chapter 7 Adrenergic Drugs
孕妇禁服的药物（Drugsforpregnantwomen）
孕妇禁服的药物（Drugs for pregnant women）There are many taboos in pregnant women medication. Because some drugs are more harmful to the fetus, and even lead to fetal malformations. There are many kinds of teratogenic agents, usually with the following drugs:1. Antibiotics. Such as tetracycline, oxytetracycline, streptomycin, gentamicin, neomycin and so on. Tetracycline, oxytetracycline may cause fetal short limb malformations, congenital cataract, fontanelle bulge, late pregnancy taking can cause childhood enamel hypoplasia; streptomycin, gentamicin drugs can damage the fetus eighth of the brain, resulting in congenital deafness, also can damage the kidney function; neomycin can make fetal bone dysplasia, parallel to kidney, pulmonary artery stenosis, congenital cataract, intellectual disability.2. Antimalarial drugs. Such as quinine, chloroquine, pyrimidine, can cause multiple malformations of the fetus. Such as deafness, limb defect, hydrocephalus and so on.3, the treatment of diabetes drugs. Such as chlorine sulfur C, McCann, urine sugar, equal, can cause limb malformation, cleft lip, stillbirth etc..4. Barbiturates and other sedative hypnotic drugs. Such as phenytoin, primidone, stability, limb, facial deformity and can cause brain development.5. Anticancer drugs. Such as actinomycin D, cyclophosphamide, 5 - fluorine Wo pyrimidine, thiotepa, can cause anencephaly,hydrocephalus, cleft palate, cleft lip, kidney and ureter defect, deformity of limbs and eyes.6. Hormone drugs. Such as diethylstilbestrol, progesterone, androgen, cortisone. Oral contraceptives cause malformations of fetal genital organs. Such as female fetal masculine, Yang pedicle hypertrophy, labia fusion, male fetal urethral following abnormalities.7. Anticoagulant drugs. Such as heparin, coumarin, aspirin, salicylic acid, etc. can also teratogenic, and can induce hemorrhagic diseases. In short, pregnancy should pay attention to avoid drug abuse, but in case of emergency situations endanger the safety of pregnant women, to medication, should be to save the life of the pregnant woman, when emergency situations in the past, should prompt a reduction or withdrawal. The idea that the fetus was refused medication was wrong. If the pregnant woman had a dangerous life, the fetus would talk about He Anquan. Therefore, in pregnant women medication problems, should distinguish between the primary and secondary contradictions, comprehensive consideration.1. penicillin: safer, including broad-spectrum penicillins, such as piperacillin. Oral, intramuscular, intravenous drip can be used for pregnant women. Warning: according to the recommended dosage, can not be excessive.2.: the same medicine and bacteria to erythromycin and roxithromycin, yarn, high molecular weight, is not easy to reach the fetus through the placenta, penicillin allergy can use the drug of choice for chlamydia and Mycoplasma infection.3. cephalosporin: there is no teratogenic effect at present.Tips: dangerous antibiotics ReportSome antibiotics can not be used by pregnant women because of their different side effects:Tetracycline: can cause yellow brown pigmentation of teeth, or storage in the fetal skeleton, but also can cause acute fatty liver and renal insufficiency in pregnant women.Gentamicin: kanamycin, and so on can cause damage to the fetal auditory nerve and kidney.Chloramphenicol: cause grey baby syndrome.Conclusion compound sulfamethoxazole and sulfamethoxazole tablets can cause neonatal jaundice, and can also antagonize folic acid.Furan gall bites: women suffering from urinary tract infection often choose, because it can cause hemolysis, should be used with caution.There is no report on the vancomycin: Although fetal risk, but renal toxicity to pregnant women, ototoxicity.The ciprofloxacin, norfloxacin, ofloxacin, irreversible arthritis occurred in the dog experiment.The anti tuberculosis drug use: when considering the pros and cons according to their size please ask the doctor.9 antifungal drugs: clotrimazole, nystatin, griseofulvin, pregnant women are not the best.The antiviral: do not advocate for pregnant women.4. metronidazole: insecticide, the treatment of Trichomonas infection, advocated early pregnancy does not use.5.: the treatment of Toxoplasma gondii infection, no adverse effects on the fetus.6. anthelmintic: animals have teratogenic effect, should be used with caution.7. digoxin: cardiac drug,It is easy to pass through the placenta and has no obvious adverse effect on the fetus, and the pregnant women with heart failure can be used.8. beta blockers: a report of fetal retardation.9. antihypertensive drugs: definite teratogenic effects of pregnant women is angiotensin converting enzyme inhibitors, such as Kato Pury, angiotensin II receptor antagonists such as losartan, other types of drugs such as calcium antagonists (on behalf of the heart medicine education, cause uterine blood flow can be reduced, diuretic administration can reduce thenear term should be used with caution, the cause of neonatal platelet work experiment acetazolamide limb deformity, pregnant women do not use.10. drugs for the treatment of asthma: such as tea, epinephrine, sodium citrate, prednisone, no teratogenic effect.11. anticonvulsant drugs: the incidence of fetal congenital malformations was 2-3 times higher than that of women who took anticonvulsant drugs during pregnancy. Commonly used phenytoin sodium, C Masi Bing, trimethyl ketone, valproic acid and so on.12. antipsychotic drugs have teratogenic effects.13.: sedative drugs such as diazepam, estazolam, individual teratogenic effect.14. analgesic: acetaminophen can produce hepatotoxicity. Aspirin may be accompanied by oligohydramnios and premature closure of fetal ductus arteriosus. Bloven, Nai Pusheng, indomethacin can cause fetal arterial contraction leads to pulmonary hypertension and oligohydramnios, after 34 weeks of pregnancy should not use indomethacin, can cause fetal intraventricular hemorrhage, bronchopulmonary dysplasia and adverse effects of necrotizing enterocolitis.15. antiemetic drugs: no deformity and increasing the service road.16. antitumor drugs: a clear teratogenic effect.17.: immunosuppressant azathioprine, cyclosporine has obvious toxicity on mother and infant.18. vitamin A: a large number of use can cause birth defects, the smallest human teratogenic quantity is 25000-50000iuld.19. vitamin A isomer: the treatment of skin diseases, retinoic acid in the embryonic phase of medication can produce a variety of malformations.20. acitretin (aromatic retinoic acid): for the treatment of psoriasis, half-life is very long, withdrawal of drugs in >2 years, there are still drug testing, so at least 2 years of drug withdrawal can be conceived.The 21. hormone class: albendazole, diethylstilbestrol, should not be used for pregnant women, oral contraceptive sand dune degree has a positive teratogenic effect.The standard of risk for pregnancy was issued by the American drug and Food Administration (FDA) during pregnancy:Type A: control studies showed no harm. It has been proved that this kind of medicine has no adverse effects on human fetus, and is the safest.Class B: no evidence of harm to human beings. Animal experiments are harmful to fetal animals, but have not been proven to be harmful to the fetus or animal experiments are harmless to the fetus, but there is no adequate study in humans.Class C: non exception hazards. Animal experiments may be harmful or lack of research on fetal animals, but lack of relevant studies in humans, but the benefits for pregnant women are greater than the harm to the fetus.Class D: harm to the fetus. Market research or research confirms that it is harmful to the fetus, but the benefits for pregnant women outweigh the risks to the fetus.Class X: forbidden during pregnancy. In human or animal studies, or market research shows that the harm to the fetus more than the benefit of pregnant women, pregnancy prohibited drugs.Grade standard of commonly used drugs:Antihistamines:Chlorpheniramine (B), Simiti Martin (B), diphenhydramine (B) and promethazine (C)Two. Anti infective drugs:1. anthelmintic: gentian violet (C)2. antimalarial drug: chloroquine (D)3. Trichomonas agents: metronidazole (B)4. antibiotics: amikacin (C), gentamicin (C), kanamycin (D), neomycin (D),Cephalosporins (B), streptomycin (D), penicillins (B), tetracycline (D) and oxytetracycline (D),Chlortetracycline (D) and Bacillus peptide (C), chloramphenicol (C), erythromycin (B), Lincomycin (B) and stickyActinomycin B (B) and vancomycin (C)5. other antibiotics: SMZ-TMP (B/C) and trimethoprim (C), furazolidone, nitrofurantoin (C)Cause (B)6. anti tuberculosis drugs: ethambutol (B), isoniazid (C), Li Fuping (C), and salicylic acid (C)7. antifungal agents: clotrimazole (C), miconazole (C), nystatin (B)8. antiviral agents: amantadine (C), adenosine arabinoside (C), ribavirin (X), C, and noneCyclic guanosine (C)Three. Antineoplastic agents:Bleomycin (D), cyclophosphamide (D), D, cisplatin (D), cytarabine (D), and moreLincomycin (D), thiotepa (D) and daunorubicin (D), adriamycin(D) and 5-fluorouracil (D), nitrogenMustard (D), Ma Falan (D), methotrexate (D), vincristine (D)Four. Autonomic nervous system drugs:1. cholinergic drugs: acetylcholine (C) and neostigmine (C)2. anticholinergic drugs: atropine, belladonna (C) (C), Proulx Bernd Sin (C)3. adrenergic drugs: epinephrine (C), norepinephrine (D), ephedrine (C), and isoproterenolC, D, Dobaamine (C), dobutamine (C), B, and hydroxyEphedrine (B)Five. Central nervous system drugs:1. central stimulant: caffeine (B)2. antipyretic analgesics: acetylsalicylic acid (C/D), Fi Bernard Shiden (B), sodium salicylate (C/D)3. non steroidal anti-inflammatory drugs: indomethacin (B/D)4.: analgesic codeine, morphine (B/D) (B/D), opioid (B/D) and pethidine (B/D), narloKetone (C)5. sedative, hypnotic: amobarbital (C), Babito (C), Bernd Bobby Toy (B), chloral hydrate (C), ethanol (D/X), diazepam (D) and nitro (C)6. diazepam: droperidol (C) and chlorpromazine (C)7. antidepressants: doxepin (C)Six. Cardiovascular drugs:1.: digitalis cardiac glycosides (B) (B), digoxin, digitoxin(B), quinidine (C)2. antihypertensive drugs: clonidine (C), Ca Guido Ba (C), B,D and prazosin(C)3. vasodilator drugs: C, Pan Shengding (C), two isosorbide dinitrate (C),Result (C)Seven. DiureticsHydrochlorothiazide (D) and ethacrynic acid (D) and furosemide (C), Gan Luchun (C), triamterene (D)Eight. Digestive system drugs:Compound Camphor Tincture (B/D)Nine. Hormones:1. adrenal cortex hormone: cortisone (D), Batamison (C), dexamethasone (C), hydrocortisone (prednisone)B)2. estrogen: diethylstilbestrol (X), estradiol (D), oral contraceptive pill (D)3. progesterone: progesterone (D)4. hypoglycemic drugs: insulin (B), sulfonylurea (D), methyl sulfonyl Ding Niao (D)5.: antithyroid drug propylthiouracil (D) and methimazole (D)This paper is reproduced from QQ spacePenicillin: can destroy fetal red blood cell, cause serious jaundice, cause fetal death. Yangzhou First People's Hospital gynecology YulinStreptomycin: congenital deafness, skeletal deformity.Tetracycline induced amelogenesis imperfecta, skeletal and heart malformations, congenital cataract, short limb or defect (e.g. four fingers), neonatal jaundice, the most serious personcan appear kernicterus and even death.Oxytetracycline and doxycycline: make fetal short limb deformity.Chloramphenicol induced blood circulation disorders, respiratory insufficiency, cyanosis, neonatal abdominal distension (i.e. "gray baby syndrome"). If used in the end of pregnancy, it can cause neonatal thrombocytopenia, aplastic anemia or fetal death.Cara: deafness.Erythromycin: congenital cataract, limb deformities and so on.Gentamicin: fetal ear damage, and even lead to congenital gastric vascular malformation and polycystic kidney.Sulfa drugs (mainly based on long-acting sulfonamides and antibacterial synergist): hyperbilirubinemia, brain nuclear jaundice, deformity.Heroin: respiratory depression and death in the fetus.Pethidine: caused by neonatal asphyxia.Morphine: the inhibition of neonatal respiration and the withdrawal of the newborn like withdrawal, such as taking a week before delivery, can cause neonatal spasms, excitement and shrill cry.Aspirin: cause fetal small, malformation, cause neonatal prothrombin reduction group and bleeding and liver detoxification dysfunction.Finasteride and paracetamol: neonatal hypercholesterolemia.Indomethacin: cause jaundice and aplastic anemia.Barbiturate induced fetal heart: congenital malformation, facial and hand retardation, cleft lip and cleft palate.Primidone: fetal finger and toe deformities, late pregnancy can cause fetal asphyxia, taking hemorrhage and brain injury.Sleeping pills: malformations.Valium, tranquility, insomnia, and sleep induction can cause fetal abnormalities and become pregnant women.Activin induced cleft palate.Insulin: causes miscarriage, premature birth, stillbirth, and other congenital malformations.Progesterone: masculine female fetus.Cortisone and prednisone: fetal cleft lip and cleft palate. Cortisone can also cause fetal absence, premature delivery, premature death.Progesterone and testosterone: abnormalities of fetal externalgenital organs.Vitamin D: large doses, can cause fetal hypercalcemia and mental retardation.Vitamin K: a large number of taking, can cause hyperbilirubinemia, nuclear jaundice.Vitamin B6: a large number of taking, can cause neonatal vitamin B6 dependence, convulsions. Vitamin B6 derivatives naofuxin, caused by cleft lip in animal experiments, should be used with caution.Vitamins: if taken during pregnancy in the first three months of the risk of neurological deficiency in infants go through thick and thin together up to 60%.Promethazine hydrochloride: fetal limb deformities.Antimalarial drugs quinine, chloride, and pyrimidine: can cause hydrocephalus, bulging, cleft palate, renal arrest, development or malformation, retinal damage.Chlorpheniramine, Meclozine, An Qimin, and other anti allergy medicine diphenhydramine Dramamine: in addition to potentially induced cleft palate, cleft lip, short limb function, can also cause liver poisoning and brain injury, neonatal respiratory inhibition.Fluorouracil, cyclophosphamide, can cause fetal limb, nose, palate, urinary tract deformity and death.Methotrexate: no fetal brain, hydrocephalus, encephalocele, cleft lip, cleft palate, or limb deformities.Hydroxyurea and busulfan induced multiple malformations.Bai Ning: caused by the injury of central nervous system and brain.6- purine, testosterone propionate and L- L-asparaginase: fetal malformations.It can cause kidney and ureter defect.Fetal death caused by pethidine, 5-, fluorouracil, mitomycin C and colchicine. It is safer to use these antineoplastic agents after sixteenth weeks of pregnancy.Coumarin drugs: can cause fetal skin bleeding spots, brain disorders, placental abruption, bone and facial deformity, mental retardation or fetal death.Warfarin: nasal dysplasia, malformations.D860, a kind of sulfonylurea, can induce abortion and premature delivery, and has the effect of promoting distortion.MTU, propylthiouracil, methimazole, jiakangping, potassium iodide: induced hypothyroidism, cretinism, delayed ossification and hypospadias.Hydrochlorothiazide or cyclopenthiazide: can cause neonatal thrombocytopenia.Reserpine: cause neonatal poisoning, nasal congestion, respiratory obstruction, and even death due to lack of oxygen.Caffeine causes cleft lip and palate.Ether: a large number of continuous use, can cause fetal death.All arsenic containing drugs: all cause fetal death.Polymyxin E, B and vancomycin: taking too much time, so that pregnant women suffered from acute renal failure, the children are susceptible to neuromuscular blockade, ataxia, vertigo, seizures and mouth week after birth 3 years paresthesia. Vancomycin can also cause temporary or permanent hearing loss in infants.Rifampicin: fetal malformation.Anti fungal drugs griseofulvin, amphotericin B, nystatin, clotrimazole: serious adverse reactions of pregnant women's nervous system, hematopoietic system, liver and kidney function. Griseofulvin also led to abortion and teratism.Triamterene (three methotrexate): liver damage, change of maternal blood.Hydrochlorothiazide: adverse effects on the fetus.Furosemide: nausea and vomiting, diarrhea, drug rash, itching, blurred vision, postural hypotension and even water and electrolyte disorders in pregnant women and parturient.Diuretics: can cause transient hearing loss and sometimes develop permanent hearing loss.Other: alcoholism pregnant women newborns showed withdrawal like inhibitory state; multiple abnormalities can cause fetal alcohol. The contraceptive pill should be pregnant after six months of complete withdrawal of the drug, so as to avoid the birth of malformation or dementia caused by improper medication。
富马酸福莫特罗吸入溶液说明书
HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use PERFOROMIST safely and effectively. See full prescribing information for PERFOROMIST.These highlights do not include all the information needed to use PERFOROMIST Inhalation Solution safely and effectively. See full prescribing information for PERFOROMIST Inhalation Solution. PERFOROMIST® (formoterol fumarate) Inhalation SolutionInitial U.S. Approval: 2001WARNING: ASTHMA-RELATED DEATHSee full prescribing information for complete boxed warning• Long-acting beta2-adrenergic agonists (LABA) increase the risk of asthma-related death. (5.1)• A placebo-controlled study with another long-acting beta2-adrenergic agonist (salmeterol) showed an increase in asthma-related deaths in patients receiving salmeterol. (5.1)• The finding of an increased risk of asthma-related death with salmeterol is considered a class effect of LABA, including formoterol, the active ingredient in PERFOROMIST. The safety and efficacy of PERFOROMIST in patients with asthma have not been established. All LABA, including PERFOROMIST, are contraindicated in patients with asthma without use of a long-term asthma control medication. (4, 5.1)INDICATIONS AND USAGEPERFOROMIST Inhalation Solution is a long-acting beta2-adrenergic agonist (beta2-agonist) indicated for:• Long-term, twice daily (morning and evening) administration in the maintenance treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. (1.1)Important limitations of use:• PERFOROMIST Inhalation Solution is not indicated to treat acute deteriorations of chronic obstructive pulmonary disease. (1.2, 5.2)• PERFOROMIST Inhalation Solution is not indicated to treat asthma. (1.2)DOSAGE AND ADMINISTRATIONFor oral inhalation only.• One 20 mcg/2 mL vial every 12 hours (2)• For use with a standard jet nebulizer (with a facemask or mouthpiece) connected to an air compressor (2)DOSAGE FORMS AND STRENGTHSInhalation Solution (unit dose vial for nebulization); 20 mcg/2 mL solution (3)CONTRAINDICATIONS• All LABA, including PERFOROMIST, are contraindicated in patients with asthma without use of a long-term asthma control medication. (4)WARNINGS AND PRECAUTIONS• Do not initiate PERFOROMIST Inhalation Solution in acutely deteriorating patients. (5.2)• Do not use for relief of acute symptoms. Concomitant short-acting beta2 agonists can be used as needed for acute relief. (5.2)• Do not exceed the recommended dose. Excessive use of PERFOROMIST Inhalation Solution, or use in conjunction with other medications containing long-acting beta2-agonists, can result in clinically significant cardiovascular effects, and may be fatal. (5.3, 5.5)• Life-threatening paradoxical bronchospasm can occur. Discontinue PERFOROMIST Inhalation Solution immediately. (5.4)• Use with caution in patients with cardiovascular or convulsive disorders, thyrotoxicosis, or with sensitivity to sympathomimetic drugs. (5.6, 5.7)ADVERSE REACTIONSMost common adverse reactions (>2% and more common than placebo)are diarrhea, nausea, nasopharyngitis, dry mouth, vomiting, dizziness, and insomnia (6.2)To report SUSPECTED ADVERSE REACTIONS, contact Dey Pharma, L.P. at 1-800-429-7751 or FDA at 1-800-FDA-1088 or / medwatch.To report SUSPECTED ADVERSE REACTIONS, contact Dey Pharma, LP at or FDA at 1-800-FDA-1088 or /medwatchDRUG INTERACTIONS• Other adrenergic drugs may potentiate effect. Use with caution. (5.3, 7.1) • Xanthine derivatives, steroids, diuretics, or non-potassium sparing diuretics may potentiate hypokalemia or ECG changes. Use with caution. (5.7, 7.2, 7.3)• MAO inhibitors, tricyclic antidepressants and drugs that prolong QTc interval may potentiate effect on the cardiovascular system. Use with extreme caution. (7.4)• Beta-blockers may decrease effectiveness. Use with caution and only when medically necessary. (7.5)See 17 for PATIENT COUNSELING INFORMATION and the FDA-approved Medication GuideRevised: 05/2010FULL PRESCRIBING INFORMATION: CONTENTS *WARNING: ASTHMA-RELATED DEATH1 INDICATIONS AND USAGE1.1 Maintenance Treatment of COPD1.2 Important Limitations of Use2 DOSAGE AND ADMINISTRATION3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS5.1 Asthma-Related Deaths5.2 Deterioration of Disease and Acute Episodes5.3 Excessive Use and Use with Other Long-Acting Beta2-Agonists5.4 Paradoxical Bronchospasm5.5 Cardiovascular Effects5.6 Coexisting Conditions5.7 Hypokalemia and Hyperglycemia5.8 Immediate Hypersensitivity Reactions6 ADVERSE REACTIONS6.1 Beta2-Agonist Adverse Reaction Profile6.2 Clinical Trials Experience6.3 Postmarketing Experience7 DRUG INTERACTIONS7.1 Adrenergic Drugs7.2 Xanthine Derivatives, Steroids, or Diuretics7.3 Non-potassium Sparing Diuretics7.4 MAO Inhibitors, Tricyclic Antidepressants, QTc Prolonging Drugs7.5 Beta-blockers8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.2 Labor and Delivery8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility13.2 Animal Pharmacology14 CLINICAL STUDIES14.1 Adult COPD Trial16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION* Sections or subsections omitted from the full prescribing information are not listedFULL PRESCRIBING INFORMATIONWARNING: ASTHMA-RELATED DEATHLong-acting beta2-adrenergic agonists (LABA) increase the risk of asthma-related death. Data from a large placebo-controlled US study that compared the safety of another long-acting beta2-adrenergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including formoterol, the active ingredient in PERFOROMIST Inhalation Solution. The safety and efficacy of PERFOROMIST in patients with asthma have not been established. All LABA, including PERFOROMIST, are contraindicated in patients with asthma without use of a long-term asthma control medication [see CONTRAINDICATION (4), WARNINGS AND PRECAUTIONS (5.1)].1 INDICATIONS AND USAGE1.1 Maintenance Treatment of COPDPERFOROMIST (formoterol fumarate) Inhalation Solution is indicated for the long-term, twice daily (morning and evening) administration in the maintenance treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.1.2 Important Limitations of UsePERFOROMIST Inhalation Solution is not indicated to treat acute deteriorations of chronic obstructive pulmonary disease [see WARNINGS AND PRECAUTIONS (5.2)].PERFOROMIST Inhalation Solution is not indicated to treat asthma. The safety and effectiveness of PERFOROMIST Inhalation Solution in asthma have not been established.2 DOSAGE AND ADMINISTRATIONThe recommended dose of PERFOROMIST (formoterol fumarate) Inhalation Solution is one 20 mcg unit-dose vial administered twice daily (morning and evening) by nebulization. A total daily dose greater than 40 mcg is not recommended. PERFOROMIST Inhalation Solution should be administered by the orally inhaled route via a standard jet nebulizer connected toan air compressor. The safety and efficacy of PERFOROMIST Inhalation Solution have been established in clinical trials when administered using the PARI-LC Plus® nebulizer (with a facemask or mouthpiece) and the PRONEB® Ultra compressor. The safety and efficacy of PERFOROMIST Inhalation Solution delivered from non-compressor based nebulizer systems have not been established.PERFOROMIST Inhalation Solution should always be stored in the foil pouch, and only removed IMMEDIATELY BEFORE USE. Contents of any partially used container should be discarded.If the recommended maintenance treatment regimen fails to provide the usual response, medical advice should be sought immediately, as this is often a sign of destabilization of COPD. Under these circumstances, the therapeutic regimen should be re-evaluated and additional therapeutic options should be considered.The drug compatibility (physical and chemical), efficacy, and safety of PERFOROMIST Inhalation Solution when mixed with other drugs in a nebulizer have not been established.3 DOSAGE FORMS AND STRENGTHSPERFOROMIST (formoterol fumarate) Inhalation Solution is supplied as a sterile solution for nebulization in low-density polyethylene unit-dose vials. Each vial contains formoterol fumarate dihydrate, USP equivalent to 20 mcg/2 mL of formoterol fumarate.4 CONTRAINDICATIONSAll LABA, including PERFOROMIST, are contraindicated in patients with asthma without use of a long-term asthma control medication. [see WARNINGS and PRECAUTIONS (5.1)].5 WARNINGS AND PRECAUTIONS5.1 Asthma-Related Deaths[See BOXED WARNING]Data from a large placebo-controlled study in asthma patients showed that long-acting beta2-adrenergic agonists may increase the risk of asthma-related death. Data are not available to determine whether the rate of death in patients with COPD is increased by long- acting beta2-adrenergic agonists.A 28-week, placebo-controlled US study comparing the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs.3/13,179 in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). The increased risk of asthma-related death is considereda class effect of the long-acting beta2-adrenergic agonists, including PERFOROMIST Inhalation Solution. No study adequateto determine whether the rate of asthma related death is increased in patients treated with PERFOROMIST Inhalation Solutionhas been conducted. The safety and efficacy of PERFOROMIST in patients with asthma have not been established. All LABA, including PERFOROMIST, are contraindicated in patients with asthma without use of a long-term asthma control medication. [see CONTRAINDICATIONS (4)].Clinical studies with formoterol fumarate administered as a dry powder inhaler suggested a higher incidence of serious asthma exacerbations in patients who received formoterol than in those who received placebo. The sizes of these studies were not adequate to precisely quantify the differences in serious asthma exacerbation rates between treatment groups.5.2 Deterioration of Disease and Acute EpisodesPERFOROMIST Inhalation Solution should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. PERFOROMIST Inhalation Solution has not been studied in patients with acutely deteriorating COPD. The use of PERFOROMIST Inhalation Solution in this setting is inappropriate.PERFOROMIST Inhalation Solution should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. PERFOROMIST Inhalation Solution has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled short-acting beta2-agonist.When beginning PERFOROMIST Inhalation Solution, patients who have been taking inhaled, short-acting beta2-agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute respiratory symptoms. When prescribing PERFOROMIST Inhalation Solution, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient how it should be used. Increasing inhaled beta2-agonist useis a signal of deteriorating disease for which prompt medical attention is indicated. COPD may deteriorate acutely over a periodof hours or chronically over several days or longer. If PERFOROMIST Inhalation Solution no longer controls the symptoms of bronchoconstriction, or the patient’s inhaled, short-acting beta2-agonist becomes less effective or the patient needs more inhalation of short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting, a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dosage of PERFOROMIST Inhalation Solution beyond the recommended 20 mcg twice daily dose is not appropriate in this situation.5.3 Excessive Use and Use with Other Long-Acting Beta2-AgonistsAs with other inhaled beta2-adrenergic drugs, PERFOROMIST Inhalation Solution should not be used more often, at higherdoses than recommended, or in conjunction with other medications containing long-acting beta2-agonists, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.5.4 Paradoxical BronchospasmAs with other inhaled beta2-agonists, PERFOROMIST Inhalation Solution can produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, PERFOROMIST Inhalation Solution should be discontinued immediately and alternative therapy instituted.5.5 Cardiovascular EffectsPERFOROMIST Inhalation Solution, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic and/or diastolic blood pressure, and/or symptoms. If such effects occur, PERFOROMIST Inhalation Solution may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, PERFOROMIST Inhalation Solution, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.5.6 Coexisting ConditionsPERFOROMIST Inhalation Solution, like other sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to sympathomimetic amines. Doses of the related beta2 agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.5.7 Hypokalemia and HyperglycemiaBeta-agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see CLINICAL PHARMACOLOGY (12.2)]. The decrease in serum potassium is usually transient, not requiring supplementation. Beta-agonist medications may produce transient hyperglycemia in some patients. Clinically significant changes in serum potassium and blood glucose were infrequent during clinical studies with long-term administration of PERFOROMIST Inhalation Solution at the recommended dose.5.8 Immediate Hypersensitivity ReactionsImmediate hypersensitivity reactions may occur after administration of PERFOROMIST Inhalation Solution, as demonstrated by cases of anaphylactic reactions, urticaria, angiodema, rash, and bronchospasm.6 ADVERSE REACTIONSLong acting beta2-adrenergic agonists such as formoterol increase the risk of asthma-related death [See BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1)].6.1 Beta2-Agonist Adverse Reaction ProfileAdverse reactions to PERFOROMIST Inhalation Solution are expected to be similar in nature to other beta2-adrenergic receptor agonists including: angina, hypertension or hypotension, tachycardia, arrhythmias, nervousness, headache, tremor, dry mouth, muscle cramps, palpitations, nausea, dizziness, fatigue, malaise, insomnia, hypokalemia, hyperglycemia, and metabolic acidosis.6.2 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Adults with COPDThe data described below reflect exposure to PERFOROMIST Inhalation Solution 20 mcg twice daily by oral inhalation in 586 patients, including 232 exposed for 6 months and 155 exposed for at least 1 year. PERFOROMIST Inhalation Solution was studied in a 12-week, placebo-and active-controlled trial (123 subjects treated with PERFOROMIST Inhalation Solution) and a 52-week, active-controlled trial (463 subjects treated with PERFOROMIST Inhalation Solution). Patients were mostly Caucasians (88%) between40-90 years old (mean, 64 years old) and had COPD, with a mean FEV1 of 1.33 L. Patients with significant concurrent cardiac and other medical diseases were excluded from the trials.Table 1 shows adverse reactions from the 12-week, double-blind, placebo-controlled trial where the frequency was greater than or equal to 2% in the PERFOROMIST Inhalation Solution group and where the rate in the PERFOROMIST Inhalation Solution group exceeded the rate in the placebo group. In this trial, the frequency of patients experiencing cardiovascular adverse events was 4.1% for PERFOROMIST Inhalation Solution and 4.4% for placebo. There were no frequently occurring specific cardiovascular adverse events for PERFOROMIST Inhalation Solution (frequency greater than or equal to 1% and greater than placebo). The rate of COPD exacerbations was 4.1% for PERFOROMIST Inhalation Solution and 7.9% for placebo.TABLE 1Number of patients with adverse reactions in the 12-week multiple-dose controlled clinical trial Adverse Reaction PERFOROMIST PlaceboInhalationSolution20 mcgn (%) n (%) Total Patients 123 (100) 114 (100)Diarrhea 6 (4.9) 4 (3.5)Nausea 6 (4.9) 3 (2.6) Nasopharyngitis 4 (3.3) 2 (1.8)Dry Mouth 4 (3.3) 2 (1.8)Vomiting 3 (2.4) 2 (1.8)Dizziness 3 (2.4) 1 (0.9)Insomnia 3 (2.4) 0 0 Patients treated with PERFOROMIST Inhalation Solution 20 mcg twice daily in the 52-week open-label trial did not experience an increase in specific clinically significant adverse events above the number expected based on the medical condition and age of the patients.6.3 Postmarketing ExperienceThe following adverse reactions have been reported during post-approval use of PERFOROMIST. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Anaphylactic reactions, urticaria, angioedema (presenting as face, lip, tongue, eye, pharyngeal, or mouth edema), rash, and bronchospasm.7 DRUG INTERACTIONS7.1 Adrenergic DrugsIf additional adrenergic drugs are to be administered by any route, they should be used with caution because the sympathetic effects of formoterol may be potentiated [see WARNINGS AND PRECAUTIONS (5.3, 5.5, 5.6, 5.7)].7.2 Xanthine Derivatives, Steroids, or DiureticsConcomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate any hypokalemic effect of adrenergic agonists [see WARNINGS AND PRECAUTIONS (5.7)].7.3 Non-potassium Sparing DiureticsThe ECG changes and/or hypokalemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the co-administration of beta-agonists with non-potassium sparing diuretics.7.4 MAO Inhibitors, Tricyclic Antidepressants, QTc Prolonging DrugsFormoterol, as with other beta2-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval because the effect of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias.7.5 Beta-blockersBeta-adrenergic receptor antagonists (beta-blockers) and formoterol may inhibit the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta-agonists, but may produce severe bronchospasm in COPD patients. Therefore, patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with COPD. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.8 USE IN SPECIFIC POPULATIONS8.1 PregnancyTeratogenic Effects: Pregnancy Category CFormoterol fumarate administered throughout organogenesis did not cause malformations in rats or rabbits following oral administration. However, formoterol fumarate was found to be teratogenic in rats and rabbits in other testing laboratories. When given to rats throughout organogenesis, oral doses of 0.2 mg/kg (approximately 40 times the maximum recommended daily inhalation dose in humans on a mg/m2 basis) and above delayed ossification of the fetus, and doses of 6 mg/kg (approximately 1200 times the maximum recommended daily inhalation dose in humans on a mg/m2 basis) and above decreased fetal weight. Formoterol fumarate has been shown to cause stillbirth and neonatal mortality at oral doses of 6 mg/kg and above in rats receiving the drug during thelate stage of pregnancy. These effects, however, were not produced at a dose of 0.2 mg/kg. Because there are no adequate and well-controlled studies in pregnant women, PERFOROMIST Inhalation Solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Women should be advised to contact their physician if they become pregnant while taking PERFOROMIST Inhalation Solution.8.2 Labor and DeliveryThere are no adequate and well-controlled human studies that have investigated the effects of PERFOROMIST Inhalation Solution during labor and delivery.Because beta-agonists may potentially interfere with uterine contractility, PERFOROMIST Inhalation Solution should be used during labor only if the potential benefit justifies the potential risk.8.3 Nursing MothersIn reproductive studies in rats, formoterol was excreted in the milk. It is not known whether formoterol is excreted in human milk, but because many drugs are excreted in human milk, caution should be exercised if PERFOROMIST Inhalation Solution is administered to nursing women. There are no well-controlled human studies of the use of PERFOROMIST Inhalation Solution in nursing mothers. Women should be advised to contact their physician if they are nursing while taking PERFOROMIST Inhalation Solution.8.4 Pediatric UsePERFOROMIST Inhalation Solution is not indicated for use in children. The safety and effectiveness of PERFOROMIST Inhalation Solution in pediatric patients have not been established. The pharmacokinetics of formoterol fumarate has not been studied in pediatric patients.8.5 Geriatric UseOf the 586 subjects who received PERFOROMIST Inhalation Solution in clinical studies, 284 were 65 years and over, while 89 were 75 years and over. Of the 123 subjects who received PERFOROMIST Inhalation Solution in the 12-week safety and efficacy trial,48 (39%) were 65 years of age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.The pharmacokinetics of PERFOROMIST Inhalation Solution has not been studied in elderly subjects.10 OVERDOSAGEThe expected signs and symptoms with overdosage of PERFOROMIST Inhalation Solution are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms listed under ADVERSE REACTIONS. Signs and symptoms may include angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, and metabolic acidosis. As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose of PERFOROMIST Inhalation Solution.Treatment of overdosage consists of discontinuation of PERFOROMIST Inhalation Solution together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearingin mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of PERFOROMIST Inhalation Solution. Cardiac monitoring is recommended in cases of overdosage.The minimum lethal inhalation dose of formoterol fumarate in rats is 156 mg/kg (approximately 32,000 times the maximum recommended daily inhalation dose in humans on a mg/m2 basis). The median lethal oral doses in Chinese hamsters, rats, and mice provide even higher multiples of the maximum recommended daily inhalation dose in humans.For additional information about overdose treatment, call a poison control center (1-800-222-1222).11 DESCRIPTIONPERFOROMIST (formoterol fumarate) Inhalation Solution is supplied as 2 mL of formoterol fumarate inhalation solution packaged in a 2.5 mL single-use low-density polyethylene vial and overwrapped in a foil pouch. Each vial contains 2 mL of a clear, colorless solution composed of formoterol fumarate dihydrate, USP equivalent to 20 mcg of formoterol fumarate in an isotonic, sterile aqueous solution containing sodium chloride, pH adjusted to 5.0 with citric acid and sodium citrate.The active component of PERFOROMIST Inhalation Solution is formoterol fumarate dihydrate, USP, a racemate. Formoterol fumarate dihydrate is a beta2-adrenergic bronchodilator. Its chemical name is (±)-2-hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS)-2-(4methoxyphenyl)-1-methylethyl]-amino]ethyl]formanilide fumarate dihydrate; its structural formula is:Formoterol fumarate dihydrate, USP has a molecular weight of 840.92 and its empirical formula is (C19H24N2O4)2•C4H4O4•2H2O. Formoterol fumarate dihydrate, USP is a white to yellowish crystalline powder, which is freely soluble in glacial acetic acid, soluble in methanol, sparingly soluble in ethanol and isopropanol, slightly soluble in water, and practically insoluble in acetone, ethyl acetate, and diethyl ether.PERFOROMIST Inhalation Solution does not require dilution prior to administration by nebulization. Like all other nebulized treatments, the amount delivered to the lungs will depend on patient factors and the nebulization system used and its performance. Using the PARI-LC Plus® nebulizer (with a facemask or mouthpiece) connected to a PRONEB® Ultra compressor under in vitro conditions, the mean delivered dose from the mouthpiece was approximately 7.3 mcg (37% of label claim). The mean nebulizerflow rate was 4 LPM and the nebulization time was 9 minutes. PERFOROMIST Inhalation Solution should be administered from a standard jet nebulizer at adequate flow rates via a facemask or mouthpiece.12 CLINICAL PHARMACOLOGY12.1 Mechanism of ActionFormoterol fumarate is a long-acting, beta2-adrenergic receptor agonist (beta2-agonist). Inhaled formoterol fumarate acts locally in the lung as a bronchodilator. In vitro studies have shown that formoterol has more than 200-fold greater agonist activity at beta2-receptors than at beta1-receptors. Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1 receptors are the predominant receptors in the heart, there are also beta2-receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta2-agonists may have cardiac effects.The pharmacologic effects of beta2-adrenoceptor agonist drugs, including formoterol, are at least in part attributable to stimulationof intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.In vitro tests show that formoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, fromthe human lung. Formoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-responsiveness. The relevance of these in vitro and animal findings to humans with COPD is unknown.12.2 PharmacodynamicsSystemic Safety and Pharmacokinetic / Pharmacodynamic RelationshipsThe major adverse effects of inhaled beta2-agonists occur as a result of excessive activation of the systemic beta-adrenergic receptors. The most common adverse effects in adults include skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in plasma potassium, and increases in plasma glucose.Changes in serum potassium and serum glucose were evaluated in 12 COPD patients following inhalation of single doses of PERFOROMIST Inhalation Solution containing 10, 20 and 244 mcg of formoterol fumarate (calculated on an anhydrous basis) in a crossover study. At 1 hour after treatment with formoterol fumarate inhalation solution, mean (± standard deviation) serum glucose rose 26 ± 30, 29 ± 28, and 38 ± 44 mg/dL, respectively, and was not significantly different from baseline or trough level at 24 hours post-dose. At 1 hour after dosing with formoterol fumarate inhalation solution 244 mcg, serum potassium fell by 0.68 ± 0.4 mEq/L, and was not different from baseline or trough level at 24 hours post-dose.。
抗肾上腺素药
（三） 、ß -R阻断药
拉贝洛尔（柳胺苄心定）
【作用、用途】
基本作用：阻断 1＞2＞ 应用： 抗高血压：治疗因外周血管阻力增加所致 的中-重度高血压病，作用强于普萘洛尔。
【不良反应】直立性低血压。
小结
抗肾上腺素药实际上是一类肾上腺素受 体阻断药，根据其对受体的选择性，可分 为两大类： 一、Байду номын сангаасR阻断药：
选择性阻断1－R→血管扩张→BP↓ ↓ 心脏负荷（前、后）↓
特点：
1.不反射性兴奋交感神经，不引起HR↑和肾 素释放↑，故优于非选择性α-R阻断药及直接 扩血管药。 2.降压时不明显影响肾血流量和肾小球滤过率， 故伴有肾功能不良者亦可用。
用于： 1.中－重度高血压；2.充血性心衰 【不良反应】
主要是首剂现象(即首次用药后出现体位 性低血压)。防治： 首剂为正常量的1/4-1/3，睡 前服，不与－R阻断药合用（首剂时）
2. 1-R阻断药：伴有肺功能受损的高血压。
3.、 -R阻断药
兼有阻断 1 、－R的作用，故多用于中度或 重度高血压等。拉贝洛尔
思考题
-R、－R阻断的药理作用、临床用途
和不良反应？
心缩力↓:诱发或加重心衰
（1）抑制心脏
（ 1）
HR↓ 抗心律失常 传导↓ 耗02↓:抗心绞痛 抗心肌梗死 心输出量↓ 抗高血压
（2）抑制交感中枢（中枢－R） （3）抑制NA释放（ 2－R） （4）抑制肾素释放（ 1－R）
脂肪分解↓ （5）抑制代谢 糖原分解↓
（ 1、 2）
组织耗02↓：抗甲亢
二、 －R阻断药
【分类】
经历了三代演变，根据对受体的选择性，可分为三类 (1类：1、2受体阻断药；2类：1受体阻断药；3类：、 受体阻断药)
肾上腺素
+
OH C H2 H NHCH3 H+ HO HO NHCH3 C H H2
+
H
OH2
+ ¦Ä C
+
H2
NHCH3 H
+
.. HOH
-H+
HO HO HO
H C H2 NHCH3
16
合成方法：
氯乙酰化邻苯二酚，再经甲胺胺化，氢化，最后经拆分制得。
17
★★★ 盐酸多巴胺 Dopamine Hydrochloride
利美尼定 Rilmenidine
胍那苄 Guanabenz
胍法辛 Guanfacine
莫索尼定 Moxonidine
胍啶
32
三、选择性β受体激动剂 Selective β agonists
★
盐酸异丙肾上腺素 Isoprenaline hydrocholride
β1/β2
为最早的人工合成品，用其盐酸盐外消旋体 能兴奋β1和β2受体，有强心、扩张外周血管和松弛支气管平滑肌的作 用，有加快心率副作用。但产生心悸、心动过速等较强的心脏兴奋副作用
α1/a2
兼具直接和间接作用，作用于α和β受体，以α受体为主。可被肾 上腺素能神经末梢摄取，进入囊泡，通过置换作用促使NA释放 较强的收缩周围血管和中度增加心肌收缩力作用 临床用途：升压
24
去氧肾上腺素 Phenylephirine 苯福林
α1
选择性作用于α1受体，具收缩血管、升压作用 不含儿茶酚结构，不被儿茶酚-O-甲基转移酶（COMT）代谢，作 用时间长 中等升压作用，不增加心输出量，不用于抗休克。可兴奋虹膜瞳 孔扩大肌 临床用途：散瞳、升压
药理学 拟肾上腺素药
传出神经系统受体 a型肾上腺素受体
肾上腺素受体 Adrenergic receptors
α2:
主要存在于肾上腺素能神经末梢突触前膜，对 NE的释放起负反馈作用。此外，血管平滑肌 及中枢也有a2受体存在。
α2受体后信号转导：
α2 → Gi →cAMP↓
传出神经系统受体 b型肾上腺素受体
β型肾上腺素受体（Beta receptors）
血压
小剂量和治疗量：收缩压升高，舒张压不变或下降， 脉压差↑
大剂量：收缩压和舒张压均↑
血压改变呈双相反应：先迅速明显升压，随后出现微 弱的降压反应，后者持续时间较长。
Adr对血压的翻转作用
给药后迅速出现明显的升压作用，继后出现微弱的 降压反应，后者作用持续时间较长。如事先给予α1受 体阻断药，对抗了其缩血管作用，再用原来升压剂量 Adr，反而呈现明显的降压反应，这种现象称Adr对血压 的翻转作用。充分体现了Adr对血管平滑肌上的β2受体 的激活作用。
摘自第6版《医用药理学基础》
摘自第6版《医用药理学基础》
平滑肌
取决于组织和器官上肾上腺素受体的类型 支气管平滑肌β2-R（+） 支气管平滑肌松弛，特别当支气管平滑肌处于痉 挛状态时，发挥强大的解痉作用，并可抑制组织 和肥大细胞释放过敏反应物质；
支气管粘膜血管α1-R（+） 血管收缩，减轻充血水肿；
β1 receptors:
主要存在于心脏 (窦房结和房室结,心肌,希氏 束浦肯野氏系统)，引起兴奋性效应。
β1 受体后信号转导：
β1 → Gs→cAMP↑
β型肾上腺素受体（Beta receptors）
β2 receptors:
存在于多数平滑肌（子宫,支气管,胃肠道,膀胱）， 引起平滑肌松弛。
7 抗肾上腺素药-09
4．治疗急性心肌梗死 顽固性充血性心力衰竭
机制:
外周阻力↓ 心脏前后负荷↓ 心输出量↑
5．嗜铬细胞瘤的鉴别诊断
【不良反应】
大剂量: 体位性低血压 注射给药： 心动过速、心律失常、诱发或加重心绞痛 其它: 腹痛、恶心、呕吐、诱发溃疡
慎用:
冠心病、胃炎、胃、十二指肠溃疡病人
二、长效α 受体阻断药
***酚苄明（phenoxybenzamine） 非竞争性阻断 特点: 起效慢、强、持久 口服吸收少，局部应用刺激性大, 只作静 脉给药 贮存于脂肪, 缓慢释放
第10 章
抗肾上腺素药
Antiadre根据药物对受体(、)的 选择性不同： 受体阻断药 受体阻断药
10.1 α 受体阻断药
主要药理作用与机制
肾上腺素作用的翻转 (Adrenaline reversal) 拮抗NE和Adr的升压作用，并将Adr的升 压作用翻转为降压作用。 机理： 阻断受体(血管收缩) 不影响受体 ——Adr兴奋受体作用表现充分，降压
增敏
—— 逐步减量停药
5．眼 - 皮肤粘膜综合症 自家免疫反应
6. 其它:疲乏、失眠、抑郁
精神抑郁病人: 忌用普萘洛尔 糖尿病人：掩盖低血糖症状
【药理作用】
1.扩张血管→血压明显下降
静卧和休息的正常人：
舒张压略下降 病理情况或直立时： 血压明显下降 反射性心率加快 2.其它：
抗5-HT、抗组胺作用
10.2 β 受体阻断药
【药理作用】
1. β 受体阻断作用
(1)心血管:
心脏抑制: (-)1-R 心率↙ 心收缩力↙ 传导↙ 耗氧量↙ 输出量↙ 血管收缩: (-)2-R、 心脏(-)--反射调节 → 血管收缩，器官血流量↙ 冠脉流量↙ 血压： 正常人短时给药：影响不大 高血压患者：明显、可靠的降压作用
3.拟、抗肾上腺素药
心脏 心率↑ 传导↑，心肌收缩力↑ 血管 血管舒张，主要是使骨骼肌、冠状血 管舒张（激动β2受体） 血压 心脏兴奋和血管舒张，使收缩压↑/-， 舒张压↓ ，脉压↑。加大剂量Bp ↓ 支气管平滑肌松弛 - 舒张作用比Adr强 - 同时抑制过敏介质释放 代谢 血糖↑脂肪分解↑
天津医科大学
麻黄碱（ephedrine） [α 、β 受体 + 促进NA释放]
特点： 性质稳定，可口服； 易透过血脑屏障，中枢兴奋作用较显著； 收缩血管、兴奋心脏、升高血压及松弛支气管平滑肌 作用与Adr相似但较弱，而且缓慢持久； 连续使用可发生快速耐受性 原因:①递质耗竭；②受体向下调节 应用： 预防蛛网膜下腔麻醉和硬膜外麻醉的低血压 鼻塞 消除鼻粘膜充血和肿胀 防治轻度支气管哮喘
——哌唑嗪（prazosin）和特拉唑啉（terazosin）
天津医科大学
β 受体阻断药
(β blockers )
定义 选择性和β受体结合，竞争性阻断β受体激动 药与β受体结合，拮抗该受体激动后产生的一 系列作用 分类 - β 1、 β 2受体阻断药 普萘洛尔、噻吗洛尔、索他洛尔；吲哚洛尔、 阿普洛尔等 - β 1受体选择性阻断药 阿替洛尔、美托洛尔；醋丁洛尔等
天津医科大学
受体阻断药
受体阻断药能选择性地与受体结合， 它们主要的药理作用是拮抗去甲肾上腺 素和肾上腺素的升压作用，并将Adr的升 压作用翻转为降压作用，此现象称为 “肾上腺素作用的翻转”(adrenaline reversal )。这是因为受体阻断药阻断 与血管收缩有关的受体，但不影响与血 管舒张有关的受体。
天津医科大学
拟肾上腺素药分类
外周神经系统药物
Choline receptor
毒蕈碱型受体：副交感神经的节后纤维的胆 碱受体对毒蕈碱较为敏感，故称为M-胆碱受体 烟碱型受体：位于神经节细胞和骨骼肌膜上 的胆碱受体，对尼古丁比较敏ห้องสมุดไป่ตู้，故称为N-胆 碱受体
受体 M M1 分布 大脑皮质、海马、 大脑皮质、海马、纹状体 、周围神经节和分泌腺体 生理功能 与传递神经元的兴奋冲 动有关、调节大脑的各 动有关、 种功能， 种功能，并调节汗腺和 消化腺体的分泌 引起心肌收缩力减弱、 引起心肌收缩力减弱、 心率降低、 心率降低、传导减慢 激动剂药物作用 治疗早老性痴呆 拮抗剂药物作用 治疗消化道溃疡
槟榔碱： 槟榔碱：A cycle “reverse ester” ” 反向酯 of acetylcholine Act at both N- and M-receptor,Partial agonist at M1 and M2 used as animal drug
占诺美林
promising for AD
M2 M3
中枢神经系统较低脑区和 心脏等周围效应器组织 腺体和平滑肌
有可能用于治疗冠 有可能用于治疗冠 心病和心动过速
治疗心动徐缓性心 治疗心动徐缓性心 率失常
血管平滑肌舒张、 治疗痉挛性血管病 治疗慢性阻塞性呼 痉挛性血管病、 血管平滑肌舒张、胃肠 治疗痉挛性血管病、 治疗慢性阻塞性呼 吸道疾病、 道和膀胱平滑肌收缩、 手术后腹气胀、 道和膀胱平滑肌收缩、 手术后腹气胀、尿 吸道疾病、尿失禁 括约肌松弛、瞳孔缩小、 潴溜 括约肌松弛、瞳孔缩小、 腺体分泌增加 抑制钙离子通道 孤儿受体 释放乙酰胆碱 缺乏特异性配基 缺乏特异性配基 治疗早老性痴呆 治疗高血压 松弛骨骼肌
((3s-cis)-3-ethyl-dihydro-4-[(1-methyl-1Himidazol-5-yl) methyl]-2(3H)-furanone Reduction of intraocular pressure in some types of glaucoma
药物化学CJ-07 肾上腺素能药物
6
NH2
分类（按作用方式）
直接作用药 间接作用药 肾上腺素受体激动剂 促进肾上腺素能神经末梢释放递质
混合作用药
兼有直接和间接作用的药物
•本书介绍直接作用药和混合作用药
7
一、内源性拟交感胺
R1=OH, R2=CH3 肾上腺素 α 、β 受体激动剂； R1=OH, R2=H 去甲肾上腺素 α受体激动剂； R1=R2=H 多巴胺 HO α、β受体激动剂；
29
HO HO
Cl
CH3NH2,HCl
OH H N CH3 . HCl H2/Pd-C HO HO OH H N CH3 H N CH3 . HCl NH3
酒石酸拆分
生物前体——多巴胺
在体内经过酶催化的，除水解反应以外的氧化、 还原、磷酸化和脱羧反应等方式活化的前药 称生物前体前药，简称生物前体
40
2000年西药感冒药PPA危机
OH NH2 CH3
去甲麻黄碱， 苯丙醇胺 Phenylpropanolamine
PSE(伪麻黄碱)
41
b-受体激动剂
b1-受体激动剂： 主要引起心率增加、心肌收缩力增强等。用作 强心药。 b2-受体激动剂： 舒张支气管平滑肌，临床主要用于平喘。少数 品种因对子宫平滑肌或周围血管平滑肌作用较 强，临床也用于抗早产及血管痉挛性疾病。
15
一）肾上腺素Adrenaline
结构特点
邻 苯 二 酚
OH HO HO
*
H N
苯乙胺 光学活性
16
一）肾上腺素Adrenaline
理化性质
1, 还原性 2, 酸碱性 邻 3, 消旋化
苯 二 酚
OH HO HO
药理学医学英语词汇.
协同作用 治疗效应 治疗指数 阈浓度 毒性反应
Chapter 3 Pharmacokinetics
英文 absorption active transport apparent volume of distribution(vd) bioavailability biotransformation blood-brain-barrier clearance, cl distribution drug transport rate elimination enzyme inducer enzyme inhibitor first order kinetics first-pass effect half life( t1/2) hepatoenteral circulation maintenance dose metabolism one-compartment model passive diffusion peak concentration (cmax ) placental barrier redistribution of drugs steady state concentration(css ) Plateau concentration time-concentration curve two-compartment model zero order kinetics
中文 卡巴胆碱 胆碱酯酶抑制剂 胆碱受体激动剂 调节麻痹 调节痉挛 加兰他敏 新斯的明 毒扁豆碱 毛果芸香碱 有机磷酸酯类 胆碱酯酶复活剂
Chapter 7 Cholinoceptor blocking drugs
英文
anisodamine
atropine
homatropine
pirenzepine
作用于肾上腺素能受体的药物
“十二五”普通高等教育本科国家级规划教材
一、拟肾上腺素药物 Adrenergic Agents
—— 非选择性肾上腺素受体激动药 non selective adrenergic agonists
肾上腺素 Adrenaline
R
化学名： （R）- 4-[2-（甲氨基）-1-羟基乙基]-1，2-苯二酚 水中微溶，制成盐酸盐或酒石酸盐注射液
抗肾上腺素药 adrenergic antagonists
1
“十二五”普通高等教育本科国家级规划教材
AD和NA的基本结构：
含有儿茶酚catechol结构——儿茶酚胺catecholamines
肾上腺素能受体生理功能：
• • 调节血压、心率、心力 调节胃肠运动和支气管平滑肌张力
2
“十二五”普通高等教育本科国家级规划教材
β1
心脏、肾脏、脑 干
β 受体 β2
子宫肌、气 管、胃肠道、 血管壁 舒张支气管、 子宫和血管 平滑肌 平喘和改善 微循环 引起支气管 痉挛、 糖代谢 紊乱等
β3
脂肪组织
主要分布
激动后效应
激动剂作用 阻断剂作用
增强心脏功能， 升压，松弛胃肠 道平滑肌，分解 脂肪 强心和抗休克 治疗心律失常
分解脂肪， 促 进氧耗
• 极性较大，不易透过BBB • 生理作用：主要为外周作用。兴奋α和β受体。轻微收缩外周 血管，扩张肾脏、肠系膜及冠状血管，为选择性血管扩张药 • 临床应用：急性心肌梗死、创伤、肾功能衰竭及心脏手术等 引起的休克
14
“十二五”普通高等教育本科国家级规划教材
• 合成方法：香草醛与硝基甲烷缩合，再经锌汞齐还原， 去甲基制得
“十二五”普通高等教育本科国家级规划教材
药物化学术语词典
药物化学术语词典第一章绪论1、药物（drug）：药物是人类用来预防、治疗、诊断疾病、或为了调节人体功能，提高生活质量，保持身体健康的特殊化学品。
2、药物化学（medicinal chemistry）：药物化学是一门发现与发明新药、研究化学药物的合成、阐明药物的化学性质、研究药物分子与机体细胞（生物大分子）之间相互作用规律的综合性学科，是药学领域中重要的带头学科以及极具朝气的朝阳学科。
3、国际非专有药名（international non-proprietary names for pharmaceutical substance，INN）：是新药开发者在新药研究时向世界卫生组织（WHO）申请，由世界卫生组织批准的药物的正式名称并推荐使用。
该名称不能取得任何知识产权的保护，任何该产品的生产者都可使用，也是文献、教材及资料中以及在药品说明书中标明的有效成分的名称。
在复方制剂中只能用它作为复方组分的名称。
目前，INN名称已被世界各国采用。
4、中国药品通用名称（Chinese Approved Drug Names，CADN）：依据INN的原则，中华人民共和国的药政部门组织编写了《中国药品通用名称》（CADN），制定了药品的通用名。
通用名是中国药品命名的依据，是中文的INN。
CADN主要有以下的一些规则：中文名使用的词干与英文INN对应，音译为主，长音节可简缩，且顺口；简单有机化合物可用其化学名称。
第二章中枢神经系统药物1、巴比妥类药物（barbiturates agents）：具有5，5二取代基的环丙酰脲结构的一类镇静催眠药。
20世纪初问市的一类药物，主要由于5，5取代基的不同，有数十个各具药效学和药动学特色的药物供使用。
因毒副反应较大，其应用已逐渐减少。
2、内酰胺-内酰亚胺醇互变异构（lactam- lactim tautomerism）：类似酮-烯醇式互变异构，酰胺存在酰胺-酰亚胺醇互变异构。
即酰胺羰基的双键转位，羰基成为醇羟基，酰胺的碳氮单键成为亚胺双键，两个异构体间互变共存。
肾上腺素受体
α2- R—突触前膜—负反馈调节NA释
放
β肾上腺素受体 （β-R）
β1- R—心脏—兴奋
β2- R—骨骼肌血管--扩张
冠脉血管 支气管平滑肌--松弛
突触前膜—正反馈调节NA释放.
肾上腺素受体结构
肾上腺素受体结构
药物的作用方式
1. 直接作用于受体
激动药(agonist)—与肾上腺素能受体结合后能 激动受体，呈拟似递质作 用
[临床应用]
1.防治轻度支气管哮喘鼻塞，0.5~1% 溶液滴鼻。
3.防治低血压状态 4.缓解荨麻疹和血管神经性水肿的皮肤
粘膜症状。
多巴胺(dopamine,DA)
DA为NA的前体物，药用为人工合成品。
[体内过程]
1.DA口服易在肠和肝中破坏，口服无效。
酚妥拉明生物利用度低，口服吸收差，口服给
药的疗效只有注射给药的20%，口服后30min疗
效达高峰，维持3~6h；肌肉注射维持30~50min。
[药理作用]
作用机制：
选择性阻断1、2受体，对受体无作用。 酚妥拉明与受体结合较松散，易于解离，为 竞争性受体阻断药。 1.血管：
血管扩张，外周阻力降低，血压下降(具有明 显的AD翻转作用)。直接血管扩张作用和阻断 1受体作用。
3.支气管哮喘急性发作
病理 支气管痉挛 喉头水肿 过敏
药理 β２ α１ 抗过敏
[临床应用]
4.与局麻药配伍 目的：收缩血管，减少局麻药吸收，延长局麻作
用时间，减少局麻药吸收中毒。 局麻药中AD的浓度为1:25000(一次用量不超过
0.3mg)。
[不良反应]
心悸、烦躁、头痛、血压升高、心律失常，心室颤动。 禁用于心、脑血管疾病患者，糖尿病及甲亢患者。
肾上腺素受体阻断药
选择性1受体阻滞药
哌唑嗪（Prazosin）
用途：
1.治疗高血压 2.治疗前列腺增生引起的排尿困难。
特拉唑嗪（Trazos
二、-R阻断药
选择性结合-R，竞争性阻断-R， 拮抗-R激动后的效应
按药物对1、 2受体的选择性分：
非选择性-R阻断药—普萘洛尔、吲哚洛尔、
纳多洛尔、噻吗洛尔
选择性1-R阻断药—美托洛尔、醋丁洛尔、
阿替洛尔
已有30余种，它们的作用存在若干差别
1）对心脏β1-R是否有选择性阻断作用
2）对细胞膜是否有膜稳定作用
3) 是否有内在拟交感活性 (intrinsic
sympathomimetic activity, ISA)
临床应用：
临床应用地位重要，可治疗——高血压、 快速型心律失常、心绞痛等心血管疾病 （有专章介绍） 。
也可用于甲亢、肌震颤、偏头痛的治
疗及局部用药降低眼内压治疗青光眼
(阻断睫状体-R,↓房水生成)
不良反应
1.心脏外的β-R阻断所引起的不良反应：
支气管-R阻断—哮喘(禁用) 消化道-R阻断—消化不良、恶心、腹泻
故，对患心血管疾病同时兼有哮喘患者可选用 选择性的1-R阻断药（阿替洛尔、美托洛尔为好）
(3)肾素释放↓ ：阻断肾小球旁器1-R， 抑制肾素释放→AⅡ↓→BP↓ (4)代谢：① 糖尿病：抑制AD引起的高血糖 反应；抑制糖原分解，掩盖 胰岛素引起的低血糖反应； ② 甲亢：↓对儿茶酚胺的敏感性， 抑制T4 →T3
特点：作用似酚妥拉明，与酚妥拉明比较：
1. -R阻断作用弱 2. 拟胆碱作用、组胺样作用强 →不良反应发生率高。 应用: 外周血管痉挛性疾病； 静滴NA外漏时治疗
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O CH3O CH3O N N NH2 N N C
O
母核为喹唑啉; 4－氨基，6,7－二甲氧基; • 2-位与1-哌嗪的氮相连联； • 4-哌嗪的氮与羰基、呋喃的2-位相连
•
analogs: 哌唑嗪; 特拉唑嗪; 曲马唑嗪; 美他唑嗪; 多沙唑嗪
O CH3O CH3O N N NH2
CH3 OCH2 C OH CH3 O CH OCH3
2．麻黄碱 Ephedrine
• Ephedrine is seperated from several Ephedra plants. in 1887, isolated from the Chinese herb Ephedra and pure Ephedrine was crystallized. Its clinical application was earlier than norepinephrine and epinephrine
• receptor agonist, slight effective to receptor. • A strong vasoconstriction.
• Increase the blood pressure, treat shock
• activity of (-)-body is 27 times than (+)-body.
Adrenergic Antagonists
• 1. Α-receptor antagonist • (A) short-acting type • (B) long-acting type
α1-receptor blocking agents: Prazosin is the first α1 - receptor antagonist, antihypertensive agents
-H αreceptor -CH3 α,βreceptor -CH(CH3)2 ，-C(CH3)3 βreceptor
OH
1 2
H N R1
R3
R2
• 2. R2: -H ， -CH3（ 手性碳, 如麻黄缄） • 3. R3: a. 3,4-二羟基是基本结构,易被氧化； b. 无羟基,活性低,较稳定； c. 3-CH2OH, 4-OH; 3,5-二羟基(口服) d. 酯化,前药
7.2 Adrenergic drugs
• 1. α-receptor or α-, β-receptor agonists (1) α-receptor agonists
Norepinephrine Bitartrate
CH2NH2 H C OH COOH H C OH HO C H OH OH COOH H2O
N
N C R
R=
O
;
O
; ;
;
CH3
O
R基团的不同，使它们的药动学性质有很 大的差异
receptor antagonist (1) The development of -receptor antagonist
Cl Cl
CH3 CH CH2NHCH OH CH3
Pronethalol
CH3 CH CH2NHCH CH 3 OH
• Epinephrine was found tobe the active comound in the early 20th century. In 1940s, norepinephrine was recognized as the real neurotransmitters in the peripheral nervous system.
• 用碳桥替代DCI 中3,4二氯得丙萘洛尔， 1962年曾作为临床候选药物，因动物 试验发现致癌，1963年即被撤消
The first successful clinical antagonist---Propranolol
CH3 O OH N H CH3
• 芳环和侧链之间插入 氧亚甲基（OCH2）， • 将侧链从萘环的位移至位
• R-(-)-4-(2-氨基-1-羟基乙基)-1,2-苯二酚 R,R-2,3-二羟基丁二酸盐一水合物 • R-(-)-4-(2-Amino-1-hydroxyethyl)-1,2benzenediol R,R-2,3-dihydroxybutanedionate (1:1) salt monohydrate
7.1 The biosynthesis, metabolism and acting mechanism of Catecholamines such as norepinephrine and epinephrine
• Noradrenaline is the main neurotransmitters released by adrenergic nerve endings, the content in the nerve endings is about 3-300 times than in the cells. • Norepinephrine can bind withα or βadrenergic receptor reversibly, promote the effector to produce physiological effects.
• heat for 3 minutes at 120 ℃ or heat with concentrated sulfuric acid at 80 ~ 90 ℃ for 2 hours, racemization will be occurred; • norepinephrine is easily oxidized under light or air, so it should be preserved without contacting with air. • norepinephrine will be oxidized into norepinephrine red in the buffer solution of pH 6.5 added with iodine solution, sodium thiosulfate can fade the colour of iodine solution and then change into red.
The biosynthesis and metabolism of noradrenaline (1)
L-tyrosine
COOH HO NH2 HO HO
dopa
COOH NH2
dopamine
HO HO NH2
OH HO HO NHCH3 HO HO
OH NH2
The biosynthesis and metabolism of noradrenaline (2)
OH HO HO OH HO HO CHO NHCH3 HO HO OH NH2
COMT MAO
CH3O HO OH NH2
•
• • •
MAO(Monoamine oxidase) COMT(Catechol-O-methyltransferase) AR(aldehyde reductase ) AD (aldehyde dehydrogenase)
• Propranolol: for the treatment of a variety of cardiovascular diseases. • First for angina pectoris,laterly as antiarrhythmic drugs, in clinical practice found the anti-hypertensive activity.
• α-receptor agonist, contract blood vessels, increase blood pressure.For emergency treatment of anaphylactic shock; • β1-receptor agonist, excite cardiac muscle. treatment of cardiac arrest; • β2- receptor agonist, relax bronchia. Remission of asthma
(-)ephedrine* (-)pseudo~ (+)ephedrine (+)pseudo~ (1R,2S) (1R,2R) (1S,2R) (1S,2S)
CH3 H C NHCH3 H C OH CH3HN CH3 C H CH3HN HO H C OH CH3 C H C H HO CH3 H C NHCH3 C H
(二) α-、β-受体激动剂 1．肾上腺素 Epinephrine
OH HO HO
•
NHCH3
R-4-[(甲胺基)-1-羟基乙基]-1,2苯二酚
• Although there is no oral adrenergic activity, the clinical use is much borader than norepinephrine.
Stability: auto-oxidation
• Reducibility of Phenolic substances is different by different conditions. in alkaline medium, phenoxy anion accelerate the auto-oxidation, wheras in acidic medium, reducibility is decreased. • 去甲肾上腺素、肾上腺素、异丙肾上腺素易生成 红色色素，并可进一步聚合成棕色多聚物。
Chapter 7 Adrenergic Drugs
Epinephrine or adrenaline Norepinephrine or noradrenaline belong to Catecholamines 邻苯二酚,儿茶酚:Catechol