Pharmacological properties of the drug Tenox
Selective blocker of slow calcium channels with a predominant effect on blood vessels, a dihydropyridine derivative. Amlodipine is used as an antianginal and antihypertensive agent. The drug blocks calcium channels and reduces the transmembrane transition of calcium ions into arterial smooth muscle cells and cardiomyocytes. Amlodipine has a more pronounced selectivity for vascular muscle cells compared to myocardial cells. As a result, the main hemodynamic effect of the drug is systemic peripheral vasodilation, which leads to a decrease in peripheral vascular resistance and determines its antihypertensive effect. The antianginal effect of amlodipine is realized through two mechanisms: a decrease in myocardial oxygen demand due to a decrease in afterload (a decrease in peripheral resistance without reflex tachycardia); improving oxygen delivery to the myocardium due to the direct effect of the drug on the coronary vessels. After oral administration, amlodipine is slowly and completely absorbed from the digestive tract. The average absolute bioavailability is 64%, the maximum concentration in the blood plasma is achieved 6–9 hours after oral administration. Stable plasma concentrations are achieved after 7 days from the start of treatment. The mean volume of distribution is 21 L/kg body weight, indicating that most of the drug is found in body tissues and a relatively small portion in the blood. 95% of the drug binds to blood plasma proteins. The plasma half-life after a single dose of the drug ranges from 31 to 48 hours, and after multiple doses - approximately 45 hours. About 60% of an orally administered dose is excreted in the urine, mainly in the form of metabolites, and 20-25% is excreted in the feces. The total clearance of amlodipine is 0.116 ml/s/kg (7 ml/min/kg, 0.42 l/h/kg). Elderly patients (over 65 years of age) eliminate amlodipine more slowly than younger patients, although this difference is not clinically significant. An increase in half-life in patients with liver failure indicates that with long-term use of the drug there may be an increase in its accumulation in the body. The presence of renal failure does not significantly affect the kinetics of amlodipine.
Instructions for use TENOX
Calcium channel blocker. Antianginal and antihypertensive drug. Amlodipine inhibits the flow of calcium ions through L-type calcium channels of the cell membranes of the smooth muscles of the heart and blood vessels, which leads to a decrease in vascular muscle tone.
The antihypertensive effect of amlodipine is due to a direct relaxing effect on the arteries and arterioles, which leads to a decrease in peripheral vascular resistance. The direct effect of the drug on the heart muscle is insignificant. Amlodipine selectively acts on blood vessels, approximately 80 times stronger than on the heart muscle.
In patients with angina pectoris, the antianginal effect of amlodipine is due to a decrease in oxygen consumption by the myocardium, a decrease in its oxygen demand as a result of a decrease in peripheral vascular resistance (without the development of reflex tachycardia), and an improvement in oxygen delivery to the myocardium due to the expansion of the coronary arteries and arterioles.
The use of the drug promotes regression of myocardial and vascular hypertrophy.
When using Tenox, there is no effect on the sinoatrial or atrioventricular nodes.
The drug increases renal blood flow and glomerular filtration, reduces renovascular resistance, causes moderate natriuresis, and reduces urinary albumin excretion.
Tenox has a protective effect on the myocardium by reducing the accumulation of calcium in cells, maintaining the normal structure and function of myocyte membranes, and maintaining normal mitochondrial function.
Tenox has an anti-atherosclerotic effect by modulating lipid metabolism, reducing cell migration into smooth muscle, inhibiting smooth muscle cell proliferation, reducing the expression and adhesion of molecules, and reducing the activity of proteolytic enzymes.
Reduces platelet aggregation. Does not change insulin sensitivity, does not affect carbohydrate or lipid metabolism.
Use of the drug once a day provides a prolonged and gradual antihypertensive effect. Maintains normal blood pressure for 24 hours while maintaining rhythm without reflex sympathetic activation.
After oral administration, a significant decrease in blood pressure is observed after 6–10 hours or more. With long-term treatment, the maximum reduction in blood pressure is observed after 6-12 hours.
When amlodipine is discontinued after long-term treatment, the effective reduction in blood pressure persists for 48 hours after the last dose. Blood pressure gradually returns to baseline levels over 5–6 days.
In patients with angina pectoris, a single dose of amlodipine significantly improves exercise tolerance, reduces the frequency of angina attacks and the consumption of short-acting nitrates.
The results of controlled clinical trials show that in patients with heart failure, amlodipine does not have a negative effect on symptoms, morbidity and mortality.
In placebo-controlled clinical trials in patients with heart failure (NYHA functional class II–IV) receiving standard therapy (ACE inhibitors, diuretics and digoxin), the risk of neither cardiovascular nor all-cause mortality was increased.
Side effects of the drug Tenox
Most often - headache, peripheral edema, palpitations, dizziness, drowsiness, fatigue, abdominal pain, nausea. Some side effects, such as asthenia, malaise, fainting, dyspepsia, bowel disorders, pancreatitis, gingival hyperplasia, dry mouth, increased sweating, alopecia, shortness of breath, cramps, muscle pain, joint pain, back pain, peripheral neuropathy, mood lability , thrombocytopenia, leukopenia, vasculitis, impotence, gynecomastia, hyperglycemia, increased frequency of urination and visual disturbances were sometimes noted in patients during treatment with amlodipine, but in most cases the relationship with the drug was not established. Isolated undesirable effects include increased liver enzymes, hepatitis and jaundice. Some patients have experienced allergic reactions such as skin rash, itching, angioedema and erythema multiforme. Some undesirable effects noted in individual patients could not be distinguished from symptoms characteristic of the course of the underlying disease; this applies to myocardial infarction, arrhythmias (including ventricular tachycardia and atrial fibrillation) and chest pain.
Special instructions for the use of Tenox
Amlodipine is primarily metabolized in the liver, so the half-life of the drug may be prolonged in patients with hepatic impairment. The drug should be prescribed to such patients with caution. For elderly patients, no dosage adjustment is required, however, increased sensitivity to amlodipine used in normal doses may occur, so treatment should be carried out under medical supervision. There is insufficient data on the use of amlodipine in acute myocardial infarction or within 1 month after it. It is not recommended to prescribe the drug to children under 18 years of age. During pregnancy and breastfeeding. Amlodipine is not recommended for use during pregnancy and breastfeeding. When planning pregnancy, you must stop taking the drug at least 1 month in advance. Impact on the ability to drive vehicles and operate other machinery . Amlodipine does not affect the ability to drive vehicles or operate other machinery. However, this drug may cause drowsiness and dizziness in some patients, especially at the beginning of treatment. In such cases, patients are advised to be especially careful when driving vehicles and operating other mechanisms.
Tenox (amlodipine) in preventive angioneurology
About the article
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Regular issues of "RMZh" No. 9 dated 05/03/2006 p. 670
Category: General articles
Author: Shirokov E.A. 1 1 Branch of the Military Medical Academy named after S.M. Kirov, Moscow, Russia
For quotation:
Shirokov E.A. Tenox (amlodipine) in preventive angioneurology. RMJ. 2006;9:670.
According to the stroke registry of the Research Institute of Neurology of the Russian Academy of Medical Sciences, vascular diseases of the brain have been identified in 20% of people of working age, of which 65% suffer from arterial hypertension (AH). Despite the significant arsenal of antihypertensive drugs, the problem of treating hypertension remains relevant. In the Russian Federation, elevated blood pressure levels are observed in 20–30% of the adult population [1,2]. Arterial hypertension and hypertensive crises (HC) are associated with most cases of acute and chronic forms of cerebrovascular accidents. GCs account for 30–40% of all emergency room visits [3]. About 500 thousand strokes per year and more than 1 million stroke patients determine a significant social, economic and medical burden associated with vascular diseases of the brain. Effective prevention of acute cerebrovascular accidents (ACVA) remains one of the most significant problems of modern medicine [2].
In most cases, the immediate causes of stroke are associated with hypertension, atherosclerosis of the brachiocephalic arteries, cardiac arrhythmias and a tendency to intravascular thrombus formation [4,5,6]. The immediate causes of stroke are due to a critical decrease in hemodynamic, hemostatic reserves and hemodynamic crises (hypertensive, hypotonic, arrhythmic, coronary, angiodystonic). Correction of the most significant risk factors and prevention of hemodynamic crises, in fact, form the basis of the modern approach to stroke prevention [5,6]. Hypertensive crisis is the most common cause of failure of cerebral hemodynamic compensation. GCs lead to the development of hemorrhagic forms of stroke, lacunar or hemodynamic ischemic stroke. In the pathogenesis of stroke that occurs against the background of GC, an important role is played by suddenly increasing disturbances of central hemodynamics, which are characterized by an increase in peripheral resistance, systolic and diastolic blood pressure, an increase in pressure load on the myocardium and a decrease in minute blood volume (MBV). A lack of blood supply to the brain, which develops against the background of hypertensive vasculopathy, in conditions of a sharp increase in peripheral resistance and a decrease in cardiac output, leads to focal (stroke) or diffuse (hypertensive encephalopathy) brain damage. The pathogenesis of stroke associated with coronary, arrhythmic or angiodystonic crisis is complex, but is ultimately due to a short-term decrease in the effective functioning of the heart, vasospasm and intravascular thrombus formation or thromboembolism. The heterogeneity of stroke presents the attending physician with the problem of choosing optimal treatment regimens with minimal pharmacological and economic burden on the patient. The choice of medications for patients at high risk of stroke is determined by a number of sometimes mutually exclusive requirements. Ideally, they should effectively reduce blood pressure without allowing significant fluctuations during the day and hypotonic episodes, not significantly reduce cardiac output, not cause arrhythmias and disturbances in the adaptation of the cardiovascular system to physical activity, not increase blood viscosity and coagulability, and not lead to lipid metabolism disorders, have a neuro- and cardioprotective effect. These requirements are best met by calcium channel blockers (CCBs), or calcium antagonists. The general properties of this group of drugs are [7,8]: • reduction in the tone of the smooth muscles of the vascular wall, general peripheral resistance, elimination of spasm and reduction in blood pressure; • reduction of resistance in the systemic circulation and reduction of afterload on the myocardium; • increased coronary blood flow in ischemic areas of the myocardium, decreased coronary spasm; • influence on the transmembrane entry of calcium through slow channels into cardiomyocytes, which leads to a decrease in calcium-dependent breakdown of ATP and the force of myocardial contraction; • decreased platelet aggregation; • limiting lipid peroxidation and reducing oxidative stress. Over the past two decades, the effectiveness and safety of CCBs - first generation dihydropyridine derivatives (short-acting nifedipines) have been actively discussed in connection with the identified adverse outcomes in patients with coronary heart disease with their long-term use [7]. Well-founded concerns regarding short-acting CCBs turned out to be unfounded when using long-acting forms of nifedipine and third-generation CCBs (amlodipine). Large multicenter placebo-controlled studies (STONE, TIBET, CASIS, CAPE) have shown the high effectiveness of amlodipine in the treatment of coronary artery disease. The SYST-Eur study demonstrated the long-term safety of long-acting dihydropyridines for stroke prevention. Amlodipine is one of the most suitable calcium antagonist drugs for use in preventive programs. The drug does not change heart rate, does not affect the function of the sinus node and atrioventricular conduction, increases cardiac output and coronary blood flow, has distinct peripheral vasodilation, reduces myocardial oxygen demand, and improves diastolic myocardial function [7,9]. The neuroprotective effect of CCBs should be considered important for preventive angioneurology [10]. Amlodipine has proven itself well in the treatment of hypertension in the elderly, successfully fulfilling the task of reducing systolic blood pressure and maintaining DBP at a level of at least 70 mm Hg. [11,12]. There is little data in the literature on differences in the effectiveness of the same drug in patients of different age categories. Previously, in a comparative Polish study, good results were obtained on the clinical efficacy and safety of Tenox (amlodipine, KRKA) in monotherapy for hypertension in middle-aged patients. The Russian ETNA study was designed to study the antihypertensive effectiveness of Tenox in patients with arterial hypertension of different age groups. Effective prevention of HA is one of the advantages of long-acting antihypertensive drugs. Amlodipine allows for daily blood pressure control with a single dose. An important property of third-generation CCBs is the absence of a “ricochet” effect with episodes of a decrease in blood pressure that is critical for cerebral hemodynamics. Randomized controlled trials indicate the increasing importance of CCBs in modern stroke prevention. In the VALUE study, a significant reduction in the number of strokes was revealed in patients taking amlodipine; blood pressure control with monotherapy was achieved in 63% of patients under observation. The PREVENT study demonstrated the effect of amlodipine on atherogenesis - a decrease in the rate of progression of atherosclerosis of the carotid arteries was established according to Doppler ultrasound. The use of the drug reduced the risk of cardiovascular complications by 31% compared to placebo. Amlodipine, a third-generation calcium channel antagonist of the dihydropyridine series, blocks slow calcium channels (L-type channels) and prevents intracellular hypercalcemia and contraction of smooth muscle cells, producing a vasodilator effect. The drug has a long-lasting effect, which allows it to be used once a day to effectively lower blood pressure. The combination of hypertension with exertional angina can be considered optimal for prescribing amlodipine, including with a pronounced vasospastic component of ischemia and congestive heart failure [9,13–15]. Amlodipine is also widely used for the treatment of stable angina pectoris, significantly reducing the frequency, duration and severity of ischemic episodes. One of the possible beneficial protective effects of amlodipine on the state of the myocardium after an episode of ischemia is considered to be its ability to reduce calcium overload of cells, which is the cause of myocardial damage. The drug is well tolerated and rarely causes undesirable effects, the most noticeable of which is skin hyperemia. When taken orally, amlodipine is slowly and almost completely absorbed from the gastrointestinal tract, regardless of food intake. The bioavailability of the active substance is high and ranges from 60 to 80%. The volume of distribution of the drug is on average 20–21 l/kg body weight, which is significantly more than that of other representatives of the dihydropyridine series. In serum, 95–98% of the drug dose is bound to plasma proteins. The maximum concentration of amlodipine in the blood is achieved 6–12 hours after administration. The duration of action of the drug is due to its slow release from the receptors, which allows it to control blood pressure evenly throughout the day. This leads to a relatively greater effectiveness of the drug in controlling the early morning rise in blood pressure, regardless of the time of administration (morning or evening once a day) and prevents the course of the hypertension crisis [9,15]. For patients with clinical signs of cerebrovascular insufficiency and hypertension, the optimal dose of amlodipine is 10 mg. At the beginning of treatment and when target blood pressure levels are achieved, the daily dose can be reduced to 5 mg. Thus, the “second coming” of CCBs into clinical practice is associated with the development of third-generation long-acting drugs that combine the advantages of dihydropyridines and are free of their inherent disadvantages. The use of amlodipine in preventive angioneurology seems particularly promising due to the possibility of combining the antihypertensive effect with an antianginal effect and a neuroprotective effect. These properties are especially necessary in treatment programs for the elderly. In some cases, they make it possible to achieve a sustainable clinical effect and avoid polypharmacy. Literature 1. Gusev E.I. The problem of stroke in Russia // Journal of Neurology and Psychiatry named after S.S. Korsakov (STROKE supplement to the journal). 2003; 9: 3–7. 2. Vereshchagin N.V., Morgunov V.A., Gulevskaya T.S. Pathology of the brain in atherosclerosis and arterial hypertension // – M.: Medicine, 1997. – 288 p. 3. Bokarev I.N. Hypertensive crises. // Clinical medicine. 2005; 8: 84 – 86. 4. Shulutko B.I. Hypertension and other forms of arterial hypertension. St. Petersburg, 1998. –188 p. 5. Gusev E.I., Skvortsova V.I. Cerebral ischemia. M. Medicine, 2001.–328 p. 6. Shirokov E.A., Simonenko V.B. Modern ideas about the role of hemodynamic crises in the etiology and pathogenesis of stroke. Clinical Medicine.2001; 8: 4 – 7. 7. Maksimov M.L., Starodubtsev A.K., Svety L.I. Efficacy of calcium channel blockers in the treatment of coronary heart disease//Breast cancer. 2005; 27:1–6. 8. Drapkina O.M. Calcium blockers in stroke prevention//Consilium medicum (appendix). 2005; 2:3–6. 9. Chou TC, Li CY, Yen MH, Ding YA Antiplatelet effect of amlodipine: a possible mechanism through a nitric oxide–mediated process. Biochem. Pharmacol., 1999, 15; 58(10):1657–1663. 10. Shirokov E.A., Denishchuk I.S., Polkhovsky A.A. Nimotop: scope of application in clinical practice//Clinical Medicine. 1988; 5: 37 – 39. 11. Chazova I.E., Ratova L.G. Calcium antagonists in the treatment of arterial hypertension (ETNA study)//Consilium medicum (appendix). 2005; 2:25–27. 12. Ault MJ, Ellrodt AG. Pathophysiological events leading to the end–organ effects of acute hypertension. Am J Emerg Med 1985; 3:10–15. 13. Grimm RH Jr., Flack JM, Grandits GA et al. Long–term effect on plasma lipids of diet and drugs to treat hypertension. Treatment of Mild Hypertension Study (TOMHS) Research Group. JAMA, 1996; 275(20):1549–1556. 14. Grimm RH Jr., Grandits GA, Culter JA et al. Relationships of quality–of–life measures to long–term lifestyle and drug treatment in the Treatment of Mild Hypertension Study. Arch. Intern. Med., 1997; 157(6):638–648. 15. Vaughan CJ, Delanty N. Hypertensive emergencies // Lancet 2000; 5:411–417.
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Drug interactions Tenox
When treating patients with hypertension (arterial hypertension), amlodipine can be safely used simultaneously with thiazide diuretics, α- and β-adrenergic receptor blockers or ACE inhibitors. For patients with stable angina, this drug can be combined with other antianginal agents, such as long-acting nitrates, beta-blockers, or sublingual nitroglycerin. Amlodipine can be safely used concomitantly with NSAIDs, antibiotics and oral hypoglycemic agents. The results of pharmacokinetic studies with cyclosporine indicate that amlodipine does not significantly alter the pharmacokinetics of cyclosporine. In healthy people, simultaneous use of amlodipine and digoxin did not lead to changes in plasma digoxin concentrations or renal clearance of digoxin. The pharmacokinetics of amlodipine does not change with the combined use of cimetidine. When taken concomitantly, amlodipine does not significantly change the effect of warfarin on prothrombin time. In vitro experiments using human plasma showed that amlodipine does not affect the protein binding of digoxin, phenytoin, warfarin or indomethacin. Grapefruit juice may increase plasma concentrations of amlodipine, but the increase is very small to significantly alter the effect of amlodipine.
Tenox, 5 mg, tablets, 30 pcs.
It is possible to enhance the antianginal and antihypertensive effect of slow calcium channel blockers when used together with thiazide and loop diuretics, ACE inhibitors, beta-blockers and nitrates, as well as enhance their antihypertensive effect when used together with alpha1-blockers, antipsychotics.
Although negative inotropic effects have not generally been observed in amlodipine studies, some calcium channel blockers may enhance the negative inotropic effects of antiarrhythmic drugs that cause QT prolongation (eg, amiodarone and quinidine).
Simultaneous repeated use of amlodipine at a dose of 10 mg and simvastatin at a dose of 80 mg leads to an increase in the bioavailability of simvastatin by 77%. In such cases, the dose of simvastatin should be limited to 20 mg.
Antiviral drugs (for example, ritonavir) increase plasma concentrations of slow calcium channel blockers, incl. amlodipine.
With the simultaneous use of sympathomimetics and estrogens, the antihypertensive effect may be reduced due to sodium retention in the body.
Neuroleptics and isoflurane enhance the antihypertensive effect of dihydropyridine derivatives. With the simultaneous use of inhalation anesthesia, the hypotensive effect may be enhanced.
With simultaneous use of amiodarone, the antihypertensive effect may be enhanced.
With simultaneous use of lithium carbonate, manifestations of neurotoxicity (including nausea, vomiting, diarrhea, ataxia, tremors and/or tinnitus) are possible.
With simultaneous use, orlistat reduces the antihypertensive effect of amlodipine, which can lead to a significant increase in blood pressure and the development of a hypertensive crisis.
With the simultaneous use of indomethacin and other NSAIDs, the antihypertensive effect of amlodipine may be reduced due to inhibition of prostaglandin synthesis in the kidneys and fluid retention under the influence of NSAIDs.
With simultaneous use of quinidine, the antihypertensive effect may be enhanced.
Calcium supplements may reduce the effect of slow calcium channel blockers.
With simultaneous use of diltiazem (CYP3A4 isoenzyme inhibitor) at a dose of 180 mg and amlodipine at a dose of 5 mg in elderly patients (69 to 87 years) with arterial hypertension, an increase in the bioavailability of amlodipine by 57% was observed. Concomitant use of amlodipine and erythromycin in healthy volunteers (18 to 43 years of age) does not lead to significant changes in amlodipine exposure (22% increase in AUC). Although the clinical significance of these effects is unclear, they may be more pronounced in older patients. Potent inhibitors of the CYP3A4 isoenzyme (for example, ketoconazole, itraconazole) may increase the plasma concentration of amlodipine to a greater extent than diltiazem. Amlodipine and inhibitors of the CYP3A4 isoenzyme should be used with caution.
There are no data on the effect of inducers of the CYP3A4 isoenzyme on the pharmacokinetics of amlodipine. Blood pressure should be carefully monitored while using amlodipine and inducers of the CYP3A4 isoenzyme.
Tenox drug overdose, symptoms and treatment
Data on overdose cases in humans are limited. Overdose can cause pronounced peripheral vasodilation with further severe and possibly prolonged systemic hypotension. Cardiovascular collapse and shock may also occur. Treatment. Emergency measures should primarily be aimed at removing the drug from the body and stabilizing hemodynamics. In patients, it is necessary to constantly monitor the functions of the cardiovascular and respiratory systems, levels of glucose and electrolytes (potassium, calcium) in the blood plasma, daily diuresis and blood volume. It is possible to administer calcium supplements. To maintain vascular tone, the administration of vasoconstrictors can be effective and beneficial. Since amlodipine is characterized by a high degree of binding to plasma proteins, hemodialysis is ineffective.
