Pimobendan ( INN, or pimobendane; tradenames Vetmedin, Acardi) is a veterinary medication. It is a calcium sensitizer and a selective inhibitor of

phosphodiesterase 3 PDE3 is a phosphodiesterase. The PDEs belong to at least eleven related gene families, which are different in their primary structure, substrate affinity, responses to effectors, and regulation mechanism. Most of the PDE families are composed of ...

(PDE3) with positive

inotropic An inotrope is an agent that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions. Positively inotropic agents increase the strength of muscular contraction. The term ''inotro ...

and

vasodilator Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...

effects. Pimobendan is used in the management of

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...

in dogs, most commonly caused by myxomatous mitral valve disease (also previously known as endocardiosis), or dilated cardiomyopathy. Research has shown that as a monotherapy, pimobendan increases survival time and improves quality of life in canine patients with congestive heart failure secondary to mitral valve disease when compared with benazepril, an

ACE inhibitor Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of hypertension, high blood pressure and heart failure. They work by causing relaxation of blood vessels as well as a decrease i ...

. However, in clinical practice, it is often used in conjunction with an ACE inhibitor like enalapril or benazepril. Under the trade name Acardi, it is available for human use in Japan.

Mechanism of action

Pimobendan is a positive inotrope (increases myocardial contractility). It sensitizes and increases the binding efficiency of cardiac troponin in the myofibril to the calcium ions that are already present in systole. In normal hearts it increases the consumption of oxygen and energy to the same degree as dobutamine but in diseased hearts it may not. Pimobendan also causes peripheral vasodilation by inhibiting the function of PDE3. This results in decreased resistance to blood flow through systemic arterioles, which decreases

afterload Afterload is the pressure that the heart must work against to eject blood during systole (ventricular contraction). Afterload is proportional to the average arterial pressure. As aortic and pulmonary pressures increase, the afterload increases on ...

(decreases the failing heart's workload) and reduces the amount of mitral regurgitation.

Pharmacokinetics

Pimobendan is absorbed rapidly when given via the oral route and has a bioavailability of 60-65%. Bioavailability is markedly decreased when ingested with food. It is metabolized into an active metabolite (desmethylpimobendan) by the liver. The parent compound, pimobendan, is a potent calcium sensitizer while desmethylpimobendan is a more potent phosphodiesterase III inhibitor.Hanzlicek AS1, Gehring R, Kukanich B, Kukanich KS, Borgarelli M, Smee N, Olson EE, Margiocco M. "Pharmacokinetics of oral pimobendan in healthy cats." ''J Vet Cardiol''. 2012 Dec;14(4):489-96. The half-life of pimobendan in the blood is 0.4 hours, and the half-life of its metabolite is two hours. Elimination is by excretion in the bile and then feces. Pimobendan is 90–95% bound to plasma proteins in circulation. This may have implications in patients with low blood protein levels ( hypoproteinemia/ hypoalbuminemia) and in patients that are on concurrent therapies that are also highly protein bound.

Combinations

Pimobendan is often used in combination with three other drugs to palliate dogs with heart failure (pulmonary edema, pleural effusion, ascites). These are: * Furosemide, a diuretic, to reduce

edema Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's Tissue (biology), tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels t ...

and effusion. * Spironolactone, an

aldosterone antagonist An antimineralocorticoid, also known as a mineralocorticoid receptor antagonist (MRA or MCRA) or aldosterone antagonist, is a diuretic drug which antagonizes the action of aldosterone at mineralocorticoid receptors. This group of drugs is often u ...

. This has two actions, firstly, as a potassium-sparing diuretic, although its diuretic properties are small compared with those of furosemide. Secondly, it reduces aldosterone-mediated myocardial fibrosis, possibly slowing the progression of heart disease. *An

, often enalapril (trade name Enacard) or benazepril (Fortekor). These drugs inhibit the action of

angiotensin-converting enzyme Angiotensin-converting enzyme (), or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasoconstr ...

, producing a balanced vasodilation, along with other potentially favorable effects. Other drugs may also be used as required to manage certain arrhythmias that are often associated with heart disease.

Synthesis

The reaction between p-anisoyl chloride

00-07-2 The hyphen-minus is the most commonly used type of hyphen, widely used in digital documents. It is the only character that looks like a minus sign or a dash in many character sets such as ASCII or on most keyboards, so it is also used as such. ...

(1) an
CID:20516917
(2) gives 4- -[(4-Methoxybenzoyl)amino3-nitrophenyl">4-Methoxybenzoyl)amino.html" ;"title="-[(4-Methoxybenzoyl)amino">-[(4-Methoxybenzoyl)amino3-nitrophenyl3-methyl-4-oxobutanoic acid
CID:20516902
(3). The reaction of this with hydrazine gives 5-methyl-6-[3-nitro-4-(4-methoxy-benzoylamino)-phenyl]-3-oxo-4,5-dihydro-2H-pyridazine [74149-73-8]. Catalytic hydrogenation reduces the nitro group giving [74149-74-9] (4). cyclization of the resulting ortho amino amide by means of a strong acid leads to the formation of the corresponding benzimidazole. There is thus obtained pimobendan (5).

References

External links

Official Vetmedin Product Website
{{Vasodilators used in cardiac diseases Benzimidazoles Lactams PDE3 inhibitors Calcium sensitizers Inotropic agents Vasodilators Pyridazines Phenol ethers Dog medications