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Pharmacological particulars
Pharmacotherapeutic group: Calcium channel blockers. ATCvet code: QC08CA01
Pharmacodynamic properties
Amlodipine is a voltage dependent calcium channel blocker, member of the dihydropyridine group, binding selectively to the L-type of channels found in vascular smooth muscle, cardiac muscle and cardiac nodal tissue. Amlodipine favours the L-type calcium channels found in vascular smooth muscle acting hence predominantly by decreasing vascular resistance. The major blood pressure lowering effect of amlodipine is related to its dilatory action on arteries and arterioles, while amlodipine has little effect on the venous circulation. The duration and waning of anti-hypertensive effects are dose-dependent. Although amlodipine has a greater affinity for the vascular L-type calcium channels, it can also act on those found in the cardiac muscle and cardiac nodal tissue. A decrease in heart rate and a negative inotropic effect on the heart have been observed in vitro in guinea-pig isolated hearts. In a 26-week target animal safety study conducted in cats, amlodipine, at a dose of 0.25 to 1.25 mg/kg administered orally, did not affect heart rate and no electrocardiogram (ECG) abnormalities were observed.
Binding of amlodipine to the L-type calcium channels is slow, avoiding hence rapid reductions in blood pressure which lead to reflex tachycardia as a result of activation of baroreceptors. In cats with hypertension, once daily dosing with amlodipine tablets provided clinically significant reductions in blood pressure and due to the slow onset of action of amlodipine, acute hypotension and reflex tachycardia tend not to occur. In vitro data showed amlodipine improves endothelial cell function by increasing the generation of nitric oxide and through anti-oxidant and anti-inflammatory actions. In humans, this is an important effect as endothelial dysfunction accompanies hypertension, coronary heart disease and diabetes, all conditions in which amlodipine is used as part of the treatment regimen. In cats, the importance of these additional effects remains to be determined since the role of endothelial dysfunction in the pathophysiology of feline hypertension has, so far, not been studied. The kidney is, along with the heart, the eye and the CNS, a major target organ of hypertension receiving 20 to 25% of the cardiac output and having a high pressure first capillary bed (the glomerular capillary bed) to facilitate the formation of glomerular filtrate. Calcium channel blockers such as amlodipine are thought to preferentially dilate the afferent arteriole over the efferent arteriole. Since ACEI preferentially dilate the efferent arteriole, they lower the intraglomerular pressure and frequently decrease the magnitude of proteinuria. For this reason, combination of ACEI and calcium channel blockers may be especially beneficial in hypertensive cats with proteinuria.
In a clinical study, a field-representative sample of client-owned cats with persistent hypertension (systolic blood pressure (SBP) >165 mmHg) were randomised to receive amlodipine (initial dose of 0.125-0.25 mg/kg, rising to 0.25 - 0.50 mg/kg if response was not satisfactory after 14 days) or placebo, once daily. SBP was measured after 28 days and treatment was considered successful if SBP was reduced by 15% or more of pre-treatment SBP or to below 150 mmHg. 25 out of 40 cats (62.5%) given amlodipine were successfully treated compared with 6 out of 34 (17.6%) given placebo. It was estimated that amlodipine treated animals have 8 times greater odds of treatment success than placebo treated cats (OR 7.94, 95% confidence interval 2.62 - 24.09).
Pharmacokinetic particulars
After oral administration of therapeutic doses, amlodipine is well absorbed with peak plasma levels between 3 to 6 hours post dose. After a single dose of 0.25 mg/kg, absolute bioavailability is estimated to be 74% and the peak plasma level is 25 ng/ml, in fasted state. Absorption of amlodipine is not influenced by concomitant food intake in humans. Amlodipine tablet may be given with or without food to cats in clinical use.
The pKa of amlodipine is 8.6. Amlodipine is highly bound to plasma proteins. In vitro protein binding in cat plasma is 97%. The volume of distribution is approximately 10 l/kg.
Amlodipine is extensively metabolised by the liver in laboratory animals and humans. All known metabolites lack pharmacological activity. All amlodipine metabolites found in vitro in cat hepatocytes have been earlier identified in incubations of rat, dog and human hepatocytes. Thus, none of them are unique to the cat.
The mean plasma elimination half-life of amlodipine is 53 hours in healthy cats. At 0.125 mg/kg/day, plasma level of amlodipine was approaching steady-state by 2 weeks in healthy cats. Total plasma clearance in healthy cats is estimated to be 2.3 ml/min/kg.
Excretion balance has been characterised in humans and several animal species, but not in the cat. In dogs, equal distribution of radioactivity was found in the urine and faeces.