What Is the Connection Between Mifepristone and Misoprostol?

Misoprostol is a prostaglandin E1 derivative, which has a strong inhibitory effect on gastric acid secretion, and has a contractile effect on the pregnant uterus. In addition, misoprostol has the pharmacological activity of a class E prostaglandin, which can soften the cervix, increase uterine tension and intrauterine pressure. Sequential application of induction of labor with mifepristone has become one of the main methods of mid-term induction of labor, which can better replace surgical operations such as forceps and amniocentesis. The abortion success rate is about 96.1%, which is a safe and effective method. Induction of labor. Misoprostol is the first PGE (prostaglandin E) derivative to be used clinically, and has obvious effects on various ulcers (except duodenal ulcers). However, its price is relatively expensive. At present, it is generally used as a second-line drug for treating ulcers, mainly for refractory ulcers or repeated authors. .

Drug type: Essential medicines
Drug name: Misoprostol

English name: Misoprostol
Chinese alias: Misoprotol
English alias: Miso; Cytotec

Brief introduction of misoprostol compounds

Misoprostol Basic Information

Chinese name: Misoprostol

Chinese alias: Misoptop; (11a, 13E) -11,16-dihydroxy-16-methylprostane-9-one-13-ene-1-acid methyl ester; 11, 13E) -11,16 -Dihydroxy-16-methyl-9-oxoprost-13-ene-1-acid methyl ester; Xike feed; Miso; Misoprostol; Misoput; Xikeku

English name: Misoprostol

English alias: MISOPROSTOL ACID; SC 2933; Misoprosto; Misoprostil; Cytotec

CAS number: 59122-46-2

Molecular formula: C ₂₂ H ₃₈ O ₅

Structural formula:

Molecular weight: 382.53400

Exact mass: 382.27200

PSA: 83.83000

LogP: 3.95360

Physicochemical properties of misoprostol

Appearance and properties: water-soluble, viscous liquid

Density: 1.078 g / cm ³

Boiling point: 497.3ºC at 760 mmHg

Flash point: 160.3ºC

Refractive index: 1.51

Storage conditions: -20ºC

Like PGE1, this product is very unstable at room temperature and extremely sensitive to pH and temperature. Under acidic or alkaline conditions, it can remove the C-11 hydroxyl group to become A-type prostaglandin, and then isomerize to B-type prostaglandin. Under thermal conditions, a thermal difference occurs and the material becomes an 8-foreign object. However, the dispersion system of this product in hydroxypropyl methylcellulose is much more stable than pure this product, and can be stored at room temperature.

Misoprostol safety information

Symbol: GHS06 GHS08

Signal Word: Danger

Hazard statement: H301; H360

Cautionary statement: P201; P301 + P310 + P330; P308 + P313

Dangerous Goods Transport Code: UN 2810 6.1 / PG 3

WGK Germany: 2

Danger category code: R60; R61; R25

Safety instructions: S53-S22-S36 / 37 / 39-S45

RTECS number: UK8390000

Dangerous goods mark: T ^[1]

Production method of misoprostol

Azelaic acid is used as a raw material to react with diimidazole sulfoxide to form an acylated product of imidazole. This product has strong acylation activity. After reacting with monomethyl malonate, it is acidified and decarboxylated to form 2- [8- (Methoxycarbonyl) octanoyl] methyl acetate, and then hydrolyzed and decarboxylated to form 8-oxodecanoic acid, and dimethyl oxalate is cyclized and then decarboxylated to generate 3-substituted cyclopentatrione, and one of them is selectively hydrogenated. The carbonyl group is a hydroxyl group. After reaction with acetone acetal, it is reduced to form 4-hydroxy-2- (methyl heptanoate-7-yl) -2,3-cyclopentenone. Finally, it is reacted with an organoaluminum reagent to obtain misoprost. Alcohol ^[1] .

Misoprostol uses

The first chemically synthesized prostaglandin E1 class anti-ulcer drug, which has a strong effect on inhibiting gastric acid secretion and preventing ulcer formation. The gastric acids that can be inhibited include basal gastric acid secretion and those caused by histamine pentagastrin, food or coffee. Stomach acid secretion can also reduce gastric acid secretion at night. It is the earliest anti-peptic ulcer drug used in clinic. It is better than prostaglandin antagonists in prolonging the recurrence of ulcers, but it is not as effective as island receptor antagonists in relieving pain in peptic ulcers. It is used for gastric and duodenal ulcers, especially for cases with low prostaglandin levels ^[1] .

Misoprostol Pharmacopoeia Standard

[Main active ingredients]

This product is (±) (11, 13E), 11,16 dihydroxy-16-methylprostane-9-one-13-ene-1-acid methyl ester, containing C22H38O5 not less than 96.5%.

[Character]

Light yellow sticky oily substance; slightly smelly.

This product is very soluble in dioxymethane, easily soluble in methanol, ethanol and ethyl acetate, and almost insoluble in water.

[Identification] (1) Take about 1mg of this product, add 5ml of ethanol to dissolve, shake well, take 0.5ml, add 1.5ml of 1% m-dinitrobenzene ethanol solution, cool in an ice bath, add 10% in the dark Potassium hydroxide acetic acid solution 1.5ml, the solution was pink. (2) The infrared light absorption spectrum of this product should be the same as that of the reference substance (Chinese Pharmacopoeia 2000 Edition Appendix II IVC).

[Inspection] Take this product and add acetonitrile-water (55:45) to make a test solution containing 1ml per 1ml and a preliminary test solution containing 50g per 1mg. Conditions, take 20l of the pre-test solution and inject it into the liquid chromatograph, adjust the detection sensitivity, so that the peak height of the main component chromatographic peak is about 20% ~ 25% of the full recording range, and then take 20l of the test solution for injection The retention time of the chromatogram to the main component peak is three times. According to the peak area normalization method, the ratio of the total peak area of all impurities to the total peak area must not exceed 3.5%, and the largest impurity peak area must not exceed 2.5%.

[Determination of content] It is determined according to effective liquid chromatography (Chinese Pharmacopoeia 2000 edition, Appendix VD). Chromatographic conditions and system adaptability test: Octadecylsilane bonded silica gel is used as filler, acetonitrile-water (55:45) is used as mobile phase; detection wavelength is 200nm. In 2000. The appropriate amount of this product is determined by the determination method, accurately weighed, dissolved with mobile phase and quantitatively diluted to make a solution containing about 0.2 mg per 1 ml, and a precise amount of 10 l is injected into the liquid chromatograph, and the chromatogram is recorded; Control substance, the same method. Calculate the peak area according to the external standard method.

[Category] Termination of early pregnancy medicine.

[Storage] Sealed with nitrogen and stored in a cold place.

Misoprostol Drug Description

Misoprostol Pharmacology

Prostaglandins and their derivatives are a class of anti-peptic ulcer drugs discovered in the past 20 years and attracting increasing attention. This product is the first synthetic prostaglandin I derivative to enter the clinic. It has been proven in animals and humans that it has a strong inhibitory effect on gastric acid secretion. Both the basal gastric acid or histamine, gastrin, and food stimulation caused a significant decrease in gastric secretion and acid excretion, and prion protease excretion also decreased after administration. However, the mechanism of action has not been elucidated, which may be related to affecting the activity of adenylate cyclase and thereby reducing cAMP levels in parietal cells. Animal experiments have also proven to prevent the formation of ulcers. Therefore, in addition to inhibiting gastric acid secretion, this product has a strong cytoprotective effect. In addition, this product also has the pharmacological activity of E-type prostaglandins, which can soften the cervix, enhance uterine tension and intrauterine pressure. Sequential use with mifepristone can significantly increase and induce the frequency and amplitude of spontaneous contraction of the uterus in early pregnancy, which is used to terminate early pregnancy. Its adverse reactions are less than that of thioprostone and carboprost methyl ester, and it is easy to use. Oral absorption is good. After a single oral dose, tmax is 0.5 hours and elimination half-life is 20-40 minutes. The plasma protein binding rate is 80 ~ 90%. The concentration of the drug in liver, kidney, intestine, stomach and other tissues is higher than blood. This product, labeled with radioactive elements, is excreted from the urine by about 75%, excreted from feces by about 15%, and excreted in the urine within 56 hours.

Misoprostol pharmacokinetics

Misoprostol is rapidly absorbed orally and can be completely absorbed after 1.5 hours. After 15 minutes of oral administration, the plasma active metabolite misoprost acid reached its peak. With a single oral administration of 200 g, the average peak drug concentration was 0.309 g / L. The misoprostol plasma protein binding rate is 80% to 90%. The concentration of the drug in liver, kidney, intestine, stomach and other tissues is higher than the blood drug concentration. The elimination half-life of misoprostol is 20 to 40 minutes, and 400 g of misoprostol is administered orally every 12 hours without accumulation in the body. About 75% of misoprostol is excreted by the kidney through the urine, and about 15% is excreted from the feces; the urine output is 56% within 8 hours.

Misoprostol indications

Applicable to gastric and duodenal ulcers. For duodenal ulcers, 200 g of this product was taken orally 4 times a day, and the healing rate was 54% after 4 weeks. The control group was treated with cimetidine 300 mg orally 4 times a day, and the healing rate was 61% after 4 weeks. Seems slightly lower than cimetidine, but this product is more effective than cimetidine in protecting gastric mucosa from damage. This product is also used to fight early pregnancy.

Misoprostol dosage

1. Gastric ulcer and duodenal ulcer: 200 g each time, 4 times a day, orally before meals and before bedtime. The course of treatment is 4-8 weeks. If the ulcer relapses, the course of treatment can be extended.

2. Prevention of peptic ulcer caused by anti-inflammatory: 200 g each time, 2 to 4 times a day, the dosage should be based on individual differences and clinical conditions.

3. Anti-early pregnancy: Healthy early pregnant women who have stopped taking medicine for less than or equal to 49 days, when they require medical abortion, take 150 mg of mifepristone in divided doses (25 mg each time, twice a day for 3 days.) Take 200mg orally and fast for 2h before and after taking the medicine. After taking Mifepristone for 36 to 48 hours, take Misoprostol 400-600 g on an empty stomach.

Misoprostol adverse reactions

Gastrointestinal reactions are the most common adverse effects of misoprostol and are dose-dependent. It is mainly loose stools or diarrhea. Most of them do not affect the treatment. Occasionally, the condition is severe and lasts for a long time. Others may include mild nausea, vomiting, abdominal discomfort, abdominal pain, indigestion, headache, dizziness, and fatigue. Very few women can develop rashes, facial flushing, itchy palms, chills, transient fever, and even anaphylactic shock.

Misoprostol contraindications

1. Prohibition of prostaglandin allergies.

2. Those who are contraindicated in the use of prostaglandins, such as glaucoma, asthma, allergic colitis and allergies should be banned.

3. Patients with heart, liver, kidney or adrenal insufficiency are prohibited.

4. Disable pregnant women.

Misoprostol precautions

1. Use with caution in patients with cerebrovascular or coronary artery disease, hypotension, and epilepsy. (Misoprostol should only be used when epilepsy is controlled or the benefits outweigh the disadvantages).

2. The safety and efficacy of misoprostol in children have not been determined.

3. Misoprostol has a contractile effect on the uterus of the pregnancy, except for termination of early pregnancy, pregnant women are prohibited. Women must have a negative serum pregnancy test within 2 weeks before the start of treatment with misoprostol. Women must use effective contraception during medication; if pregnancy is suspected, misoprostol should be discontinued immediately.

4. Whether the active metabolite of misoprostol can be excreted through milk is unclear, so it should not be used in lactating women.

5. Misoprostol can cause diarrhea. For high-risk patients, monitor for dehydration.

6. When misoprostol is used to terminate early pregnancy, it must be sequentially compatible with mifepristone and must be observed and followed up according to the requirements of routine medical abortion.

7. When misoprostol is used in peptic ulcer, the success of treatment should not be judged by symptomology.

8. The symptoms of overdose are tolerable. Misoprostol was used at 1 200 mg per day for 3 months without serious adverse reactions.

Misoprostol Drug Interactions

1. Antacids (especially magnesium-containing antacids) combined with misoprostol will aggravate diarrhea and abdominal pain caused by misoprostol.

2. There have been reports of adverse neurological reactions following the combined use of butaprost and misoprostol, with symptoms including headache, dizziness, hot flashes, excitement, transient diplopia, and ataxia.

3. Taking misoprostol while eating can delay the absorption of the latter, which shows that the peak time is prolonged and the peak concentration of blood drug is reduced, which also reduces the incidence of adverse reactions.

Misoprostol

Tablets: 200 g each.

^[2-6]

Misoprostol Expert Reviews

Misoprostol is a prostaglandin E1 derivative, which has a strong inhibitory effect on gastric acid secretion, and has a contractile effect on the pregnant uterus. In addition, misoprostol has the pharmacological activity of a class E prostaglandin, which can soften the cervix, increase uterine tension and intrauterine pressure. Sequential application of induction of labor with mifepristone has become one of the main methods of mid-term induction of labor, which can better replace surgical operations such as forceps and amniocentesis. The abortion success rate is about 96.1%. Induction of labor. Misoprostol is the first PGE (prostaglandin E) derivative to be used clinically, and has obvious effects on various ulcers (except duodenal ulcers). However, its price is relatively expensive. At present, it is generally used as a second-line drug for treating ulcers, mainly for refractory ulcers or repeated authors ^[6] .

Misoprostol tablets

Indications: This product is used in combination with mifepristone sequentially, and can be used to terminate early pregnancy within 49 days of menopause.

Dosage: This product is sequentially combined with mifepristone. After taking mifepristone for 36 to 72 hours, 0.6 mg (3 tablets) of misoprostol is administered orally on a single fasting.

Dosage form: tablet

Adverse reactions: Some early pregnant women have mild nausea, vomiting, dizziness, fatigue, and lower abdominal pain after taking the medicine. Very few women can experience flushing, fever, itching of the palms, and even anaphylactic shock.

Taboo:

1. Patients with heart, liver and kidney disease and adrenal insufficiency;

2. Those who are contraindicated in the use of prostaglandins, such as glaucoma, asthma and allergies;

3 Pregnancy with IUD and suspected ectopic pregnancy.

Precautions:

1. When this product is used to terminate early pregnancy, it must be compatible with mifepristone, and it is strictly prohibited to use it alone.

2. When this product is compatible with mifepristone to terminate early pregnancy, it must be prescribed by a doctor and used by units with emergency curettage and infusion and blood transfusion conditions under the supervision of a doctor. This product must not be sold on its own in a pharmacy.

3 Before taking the medicine, the user must be informed in detail about the treatment effect and possible side effects. When taking this product, you must observe in the hospital for 4-6 hours. During the treatment or follow-up, if there is a lot of bleeding or other abnormal conditions, you should seek medical treatment in a timely manner.

4 After taking the medicine, a small amount of vaginal bleeding usually occurs earlier, and some women have a longer bleeding time after abortion. A few early pregnant women can take a natural abortion after taking mifepristone, but they must still take this medicine as usual. About 80% of pregnant women discharge villous fetal sac within 6 hours after using this product. About 10% of pregnant women discharge their pregnancy within one week of taking the medicine.

5. 8 to 15 days after taking the medicine, the original treatment unit should be revisited to determine the effect of abortion. If necessary, do a B-ultrasound or blood HCG measurement. If it is confirmed that the abortion is incomplete or the pregnancy continues, it should be handled in time.

6. Failure to use this product to terminate early pregnancy must be aborted to terminate the pregnancy.

Ingredients: [chemical name] The main ingredient of this product is misoprostol. Its chemical name is: (±) (11a, 13E) -11,16dihydroxy-16-methylprostane-9-one-13-ene-1-acid methyl ester.

Properties: This product is white or off-white film.

Medication for pregnant women and lactating women: Except for the termination of early pregnant women, other pregnant women are prohibited. Breastfeeding women should weigh the pros and cons and use with caution.

Pediatric use: Unclear.

Elderly medication: Not clear.

Drug interactions: Avoid taking aspirin and other non-steroidal anti-inflammatory drugs within 1 week of taking this product.

Pharmacological effects: Termination of early pregnancy drugs. This product has cervical softening, enhance uterine tension and intrauterine pressure. Sequential combination with mifepristone can significantly increase or induce the frequency and amplitude of spontaneous contraction of the uterus in early pregnancy. This product has the pharmacological activity of E-type prostaglandin, has a mild stimulating effect on the gastrointestinal smooth muscle, and inhibits gastric acid secretion at high doses.

Overdose: Unclear.

Pharmacokinetics: This product is quickly absorbed orally and can be completely absorbed in 1.5 hours. Its plasma active metabolite misoprostol has a peak time of 15 minutes, 200 g orally, an average peak concentration of 0.309 g / L, and an elimination half-life of 36 to 40 minutes. Mainly excreted through urine.

Storage: shading, sealed, and stored in a cool (not more than 20 ) dry place.

Validity of the drug: 24 months ^[7]