What Is Verapamil?

Verapamil, a papaverine derivative, was used as a coronary dilator in 1962. Verapamil, also known as verapamil and Wumai'an, is a calcium channel blocker. In recent years, it has been used to treat hypertension, angina pectoris, arrhythmia, cerebrovascular disease, finger vasospasm, abdominal pain, esophageal tachycardia, migraine, pulmonary hypertension and prevention of premature birth.

Chinese name: Verapa
nickname: Verapamil, valapamil, asystole
English name: Verapamil

M F: C27H38N2O4
M W: 454.6
CAS: 52-53-9

Verapamil compounds

Verapami Basic Information

Chinese name: Verapamil

Chinese alias: 5-((3,4-dimethoxyphenethyl) methylamino) -2- (3,4-dimethoxyphenyl) -2-isopropylvaleronitrile; Isoptin ; Arrest; Wumai'an; Vanapamil; Gaiheng; Verapamil hydrochloride sustained-release tablets; Verapamil hydrochloride

English name: 2- (3,4-dimethoxyphenyl) -5-{[2- (3,4-dimethoxyphenyl) ethyl] (methyl) amino} -2- (propan-2-yl) pentanenitrile

English alias: eronitrile; aleronitrile; VPL; Vasolan; Verapamil; Cordilox; Isproveratril; Veraloc; Verapamilum Iproveratril ISOPTIN; Isoptin; Veraloc; Iproveratril

CAS number: 52-53-9

Molecular formula: C ₂₇ H ₃₈ N ₂ O ₄

Structural formula:

Molecular formula

Molecular weight: 454.60200

Exact mass: 454.28300

PSA: 63.95000

LogP: 5.09308

Verapamil Physical and Chemical Properties

Appearance and properties: sticky, light yellow oily, commonly used as its hydrochloride salt, white powder; odorless. Soluble in methanol, ethanol or chloroform, and soluble in water.

Melting point: 140 ° C ~ 145 ° C.

Density: 1.058 g / cm ³

Boiling point: 243-246 ° C (1.3 Pa)

Flash point: 308.3ºC

Refractive index: 1.5448

Stability: stable under normal temperature and pressure

Storage conditions: sealed and stored in a cool, dry environment

Verapamil Safety Information

Packing level: II

Danger category: 8

Dangerous Goods Transport Code: UN 1939 8 / PG 2

WGK Germany: 3

Danger category code: R14; R34; R37

Safety instructions: S26; S36 / 37/39; S43

Dangerous goods mark: C ^[1]

Verapamil production method

After the hydrocarbonization reaction of dimethoxyphenylacetonitrile and bromoisopropane, chloropropylation reaction with 1,3-chlorobromopropane, and then condensation with 3,4-dimethoxyphenethylamine to form verapapa Meter.

Verapamil Drug Description

Verapamil Classification

Circulatory Drugs> Antiarrhythmic Drugs> Calcium Channel Blockers

Verapamil dosage form

1. Tablet: 40mg;

2. Sustained-release tablets: 240mg;

3. Injection: 2ml, 5ml.

Verapamil Action and Use

For calcium channel blockers (calcium antagonists). Since the inhibition of calcium influx can reduce the rate of auto-depolarization during diastole,

Verapami And slowing the sinus node's issuance impulse can also slow conduction. It slows forward conduction and thus eliminates AV node reentry. It has a dilating effect on peripheral blood vessels, which lowers blood pressure, but it is weaker, which generally causes heart rate to slow down, but can also increase reflex heart rate due to blood pressure drop. It has a diastolic effect on the coronary arteries, can increase coronary flow and improve myocardial oxygen supply. In addition, it can also inhibit platelet aggregation.

Verapamil Pharmacology and Pharmacokinetics

Pharmacodynamics

It belongs to class IV antiarrhythmic drugs and is an inhibitor of calcium ion influx (slow channel blocker). In the heart, the inhibition of calcium ion inflow reduces the autonomy of the sinoatrial node and the atrioventricular node, and slows the conduction, but rarely affects the atrial and ventricular decreases, affects the activity of contractile proteins, weakens myocardial contraction, reduces cardiac work, and myocardium. Reduced oxygen consumption. For blood vessels, calcium inflow arterial pressure decreases, and ventricular postload decreases.

Pharmacokinetics

More than 90% are absorbed after oral administration, and the bioavailability is low, about 20 to 35%. The protein binding rate was 90% (87-93%). It is mainly metabolized in the liver. After oral administration, only 20 to 35% enter the blood circulation after the first checkpoint effect. Therefore, the oral dose needs to be 10 times the intravenous dose to achieve the same blood concentration. The metabolite, norverapamil, has a heart. active. The oral half-life of a single dose is 2.8 to 7.4 hours, and the multiple dose is 4.5 to 12 hours. The intravenous-drug curve is biphasic, with a half-life of about 4 minutes and a half-life of 2 to 5 hours; norverapamil The half-life is about 9 hours. The effect begins 1 to 2 hours after oral administration, and reaches the maximum effect 3 to 4 hours for 6 hours. The antiarrhythmic effect of intravenous administration starts at 2 minutes (1 to 5 minutes), the maximum effect is reached at 2 to 5 minutes, the effect lasts about 2 hours, and the hemodynamic effect starts at 3 to 5 minutes, lasting about 10 to 20 minutes. It is mainly cleared by the kidneys. Metabolites are excreted in 50% within 24 hours, 70% in 5 days, 3% in the original medicine, and 9-16% in the digestive tract and removed into the feces. Hemodialysis cannot remove the product.

Verapamil indications

Oral is suitable for treatment: various types of angina pectoris, including stable or unstable angina pectoris, and angina pectoris caused by coronary artery spasm, such as variant angina pectoris; premature atrial pulsation to prevent angina pectoris or paroxysmal supraventricular Tachycardia; hypertrophic cardiomyopathy; hypertension.

Intravenous injection is suitable for the treatment of rapid supraventricular arrhythmias, making paroxysmal supraventricular tachycardia into sinus, and slowing the ventricular rate of atrial flutter or atrial fibrillation.

Oral for the treatment of atrial premature beats or prevention of supraventricular tachycardia. It is also used to treat mild to moderate hypertension, hypertrophic cardiomyopathy, stuttering, esophageal spasm, and esophageal achalasia. Intravenous boluses are used to discontinue paroxysmal supraventricular tachycardia, atrial fibrillation with rapid ventricular rate, and are used to discontinue triggering activity caused by extremely short synapses or idiopathic tip-torsional ventricular tachycardia. This product is effective in stopping paroxysmal supraventricular tachycardia and has a significant effect. It is the drug of choice for the treatment of supraventricular tachycardia.

Verapamil dosage

1. Oral absorption is complete, the blood concentration reaches a peak within 30 to 45 minutes, and it takes effect in 90 minutes, maintaining it for 5 to 6 hours. Oral 85% is inactivated by the liver, so the oral dose is 10 times greater than that of intravenous injection. 90% of plasma binds to plasma proteins. The effect started 1 to 2 minutes after the intravenous injection, and the maximum effect was achieved at 10 minutes, and the effect lasted 15 minutes.

2. Commonly used doses for adults: Orally, starting at 40 80mg once a day, 3 4 times a day, the dosage can be increased daily or weekly as needed and tolerated, the total daily amount is generally 240 480mg; intravenously, Start with 5mg (or 0.07S-0.15mg / kg according to body weight), intravenously for 2 ~ 3 minutes, if it is not effective, re-inject it after 10 ~ 30 minutes; in elderly patients, in order to reduce the adverse reactions, the above dose should be 3 ~ Slowly inject for 4 minutes; Intravenous infusion, 5-10 mg per hour, add sodium chloride injection or 5% glucose injection by intravenous drip, and the total amount in one day should not exceed 50-100 mg.

3. Adults should take 480mg orally a day, and take it in divided doses.

4. Commonly used amount in children Orally, 20mg once under 2 years old, 2 or 3 times a day; 40 120mg once a year over 2 years old, 2 or 3 times a day, depending on age and response; Intravenous, newborn to The first dose at the age of 1 year is 0.1 0.2mg / kg; the first dose at the age of 1 to 15 years is 0.1 0.2mg / kg, the total amount does not exceed 5mg, slow intravenous injection for 2-3 minutes, continuous monitoring of ECG, if necessary, 30 Give another dose in minutes.

Verapamil adverse reactions

Mostly related to the dose, often occurs when the dose is not adjusted.

Cardiovascular: bradycardia (less than 50 beats per minute), occasionally developing II or III degree AV block and cardiac arrest; may bypass preexcitation or LGL syndrome with atrial fibrillation or atrial flutter Accelerated conduction leading to faster heart rate; heart failure; hypotension; lower extremity edema.

Sacral nerve: dizziness or dizziness, which can cause cold pain, numbness and burning sensation in the limbs.

(3) Allergic reactions: occasionally nausea, mild headache and joint pain, itching of the skin and urticaria may occur.

endocrine: occasionally can increase blood prolactin concentration or galactorrhea.

Treatment of adverse reactions: general reactions can be reduced or discontinued. Serious adverse reactions require urgent treatment. Bradycardia, conduction block, or cardiac arrest can be given intravenously to atropine, isoproterenol, norepinephrine, or an artificial cardiac pacemaker. Tachycardia occurs in patients with pre-excitation or LGL syndrome, which can be converted to direct heart rhythm and given intravenous lidocaine or procainamide. Hypotension can be given intravenously with isoproterenol, m-hydroxylamine or norepinephrine.

Dizziness, nausea, vomiting, constipation, palpitations, hypotension (decreased blood pressure), bradycardia, conduction block, and even cessation of esthesia. Individual cases of extraventricular contractions can cause liver damage, nightmares or dreams, acidosis , Congestive heart failure, skin necrosis, local tissue damage in individual cases. Cerebral thrombosis in individual cases in severe overdose. Renal insufficiency can cause poisoning.

There may be adverse reactions such as nausea, vomiting, constipation, palpitations, and dizziness. Intravenous bolus injection can cause hypotension, and occasionally sinus bradycardia, sinus arrest, and or degree atrioventricular block.

Verapamil contraindications

The following conditions should be disabled: Cardiogenic shock; Congestive heart failure, unless it is effective for this product secondary to supraventricular tachycardia; Grade II to III atrioventricular block; Severe hypotension Systolic blood pressure <12kPa (90mmHg); Sinus node syndrome, unless artificial cardiac pacing; Preexcitation or LGL syndrome with atrial fibrillation or atrial flutter, unless artificial cardiac pacing.

The following cases should be used with caution: Extreme bradycardia; Heart failure, digitalis and diuretics must be used to control heart failure before giving this product, moderate or severe heart failure [ie pulmonary wedge pressure> 2.67kPa (20mmHg) , Spraying fraction <20%] to the product can worsen the condition; liver damage; mild to moderate hypotension, the peripheral vasodilation of the product aggravates hypotension; renal function damage.

Renal insufficiency can cause poisoning. Bronchial asthma should be used with caution, heart failure should be used with caution or disabled. Conduction block and cardiogenic shock ^[2] are disabled.

Have hypotension, severe heart failure, cardiogenic shock, or degree atrioventricular block, sick sinus syndrome, pre-excitation syndrome with bypass anterior reentrant tachycardia, especially with atrial fibrillation, atrial Flutter is disabled.

Bronchial asthma and liver dysfunction should be used with caution.

The speed of intravenous bolus injection should not be too fast, otherwise it may cause the risk of cardiac arrest.

Sinus node dysfunction or atrioventricular block in patients with sinus bradycardia, sinus arrest, heart block, hypotension, shock, or even cardiac arrest. Do not use for abnormal tachyarrhythmia with abnormal QR conduction and QRS widening. For hypertrophic cardiomyopathy, severe conduction disorders can occur. Patients with pulmonary hypertension can develop cardiac arrest and death with this drug. Application in patients with heart failure should be careful.

Verapamil drug interactions

When combined with antihypertensive drugs, the dose of this product must be carefully adjusted to avoid low blood pressure. Do not drink.

blockers, for those with normal atrioventricular conduction function and left ventricular systolic function, mean that oral administration of this product and blockers will not cause serious adverse reactions. If administered intravenously, the two drugs must be separated for several hours and should not be combined, otherwise the contraction of the myocardium and the sinus node and atrioventricular node conduction functions will be inhibited.

(3) Under close observation, oral digitalis preparations are used in the same way as oral or injectable products, which will not cause serious adverse reactions, but both slow down atrioventricular conduction. Therefore, monitoring must be performed to detect atrioventricular conduction block or cardiac dysfunction. slow. When digitalis is poisoned, this product should not be injected intravenously, because severe atrioventricular block may occur. This product can reduce the renal clearance of digoxin. This effect is related to the dose, so the dose of digoxin should be reduced when the two drugs are combined.

Propofylamine should not be given within 48 hours or 24 hours after giving this product. Both drugs have a negative inotropic effect, which may cause atrioventricular block, bradycardia, or increase the forward conduction velocity of the pre-excitation syndrome bypass.

Drugs with high prion protein binding capacity, due to competitive binding, increase the free blood concentration of the product, so care must be taken when combining them.

Because this product can inhibit the metabolism of cytochrome P450, it can cause the blood concentration of carbamazepine, cyclosporine, aminophylline, quinidine or valproate to increase, thereby increasing toxicity.

This product is used in combination with -blockers. Due to the additive effect of the negative muscle strength and negative frequency of the two, it can cause hypotension, sinus node dysfunction, atrioventricular block, and even cause cardiac arrest. Stop danger. Combined with digoxin, it can increase the serum concentration of digoxin and easily cause digitalis poisoning. In combination with quinidine, it can cause hypotension. Combination with amiodarone can cause significant bradycardia or atrioventricular block.

This drug significantly increases the plasma digoxin concentration in healthy people or patients with atrial fibrillation, and its mechanism is unknown.

This drug is used in combination with -blockers, especially for intravenous administration or myocardial insufficiency can cause severe hypotension and heart failure. Sinus node dysfunction, atrioventricular block, or complete heart block may occur in patients who have used beta blockers when given this drug intravenously. Severe bradycardia occurred with timolol eye drops and oral administration of 160 mg of the drug.

The combination of this drug and a volatile anesthetic can enhance the negative contraction effect of the anesthetic. After intravenous infusion of this drug in one patient, anesthesia occurred with halothane anesthesia.

This drug inhibits the elimination of digoxin from the kidney, which usually disappears within a few weeks, but the inhibition of extrarenal elimination of digoxin is persistent, and the overall result increases the plasma digoxin concentration.

Shock and / or cardiac arrest may occur in patients receiving digoxin alone or digoxin in combination with quinidine, propranolol, or propiramine given intravenous verapamil.

This medicine combined with theophylline can cause theophylline poisoning.

This drug inhibits carbamazepine metabolism in the liver, resulting in increased serum concentrations and neurotoxic symptoms such as dizziness. Nausea, ataxia and diplopia.

Calcium salts and vitamin D2 for osteoporosis can combat the antiarrhythmic effect of verapamil ^[3] .

Verapamil Notes

1. (1) Bradycardia. (2) Mild heart failure, digitalis and diuretics must be used to control heart failure before giving verapamil; moderate or severe heart failure, pulmonary capillary wedges increase hypotension. (4) Impaired liver function. (5) Impaired renal function. (6) Bronchial asthma. (7) Pregnant women.

2. The effects of drugs on breastfeeding: breastfeeding is safe.

3. The effect of drugs on the test value or diagnosis: (1) When the blood concentration is less than 30ng / ml, there is no change in the PR interval of the electrocardiogram, and when it is greater than 30ng / ml, the PR interval is prolonged, and the extent of the increase is proportional to the blood concentration. There were no changes in the interval and QT interval. (2) Aminotransferase and alkaline phosphatase can be increased. (3) The total serum calcium concentration is not affected. (4) Blood pressure may decrease.

4. Check or monitor before and after medication and when taking medication: (1) Blood pressure. (2) Pay attention to monitoring the electrocardiogram when intravenously or adjusting the oral dose. (3) Verapamil can cause liver cell damage, and liver function must be measured regularly during long-term treatment.

5. Oral is suitable for the treatment of angina pectoris, but the dosage should be adjusted according to the needs of patients and tolerance status.

6. Heart failure and diuretics should be added to those with heart failure or exacerbation of original heart failure when using verapamil.

7. Intravenous injection is suitable for the treatment of arrhythmia. The injection speed should not be too fast, otherwise it can cause sudden cardiac arrest. First aid equipment and medicines should be available to closely monitor changes in heart rate, heart rhythm and blood pressure. Verapamil cannot be given intravenously to those already on beta-blockers or digitalis poisoning. Verapamil injection is not compatible with Ringer's solution, 5% glucose injection or sodium chloride injection.

8. Treatment of adverse reactions: general reactions can be reduced or discontinued, and severe adverse reactions require urgent treatment. Bradycardia, conduction block, or cardiac arrest can be given intravenously to atropine, isoproterenol, norepinephrine, or an artificial cardiac pacemaker. Patients with tachycardia who have pre-excitation syndrome can use direct current to replenish heart rhythm, and intravenous lidocaine or procainamide. Hypotension can be administered intravenously with isoproterenol, meta-hydroxylamine, or norepinephrine.

Verapamil poisoning

Verapamil (Venipadine, Wumai'an, Vanapamil, Cardiac Arrest) is a calcium channel blocker used to treat arrhythmias, mainly supraventricular arrhythmias. It can dilate blood vessels and increase coronary flow and renal blood flow. It can reduce blood pressure, reduce myocardial contractility, and reduce myocardial oxygen consumption. It is used for the treatment of coronary heart disease. The plasma concentration peaked at 2 to 3 hours after oral administration, and the maximum effect occurred at 5 hours. Intravenous injection is effective for 1 to 5 minutes, peaks at 10 minutes, and lasts 20 minutes. Most are excreted by the kidney, 25% are excreted by the gastrointestinal tract, and the half-life is 5-7 hours. Orally take 40 80mg, 3 4 / d, the extreme amount is 480mg / d, and the maintenance amount is 40mg, 3 / d.

Intravenous injection or intravenous drip, use 0.075 0.15mg / kg, dissolved in 5% glucose solution 20 40ml, after 5min injection, can be repeated once in 15min. Intravenous dripping is performed at a dropping rate of 5 to 10 mg / h, and the extreme amount is 50 to 100 mg / d.

The oral LD50 of the mice was 170 mg / kg, and the intravenous LD50 was 17 mg / kg. This medicine mainly damages the heart and digestive system (liver).

Clinical manifestation

1. Adverse reactions Nausea, vomiting, bloating, diarrhea, constipation, rash, pruritus, dizziness, drowsiness, numbness of the limbs; bradycardia, inducing or exacerbating heart failure, lower limb edema, conduction block.

2. Poisoning performance

(1) Cardiovascular system performance: severe bradycardia, sinus stagnation, sinus arrest, sinoatrial block, atrioventricular block, borderline rhythm, pre-systole, atrial fibrillation, ventricular fibrillation, and heart Arrest, decreased blood pressure, and cardiogenic shock.

(2) Nervous system manifestations: hallucinations, tinnitus, syncope, lethargy, convulsions, coma, cerebral infarction, etc.

(3) Respiratory system performance: non-cardiogenic pulmonary edema, bronchial asthma.

(4) Others: liver and kidney damage; elevated blood sugar and metabolic acidosis.

treatment

The main points of treatment for verapamil poisoning are:

1. Poisoning should be stopped immediately.

2. For a large amount of oral administration, wash the stomach with water, take 1g / kg of medicinal charcoal, and then use diarrhea with magnesium sulfate, and then take 0.5g / kg of medicinal charcoal for 4-6 hours each time until the stool containing medicinal charcoal is discharged. until.

3. Apply calcium, add 10ml of 10% calcium chloride to 20ml of glucose solution, and slowly inject it intravenously, followed by 20 50mg / (kg · h), intravenous drip.

4. Bradycardia, given atropine or isoprenaline, especially on the basis of calcium.

5. Hypotension, bradycardia, atrioventricular block, when do not use enough calcium, dopamine, epinephrine, isoprenaline can be used.

6. Application of glucagon, when the above-mentioned calcium, atropine, and dopamine are not effective, glucagon can be used. The starting amount for adults is 5-10 mg intravenously, followed by 25 mg / h intravenous infusion, maintaining 12 24h, up to 48h. It is advisable to monitor blood calcium levels during treatment during normal levels.

7. Severe arrhythmia is treated with artificial cardiac pacemaker and electrical cardioversion.

8. Blood exchange therapy ^[4] .

Verapami Expert Reviews

Verapamil is a drug with a variety of therapeutic effects, and has significant effects on hypertension, angina pectoris, hypertrophic cardiomyopathy, and tachyarrhythmia. Its antihypertensive effect is no less than that of beta blockers or diuretics; it has significant effects in the treatment of variant angina pectoris and labor angina pectoris; HCM ineffective for beta blockers often also works, and the effective rate of terminating PSVT is more than 85% ^[5] .