Pharmacological action Verapamil SR
Verapamil Sr Calcium channel blocker. Inhibits transmembrane calcium current in smooth muscle cells of the myocardium and blood vessels. Has antianginal, antiarrhythmic and antihypertensive activity.
Antianginal effect is due to a direct effect on the myocardium and the effect on peripheral hemodynamics (lowers the tone of peripheral arteries, PR). Blockade of calcium ions in income leads to a reduction cell transformation contained in high-energy bonds of ATP energy into mechanical energy and to reduce myocardial contractility.
Antihypertensive effect of the drug due to reduced peripheral vascular resistance without increasing heart rate as a reflex response. BP begins to fall directly on the first day of treatment and this effect persists for long-term therapy.
The drug has vasodilating, negative foreign-and chronotropic effect.
The drug has a pronounced antiarrhythmic action, particularly effective for supraventricular arrhythmias. Delays impulse conduction in AV-node, resulting in sinus rhythm is restored and / or heart rate to normal, depending on the type of arrhythmia. Normal heart rate is unchanged or slightly reduced.
Pharmacokinetics Verapamil SR
Absorption
When administered quickly and almost completely absorbed from the small intestine. The degree of absorption is 90-92%. Bioavailability in healthy volunteers after a single dose of the drug is 22%. Studies in patients with atrial fibrillation or angina showed that the average levels of bioavailability of 35% and 24% after a single oral dose of the drug inside and I / dose, respectively. Repeated employment drug bioavailability increased almost 2-fold compared with single-dose (this effect is probably due to partial saturation of hepatic enzyme systems, or transient increase in blood flow in the liver after a single dose of verapamil).
Distribution
When coronary artery disease and hypertension was not found a correlation between therapeutic effect and drug concentration in plasma is only a definite relationship between the level of drug in the blood and the influence of the interval PR.
After oral dosage form sustained-release verapamil concentration curve in plasma expands and becomes more shallow than when administered dosage forms with a normal release.
Plasma protein binding is 90%.
Crosses the placental barrier, the concentration found in blood plasma of the umbilical vein, were 20-92% of concentrations in blood plasma of the mother.
Excreted in the breast milk, but the application of therapeutic doses of its concentration is so low that the clinical effect in infants is unlikely.
Metabolism
Verapamil undergoes the effect of “first pass” through the liver. Almost completely metabolized. The main metabolite is norverapamil having pharmacological activity, other metabolites are mainly inactive.
Breeding
T1 / 2 from 3 to 7 h after a single oral administration. Repeated reception of T1 / 2 of verapamil almost doubled compared with a single dose.
Verapamil and its metabolites are excreted primarily in urine (3-4% unchanged). Within 24 hours, displayed 50% of the administered dose within 48 hours – 55-60%, within 5 days – 70%. Up to 16% is excreted in the feces.
Pharmacokinetics in special clinical situations
In patients with hepatic impairment compared with those with normal liver function bioavailability of verapamil was much higher, and there was lengthening of T1 / 2.
Recent findings indicate that there is no difference of the pharmacokinetics of verapamil in patients with normal renal function and in patients with end-stage renal failure.
Statement Verapamil SR
- Arterial hypertension: mild or moderate – in the form of monotherapy, severe – in a combination therapy;
- Stable angina (angina);
- Angiospastic angina (Prinzmetal angina);
- Paroxysmal supraventricular tachycardia;
- Fibrilloflutter, accompanied by a tachyarrhythmia (except Syndrome WPW).
Dosage regimen Verapamil SR
The average daily dose is 240-360 mg. Long-term treatment should not exceed 480 mg daily dose, possibly a temporary increase in dose above this level.
When coronary artery disease (stable angina, Prinzmetal’s angina) Izoptin 240 Wed administered in a daily dose of 240-480 mg (1/2-1 tab. 2 times / day every 12 h).
Hypertension (mild or moderate) Wed Izoptin 240 appoint 240 mg (1 tab.) 1 times / day in the morning. If you prefer a slow decrease in blood pressure, treatment should begin with a dose of 120 mg (1 / 2 tab. Izoptina Wed 240). If necessary, additional appoint 1/2-1 tab. in the evening with an interval between doses of approximately 12 h. The dose should be increased every 2 weeks of treatment.
In paroxysmal supraventricular tachycardia, a form of tahiaritmicheskoy fibrilloflutter Izoptin 240 Wed appoint 120-240 mg (1/2-1 tab.) 2 times / day every 12 hours
If abnormal liver function effect of the drug increases and becomes more prolonged as a result of slower metabolism of verapamil, which depends on the severity of liver dysfunction. In such cases, the dose should be installed with special care and treatment should begin with taking the drug at lower doses (ie, patients with liver cirrhosis prescribers Izoptin 40 mg 2-3 times / day.
Tablets should be taken during meals or after eating, swallowing and completely with water.
Side effect Verapamil SR
Cardio-vascular system: sometimes (when taken in high doses or in the presence of cardiovascular disorders) – against the background of arrhythmia bradycardia (sinus bradycardia, sinoatrial block, AV-block II or III level or bradyarrhythmia with atrial fibrillation), hypotension , palpitations, tachycardia, development or worsening symptoms of heart failure.
From the central and peripheral nervous system: rarely – headache, dizziness, drowsiness, fatigue, excessive nervousness, tremor, paresthesia.
From the digestive system: common – constipation, rarely – nausea, vomiting, bowel obstruction, pain and discomfort in the abdomen; described reversible increase in liver transaminase levels and / or alkaline phosphatase, and in some cases – gingival hyperplasia, fully reversible after drug withdrawal.
On the part of the musculoskeletal system: in some cases – myalgia and arthralgia.
Allergic reactions: seldom – rash, urticaria, angioedema, Stevens-Johnson syndrome.
Part of the endocrine system: increased prolactin levels, rarely (in elderly patients with prolonged therapy) – gynecomastia, fully reversible after drug withdrawal, and in some cases – galactorrhea and impotence.
Other: rarely – swelling shins, rodonalgia and tidal waves.
Contraindications Verapamil SR
Absolute contraindications
- Cardiogenic shock;
- Complications of acute myocardial infarction (bradycardia, marked hypotension, left ventricular failure);
- AV-block II or III degree;
- SSS syndrome (bradycardia-tachycardia);
- Sinoatrial block.
Relative contraindications
- AV-block I degree;
- Bradycardia (less than 50 beats / min);
- Hypotension (systolic blood pressure below 90 mm Hg);
- Flicker / atrial flutter syndrome WPW (risk of ventricular tachycardia);
- Heart failure (if necessary prior to treatment with 240 Izoptin Wed prescribed cardiac glycosides).
Pregnancy and breastfeeding Verapamil SR
Use of the drug Izoptin Wed 240 of pregnancy (especially in the I trimester) and lactation is possible only if the expected benefit to the mother outweighs the potential risk to the fetus.
If necessary, use during lactation breastfeeding should be discontinued.
Use in hepatic dysfunction Verapamil SR
If abnormal liver function effects of verapamil increases and becomes more prolonged as a result of slower metabolism of verapamil, which depends on the severity of liver dysfunction. In such cases, the dose should be installed with special care and treatment should begin with taking the drug at lower doses (ie, patients with liver cirrhosis prescribers Izoptin 40 mg 2-3 times / day.
Use in renal impairment Verapamil SR
Recent findings indicate that there is no difference of the pharmacokinetics of verapamil in patients with normal renal function and in patients with end-stage renal failure.
Cautions Verapamil SR
Patients with severe arterial hypertension drug Izoptin Wed 240 should be used in combination with other antihypertensive drugs (diuretics, ACE inhibitors).
Effects on ability to drive and control mechanisms
Depending on the individual response to the drug a patient’s ability to control a car or operate machinery during the period of its reception may be reduced. This is particularly important in the initial period of therapy, when translated into reception Wed Izoptina 240 after the use of another drug, and while receiving alcohol.
Overdose Verapamil SR
Symptoms of poisoning due to drug overdose Wed Izoptin 240 depends on the adoption of the drug, since the activities of detoxification and myocardial contractility, independent of age. It was reported fatal cases as a result of an overdose.
Symptoms: The fall in blood pressure (in some cases to levels that can not be measured), shock, loss of consciousness, AV-block I or II degree, often in the form of periods Venkenbaha with or without slip rate, complete AV-block with complete AV-dissociation , slip rate, cardiac arrest, sinus bradycardia, cardiac sinus node.
In case of overdose Wed Izoptina 240 must keep in mind that the active substance is released and absorbed in the intestine within 48 hours after oral administration. Depending on the time the drug remains some conglomerates of swollen tablets that act as an active depot will be located throughout the gastrointestinal tract.
Treatment: It is shown conducting activities aimed at elimination of the drug (for example, should induce vomiting, wash out the stomach and small intestine in combination with endoscopic examination, appoint laxatives, emetics). If there is no stomach and intestinal motility (peristalsis signs on auscultation), it is advisable to carry out gastric lavage, even after 12 hours after ingestion vnutr.Obychnye immediate resuscitative measures include closed cardiac massage, artificial respiration and electrical stimulation of the heart.
Calcium is the specific antidote: injected 10-30 ml 10% solution of calcium gluconate in the form of I / O infusion (2.25-4.5 mmol), if necessary, re-enter, or as a slow drip infusion (5 mmol / h).
In the case of AV-block II or III degree, sinus bradycardia, heart failure shows the introduction of atropine, isoprenaline, ortsiprenalina holding stimulation of the heart. In the case of arterial hypotension is administered dopamine, dobutamine, norepinephrine (noradrenaline).
In the case of stable disease signs of myocardial administered dopamine, dobutamine, when necessary, a calcium supplementation.
Drug Interactions Verapamil SR
In vitro studies suggest that verapamil hydrochloride is metabolized with the participation of isozymes CYP3A4, CYP1A2, CYP2S8, CYP2C9 and CYP2C18 cytochrome P450. Clinically significant interaction was observed with the simultaneous use of inhibitors of CYP3A4, which caused increased levels of verapamil in plasma, while inducers of CYP3A4 reduced its concentration in plasma. Accordingly, while the application of such funds must consider the possibility of interaction.
The following table provides a list of possible drug interactions when taking Izoptina Wed 240.
The drug may change the pharmacokinetic parameters of verapamil and other drugs during their simultaneous application
Alpha-blockers
Prazosin – prazosin increase Cmax (40%) did not affect the T1 / 2 of prazosin
The increase in AUC terazosin, terazosin (24%) and Cmax (25%)
Antiarrhythmic drugs
Flecainide – minimum effect on the clearance of flecainide in plasma ( Reduced quinidine clearance of quinidine (35%)
Bronchodilators
Reduced theophylline systemic clearance of theophylline (20%). In smokers the clearance is reduced by 11%
Anticonvulsants
Increased carbamazepine AUC of carbamazepine (46%) in patients with resistant partial epilepsy
Antidepressants
Imipramine – increase in AUC of imipramine (15%). Not affect the level of desipramine (the active metabolite of imipramine)
Hypoglycemic agents
Glyburide – glyburide increases Cmax (28%), AUC (26%)
Antibiotics
Erythromycin – may increase levels of verapamil
Rifampicin – Decreases the AUC of verapamil (97%), Cmax (94%), oral bioavailability (92%)
Telithromycin – may increase levels of verapamil
Antineoplastic
Doxorubicin – Reduces T1 / 2 of doxorubicin (27%) and Cmax (38%) *
Tranquilizers
Phenobarbital – increases the clearance of verapamil in 5 times
Buspirone – buspirone increases AUC, Cmax increased by 3.4 times
Midazolam – increases AUC of midazolam (3 times) and Cmax (2 times)
Beta-blockers
Metoprolol – increases AUC of metoprolol (32.5%) and Cmax (41%) in patients with angina
Propranolol – increases AUC of propranolol (65%) and Cmax (94%) in patients with angina
Cardiac glycosides
Reduced total body clearance of digitoxin (27%) and extrarenal clearance (29%), digitoxin
Digoxin – in healthy volunteers increased Cmax of digoxin by 45-53%, Css of 42% and AUC by 52%
Histamine – blockers H2-receptor
Cimetidine – increases AUC R-enantiomer (25%) and S-enantiomer to (40%) of verapamil with a corresponding decrease in clearance of R-and S-verapamil
Immunomodulators
Cyclosporin – increases cyclosporine AUC, Css, Cmax by 45%
Sirolimus – may increase the level of sirolimus
Tacrolimus – may increase levels of tacrolimus
Lipid-lowering drugs
Atorvastatin – may increase the level of atorvastatin
Lovastatin – may increase the level of lovastatin
Simvastatin – Increases AUC (2.6 times) and Cmax (in 4.6 times) of simvastatin
Serotonin receptor antagonists
Almotriptan – increases AUC (20%) and Cmax (24%) almotriptana
Urikozurichesk – ie funds
Sulfinpyrazone – increase clearance of verapamil (3 times), reduced bioavailability (60%)
Others
St. John’s wort is reduced AUC R – (78%) and S – (80%) with a corresponding reduction of verapamil Cmax
Grapefruit juice increase in AUC R – (49%) and S – (37%) and verapamil Cmax R – (75%) and S – (51%) of verapamil. T1 / 2 and renal clearance did not change.
* Patients with progressive tumors verapamil does not affect the level or clearance doksirubitsina. In patients with small cell lung cancer verapamil decreased the T1 / 2 and Cmax doksirubitsina.
With the simultaneous use of the drug Izoptin 240 Wed antiarrhythmics, beta-blockers may mutually reinforcing effects on the cardiovascular system (the appearance of AV-block, slowing of heart rate, increased arterial hypotension, the development of heart failure).
Wed Izoptin 240 can increase the effect of other antihypertensive drugs (including diuretics, vasodilators).
With the simultaneous use of the drug Izoptin 240 Wed prazosin, terazosin observed an additive hypotensive effect.
Ritonavir and antiviral drugs may inhibit the metabolism of verapamil, which leads to an increase in its plasma concentrations. In this regard, the dose Izoptina Wed 240 will be reduced.
With the simultaneous use of the drug Izoptin 240 Wed quinidine in patients with hypertrophic obstructive cardiomyopathy in some cases we observed the development of pulmonary edema.
With the simultaneous use of the drug Izoptin Wed carbamazepine 240 notes the increasing levels of carbamazepine in plasma and increase its neurotoxicity. May experience side effects typical of carbamazepine, such as diplopia, headache, ataxia, or dizziness.
Wed Izoptin 240, while the application increases the neurotoxicity of lithium.
Hypotensive effect Izoptina Wed 240 can be reduced in the simultaneous use of rifampicin and sulfinpirazon.
When applied simultaneously with the drug Izoptin 240 Wed muscle action can be amplified.
While the use of aspirin can increase bleeding occur.
When applied simultaneously with the drug Izoptin Wed 240 increases the level of ethanol in plasma.
Concomitant use of drug-Wed Izoptin 240 can lead to increased serum levels of simvastatin or lovastatin.
Patients receiving verapamil treatment inhibitors of HMG-CoA reductase inhibitors (ie, simvastatin / lovastatin) should start with the lowest possible dose, which is further increased. If you want to assign verapamil in patients already receiving HMG-CoA reductase inhibitors, should be revised to reduce their dose, the concentrations of serum cholesterol. Such tactics should be followed by concomitant administration of verapamil with atorvastatin (although there are no clinical data supporting the interaction of verapamil and atorvastatin), because the data are precisely known pharmacokinetic studies showing that verapamil similarly affected and the level of atorvastatin.
Fluvastatin, pravastatin, rosuvastatin, and is not metabolized by the action of isozymes CYP3A4, therefore their interaction with verapamil least likely.
