xī mǐ tì dīng
2 English referenceCimetidine
3 OverviewCimetidine is an H2 receptor blocking drug, a white or off-white crystalline powder; it is virtually odorless and has a bitter taste. It can significantly inhibit gastric acid secretion induced by food, histamine or pentagastrin *** and reduce its acidity. It has preventive and protective effects on corrosive gastritis caused by chemical ***. It is used for the treatment of active duodenal ulcer and the prevention of recurrence of duodenal ulcer. Poisoning mainly damages the nervous system, blood system, cardiovascular system and liver, kidney.
4 Cimetidine Pharmacopoeia Standard 4.1 Name 4.1.1 Chinese nameCimetidine
4.1.2 Chinese pinyinXimitiding
4.1.3 English name
Cimetidine
4.2 Structural formula 4.3 Molecular formula and molecular weightC10H16N6S 252.34< /p> 4.4 Source (name), content (potency)
This product is 1methyl 2 cyano 3[2[[(5methylimidazol4yl)methyl]thio]ethyl]guanidine. Calculated as dry product, containing C10H16N6S shall not be less than 99.0%.
4.5 PropertiesThis product is white or off-white crystalline powder; almost odorless, bitter taste.
It is soluble in methanol, soluble in ethanol, slightly soluble in isopropanol, slightly soluble in water; soluble in dilute hydrochloric acid.
4.5.1 Absorption coefficientTake this product, weigh it precisely, add hydrochloric acid solution (0.9→1000) to dissolve and dilute it quantitatively to make a solution containing about 8 μg per 1 ml, and then measure the absorbance at 218 nm according to the UV-visible spectrophotometric method (2010 version of the Pharmacopoeia, Appendix Ⅳ A), the absorption coefficient (ΔΔΔΔΔΔΔΔ) was 751～797.
4.6 Identification(1) take about 50mg of this product, add 10ml of water, slightly warm to dissolve, add 1 drop of ammonia test solution and 2 drops of copper sulfate test solution, a blue-gray precipitate; then add excess ammonia test solution, the precipitate is dissolved.
(2) take about 50mg of this product, incandescent cauterization, the resulting gas can make the lead acetate test paper black.
(3) The infrared light absorption pattern of this product should be consistent with the pattern of the control (Atlas 142).
4.7 Check 4.7.1 Clarity and color of acid solutionTake 3.0g of this product, add 1mol/L hydrochloric acid solution 12ml dissolved, diluted with water to 20ml, shaking well, the solution should be clear and colorless; if turbid, compared with the No. 1 turbidity standard solution (2010 version of the Pharmacopoeia, Part II, Appendix IX B), shall not be more concentrated; if color, compared with the yellow No. 3 standard colorimetric liquid ( If color develops, it shall not be darker when compared with the yellow No.3 standard colorimetric solution (the first method of Appendix IX A of Part II of Pharmacopoeia, 2010 edition). (For injection)
4.7.2 ChlorideTake 1.0g of the product, check according to the law (2010 version of the Pharmacopoeia, Part II, Appendix VIII A), and compare it with the control solution made from 8ml of standard sodium chloride solution, and it shall not be more concentrated (0.008%).
4.7.3 Related substancesTake the product, add mobile phase to dissolve and dilute to make a solution containing 0.4 mg per 1 ml, as a test solution; take an appropriate amount of precision, dilute with mobile phase to make a control solution containing 2 μg per 1 ml and 0.2 μg per 1 ml (1) and (2). Determined by high performance liquid chromatography (2010 version of Pharmacopoeia II Appendix V D). Using octadecylsilane bonded silica gel as filler; methanol-water (240:760) (containing 0.3 ml of phosphoric acid and 0.94 g of sodium hexanesulfonate per 1000 ml) as the mobile phase; detection wavelength of 220 nm. about 40 mg of the product, put in 100 ml of flasks, add 1 mol/L hydrochloric acid solution 10 ml, water bath heating for 2 minutes, let cool, add 1 mol/L hydrochloric acid solution 10 ml, heat for 2 minutes, then add 1 mol/L hydrochloric acid solution. Let cool, add 1 mol/L sodium hydroxide solution 10 ml neutralization, diluted with mobile phase to the scale, shaking well (clinical use of new), take 20 μl injected into the liquid chromatograph, record the chromatogram. The relative retention time of the amide analog to cimetidine was about 2.0, and the separation between the peaks of cimetidine and cimetidine should be greater than 8.0. 20μl of control solution (2) was taken and injected into the liquid chromatograph, and the signal-to-noise ratio of the peaks of cimetidine was not less than 10; a precise amount of 20μl of each of the test solution and the control solution (1) were taken and injected into the liquid chromatograph, respectively, and the chromatograms were recorded to 3.5 times of the retention time of the peaks of the main component. 3.5 times. If the chromatogram of the test solution shows impurity peaks, the area of a single impurity peak shall not be greater than 0.4 times the area of the main peak of the control solution (1) (0.2%); the sum of the areas of the impurity peaks shall not be greater than 2 times the area of the main peak of the control solution (1) (1.0%). Any peak in the test solution less than 0.5 times the area of the main peak of the control solution (2) is negligible.
4.7.4 Loss of weight on dryingTake the product, dry at 105 ℃ until constant weight, the loss of weight should not be more than 0.5% (2010 version of the Pharmacopoeia II Appendix VIII L).
4.7.5 Residue from incinerationTake 1.0g of the product, check according to law (2010 version of the Pharmacopoeia II Appendix VIII N), the residue left should not be more than 0.1%.
4.7.6 Heavy metalsTake the residue left under the cauterization residue, check according to the law (2010 version of the Pharmacopoeia, Part II, Appendix VIII H, the second method), the heavy metals shall not be more than 10 parts per million.
4.8 Content determinationTake about 0.2g of this product, precision weighing, add 60ml of glacial acetic acid to dissolve, add 1 drop of crystal violet indicator solution, titrate with perchloric acid titrant (0.1mol/L) until the solution is just blue, and the titration results are corrected with a blank test. Each 1 ml of perchloric acid titrant (0.1 mol/L) is equivalent to 25.23 mg of C10H16N6S.
4.9 ClassH2 receptor blockers.
4.10 StorageKeep sealed.
4.11 Preparation(1) Cimetidine tablets? (2) Cimetidine capsules? (3) Cimetidine sodium chloride injection
4.12 VersionChinese People's **** and State Pharmacopoeia 2010 Edition
5 Cimetidine Instructions 5.1 Name of the drugCimetidine
5.2 English nameCimetidine
5.3 Cimetidine's aliasesMethylcyanopyrimidine; Methylcyanomethylguanidine; Metacyanomethylamine; Methylcyanomethylguanidine; Methylcyanomethylguanidine; Tai Gastromet; Cimetidine; Altramet; Cimetidinum; Cimetum; Itacem; Tagamet; Tametin; Notul
5.4 ClassificationDigestive System Drugs > Acid-producing and Gastric Mucosal Protecting Drugs
5.5 Propertieswhite or off-white crystalline powder Almost odorless, bitter taste. Soluble in methanol, soluble in ethanol, slightly soluble in isopropanol, slightly soluble in water, soluble in dilute hydrochloric acid.
5.6 Dosage form1. Tablet: 200mg, 400mg, 800mg per tablet;
2. Capsule: 200mg;
3. Injectable: 200mg (2ml).
5.7 Pharmacological effects of cimetidineCimetidine is a histamine H2 receptor antagonist, which has the effect of inhibiting gastric acid secretion. Histamine activates adenylate cyclase through excitation of H2 receptors to increase the production of cAMP in gastric wall cells. cAMP activates carbonic anhydrase through protein kinase, catalyzes the production of H2CO3 from CO2 and H2O, and further dissociates and releases the H2 receptor H, which increases the secretion of gastric acid. Cimetidine mainly acts on the H2 receptor on the mural cells and competitively inhibits the effect of histamine, thus inhibiting gastric acid secretion. Its acid inhibition effect is strong, can effectively inhibit the basic gastric acid secretion and a variety of reasons such as food, histamine, pentagastrin, caffeine and insulin, etc. *** caused by gastric acid secretion, so that the amount of secretion and acidity are reduced, and can prevent or reduce bile salts, ethanol, aspirin and other non-steroidal anti-inflammatory drugs caused by the corrosive damage to gastric mucosa, on the stress ulcers and upper gastrointestinal bleeding also has significant therapeutic effect. In addition, cimetidine has an anti-androgen effect, which is valuable in the treatment of hirsutism; it also attenuates the activity of immunosuppressive cells and enhances the immune response, thus blocking tumor metastasis and prolonging the survival period.
5.8 Pharmacokinetics of cimetidineAbout 60% to 70% of cimetidine is rapidly absorbed through the intestine after oral administration. Oral bioavailability is about 70%, young people tend to absorb cimetidine better than the elderly; intramuscular bioavailability of 90% to 100%, intramuscular and static bioavailability is basically the same. After oral cimetidine 300mg, the effective blood concentration (0.5μg/ml) is reached in 0.5h; the peak blood concentration is reached after 45～90min, and the peak concentration is 1.44μg/ml; the peak blood concentration is reached in 15min after intramuscular injection. After a single dose, the effective blood concentration can be maintained for 4 h. Oral cimetidine 300 mg can inhibit 50% of the basal gastric acid secretion for 4-5 h; intramuscular or intravenous administration of cimetidine 300 mg can inhibit 80% of the basal gastric acid secretion for up to 5 h. Taking the drug with a meal can delay the absorption and prolong the duration of action. Cimetidine is widely distributed in systemic tissues, and can reach the fetus via the placenta, and can also cross the blood-cerebrospinal fluid barrier. Cimetidine is secreted into human milk, where its concentration can be higher than that in plasma. Plasma protein binding is low, 15% to 20%. The apparent volume of distribution is 2.1±1 L/kg. cimetidine is metabolized in the liver. Cimetidine is metabolized in the liver and excreted primarily by the kidneys, with a renal clearance of 12±3 ml/kg per minute. 48% of the oral dose or 75% of the injected dose is excreted in the kidneys in its original form after 24 h, and 10% may be excreted in the feces. The half-life is 2h for normal renal function; 2.9h for creatinine clearance of 20-50ml per minute; 3.7h for creatinine clearance of less than 20ml per minute; and 5h for renal insufficiency. cimetidine can be cleared by hemodialysis and peritoneal dialysis.
5.9 Indications for cimetidine1. Treatment of active duodenal ulcer and prevention of duodenal ulcer recurrence.
2. Gastric ulcers.
3. Reflux esophagitis.
4. Gastrinoma (Zo? syndrome).
5. Prevention and treatment of stress and drug ulcers.
6. Peptic ulcer with bleeding.
7. It can be used in the treatment of various causes of immune deficiency and adjuvant treatment of tumors.
8. It has also been reported that cimetidine is used in the treatment of herpes zoster and other herpetic infections, including genital. It is also used for female androgenetic alopecia, acne, hirsutism in women, and herpes zoster.
5.10 Contraindications to Cimetidine1. Hypersensitivity to cimetidine.
2. Because cimetidine can pass the placental barrier and enter breast milk, it is contraindicated in pregnant and lactating women to avoid causing liver dysfunction in the fetus and infant.
3. Cimetidine has been reported to cause acute pancreatitis in animal experiments and clinics, so cimetidine should not be used in patients with acute pancreatitis.
5.11 Precautions1. (1) Severe cardiac and respiratory diseases. (2) Chronic inflammatory diseases such as systemic lupus erythematosus (SLE), as the bone marrow toxicity of cimetidine may be increased. (3) Organic encephalopathy. (4) Renal impairment (moderate or severe). (5) Hepatic insufficiency. (6) Young children and the elderly. (7) Patients with a history of thrombocytopenia caused by the use of H2 antagonists. (8) Hypertriglyceridemia.
2. Monitor blood and renal function during administration.
3. Cimetidine may mask symptoms of gastric cancer and should be used after exclusion of malignancy.
4. Patients should take it on time and adhere to the treatment program.
5. Common overdose manifestations include dyspnea and tachycardia.
5.12 Adverse effects of cimetidine1. The more common are diarrhea, nausea, vomiting, abdominal distension, constipation, bitter taste in the mouth, dry mouth, mild elevation of serum aminotransferase, etc. Occasionally, severe hepatitis, hepatic necrosis, hepatic steatosis, etc.. In patients with cirrhosis, hepatic encephalopathy may be induced. Abrupt discontinuation of the drug may cause perforation of chronic peptic ulcers, presumably due to the high acidity of the rebound after discontinuation. Cimetidine has also been reported to cause acute pancreatitis.
2. Hematologic system: cimetidine has a certain inhibitory effect on the bone marrow, can appear neutropenia, pancytopenia; there are also reports of thrombocytopenia, granulocyte deficiency; only case reports can appear autoimmune hemolytic anemia, aplastic anemia, eosinophilia. Hematologic adverse reactions to cimetidine have been seen in patients with severe comorbidities or receiving antimetabolite hydrocarbon-based drugs or other treatments that cause granulocytopenia.
3. Neurological/psychiatric system: (1) dizziness, headache, fatigue, somnolence, etc. are more common; a small number of patients may have reversible confusion, disorientation, restlessness, sensory slowness, slurred speech, localized convulsions or epileptic seizures, delirium, depression, hallucinations, extrapyramidal reactions, and motor polysympathy, etc.. Neurotoxicity symptoms, usually only need to appropriately reduce the dose of drugs can disappear, can also be used to treat cholestatic alkaloid toxic lentil alkaloids. (2) In the treatment of gastrointestinal complications of alcoholism, delirium tremens may occur, which is similar to the alcohol withdrawal syndrome and should be distinguished. (3) Neuropsychiatric adverse reactions to cimetidine occur mainly in critically ill patients, and are also likely to occur in elderly patients, young children, persons with hepatic or renal insufficiency, persons with a history of psychosis, persons with cerebral disorders, and with high doses of the drug. In addition, persons with pseudohypothyroidism may be more sensitive to the neurotoxic effects of cimetidine.
4. Endocrine/metabolic system: Cimetidine has a mild antiandrogenic effect and may be associated with abnormal lipid metabolism, hyperprolactinemia, decreased plasma testosterone levels and increased gonadotropin levels, *** development and *** bloating in males, and breast milk spillage in females.
5. Cardiovascular system: bradycardia, facial flushing may occur. Intravenous injections occasionally see a sudden drop in blood pressure, atrial premature beats, cardiac and respiratory arrest.
6. Urinary/genital system: (1) cimetidine can cause a transient increase in serum creatinine levels and a decrease in creatinine clearance, and its mechanism is that cimetidine competes with creatinine for renal tubular secretion. Acute renal impairment has also been reported, and renal function may return to normal after discontinuation of the drug. (2) Interstitial nephritis: it can disappear after stopping the drug. (3) Sexual dysfunction: impotence, *** decrease, *** count reduction, etc. can be caused when the dose of the drug is large (more than 1.6g per day), but can return to normal after stopping the drug. (4) Cimetidine treatment in patients receiving renal allogeneic metastases can lead to acute metastatic necrosis.
7. Eye: Optic neuropathy may occur. It is hypothesized that cimetidine has a zinc chelating effect, so that the body's zinc content is insufficient, thus causing optic neuropathy. Another eye muscle *** reported.
8. Skin: cimetidine can inhibit sebum secretion, inducing exfoliative dermatitis, dry skin, sebum deficiency dermatitis, alopecia, etc.; allergic reactions (such as rashes, giant urticaria), Shijo syndrome and toxic epidermal necrolysis can also occur.
9. Musculoskeletal: muscle spasm or myalgia can occur after long-term use of the drug.
10.Carcinogenicity: long-term toxicity studies of cimetidine in rats found a higher incidence of benign Leydig cell tumors than controls, but this adverse effect was not seen clinically.
11.Other: (1) Cimetidine can reduce the acidity of the stomach, causing the growth of microorganisms in the stomach, and in the case of regurgitation can be infected, which should be taken seriously. (2) Rarely fever, loss of smell and so on.
5.13 Cimetidine dosage1. (1) Duodenal ulcer or pathologically hypersecretory state: 300 mg each time, 4 times a day, or 800 mg once at bedtime. The course of treatment is usually 4 to 6 weeks. The dosage can be up to 2g per day in the treatment of Zuoai syndrome.(2) Prevention of ulcer recurrence: 400mg per dose at bedtime.(3) Reflux esophagitis: 800～1600mg per day, the course of treatment is 4～8 weeks, and can be extended for 4 weeks if necessary. (4) Symptomatic treatment of reflux esophagitis: 200mg at the onset of burning and/or regurgitation; maximum dose is 200mg each time, 3 times daily. The course of treatment should not exceed 2 weeks.
2. Intramuscular injection: 200mg each time, every 6 hours.
3. Intravenous injection: dilute cimetidine with glucose injection or glucose chloride sodium chloride injection 20 ml and then slowly injected (longer than 5min), 200mg each time, once every 4-6 hours. The daily dose should not exceed 2g.
4. Intravenous drip: dilute cimetidine with dextrose injection or dextrose sodium chloride injection and then inject it intravenously, 200-600mg each time. the daily dose should not exceed 2g.
5.14 Drug interactions1. Cimetidine is a hepatic enzyme inhibitor, which binds to cytochrome P450 through its imidazole ring and reduces the enzyme activity. Cimetidine is a hepatic drug enzyme inhibitor, through its imidazole ring and cytochrome P450 binding and reduce the activity of drug enzyme, but also reduce hepatic blood flow. Therefore, when cimetidine is used in combination with propranolol, it can increase the blood concentration of the latter and slow down the heart rate at rest; when it is used in combination with phenytoin sodium or other beta-lactone ureas, it can increase the blood concentration of the latter, which may lead to poisoning of phenytoin sodium, and when it has to be used in combination, it is necessary to measure the blood concentration of phenytoin sodium after 5 days in order to adjust the dose.
2. When used in combination with cyclosporine, it can increase the blood concentration of the latter.
3. When combined with moclobemide, it can increase the blood concentration of the latter.
4. When combined with thebaine, the latter's desmethyl metabolic clearance can be reduced by 20% to 30%, and the blood concentration of the drug can be increased.
5. When combined with aspirin, it can lead to increased solubility of aspirin, increased absorption, and enhanced action.
6. With methadone, can increase the latter's blood concentration, there is a risk of overdose.
7. Combined with tacrine, it can increase the blood concentration of the latter, which may lead to the risk of overdose.
8. With carbamazepine, can increase the latter's blood concentration, there is a risk of overdose.
9. Cimetidine increases the absolute bioavailability of verapamil (ipratropium). Since serious adverse reactions can occur with verapamil, although rare, they should be noted.
10. Combined with coumarin anticoagulants, the latter's rate of elimination from the body can be reduced, and the prothrombinogen time is further prolonged, leading to bleeding tendency. When the two are used together, it is necessary to pay close attention to changes in the condition and adjust the amount of anticoagulant.
11. Combined with lidocaine (gastrointestinal tract external medicine), can make the latter's blood concentration increased, thus increasing the risk of neurological and cardiac adverse reactions. When combined with lidocaine, it is necessary to adjust the dose of lidocaine, and strengthen the clinical supervision.
12. Combined with caffeine, it can slow down the metabolism of caffeine, enhance its effect and prone to toxic reactions. Caffeine is contraindicated in patients with gastric ulcers, and caffeine and caffeinated beverages should be contraindicated when taking cimetidine.
13. With benzodiazepines (such as diazepam, nitrazepam, flunitrazepam, chlordiazepoxide, midazolam, and other drugs), it is not recommended to take caffeine or caffeine-containing drinks. However, lorazepam, oxazepam and temazepam appear to be unaffected.
14. Cimetidine is contraindicated in patients taking digoxin and quinidine concomitantly, because cimetidine inhibits the metabolism of quinidine, which displaces digoxin from its binding site, resulting in increased blood levels of both quinidine and digoxin.
15. and antacids (such as aluminum hydroxide, magnesium oxide), can relieve duodenal ulcer pain, but the absorption of cimetidine may be reduced, so generally do not advocate the two combined. If the combination must be used, the dose of cimetidine should be increased appropriately.
16. When used in combination with metoclopramide, the blood concentration of cimetidine can be reduced. If combined, the dose of cimetidine should be increased appropriately.
17. Because aluminum thiosulfate needs to be hydrolyzed by gastric acid to play a role, and cimetidine inhibits gastric acid secretion, so the efficacy of aluminum thiosulfate may be reduced when the two are used together.
18. Cimetidine increases the pH of gastric juice, and when combined with tetracycline, it can reduce the dissolution rate of tetracycline, reduce absorption, and weaken the effect; however, the hepatic enzyme inhibitory effect of cimetidine may increase the blood concentration of tetracycline.
19. With ketoconazole, can interfere with the absorption of the latter, reducing its antifungal activity, but with some acidic drinks can avoid these changes.
20. With captopril may cause psychotic symptoms.
21. Because cimetidine has a neuromuscular blocking effect similar to that of aminoglycosides, combining it with aminoglycoside antibiotics may lead to respiratory depression or respiratory arrest.
22. Cimetidine should be avoided in conjunction with central anticholinergics to prevent exacerbation of central neurotoxicity.
23.When used in combination with carmustine, it can increase bone marrow toxicity.
24. When combined with opioids, respiratory depression, confusion, and disorientation have been reported in patients with chronic renal failure.
5.15 Expert ReviewCimetidine not only has the effect of restoring immune function, but also has an antiviral effect. It is used for the treatment of herpes zoster infections, such as herpes orofacialis, herpetic keratitis and genital herpetic infections. There is an anti-androgen effect, can be used for the treatment of acne and inhibit prostate hyperplasia, easy to be accepted by elderly patients, but should be taken for a long time to avoid relapse.
6 Cimetidine poisoningCimetidine (Metformin, Tai Gumi) is an H2 receptor antagonist, can significantly inhibit gastric acid secretion caused by food, histamine or pentagastrin *** and other ***, and make it less acidic. It has preventive and protective effects on corrosive gastritis caused by chemical ***. It is rapidly absorbed by the small intestine after oral administration of 300mg, and the blood concentration is reached in 30min, and the peak concentration is reached in 90min. Plasma protein binding rate of about 70%, half-life of about 2 h. Widely distributed in systemic tissues, 44% to 70% of the original form from the urinary excretion, 12h can be discharged orally 80% of the amount. LD50 in mice is 2.6g/kg orally, 0.4g/kg intraperitoneally, 0.15g/kg intravenously, LD50 in rats is 5.0g/kg orally, the usual oral dosage is 200-400mg each time, 800-1600mg/d; the daily dose of injection shouldn't be more than 2g, when poisoned, it mainly damages the nervous system, the blood system, the cardiovascular system, and the liver, Kidneys. [1]
6.1 Clinical manifestations[1]
1. Adverse reactions are more frequent, common diarrhea, abdominal distension, bitter mouth, dry mouth, mild elevation of serum aminotransferases.
2. A single application of large doses or long-term larger doses can lead to poisoning. Performance:
(1) neurological symptoms: headache, dizziness, hallucinations, depression, mental disorders, drowsiness and so on.
(2) hematologic: leukopenia and thrombocytopenia and hemolytic anemia, occasionally secondary aplastic anemia. (3) Hepatotoxicity: elevated aminotransferases and serum bilirubin, and liver necrosis in severe cases.
(4) Nephrotoxicity: proteinuria, elevated urea nitrogen and creatinine, leading to renal failure in severe cases. (5) Cardiovascular system: cardiac arrhythmia can be seen, static injection occasionally lead to cardiac arrest.
(6) endocrine disorders: hypogonadism, male *** enlargement, distension and breast-feeding, impotence and *** reduction; female patients with menstrual disorders.
3. Allergic reactions such as arthralgia, muscle pain, itchy skin, rash, fever and laryngospasm, or even exfoliative dermatitis, or anaphylaxis.
6.2 DiagnosisThe key points for the diagnosis of cimetidine poisoning are[1]:
A history of cimetidine application with the above manifestations.
6.3 TreatmentThe main points in the treatment of cimetidine poisoning are[1]:
1. Generally, the adverse effects may disappear spontaneously after stopping the drug.
2. Liver and kidney function impairment should be actively taken to protect liver and kidney function treatment.
3. Serious arrhythmia, according to the type of arrhythmia can be applied to anti-arrhythmic drugs.
4. Symptoms of allergic reactions, can be treated with antihistamines or glucocorticoids.
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