Natriuresis and diuresis — drugs in this group promote sodium and water excretion via the kidneys
• Contraction and relaxation of the myocardium — these drugs improve the pumping action of the heart
• Antagonise the deleterious neurohormonal messengers that are activated in heart failure and result in its progression.

The aim of drug therapy in chronic heart failure is to control clinical signs in order to maintain as good a quality of life as possible for as long as possible. Figure 3 shows examples of drugs used in the management of heart disease and/or CHF in dogs. Treatment of acute life-threatening heart failure differs because the goal is to prevent certain death from respiratory compromise or cardiogenic shock.

Diuretics

There are different classes of diuretics that work on different parts of the nephron, and in the later stages of heart failure can be used as sequential nephron blockade to improve efficacy (Table 4). First line treatment is furosemide, which acts on the Loop of Henle, and is the most potent of the classes, which allows for the other classes to be added as and when needed. As patients can become refractory to diuretics over time, it is suggested that doses are titrated to the minimum effective dose, allowing room for manoeuvre (Luis Fuentes, 2010). There is no evidence to prove its efficacy, but it is considered irreplaceable in the treatment of CHF (Luis Fuentes 2010). A new loop diuretic has become available in veterinary medicine recently. Torasemide is more potent and has longer bioavailability than furosemide. The TEST (2017) study showed it was as good as furosemide and has the advantage of being a new treatment, if and when patients become refractory to furosemide (stage D). Another benefit is that it need only be given once daily due to its longer acting properties, in comparison to furosemide which requires dosing two or three times a day (Chetboul et al, 2017). Other classes include potassium sparing diuretics, such as spironolactone which work on the collecting duct, and thiazides like hydrochlorothiazide, that work on the distal convoluted tubule. Spironolactone also has aldosterone agonist properties, so is also used for neurohormonal blockade.

Diuretics are indicated for use in most cases with CHF. However, in cases of pericardial effusion or large pleural effusions, thoracocentesis or pericardiocentesis may be recommended instead of, or in addition to, standard diuretic therapy. Adverse effects from diuretic use include polyuria, polydipsia, hypokalaemia, increased urea and continued activation of the RAAS. Regular blood tests should monitor renal and electrolyte parameters to avoid over diuresis.

Positive inotropes

Pimobendan

Positive inotropes, such as pimobendan, increase the contractility or pumping action of the myocardium. Pimobendan also has vasodilatory effects which counteract RAAS activation. As already discussed, pimobendan is now indicated for pre-clinical DCM and stage B2 MVD, but is still useful and licensed for dogs in stage C. It is available in an injectable form as well as oral, which makes it useful for the anorexic patient.

Digoxin

Digoxin is a weak positive inotrope compared with pimobendan and is more commonly used to treat supraventricular arrhythmias like atrial fibrillation, as it decreases heart rate allowing for an improvement in cardiac filling. It has a narrow therapeutic window, and adverse effects include gastrointestinal symptoms, bradyarrhythmias and tachyarrhythmias. Blood digoxin levels should be monitored regularly.

Neurohormonal blockers

Angiotensin converting enzyme (ACE) inhibitors

ACE inhibitors block the neurohormonal conversion of angiotensin I to angiotensin II. Angiotensin II is a hormone produced in heart failure, initiating vasoconstriction and sodium (and therefore water) retention. This means that ACE inhibitors are indicated in most cases where furosemide is prescribed. Examples of ACE inhibitors are enalapril, benazepril and ramipril. Adverse effects can be azotaemia and hypotension, therefore renal and electrolytes and blood pressure should be monitored regularly.

Aldosterone antagonists

Aldosterone is another hormone produced in heart failure. It has similar vasoconstriction and sodium retention effects as angiotensin II Table 4). Aldosterone is also a potassium sparing diuretic. An example of an aldosterone antagonist is spironolactone.

Beta adrenergic antagonists

More commonly known as beta blockers, beta adrenergic antagonists have limited use in veterinary cardiology. Extrapolating theory from human medicine to dogs, beta blockers should reduce heart rate, improving ventricular filling. However, the negative effects of this class can be disastrous because they decrease contractility of the heart, thereby exacerbating heart failure. Beta adrenergic antagonists are indicated for patients with severe congenital stenosis to decrease myocardial oxygen consumption (Martin and Dukes-McEwan, 2010). If they are used it is recommended to start at the lowest dose possible and slowly titrate to effect (Luis Fuentes, 2010). Careful monitoring by veterinary staff and owners is recommended, such as resting heart rate and exercise tolerance.

Drugs used in acute heart failure management

Suitable for administration in veterinary practices equipped with continuous electrocardiography (ECG) and access to direct blood pressure monitoring only, dobutamine and nitroprusside can be very beneficial in the short term for patients with forward or output failure. Dobutamine is a potent positive inotrope, increasing blood pressure quickly. Due to its short half-life, it must be given via continuous rate infusion (CRI). It is recommended that administration starts at the lowest dose and is then titrated to effect, using regular blood pressure monitoring to accurately assess its effect (BSAVA, 2011). The main adverse effect is tachyarrhythmias, so continuous ECG monitoring is required at all times. It is generally used for a maximum of 48 hours as its efficacy reduces after that time.

Nitroprusside is another drug used in the critical management of heart failure and is often used in conjunction with dobutamine. It is a potent vasodilator and is recommended for use in cases with acute life-threatening heart failure or refractory CHF. Either direct arterial monitoring or frequent non-invasive blood pressure monitoring is essential (BSAVA, 2011). Also given as a CRI, it should be titrated to effect and tapered towards the end of the infusion to prevent crashes in blood pressure. Nitroprusside is light sensitive, so the administration set and fluid bag should be protected from light (BNF, 2018). Adverse effects include cyanide toxicity which restricts its use to 24 hours maximum (BSAVA, 2011).

Glyceryl trinitrate is an ointment applied to the skin and is indicated for use in patients with acute pulmonary oedema. It is a vasodilator and works primarily as a venodilator. Application sites, such as the ear or groin, should be rotated and recorded. Gloves should be worn when applying because it can cause headaches in humans. Its efficacy has been questioned although it is still widely used (BSAVA, 2011).

Treatment of feline heart disease and heart failure

There is even less evidence supporting feline cardiac medicine, although there do seem to be some significant differences. Atenolol, a beta-adrenergic blocker received much attention in feline cardiology because of its potential for delaying the onset of CHF. As feline hypertrophic cardiomyopathy (HCM) appears to be similar to human HCM, atenolol could have the same effects in cats that it does in humans, where it is used as a cardio protectant. Atenolol was administered to cats because theoretically, it reduces heart rate, which would therefore increase ventricular filling time, thereby decreasing myocardial oxygen demand and reducing the possibility of arrhythmias (Jackson et al, 2015). However, there is evidence to show that it does not extend survival times in cats (Schober et al, 2013). Its use in CHF is not recommended because it could worsen clinical signs and increase the risk of aortic thromboembolism (ATE) by decreasing atrial contractility (Gordon and Côté, 2015).

Feline heart disease sometimes manifests in thrombus formation in the left atrial appendage of the left atrium. Fragments can dislodge into the distal aorta (blocking blood supply to one or both hindlimbs), into the right brachial artery, or to the kidneys and/or other organs. Clopidogrel and aspirin have been used in feline medicine to prevent platelet aggregation in those at high risk, or after a thromboembolic event. The FAT CAT study (2015) reported that clopidogrel was superior to aspirin in the management of feline ATE and was well tolerated (Hogan et al, 2015). Figure 4 is an example of drugs used in the management of feline heart failure.

Furosemide appears to be effective and well tolerated in cats, but as with dogs, there is no proof of its efficacy. Spironolactone is often used as a second diuretic in cats, especially when hypokalaemia is present. However, there are concerns with cutaneous reactions in cats (MacDonald et al, 2008). Given the longer-lasting effects of torasemide, it is suggested that it could be useful for refractory heart failure, or to improve both owner and/or cat compliance. However, concerns highlight the fact that longer effects may increase renal and electrolyte depletion (Gordon and Côté, 2015). Based on extrapolation from canine and human literature, ACE inhibitors should be helpful in preventing RAAS activation and useful in conjunction with diuretics. Current recommendations are that it should be used in stable cats but stopped if anorexia occurs (Gordon and Côté, 2015).

Another drug that warrants discussion in feline management is diltiazem. It is the only drug licensed for use in cats with HCM. This was based on one study that showed that diltiazem delayed the recurrence of CHF in cats with HCM (Bright et al, 1991). However, these results were based on a small study size and the drug had to be administered three times a day. Its efficacy could not be replicated with a sustained release form of the drug, and thrice daily dosing is undesirable in cats particularly if the results are questionable (Wall et al, 2005).

Pimobendan has potential benefit in cats because it could improve left atrial function and limit platelet aggregation, therefore reducing the risk of ATE formation. It could also improve myocardial relaxation allowing for improved cardiac output. However, it is not licensed for use in cats, and its pharmacokinetic properties act differently in cats than in dogs. Its half life in cats is three times longer, and its peak serum concentration is nine times higher than the same dose (mg/kg) in dogs (Gordon and Côté, 2015). Despite this, Kittleson (2014) reported that cardiologists use it in almost all cases of feline myocardial failure and concurrent CHF.

Drugs used in the treatment of arrhythmias

Anti-arrhythmic drugs are split into two groups: those that treat tachyarrhythmias and those that treat bradyarrhythmias. All anti-arrhythmic drugs have the potential to cause proarrhythmias, effectively worsening the existing arrhythmia, and therefore should be used with care and close monitoring. Drugs used to treat tachyarrhythmias can be used for both ventricular or atrial arrhythmias. The Vaughan-Williams classification of anti-arrhythmic drugs is useful in understanding tachyarrhythmic drugs (Table 5). Lidocaine is the most commonly used drug in the treatment of tachyarrhythmias because it works quickly, effectively and is relatively safe.

Drugs used in the treatment of bradyarrhythmias aim to increase heart rate and conduction from the atria to the ventricles, by stimulating the sinoatrial and atrioventricular nodes. They are indicated for use in arrhythmias such as atrioventricular block and sinus arrest. Table 6 outlines their mode of action.

Nursing considerations

Heart failure patients are extremely challenging for any nurse. Acute heart failure patients are unstable and undue stress can be extremely harmful. Chronic heart failure patients can also become unstable despite medication. Oxygen supplementation and minimising stress are recommended for those in respiratory crisis. Diuretics are usually indicated in life-threatening cases but where intravenous injection may be too stressful, intramuscular administration is acceptable (Ferasin and DeFrancesco, 2015). For patients with large pleural or pericardial effusions, thoracocentesis/pericardiocentesis might be indicated. Successful therapeutic management of heart disease relies on accurate and timely administration of medication. For veterinary nurses, this translates to good practice and cultivating a good relationship with owners and their pets. Owners should be aware of the rather restricted treatment aims of CHF, mainly to maintain quality of life. It is also important to consider owner and patient compliance when considering the numerous medications listed above. If administration is problematic, the veterinary surgeon should be informed, and the owner given a priority list of medication, and/or alternatives sought, such as combination drugs or liquid forms of the drug. Owners should be encouraged to count resting respiratory rate and effort and communicate that with veterinary staff, as some diuretics can be titrated at home. Owners should also be aware of the side effects with cardiac medications, such as increased polydipsia and polyuria with diuretic use, exercise intolerance, and anorexia. After initiation of drug therapy, patients often require blood tests to monitor renal and electrolyte parameters and regular blood pressure measurements. Nurse-led clinics are a great place to build communication, helping owners to maximise the time they have left with their pet.

Conclusion

Drug therapy is an important part of stabilising and managing patients with heart disease, arrhythmias and heart failure. Advances in veterinary medicine are occurring all the time, as the treatment of pre-clinical heart failure has shown. While drugs can be tremendously beneficial, they can have deleterious effects, or patients can become refractory to them. Nurses can create and maintain an important bond with owners and their pets, to help maintain quality of life.

KEY POINTS

• The aim of drug therapy in chronic heart failure is to control clinical signs, thereby maintaining quality of life for as long as possible.
• The treatment goal of acute life-threatening heart failure is to prevent certain death from respiratory compromise or cardiogenic shock.
• Anti-arrhythmia drugs can have a pro-arrhythmic effect, potentially worsening arrhythmias.
• Patients prescribed heart failure medication should have regular blood pressure measurements taken and renal and electrolyte parameters monitored.
• Patient and owner compliance are essential for successful treatment.