Chinese name: Telmisartan
Chinese alias: 4-{[2-n-propyl-4-methyl-6-(1-methylbenzimidazole- 2-yl)benzimidazol-1-yl]methyl}biphenyl-2-carboxylic acid
English name: Telmisartan
English alias: 4'[(1, 4'-Dimethyl-2'-propyl[2,6'-bi-1H-benzimidazol]-1'-yl)methyl][1,1'-biphenyl]-2-carboxylic acid
CAS No.: 144701-48-4
Molecular formula: C33H30N4O2
Molecular weight: 514.62
Telmisartan is a new type of antihypertensive drug. Specific angiotensin II receptor (AT type I) antagonist. Telmisartan replaces the angiotensin II receptor and binds with high affinity to the AT I receptor subtype (the known action site of angiotensin II). Telmisartan does not have any site agonist effect at the ATⅠ receptor site. Telmisartan selectively binds to the ATⅠ receptor, and the binding effect is long-lasting. Telmisartan has no affinity for other receptors, including AT2 and other less well-characterized AT receptors. The functions of the other receptors mentioned above are not yet known, nor are the possible receptor overstimulation effects caused by telmisartan's increased angiotensin II levels. Telmisartan does not inhibit human plasma renin, nor does it block ion channels. Telmisartan does not inhibit angiotensin-converting enzyme II, which can also degrade bradykinin and cause adverse reactions caused by enhanced effects. Administration of 80 mg of telmisartan in humans can almost completely inhibit the increase in blood pressure caused by angiotensin II. The inhibitory effect lasts for 24 hours and is still detectable at 48 hours. The antihypertensive effect gradually becomes apparent within 3 hours after the first dose of telmisartan. Maximum blood pressure lowering effects are achieved 4 weeks after the start of treatment and are maintained during long-term treatment. If telmisartan treatment is suddenly interrupted, blood pressure will gradually return to the pre-treatment level after a few days without rebound hypertension. In a clinical trial study that directly compared two hypertension drugs, patients treated with telmisartan had a significantly lower incidence of dry cough than those treated with an angiotensin-converting enzyme inhibitor.
Clinical efficacy and characteristics:
1 Pharmacokinetics show: rapid action (0.3h), long duration (35.4h), little impact on heart rate during blood pressure reduction
2 Compared with enalapril: The blood pressure lowering effect is better than that of enalapril. When the two are combined with diuretics, the effect is still better than telmisartan, and the incidence of cough is less
3 Compared with lisinopril: the blood pressure lowering (systolic blood pressure and diastolic blood pressure) effect is more obvious, and the cough incidence rate in the telmisartan group (16%) is significantly lower than that in the lisinopril group (60%)< /p>
4 Compared with atenolol: The antihypertensive effect is equivalent, and the incidence of side effects (impotence and fatigue) is low
5 Compared with amlodipine: After taking the drug, the telmisartan group It can significantly reduce the heart rate within four hours and from 6 a.m. to 12 a.m.
In short, compared with other antihypertensive drugs, telmisartan has the following characteristics:
Specificity of receptor action
Significant antihypertensive effect
Good diuretic effect
Can improve myocardial stenosis disorder
The medication is safe, well tolerated and can be taken once a day and is convenient to take
Patent and administrative protection:
1 Telmisartan was originally developed by the German Boehringer Ingelheim Pharmaceutical Company in 1991 Approved German patent EP502,314, first approved for marketing in the United States in November 1998, and then marketed in Germany, the Philippines, Australia, Belgium, the United Kingdom and other countries
2 No application for patent or administrative protection in China
p>3 There are no intellectual property issues in the development of this product
Drug name
Common name: Telmisartan Tablets
English name: Telmisartan Tablets
Chinese Pinyin: Timishatan Pian
Ingredients
The main ingredient of this product is: Telmisartan, its chemical name is: 4'-[(1, 4'-Dimethyl-2'-propyl[2,6'-di-1H-benzimidazol]-1'-yl)-methyl]-[1,1'-diphenyl]-2 -carboxylic acid.
Molecular formula: C33H30N4O2
Molecular weight: 514.63
Properties: This product is white or off-white tablets.
Indications: Used for the treatment of essential hypertension.
Specification 40mg
Usage and Dosage
Adults
Dosing should be individualized. The usual initial dose is one tablet (40mg) once daily. In the dose range of 20 to 80 mg, the antihypertensive efficacy of telmisartan is dose-related. If the ideal blood pressure is not reached after taking the medicine, the dose can be increased, with the maximum dose being 80mg, once a day.
This product can be combined with thiazide diuretics such as hydrochlorothiazide. These diuretics have a synergistic antihypertensive effect with this product. Because telmisartan can achieve its maximum efficacy four to eight weeks after the start of treatment, this should be considered if you want to increase the dose of the drug.
Patients with renal insufficiency
Patients with mild or moderate renal insufficiency do not need to adjust the dosage of this product.
Telmisartan is not eliminated by hemofiltration.
Patients with hepatic insufficiency
For patients with mild or moderate hepatic insufficiency, the daily dosage of this product should not exceed 40 mg.
Elderly
Dosage adjustment is not required when taking this product.
Children and Adolescents
Safety data for this product have not been established for children and adolescents under 18 years of age.
Adverse Reactions
In placebo-controlled trials, the overall incidence of adverse events with telmisartan (41.4%) was similar to that with placebo (43.9%). The occurrence of adverse events was not dose-related, nor was it related to patient gender, age, or race.
The adverse reactions listed below were accumulated from 5788 hypertensive patients treated with telmisartan in clinical trials.
Adverse reactions are divided according to frequency of occurrence:
Very common (>1/10); Common (>1/100, <1/10); Rare (>1/1000 , <1/100); rare (>1/10000, <1/1000); very rare (<1/10000)
Systemic reactions:
Common: back pain (such as sciatica), chest pain, flu-like symptoms, symptoms of infection (such as urinary tract infection including cystitis)
Uncommon: visual abnormalities, excessive sweating
Central and peripheral nervous system: Common: dizziness
Gastrointestinal system:
Common: abdominal pain, diarrhea, indigestion, gastrointestinal disorders
Uncommon: dry mouth, flatulence
Musculoskeletal system:
Common: joint pain, leg cramps or leg pain, myalgia
Rare: tenosynovitis-like symptoms
Nervous system: Uncommon: Anxiety
Respiratory system:
Common: Upper respiratory tract infections including pharyngitis and rhinitis
Skin and adnexal system:
Common: skin abnormalities such as eczema
In addition, since the launch of telmisartan, individual cases have reported the occurrence of erythema, itching, syncope, insomnia, depression, stomach discomfort, vomiting, hypotension, and bradycardia. , tachycardia, dyspnea, eosinophilia, thrombocytopenia, weakness, decreased work efficiency. Similar to other angiotensin II antagonists, rare cases of angioedema, urticaria, and other related adverse reactions have been reported.
Laboratory findings:
Occasionally, a decrease in hemoglobin or an increase in uric acid was observed in the telmisartan treatment group compared with placebo. Increases in serum creatinine or liver enzymes with telmisartan were similar to or less than those with placebo.
Contraindications
◆Those who are allergic to the active ingredients and any excipients of this product
◆Those in the second and third trimester of pregnancy and those who are breastfeeding
< p>◆Patients with biliary obstructive disease◆Patients with severe hepatic insufficiency
◆Patients with severe renal insufficiency (creatinine clearance <30ml/min)
Precautions
Hepatic insufficiency
This product should not be used in patients with cholestasis, biliary obstructive disease or severe liver dysfunction, because telmisartan is mostly excreted through bile , and the clearance rate of this product may be reduced in these patients. This product should be used with caution in patients with mild to moderate hepatic insufficiency.
Renovascular hypertension
In cases of bilateral renal artery stenosis or unilateral functional renal artery stenosis, use drugs that affect the renin-angiotensin-aldosterone system It increases the risk of severe hypotension and renal insufficiency.
Patients with renal insufficiency and kidney transplantation
This product should not be used in patients with severe renal insufficiency (creatinine clearance <30ml/minute, see Contraindications). For patients with renal insufficiency, blood potassium levels and serum creatinine values ??should be measured regularly during use of this product. There are no data on the use of this product in the short term after recent renal transplantation.
Patients with hypovolemia
For patients with hypovolemia or low serum sodium levels caused by strong diuretic treatment, salt-restricted diet, nausea or vomiting, taking this product, Particularly after initial administration, symptomatic hypotension may result. Therefore, blood sodium and blood volume levels should be corrected before using this product.
Other conditions associated with stimulation of the renin-angiotensin-aldosterone system
In patients whose vascular tone and renal function depend primarily on the activity of the renin-angiotensin-aldosterone system (eg, in patients with severe congestive heart failure or underlying renal disease including renal artery stenosis), use of drugs that affect this system may cause acute hypotension, hyperzotaemia, oliguria, or rarely acute renal failure.
Primary aldosteronism
Antihypertensive drugs that inhibit the renin-angiotensin-aldosterone system are generally ineffective in patients with primary aldosteronism. Therefore, this product is not recommended for use in these patients.
Aortic or mitral stenosis, obstructive hypertrophic cardiomyopathy
As with other vasodilators, aortic or mitral stenosis, obstructive hypertrophic cardiomyopathy Patients with cardiomyopathy should pay special attention when using this product.
Electrolyte imbalance: hyperkalemia
The use of drugs that affect the renin-angiotensin-aldosterone system may cause hyperkalemia, especially in patients with poor renal function and /or patients with heart failure and diabetes. However, for patients at risk, serum potassium levels should be closely monitored while taking this product.
Based on experience with other drugs that affect the renin-angiotensin system, use of this product with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs that may increase serum potassium levels Concomitant use of other drugs (such as heparin) may increase serum potassium levels, so caution should be used in combination with this product (see Drug Interactions).
Others
Similar to angiotensin-converting enzyme inhibitors, the antihypertensive effect of this product and other angiotensin antagonists is lower in blacks than in other races. This may be related to the higher predominance of low renin status in black hypertensive people.
Like other antihypertensive drugs, excessive blood pressure lowering can cause myocardial infarction or stroke in patients with ischemic heart disease or ischemic cardiovascular disease.
Effects on driving and operating machinery
The effects of this product on driving and operating machinery have not been studied. But be aware when driving or operating machinery that antihypertensive treatments can sometimes cause dizziness and drowsiness.
Use in pregnant and lactating women
Use in pregnancy
There is insufficient data to show whether this product can be used in pregnant women. Animal tests did not show teratogenicity but showed embryotoxicity. Therefore, it is prudent not to use telmisartan during the first trimester of pregnancy. Appropriate replacement therapy should be taken before planning a pregnancy.
During the second and third trimesters of pregnancy (during the second and third trimesters), drugs that directly act on the renin-vasotensin system can cause fetal damage or even death, so telmisartan is contraindicated. In the second and third trimester of pregnancy. Once pregnancy is diagnosed, this product should be discontinued as soon as possible.
Use during breastfeeding
Since it is unknown whether this product is excreted in breast milk, this product is prohibited during breastfeeding.
This experiment has not been conducted on children's medicines and there are no reliable references.
This experiment has not been conducted on elderly medications and there are no reliable references.
Drug interactions
1. Lithium
The combined use of lithium and angiotensin-converting enzyme inhibitors can cause a reversible increase in blood lithium levels. and toxic reactions. There are also individual cases caused by the combined use of lithium and angiotensin II receptor antagonists. Therefore, caution should be exercised when using lithium and this product together. If coadministration is necessary, serum lithium levels should be monitored during coadministration.
2. Some drugs can affect blood potassium levels or cause hyperkalemia (such as ACE inhibitors, potassium-sparing diuretics, potassium ion supplements, potassium-containing salt substitutes, cyclosporine A or other drugs such as heparin sodium); if this product needs to be used in combination with these drugs, it is recommended to monitor serum potassium levels. Based on experience with other drugs that affect the renin-angiotensin system, concomitant use of this product with the above drugs may increase serum potassium levels (see Precautions).
3. Pharmacokinetic tests have studied the interactions of this product with digoxin, warfarin, hydrochlorothiazide, glyburide, ibuprofen, paracetamol, amlodipine and other drugs. It can increase the average trough and trough plasma concentration of digoxin by 20% (up to 39% in individual cases), so the plasma concentration of digoxin must be monitored.
4. This product can enhance the antihypertensive effect of other antihypertensive drugs. Other clinically meaningful interactions cannot be confirmed.
5. Based on their pharmacological properties, the following drugs can enhance the antihypertensive effect of antihypertensive drugs including telmisartan: baclofen and amifostine. In addition, alcohol, barbiturates, sedative-hypnotics, or antidepressants can enhance the effects of orthostatic hypotension.
6. When combined with telmisartan, the Cmax of simvastatin metabolite (simvastatin acid) is slightly increased (1.34 times) and its elimination is accelerated.
Drug Overdose
There have been no reported cases of overdose. The most likely manifestations of telmisartan overdose are hypotension and tachycardia; bradycardia may also occur. Telmisartan is not eliminated by hemodialysis. In the event of overdose, the patient should be closely observed and given symptomatic and supportive treatment. Treatment should be based on the timing of medication and the severity of symptoms. Recommended measures include induction of vomiting and/or gastric lavage. Activated charcoal may be effective in treating overdose. Serum electrolytes and creatinine should be monitored closely. If hypotension occurs, the patient should lie down and receive salt replenishment and volume expansion as soon as possible.
Pharmacology and Toxicology
Pharmacological effects
Telmisartan is an orally acting, specific angiotensin II receptor (AT1 type) It is an antagonist that binds with high affinity to the AT1 subtype of the angiotensin II receptor (the known action site of angiotensin II). The binding effect is long-lasting but does not have any partial agonist effect. Because telmisartan increases angiotensin II levels, possible receptor overstimulation is unknown. Telmisartan can cause a decrease in blood aldosterone levels. Telmisartan does not inhibit human plasma renin, nor does it block ion channels. Angiotensin-converting enzyme (kinase II) can also degrade bradykinin. Since telmisartan does not inhibit angiotensin-converting enzyme, there will be no adverse reactions caused by enhanced bradykinin action. Telmisartan has no affinity for other receptors, including AT2 and other less characterized AT receptors whose functions are unknown.
In humans, administration of 80 mg telmisartan can almost completely inhibit the increase in blood pressure caused by angiotensin II. The inhibitory effect lasts for 24 hours and can still be measured at 48 hours.
The antihypertensive effect gradually becomes apparent within 3 hours after the first dose of telmisartan. Maximum blood pressure lowering effects are achieved 4 weeks after the start of treatment and are maintained during long-term treatment.
Ambulatory blood pressure testing showed that the blood pressure-lowering effect lasted for more than 24 hours after taking the drug, including the 4 hours before the next dose. This result was confirmed in a placebo-controlled clinical experimental study: the trough-to-peak ratio after taking telmisartan 40 mg and 80 mg continued to be above 80%.
Return to baseline SBP has a significant dose-time dependence. Data on DBP are inconsistent in this area.
For patients with hypertension, telmisartan can reduce systolic and diastolic blood pressure without affecting heart rate. The antihypertensive effect of telmisartan is comparable to other types of representative antihypertensive drugs. (Clinical experimental studies have compared telmisartan with amlodipine, atenolol, enalapril, hydrochlorothiazide, losartan, and lisinopril.)
Telmisartan If treatment is suddenly interrupted, blood pressure will gradually return to the pre-treatment level after a few days without rebound hypertension.
In a clinical experimental study directly comparing two antihypertensive drugs, the incidence of dry cough in patients treated with telmisartan was significantly lower than that in the angiotensin-converting enzyme inhibitor treatment group.
The effect of telmisartan on improving mortality and cardiovascular disease prevalence is currently unknown.
Toxicological studies
The doses used in preclinical safety studies are equivalent to clinical therapeutic doses, which can cause a decrease in red blood cell index (erythrocytes, hemoglobin, hematocrit) and renal insufficiency. Hemodynamic changes (increased blood urea nitrogen and creatinine) and increased serum potassium in normotensive animals. Renal tubular dilation and atrophy can be seen in dogs. Damage to the gastrointestinal mucosa (erosion, ulceration or inflammation) is also seen in rats and dogs. These pharmacological adverse reactions are known from preclinical studies to be specific to angiotensin-converting enzyme inhibitors and angiotensin II antagonists and can be prevented with oral salt supplements.
In both of the above-mentioned genera, increased plasma renin activity and glomerular juxtaglomerular cell hypertrophy/hyperplasia can be seen. The above changes are also unique reactions to angiotensin-converting enzyme inhibitors and other angiotensin II antagonists, and have no clinical specificity.
Animal experiments show that telmisartan has some potential adverse effects on fetal postnatal development, including weight loss, delayed eye opening, and increased mortality.
No mutagenicity and related mutagenic activity were found in in vitro experiments, and no carcinogenicity was found in mice and rats.
Pharmacokinetics
Absorption:
After oral administration, Telmisartan is rapidly absorbed, with an average absolute bioavailability of approximately 50%. When telmisartan is taken with food, the area under the drug-time curve (AUC0-∞) decreases by 6% (40 mg dose) to 19% (160 mg dose). Plasma concentrations of telmisartan are similar 3 hours after administration on an empty stomach or with food. A slight decrease in AUC does not result in a decrease in efficacy.
There is no linear relationship between dose and plasma levels. A slight disproportionate increase in Cmax and AUC occurred at doses above 40 mg.
Plasma concentrations are different depending on gender. Cmax and AUC are nearly 2-3 times higher in women than in men.
Distribution:
Telmisartan is mostly bound to plasma proteins (>99.5%), mainly albumin and α-1 acid glycoprotein. The average steady-state apparent volume of distribution (VSS) is approximately 500L.
Metabolism:
Telmisartan is metabolized by conjugation of the parent compound with glucuronide. The conjugated product has no pharmacological activity.
Elimination:
Telmisartan is eliminated according to power-of-two pharmacokinetics, with a final elimination half-life of >20 hours. The maximum plasma concentration (Cmax) does not increase in proportion to the dose, and the area under the drug-time curve (AUC) does not increase in proportion to the dose. No clinically relevant accumulation of telmisartan has been seen when administered at recommended doses. Plasma concentrations are higher in women than in men, but have no effect on efficacy.
Telmisartan is almost completely excreted in the feces when administered orally (or intravenously), primarily as the unchanged compound. Cumulative urinary excretion is less than 2% of the dose. Total plasma clearance (CLtot) (approximately 1000ml/min) is high compared with hepatic blood flow (approximately 1500ml/min).
Elderly
There is no difference in the pharmacokinetics of telmisartan between the elderly and young adults.
Patients with renal impairment
Patients with renal impairment undergoing dialysis have lower plasma concentrations. Telmisartan is highly bound to plasma proteins in patients with renal insufficiency and cannot be removed by dialysis. The half-life of telmisartan is unchanged in patients with renal insufficiency.
Patients with hepatic insufficiency
Pharmacokinetic studies show that the absolute bioavailability in patients with hepatic insufficiency increases by approximately 100%. Elimination half-life is unchanged in patients with hepatic impairment.