Ch61 Antifungal Agents

药理学蓝皮圣经第 14 版 (2022) 精要

Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 14th Edition

1 Systemic Antifungal Agents: Drugs for Deeply Invasive Fungal Infections

全身性抗真菌药物：治疗深侵袭性真菌感染的药物

• Amphotericin B (两性霉素 B)，抗生素类，结合麦角固醇，增加膜通透性（氨基酸、电解质等），致真菌生长停止。
• Flucytosine (氟胞嘧啶)
• Imidazoles and Triazoles (咪唑类和三唑类)，皆使14 - 脱甲基酶系失活，导致麦角固醇（真菌细胞膜重要成分）合成受阻
  • Ketoconazole (酮康唑)，口服酮康唑已被伊曲康唑取代。
  • Itraconazole (伊曲康唑)，肝毒性低于酮康唑。由于不抑制雄激素合成，亦可避免酮康唑所发生的内分泌异常。体内外抗真菌活性较酮康唑强 5～100 倍。
  • Fluconazole (氟康唑)
  • Voriconazole (伏立康唑)
  • Posaconazole (泊沙康唑)
  • Isavuconazole (艾沙康唑)
• Echinocandins (棘白菌素)
  • Caspofungin (卡泊芬净)
  • Micafungin (米卡芬净)
  • Anidulafungin (阿尼杜拉芬净)
• Other Systemic Antifungal Agents (其他全身性抗真菌药)
  • Griseofulvin (灰黄霉素)
  • Terbinafine (特比萘芬)
• Agents Active Against Microsporidia and Pneumocystis (对小孢子虫和肺孢子虫有活性的药物)
  • Albendazole (阿苯达唑)
  • Fumagillin (烟曲霉素)
  • Pentamidine (喷他脒)

1.1 Itraconazole (伊曲康唑)

Itraconazole is a triazole that lacks the corticosteroid suppression associated with ketoconazole while retaining most of ketoconazole’s pharmacological properties and extending the antifungal spectrum. Importantly, itraconazole has activity against Aspergillus spp., whereas imidazoles do not. Itraconazole has been supplanted by other triazoles in the treatment of invasive mold infections but remains an important prophylactic agent in the prevention of mold infections in some patients (e.g., patients with chronic granulomatous disease [CGD]).

伊曲康唑是一种三唑类药物，缺乏与酮康唑相关的皮质类固醇抑制，同时保留了酮康唑的大部分药理学特性并扩展了抗真菌谱。重要的是，伊曲康唑对曲霉属有活性，而咪唑类则没有。伊曲康唑在治疗侵袭性霉菌感染方面已被其他三唑类药物取代，但在某些患者（例如，慢性肉芽肿病 [chronic kineomatous disease， CGD] 患者）中，伊曲康唑仍是预防霉菌感染的重要预防剂。

ADME: Itraconazole is available as a tablet, capsule, and a solution in hydroxypropyl-β-cyclodextrin for oral use. The capsule form of the drug is best absorbed in the fed state, but the oral solution is better absorbed in the fasting state, providing peak plasma concentrations more than 150% of those obtained with the capsule. The tablet formulation is approved only for onychomycosis. Super-bioavailable (SUBA)-itraconazole, a reformulation with enhanced GI absorption, has recently been approved by the FDA (U.S. Food and Drug Administration). Itraconazole is metabolized in the liver. It is both a substrate for and a potent inhibitor of CYP3A4. Itraconazole is present in plasma with an approximately equal concentration of a biologically active metabolite, hydroxy-itraconazole. The native drug and metabolite are more than 99% bound to plasma proteins. Neither appears in urine or in CSF. The t1/2 of itraconazole at steady state is about 30 to 40 h. Steady-state levels of itraconazole are not reached for 4 days and those of hydroxy-itraconazole for 7 days; thus, loading doses are recommended when treating deep mycoses. Severe liver disease will increase itraconazole plasma concentrations, but azotemia and hemodialysis have no effect.

ADME： 伊曲康唑有片剂、胶囊和口服羟丙基-β-环糊精溶液。药物的胶囊形式在进食状态下吸收最好，但口服溶液在空腹状态下吸收最好，提供比胶囊获得的血浆峰值浓度高 150% 以上。该片剂制剂仅被批准用于甲癣。超级生物可利用度 （SUBA）-伊曲康唑是一种增强胃肠道吸收的重新配方，最近已获得 FDA（美国食品和药物管理局）的批准。伊曲康唑在肝脏中代谢。它既是 CYP3A4 的底物，也是 CYP3A4 的有效抑制剂。伊曲康唑存在于血浆中，与生物活性代谢物羟基-伊曲康唑浓度大致相等。天然药物和代谢物与 Plasma 蛋白结合的 99% 以上。均未出现在尿液或 CSF 中。伊曲康唑在稳态下的 t1/2 约为 30 至 40 小时。伊曲康唑的稳态水平在 4 天内未达到，羟基 - 伊曲康唑在 7 天内未达到稳态水平;因此，在治疗深部真菌病时，建议使用负荷剂量。严重的肝病会增加伊曲康唑血浆浓度，但氮质血症和血液透析没有效果。

Therapeutic Uses: Itraconazole is the drug of choice for patients with indolent, nonmeningeal infections due to B. dermatitidis, H. capsulatum, P. brasiliensis, and Coccidioides immitis. The drug also is useful in the therapy of indolent invasive aspergillosis outside the CNS, particularly after the infection has been stabilized with amphotericin B. Approximately half of the patients with distal subungual onychomycosis respond to itraconazole (Evans and Sigurgeirsson, 1999). Although not approved for these uses, itraconazole is a reasonable choice for the treatment of pseudallescheriasis, an infection that does not respond to amphotericin B therapy, as well as cutaneous and extracutaneous sporotrichosis, tinea corporis, and extensive tinea versicolor. HIV-infected patients with disseminated histoplasmosis or penicilliosis have a decreased incidence of relapse if given prolonged itraconazole “maintenance” therapy. Itraconazole is not recommended for maintenance therapy of cryptococcal meningitis in HIV-infected patients because of a high incidence of relapse. Long-term itraconazole therapy has been used in non–HIV-infected patients with allergic bronchopulmonary aspergillosis to decrease the dose of glucocorticoids and reduce attacks of acute bronchospasm (Salez et al., 1999). Itraconazole solution is effective and approved for use in oropharyngeal and esophageal candidiasis. Because the solution has more GI side effects than fluconazole tablets, itraconazole solution usually is reserved for patients not responding to fluconazole. Finally, itraconazole is also used as Aspergillus prophylaxis in patients with CGD.

治疗用途： 伊曲康唑是由皮炎芽孢杆菌、荚膜嗜血杆菌、巴西假单胞菌和粗球孢子菌引起的惰性、非脑膜感染患者的首选药物。该药物还可用于治疗 CNS 外的惰性侵袭性曲霉病，特别是在用两性霉素 B 稳定感染后。大约一半的远端甲下甲真菌病患者对伊曲康唑有反应（Evans 和 Sigurgeirsson，1999）。虽然尚未批准用于这些用途，但伊曲康唑是治疗假鼻癣（一种对两性霉素 B 治疗无反应的感染）以及皮肤和皮外孢子丝菌病、体癣和广泛花斑癣的合理选择。如果给予长期伊曲康唑“维持”治疗，患有播散性组织胞浆菌病或青霉素病的 HIV 感染患者的复发率会降低。不建议将伊曲康唑用于 HIV 感染患者隐球菌性脑膜炎的维持治疗，因为其复发率高。长期伊曲康唑治疗已用于非 HIV 感染的过敏性支气管肺曲霉病患者，以减少糖皮质激素的剂量并减少急性支气管痉挛的发作（Salez 等人，1999 年）。伊曲康唑溶液有效，并获批用于口咽和食管念珠菌病。由于该溶液比氟康唑片剂具有更多的胃肠道副作用，因此伊曲康唑溶液通常仅用于对氟康唑无反应的患者。最后，伊曲康唑也用作 CGD 患者的曲霉菌预防。

Dosage: In treating deep mycoses, a loading dose of 200 mg of itraconazole is administered three times daily for the first 3 days. After the loading doses, two 100-mg capsules are given twice daily with food. Divided doses may increase the AUC. For maintenance therapy of HIV-infected patients with disseminated histoplasmosis, 200 mg once daily is used. Onychomycosis can be treated with either 200 mg once daily for 12 weeks or, for infections isolated to fingernails, two monthly cycles consisting of 200 mg twice daily for 1 week followed by a 3-week period of no therapy— so-called pulse therapy (Evans and Sigurgeirsson, 1999). Once-daily terbinafine (250 mg), however, is superior to pulse therapy with itraconazole. For oropharyngeal candidiasis, itraconazole oral solution should be taken during fasting in a dose of 100 mg (10 mL) once daily and swished vigorously in the mouth before swallowing to optimize any topical effect. Patients with esophageal thrush unresponsive or refractory to treatment with fluconazole tablets are given 100 mg of the solution twice a day for 2 to 4 weeks. The typical dose for fungal prophylaxis in patients with CGD is 5 mg/kg per day. In pediatric patients, plasma levels are very erratic and therapeutic monitoring should be considered, particularly for patients being treated for systemic fungal infections (e.g., histoplasmosis and blastomycosis) (Downes et al., 2020).

剂量：在治疗深部真菌病时，前 3 天每天 3 次，每天施用 200mg 的负荷剂量的伊曲康唑。负荷剂量后，每天两次随餐服用两粒 100mg 胶囊。分次给药可能会增加 AUC。对于播散性组织胞浆菌病 HIV 感染患者的维持治疗，使用 200mg 每日一次。甲癣可以用 200mg 每天一次治疗 12 周，或者对于孤立于指甲的感染，两个月一个周期，包括 200mg，每天两次，持续 1 周，然后是 3 周的无治疗期——所谓的脉冲疗法（Evans 和 Sigurgeirsson，1999 年）。然而，每日一次的特比萘芬（250mg）优于伊曲康唑的脉冲治疗。对于口咽念珠菌病，伊曲康唑口服溶液应在空腹期间以 100mg（10ml）的剂量服用，每天一次，并在吞咽前在口中用力漱口，以优化任何局部效果。对氟康唑片治疗无反应或难治性食管鹅口疮患者每天两次给予 100mg 溶液，持续 2 至 4 周。CGD 患者真菌预防的典型剂量为 5 mg/kg 每天。在儿科患者中，血浆水平非常不稳定，应考虑治疗监测，特别是对于正在接受全身性真菌感染（例如组织胞浆菌病和芽生菌病）治疗的患者（Downes et al.， 2020）。

Adverse Effects: Itraconazole carries an FDA boxed warning about possible serious adverse effects, including QT prolongation, heart failure, negative inotropic effects, and drug interactions. Serious hepatotoxicity has led, in rare cases, to hepatic failure and death. If symptoms of hepatotoxicity occur, the drug should be discontinued and liver function assessed. In the absence of interacting drugs, itraconazole capsules and suspension are well tolerated at 200 mg daily. Diarrhea, abdominal cramps, anorexia, and nausea are more common than with the capsules. Of patients receiving 50 to 400 mg of the capsules per day, nausea and vomiting, hypertriglyceridemia, hypokalemia, increased serum aminotransferase, and rash occurred in 2% to 10%. Occasionally, rash necessitates drug discontinuation, but most adverse effects can be handled with dose reduction. Profound hypokalemia has been seen in patients receiving 600 mg or more daily and in those who recently have received prolonged amphotericin B therapy. Doses of 300 mg twice daily have led to other side effects, including adrenal insufficiency, lower limb edema, hypertension, and in at least one case, rhabdomyolysis. Doses greater than 400 mg/day are not recommended for long-term use. Anaphylaxis has been observed rarely, as well as severe rash, including Stevens-Johnson syndrome. Itraconazole is contraindicated for the treatment of onychomycosis during pregnancy or for women contemplating pregnancy.

不良反应：伊曲康唑带有 FDA 黑框警告，关于可能的严重不良反应，包括 QT 间期延长、心力衰竭、负性肌力作用和药物相互作用。在极少数情况下，严重的肝毒性会导致肝功能衰竭和死亡。如果出现肝毒性症状，应停药并评估肝功能。在没有相互作用药物的情况下，伊曲康唑胶囊和混悬液每天 200 毫克的耐受性良好。腹泻、腹部绞痛、厌食和恶心比胶囊更常见。在每天接受 50 至 400 毫克胶囊的患者中，恶心和呕吐、高甘油三酯血症、低钾血症、血清转氨酶升高和皮疹发生在 2% 至 10% 的患者中。偶尔，皮疹需要停药，但大多数不良反应可以通过减少剂量来处理。在每天接受 600 毫克或更多剂量的患者以及最近接受长期两性霉素 B 治疗的患者中，已观察到严重低钾血症。每天两次 300 毫克的剂量导致了其他副作用，包括肾上腺皮质功能减退、下肢水肿、高血压，以及至少一例横纹肌溶解症。大于 400 毫克/天的剂量不建议长期使用。很少观察到过敏反应，以及严重的皮疹，包括 Stevens-Johnson 综合征。伊曲康唑禁用于治疗妊娠期甲癣或考虑怀孕的妇女。

Drug Interactions: Tables 61–4, 61–5, and 61–6 list select interactions of azoles with other drugs. Many of the interactions can result in serious toxicity from the companion drug, such as inducing potentially fatal cardiac arrhythmias when used with quinidine, halofantrine (an orphan drug used for malaria), levomethadyl (an orphan drug used for heroin addiction), pimozide, or cisapride (available only under an investigational limited access program in the U.S.). Other drugs may decrease itraconazole serum levels below therapeutic concentrations (Table 61–5).

药物相互作用：表 61-4、61-5 和 61-6 列出了唑类与其他药物的选择相互作用。许多相互作用可导致伴随药物产生严重毒性，例如与奎尼丁、氟蒽群（一种用于治疗疟疾的孤儿药）、左旋美沙啶（一种用于海洛因成瘾的孤儿药）、匹莫齐特或西沙必利（仅在美国的研究性限制获取计划下提供）一起使用时，会诱发可能致命的心律失常。其他药物可能会将伊曲康唑血清水平降低到治疗浓度以下（表 61-5）。

1.2 Fluconazole (氟康唑)

Fluconazole is a fluorinated bis-triazole. (氟康唑是一种氟化双三唑)

ADME: Fluconazole is almost completely absorbed from the GI tract. Plasma concentrations are essentially the same whether the drug is given orally or intravenously, and its bioavailability is unaltered by food or gastric acidity. Peak plasma concentrations are 4 to 8 μg/mL after repetitive doses of 100 mg. Renal excretion accounts for more than 90% of elimination, and the elimination t1/2 is 25 to 30 h. Fluconazole diffuses readily into body fluids, including breast milk, sputum, and saliva; concentrations in CSF can reach 50% to 90% of the simultaneous values in plasma. The dosage interval should be increased from 24 to 48 h with a creatinine clearance of 21 to 40 mL/min and to 72 h at 10 to 20 mL/min. A dose of 100 to 200 mg should be given after hemodialysis. About 11% to 12% of drug in the plasma is protein bound.

ADME： 氟康唑几乎完全从胃肠道吸收。无论药物是口服还是静脉给药，血浆浓度基本相同，并且其生物利用度不受食物或胃酸度的影响。重复给药 100 mg 后，血浆峰浓度为 4 至 8 μg/mL。肾排泄占消除的 90% 以上，消除 t1/2 为 25 至 30 h。氟康唑很容易扩散到体液中，包括母乳、痰液和唾液;CSF 中的浓度可以达到血浆中同时值的 50% 至 90%。剂量间隔应从 24 至 48 小时（肌酐清除率为 21 至 40 mL/min）增加到 72 小时（10 至 20 mL/min）。血液透析后应给予 100 至 200 mg 的剂量。血浆中约 11% 至 12% 的药物与蛋白质结合。

Therapeutic Uses (治疗用途)

• Candidiasis: Fluconazole, 100 to 200 mg daily for 7 to 14 days, is effective in oropharyngeal candidiasis. A single dose of 150 mg is effective in uncomplicated vaginal candidiasis. A loading dose of 800 mg followed by 400 mg daily is useful in treating candidemia of nonimmunosuppressed patients (Pappas et al., 2007; Rex et al., 1994). Current treatment guidelines for candidemia indicate that fluconazole is an acceptable alternative to the first-line therapy of an echinocandin in select patients. Fluconazole is recommended as a step-down therapy provided the patient’s isolate is susceptible to the azole and follow-up blood cultures are negative (Pappas et al., 2016).

• 念珠菌病：氟康唑，每天 100 至 200 毫克，持续 7 至 14 天，对口咽念珠菌病有效。单剂量 150 毫克对无并发症的阴道念珠菌病有效。每天 800 毫克的负荷剂量，然后每天 400 毫克可用于治疗非免疫抑制患者的念珠菌血症（Pappas 等人，2007 年;Rex et al.， 1994）。目前的念珠菌血症治疗指南表明，氟康唑是特定患者一线棘白菌素一线治疗的可接受替代药物。如果患者的分离株对唑类药物敏感且后续血培养呈阴性，则建议使用氟康唑作为降级疗法（Pappas 等人，2016 年）。

• Cryptococcosis: Fluconazole, 400 mg daily, is used for the initial 8 weeks of the consolidation phase of the treatment of cryptococcal meningitis in patients with AIDS, after an induction course of at least 2 weeks of intravenous amphotericin B. If, after 8 weeks at 400 mg/day, the patient is no longer symptomatic, then the dose is decreased to 200 mg daily and continued indefinitely. If the patient has completed 12 months of treatment of cryptococcosis, responds to combination antiretroviral therapy, has a CD4 count maintained above 200/mm3 for at least 6 months, and is asymptomatic from cryptococcal meningitis, it is reasonable to discontinue maintenance fluconazole as long as the CD4 response is maintained. Fluconazole, 400 mg daily, has been recommended as continuation therapy in patients without AIDS with cryptococcal meningitis who have responded to an initial course of C-AMB or L-AMB and for patients with pulmonary cryptococcosis (Perfect et al., 2010). Recent clinical trials indicate that fluconazole can be combined with flucytosine for induction therapy with efficacy similar to amphotericin B combined with flucytosine (Molloy et al., 2018).

• 隐球菌病：氟康唑，每天 400 毫克，用于治疗艾滋病患者隐球菌性脑膜炎巩固阶段的最初 8 周，经过至少 2 周的静脉注射两性霉素 B 诱导疗程。如果以 400 毫克/天的速度 8 周后，患者不再有症状，则剂量减少至每天 200 毫克并无限期持续。如果患者已完成 12 个月的隐球菌病治疗，对联合抗逆转录病毒治疗有反应，CD4 计数维持在 200/mm3 以上至少 6 个月，并且隐球菌性脑膜炎无症状，只要 CD4 反应维持，停止氟康唑维持治疗是合理的。氟康唑，每天 400 毫克，已被推荐作为对 C-AMB 或 L-AMB 初始疗程有反应的无艾滋病隐球菌性脑膜炎患者以及肺隐球菌病患者的继续治疗（Perfect 等人，2010 年）。最近的临床试验表明，氟康唑可以与氟胞嘧啶联合用于诱导治疗，其疗效类似于两性霉素 B 联合氟胞嘧啶（Molloy et al.， 2018）。

• Other Mycoses: Fluconazole is the drug of choice for treatment of coccidioidal meningitis because of good penetration into the CSF and much lower morbidity compared to intrathecal amphotericin B (Galgiani et al., 2016). In other forms of coccidioidomycosis, fluconazole is comparable to itraconazole. Although itraconazole is the first-line therapy for blastomycosis, fluconazole is an alternative. Fluconazole has no useful activity against histoplasmosis or sporotrichosis, and is not effective in the prevention or treatment of aspergillosis. Fluconazole has no activity in mucormycosis.

• 其他真菌病：氟康唑是治疗球孢子菌脑膜炎的首选药物，因为与鞘内注射两性霉素 B 相比，氟康唑对 CSF 的渗透性好，发病率要低得多（Galgiani et al.， 2016）。在其他形式的球孢子菌病中，氟康唑与伊曲康唑相当。虽然伊曲康唑是芽生菌病的一线治疗，但氟康唑是一种替代疗法。氟康唑对组织胞浆菌病或孢子丝菌病没有有用的活性，对预防或治疗曲霉菌病无效。氟康唑在毛霉菌病中没有活性。

Dosage: Fluconazole is marketed in the U.S. as tablets of 50, 100, 150, and 200 mg for oral administration, powder for oral suspension providing 10 and 40 mg/mL, and intravenous solutions containing 2 mg/mL in saline and in dextrose solution. The daily dose of fluconazole should be based on the infecting organism and the patient’s response to therapy. Generally, recommended dosages are 50 to 400 mg once daily for either oral or intravenous administration. A loading dose of twice the daily maintenance dose is generally administered on the first day of therapy. Prolonged maintenance therapy may be required to prevent relapse. Children are treated with 12 mg/kg once daily (maximum 600 mg/day) without a loading dose. In adult patients, doses of up to 1200 mg have been safely administered in clinical trials for the treatment of cryptococcal meningitis.

剂量： 氟康唑在美国销售为 50、100、150 和 200 mg 口服片剂，口服混悬剂粉末提供 10 和 40 mg/mL，以及含有 2 mg/mL 的盐水和葡萄糖溶液的静脉注射溶液。氟康唑的每日剂量应基于感染微生物和患者对治疗的反应。通常，推荐剂量为 50 至 400 毫克，每天一次，口服或静脉给药。通常在治疗的第一天给予每日维持剂量 2 倍的负荷剂量。可能需要长期维持治疗以防止复发。儿童用 12 mg/kg 每天一次（最大 600 mg/天）治疗，无负荷剂量。在成年患者中，在治疗隐球菌性脑膜炎的临床试验中，已安全地施用高达 1200 毫克的剂量。

Adverse Effects: Side effects in patients receiving more than 7 days of drug, regardless of dose, include nausea, headache, skin rash, vomiting, abdominal pain, and diarrhea (all at 2%–4%). Reversible alopecia may occur with prolonged therapy at 400 mg daily. Rare cases of deaths due to hepatic failure or Stevens-Johnson syndrome have been reported. Fluconazole has been associated with skeletal and cardiac deformities in at least three infants born to two women taking high doses during pregnancy. Although a recent clinical study found no association between fluconazole receipt by mothers and most birth defects in their children, this study did find a statistically significant increase in tetralogy of Fallot in babies born to mothers who received fluconazole (Mølgaard-Nielsen et al., 2013). Fluconazole should be avoided during pregnancy.

不良反应： 接受超过 7 天药物的患者，无论剂量如何，副作用包括恶心、头痛、皮疹、呕吐、腹痛和腹泻（均为 2%-4%）。每天 400 毫克的长期治疗可能会发生可逆性脱发。已有罕见的肝功能衰竭或 Stevens-Johnson 综合征死亡病例报道。氟康唑与两名怀孕期间服用大剂量的妇女所生的至少 3 名婴儿的骨骼和心脏畸形有关。尽管最近的一项临床研究发现母亲接受氟康唑与其孩子的大多数出生缺陷之间没有关联，但这项研究确实发现接受氟康唑的母亲所生婴儿的法洛四联症在统计学上显着增加（Mølgaard-Nielsen 等人，2013 年）。怀孕期间应避免使用氟康唑。

Drug Interactions: Fluconazole is an inhibitor of CYP3A4 and CYP2C9. Fluconazole’s drug-drug interactions are shown in Tables 61–4, 61–5, and 61–6. Patients who receive more than 400 mg daily or azotemic patients who have elevated fluconazole blood levels may experience drug interactions not otherwise seen.

药物相互作用： 氟康唑是 CYP3A4 和 CYP2C9 的抑制剂。氟康唑的药物相互作用如表 61-4、61-5 和 61-6 所示。每天接受超过 400 毫克的患者或氟康唑血液水平升高的氮质血症患者可能会出现其他情况未见的药物相互作用。

1.3 特比萘芬 (Terbinafine)

Terbinafine is a synthetic allylamine, structurally similar to the topical agent naftifine (see discussion that follows). It inhibits fungal squalene epoxidase and thereby reduces ergosterol biosynthesis.

特比萘芬是一种合成烯丙胺，在结构上类似于外用剂萘替芬（见下面的讨论）。它抑制真菌角鲨烯环氧化酶，从而减少麦角固醇（注：真菌细胞膜重要成分，其与磷脂结合增加膜的稳定性，缺乏则膜会破损）的生物合成。

ADME: Terbinafine is well absorbed, but bioavailability is about 40% due to first-pass metabolism in the liver. The drug accumulates in skin, nails, and fat. The initial t1/2 is about 12 h but extends to 200 to 400 h at steady state. Terbinafine is not recommended in patients with marked azotemia or hepatic failure. Rifampin decreases and cimetidine increases plasma terbinafine concentrations.

ADME：特比萘芬吸收良好，但由于肝脏中的首过代谢，生物利用度约为 40%。该药物在皮肤、指甲和脂肪中积累。初始 t1/2 约为 12 小时，但在稳态下延长至 200 至 400 小时。不推荐将特比萘芬用于明显氮质血症或肝功能衰竭的患者。利福平降低血浆特比萘芬浓度，西咪替丁增加血浆特比萘芬浓度。

Therapeutic Uses: Terbinafine, given as one 250-mg tablet daily for adults, is somewhat more effective than itraconazole for nail onychomycosis. Duration of treatment varies with the site of infection but typically ranges between 6 and 12 weeks. The efficacy for the treatment of onychomycosis can be improved by the simultaneous use of amorolfine 5% nail lacquer (amorolfine is not approved for use in the U.S.). Terbinafine is also effective for the treatment of tinea capitis and has been used for the off-label treatment of ringworm elsewhere on the body.

治疗用途： 特比萘芬，成人每天一片 250 毫克片剂，比伊曲康唑对指甲甲真菌病更有效。治疗持续时间因感染部位而异，但通常在 6 至 12 周之间。同时使用 5% 阿莫罗芬指甲油可以提高治疗甲癣的疗效（阿莫罗芬在美国未获批使用）。特比萘芬对治疗头癣也有效，并已用于身体其他部位的癣的超说明书治疗。

Adverse Effects: The drug is well tolerated, with a low incidence of GI distress, headache, or rash. Very rarely, fatal hepatotoxicity, severe neutropenia, Stevens-Johnson syndrome, or toxic epidermal necrolysis may occur. Systemic terbinafine therapy for onychomycosis should be postponed until after pregnancy is complete.

不良反应：该药物耐受性良好，胃肠道不适、头痛或皮疹的发生率较低。极少数情况下，可能会发生致命的肝毒性、严重的中性粒细胞减少、Stevens-Johnson 综合征或中毒性表皮坏死松解症。甲癣的全身性特比萘芬治疗应推迟到妊娠完成后。

2 Topical Antifungal Agents (外用抗真菌药)

• Topical Imidazoles and Triazoles (外用咪唑类和三唑类)
  • Clotrimazole (克霉唑)
  • Econazole (益康唑)
  • Efinaconazole (艾氟康唑)
  • Miconazole (咪康唑)
  • Luliconazole (卢立康唑)
  • Terconazole and Butoconazole (特康唑和布托康唑)
  • Tioconazole (噻康唑)
  • Oxiconazole, Sulconazole, and Sertaconazole (奥昔康唑、磺康唑和舍他康唑)
  • Ketoconazole (酮康唑)
• Structurally Diverse Antifungal Agents (结构多样的抗真菌剂)
  • Ciclopirox Olamine (环吡酮乙醇胺)
  • Haloprogin （盐丙蛋白）
  • Tolnaftate (托萘酯)
  • Naftifine (萘替芬)
  • Terbinafine (特比萘芬)
  • Butenafine (布特萘芬)
  • Tavaborole (他伐硼罗)
  • Nystatin (制霉菌素)
  • Undecylenic Acid (十一烯酸)
  • Benzoic and Salicylic Acids (苯甲酸和水杨酸)

2.1 Miconazole (咪康唑)

Miconazole readily penetrates the stratum corneum of the skin and persists for more than 4 days after application. Adverse effects from topical application to the vagina include burning, itching, or irritation in about 7% of recipients, as well as infrequent pelvic cramps (0.2%), headache, hives, or skin rash. Irritation, burning, and maceration are rare after cutaneous application. Miconazole is considered safe for use during pregnancy, although some experts advocate avoiding vaginal use during the first trimester.

咪康唑很容易渗透皮肤的角质层，并在应用后持续 4 天以上。局部应用于阴道的不良反应包括约 7% 的受者灼热、瘙痒或刺激，以及不频繁的盆腔痉挛 （0.2%）、头痛、荨麻疹或皮疹。皮肤应用后刺激、灼痛和浸渍很少见。咪康唑被认为在怀孕期间可以安全使用，尽管一些专家主张在妊娠早期避免阴道使用。

Therapeutic Uses: Miconazole nitrate is available as a 2% cream, ointment, lotion, powder, gel, aerosol powder, and aerosol solution. To avoid maceration, only the lotion should be applied to intertriginous areas. Miconazole is available as a 2% and 4% vaginal cream and as 100-, 200-, or 1200-mg vaginal suppositories to be applied high in the vagina at bedtime for 7 or 3 days or 1 day, respectively. In the treatment of tinea pedis, tinea cruris, and tinea versicolor, the cure rate exceeds 90%. In the treatment of vulvovaginal candidiasis, the mycological cure rate at the end of 1 month is about 80% to 95%. Pruritus sometimes is relieved after a single application. Some vaginal infections caused by C. glabrata also respond to this drug.

治疗用途：硝酸咪康唑以 2% 乳膏、软膏、化妆水、粉末、凝胶、气雾剂粉末和气雾剂溶液的形式提供。为避免浸渍，只能将化妆水涂抹在擦伤区域。咪康唑有 2% 和 4% 阴道乳膏以及 100、200 或 1200 mg 阴道栓剂两种，睡前涂抹于阴道高位，分别持续 7 天或 3 天或 1 天。在治疗足癣、股癣和花斑癣时，治愈率超过 90%。在治疗外阴阴道念珠菌病时，1个月结束时的真菌学治愈率约为80%至95%。瘙痒有时会在一次应用后缓解。一些由 C. glabrata 引起的阴道感染也对这种药物有反应。

2.2 Naftifine (萘替芬)

Naftifine is a synthetic allylamine that inhibits squalene-2,3-epoxidase, a key enzyme in the fungal biosynthesis of ergosterol. The drug has broad-spectrum fungicidal activity in vitro. Naftifine hydrochloride is available as a 1% cream or gel. It is effective for the topical treatment of tinea cruris and tinea corporis; twice-daily application is recommended. The drug is well tolerated, although local irritation in 3% of treated patients and allergic contact dermatitis have been reported. Naftifine also may be efficacious for cutaneous candidiasis and tinea versicolor, although the drug is not approved for these uses.

Naftifine (萘替芬) 是一种合成的烯丙胺，可抑制角鲨烯-2,3-环氧化物酶，角鲨烯-2,3-环氧化物酶是麦角固醇真菌生物合成中的关键酶。该药物在体外具有广谱杀真菌活性。盐酸萘替芬有 1% 乳膏或凝胶形式。它对股癣和体癣的局部治疗有效；建议每天使用两次。该药物耐受性良好，尽管已报道 3% 的接受治疗的患者出现局部刺激和过敏性接触性皮炎。萘替芬也可能对皮肤念珠菌病和花斑癣有效，尽管该药物未被批准用于这些用途。

2.3 Terbinafine (特比萘芬)

Like naftifine, terbinafine is an allylamine that targets ergosterol biosynthesis. Terbinafine 1% cream or spray, applied twice daily, is effective in tinea corporis, tinea cruris, and tinea pedis. Terbinafine is less active against Candida species and Malassezia furfur, but the cream also can be used in cutaneous candidiasis and tinea versicolor.

与萘替芬一样，特比萘芬是一种靶向麦角固醇生物合成的烯丙胺。1% 特比萘芬乳膏或喷雾剂，每天两次，对体癣、股癣和足癣有效。特比萘芬对念珠菌属和糠秕马拉色菌的活性较低，但该乳膏也可用于皮肤念珠菌病和花斑癣。

3 Reference

Pharmacology