Some of the few drugs proven to prolong life in dogs. Many ACE inhibitors are available, there is no obvious difference between them apart from duration of action. Most of the modern ones are prodrugs.
The renin - angiotensin - aldosterone system (diagram)
is an important mechanism for maintaining blood pressure in the face of various
challenges. Renin release from the juxtaglomerular apparatus is stimulated by
a fall in blood pressure, reduced renal blood flow, reduced sodium concentration
in the distal tubule, increased renal sympathetic activity and a host of other
factors poorly understood. b agonists and PGI2 also stimulate renin production.
Atrial natriuretic peptide reduces renin production: angiotensin II does the
same, possibly by the same mechanism. Renin then converts angiotensinogen to
angiotensin I.
ACE inhibitors block the enzyme which converts angiotensin I to angiotensin
II. Most of their effects can be attributed to a reduction in ATII levels. ATII
produces most of its effects at the confusingly named AT1 receptors (see diagram).
ACE is also responsible for breaking down bradykinin which can act as a vasodilator
by stimulating PLA2 which results in the production of prostacyclin, and by
causing the release of nitric oxide from endothelial cells.
Most ACE is bound to the surface of endothelial cells, but it can occur in other
tissues such as cardiac muscle. ACE inhibitors tend to reverse the cardiac hypertrophy
seen in heart failure.
In normal healthy animals and people, ACE inhibitors have no effect after a
single dose and cause only a small drop in blood pressure after several days’
treatment. It seems likely that there has to be increased renin release (and
thus more ATI available for conversion to ATII) before ACE inhibitors have much
effect. Most dogs with congestive heart failure will have increased sympathetic
tone, and may also have reduced arterial blood pressure leading to increased
renin release. Some dogs may be on low salt diets in an attempt to cause sodium
depletion.
The end result in dogs with CHF is that there is a decrease in venous and diastolic
intra-cardiac pressure with a concurrent decrease in afterload and so a resultant
increase in cardiac output. They relax both capacitance and resistance vessels,
but preferentially affect the kidney heart and brain. They are often used with
diuretics such as frusemide (although frusemide probably has some vasodilator
action of its own), but the interactions can cause kidney failure (see below).
ACE inhibitors have their own mild diuretic and natriuretic effect.
The vasodilatation produced by increased bradykinin may also be important in
heart failure.
vasodilator in the treatment of congestive heart failure, especially valvular disease
hypotension in overdose
anorexia, vomiting and diarrhoea
at high doses glomerular lesions and renal failure (monitor BUN and serum creatinine)
may be induced
since they also inhibit aldosterone they may cause a hyperkalaemia therefore
monitor electrolytes especially if using potassium sparing diuretics as well
In people, ACE inhibitors often cause coughing - thought to be caused by increased
bradykinin in the airways.
care in renal insufficiency patients (more)
caution in hyponatraemia, pre-existing haematological abnormalities or a collagen
vascular disease ie. systemic lupus erythematosus
breeding / pregnant dogs (uterine relaxation)
Captopril has a short half life in the dog (3 hours), so must
be given two or three times daily. Enalapril is basically the
same as captopril except that it is a prodrug, which is metabolised by plasma
esterases to the active metabolite enalaprilat. This active drug has a longer
therapeutic duration than captopril, enabling once daily dosing in dogs. It
has been proven in clinical trials to increase the life span of dogs with congestive
heart failure (in combination with the diuretic frusemide). Benazepril is similar to the other ACE inhibitors, suitable for once daily dosing. The
human drug quinapril is sometimes used in dogs because it is
cheap.
There are dozens of other ACE inhibitors in human use, which probably also work
in animals.
AT1 receptor antagonists such as losartan and candesartan are starting to be used in people. They may be slightly more effective (ATII can be formed by other routes than ACE) and have fewer side effects. They are used mainly in patients who do not tolerate ACE inhibitors, and there is no experience in domestic animals.
