Pharmacodynamics
Dihydropyridine derivative – blocker “slow” calcium channels II generation, has antianginal and hypotensive action. Communicating with the dihydropyridine receptor, blocks calcium channels reduces the transmembrane passage of calcium ions into the cell (mainly in vascular smooth muscle cells than cardiac myocytes). Antianginal effect is due to the expansion of the coronary and peripheral arteries and arterioles: angina reduces the severity of myocardial ischemia; expanding peripheral arterioles, decreases total peripheral vascular resistance, decreases the preload on the heart, reducing myocardial oxygen demand. Expanding the major coronary arteries and arterioles in the unaltered and ischemic myocardial areas, increases the supply of oxygen to the myocardium (especially in vasospastic angina); It prevents the development of constriction of the coronary arteries (including those caused by smoking). In patients with angina single daily dose increases the run-time physical activity slows the development of angina and ‘ischemic »ST segment depression, reduces the frequency of angina attacks and nitroglycerin consumption. It has a long dose-dependent hypotensive effect. The antihypertensive effect is due to the direct vasodilating effect on vascular smooth muscle. When hypertension single dose provides a clinically significant reduction in blood pressure (BP) for 24 hours (in the position of the patient “lying” and “standing”). It does not cause a sharp decline in blood pressure, reduce exercise tolerance, left ventricular ejection fraction. It reduces the degree of left ventricular hypertrophy, has anti-atherosclerotic and cardioprotective effect in ischemic heart disease. No effect on myocardial contractility and conductivity, does not cause reflex increase in heart rate (HR), inhibits platelet aggregation, increases glomerular filtration rate, has a weak natriuretic effect. In diabetic nephropathy does not increase the severity of microalbuminuria. It has no adverse effects on metabolism and plasma lipids. Time of onset of effect – 2-4 hours, duration of effect of 24 hours.

Pharmacokinetics
After receiving peroralnogo amlodipine slowly absorbed from the gastrointestinal tract. The mean absolute bioavailability of 64%, the maximum concentration in serum is observed after 6-9 hours. The concentration of stable equilibrium is reached after 7 days of treatment. Food does not affect the absorption of amlodipine. The mean volume of distribution of 21 l / kg body weight, indicating that most of the drug is in the tissues and relatively smaller – in the blood. Most of the drug present in the blood (95%), bind to plasma proteins. Amlodipine undergoes slow but extensive metabolism (90%) in the liver into inactive metabolites, has the effect of “first pass” through the liver. Metabolites not possess significant pharmacological activity. After a single oral half-life (T1 / 2) ranges from 31 to 48 hours when re-assignment of T1 / 2 of approximately 45 hours. About 60% of ingested dose excreted in the urine primarily as metabolites, 10% unchanged, and 20-25% in the feces and in breast milk. Amlodipine Total clearance is 0.116 ml / sec / kg (7 ml / min / kg and 0.42 L / h / kg).

In elderly patients (65 years) amlodipine delayed excretion (T1 / 2 65 h.) As compared to younger patients, but this difference has no clinical significance. Elongation T | d in patients with hepatic failure it is assumed that the long-term administration of the drug accumulation in the body is higher. (T1 / 2 to 60 hours). Renal failure has no significant effect on the kinetics of amlodipine. The drug crosses the blood-brain barrier. When hemodialysis is not removed

Dosing and Administration
Inside, the initial dose for the treatment of hypertension and angina is 5 mg once in one day. The dose may be increased to a maximum of 10 mg once a day. When hypertension maintenance dose may be 2.5 – 5 mg per day.

When angina and vasospastic angina – 5-10 mg per day,

once. For the prevention of angina attacks – 10 mg / day.

Thin patients, patients with a short, elderly patients, patients with impaired liver function as a hypotensive agent, a drug administered in an initial dose of 2.5 mg, as a means of antiangialnogo – 5 mg.

Do not you want to change the dose while the appointment with thiazide diuretics, beta-blockers and angiotensin-converting enzyme (ACE) inhibitors. Not required dose modification in patients with renal insufficiency.

Side effects
Since the cardiovascular system: heart rate, shortness of breath, marked reduction in blood pressure, fainting, vasculitis, edema (swelling of the ankles and feet), “tides” of blood to the face, rarely – arrhythmias (bradycardia, ventricular tachycardia, atrial flutter), pain chest, orthostatic hypotension, very rarely – the development or exacerbation of congestive heart failure, arrythmia, migraine.

On the part of the central nervous system: headache, dizziness, fatigue, drowsiness, mood changes, seizures; rare – loss of consciousness, hypoesthesia, nervousness, paresthesia, tremor, vertigo, fatigue, malaise, insomnia, depression, unusual dreams, very rarely – ataxia, apathy, agitation, amnesia.

From the digestive system: nausea, vomiting, epigastric pain, rarely -increasing the level of “liver” transaminases and jaundice (caused by cholestasis), pancreatitis, dry mouth, flatulence, gingival hyperplasia, constipation or diarrhea, rarely – gastritis, increased appetite .

With the genitourinary system: rare – pollakiuria, tenesmus, nocturia, sexual dysfunction (including reduced potency); very rarely – dysuria, polyuria.

For the skin: very rarely – dermatoxerasia, alopecia, dermatitis, purpura, skin discoloration.

Allergic reactions: itching, rash (including erythematous, maculopapular rash, urticaria), angioedema.

From the musculoskeletal system: rarely – arthralgia, arthrosis, myalgia (with prolonged use); very rarely – myasthenia gravis.

Other: rarely – gynecomastia, poliurikemiya, increase / decrease in body weight, thrombocytopenia, leukopenia, hyperglycemia, impaired vision, conjunctivitis, diplopia, eye pain, tinnitus, back pain, dyspnoea, epistaxis, increased sweating, thirst; very rarely – a cold clammy sweat, cough, rhinitis, parosmiya, taste disturbance, disturbance of accommodation, xerophthalmia:

When unforeseen effects should see a doctor.

Drug interactions
Inhibitors of microsomal oxidation increase the concentration of amlodipine in plasma, increasing the risk of side effects, and inducers of microsomal liver enzymes decrease.

Antihypertensive effect of weakening nonsteroidal anti-inflammatory drugs, especially indometain (sodium retention and renal prostaglandin synthesis blockade), Alpha adrenostimulyatorov, estrogens (sodium retention), sympathomimetic. Thiazide and “loop” diuretics, beta-blockers, verapamil, inhibitors of angiotensin converting enzyme (ACE) inhibitors and nitrates increase antianginal and antihypertensive effects.

Amiodarone, quinidine, alpha 1-blockers, antipsychotic drugs (neuroleptics) and blockers “slow” calcium channels may increase the hypotensive effect.

It has no impact on the pharmacokinetic parameters of digoxin and warfarin. Cimetidine does not affect the pharmacokinetics of amlodipine.

In a joint application with drugs lithium may increase manifestations of neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus). Calcium can reduce the effect of blockers “slow” calcium channels.

Procainamide, quinidine and other drugs causing prolongation of the interval QT, reinforce the negative inotropic effect and may increase the risk of significant lengthening of the QT interval.

The pharmacokinetics of amlodipine is not changed while the appointment with cimetidine.

Grapefruit juice may reduce amlodipine plasma concentration, but this decrease is so small that it does not significantly alter the effect of amlodipine.

Special instructions
All calcium channel blockers (including amlodipine), used with caution in patients with heart failure and severe aortic stenosis. In rare cases, patients, particularly with severe obstructive coronary artery disease, at the beginning of treatment or when increasing the dose of amlodipine, angina may occur with greater frequency, duration and severity.

Despite the lack of blockers “slow” calcium channels “cancellation” syndrome, before stopping treatment recommended a gradual reduction in dose.

There were no reports on the effect of amlodipine on driving or using machinery. However, some patients in the early treatment preferably may occur drowsiness and dizziness. If this happens, the patient must take special precautions when driving and operating machinery.

The safety of amlodipine during pregnancy and lactation has not been established. Use during pregnancy is possible only when the intended benefits to the mother prevails over potential risk to the fetus.

The drug should be stored out of reach of children and do not use after the expiration date.

Overdose
Symptoms: marked reduction of blood pressure, tachycardia, excessive peripheral vasodilation, tachycardia.

Treatment: gastric lavage, the appointment of activated carbon, the maintenance function of the cardiovascular system, the control performance of the heart and lungs, limbs elevated position, control of blood volume and diuresis. To restore vascular tone – use of vasopressors (in the absence of contraindications to their use); to eliminate the effects of calcium channel blockade – intravenous calcium gluconate. Hemodialysis is not effective

Contraindications
– Hypersensitivity to amlodipine and other derivatives of dihydropyridine;

– Severe hypotension,

– Collapse, cardiogenic shock;

– Pregnancy and lactation

-. age of 18 years (effectiveness and safety have been established).

With caution: liver dysfunction, sick sinus syndrome (bradycardia, tachycardia), decompensated chronic heart failure, mild or moderate hypotension, aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy, acute myocardial infarction (and for 1 month after) , diabetes, lipid profile, old age.