1. Antifungal Agents & Antiviral drugs
Huifang Tang

2. Part1 Antifungal Agents
Mycotic infections Categories:
Deep mycosis(深部真菌病)：
vaginal candidiasis(阴道念珠菌)
histoplasm caspsulatum (组织胞浆菌)
cryptococcal meningitis(隐球菌性脑膜炎)
coccidioidomycosis(球孢子菌病)
Superficial Mycosis（浅部真菌病）:
dermatophyte （皮肤癣菌 ）infections

3. Categories 1、Antibiotic (抗生素类): 2、Azole (唑类) : 3、Allylamine(丙烯胺类):
Amphotericin B(两性霉素B ); Nystatin（制霉菌素）
Griseofulvin(灰黄霉素)
2、Azole (唑类) :
Imidazoles （咪唑类）：ketoconazole(酮康唑),
Triazoles（三唑类）: Itraconazole(伊曲康唑),
3、Allylamine(丙烯胺类):
Terbinafine （特比萘芬）
4、Pyrimidine (嘧啶类) :
Flucytosine (氟胞嘧啶)
5、Echinocandins(棘白菌素类)
Caspofungin(卡泊芬净)

4. Mechanism of action 4.嘧啶类 3.丙烯胺类 1.抗生素类 2.唑类 5.棘白菌素类 壳多糖 葡聚糖合成酶 麦角固醇
角鲨烯环氧化酶
羊毛甾醇
5.棘白菌素类

5. Categories Echinocandins Pyrimidine (嘧啶类) : Imidazoles （咪唑类）：
Inhibit fungal cell walls synthesis
Echinocandins
Caspofungin(卡泊芬净)
Pyrimidine (嘧啶类) :
Flucytosine (氟胞嘧啶)
Griseofulvin
(灰黄霉素)
Allylamine
(丙烯胺类):
Terbinafine
（特比萘芬）
Imidazoles （咪唑类）：
Ketoconazole
(酮康唑),
Triazoles（
三唑类）: Itraconazole
(伊曲康唑),
Amphotericin B
(两性霉素B );
Nystatin
（制霉菌素）

6. 1、Antibiotic (抗生素类): Amphotericin B(两性霉素B ) Nystatin (制霉菌素)
Griseofulvin(灰黄霉素)
多烯类
polyenes

7. Mechanism of antifungal action
Amphotercin B
Amphotericin B
Mechanism of antifungal action

8. Mechanism of Action Amphotercin B
Amphotericin B is selective in its fungicidal effect because it exploits the difference in lipid composition of fungal and mammalian cell membranes.
Ergosterol(麦角固醇), a cell membrane sterol, is found in the cell membrane of fungi, whereas the predominant sterol of bacteria and human cells is cholesterol(胆固醇).
Amphotericin B binds to ergosterol and alters the permeability of the cell by forming amphotericin Bassociated pores in the cell membrane .

9. Antifungal Activity Amphotercin B Broadest spectrum.
Candida albicans and Cryptococcus neoformans (白色念珠菌和新型隐球菌);
Endemic mycoses(地方性真菌病 ): Histoplasma capsulatum(组织胞浆菌), Blastomyces dermatitidis(皮炎芽生菌), and Coccidioides immitis（粗球孢子菌）;
Pathogenic molds（致病霉菌）, such as Aspergillus fumigatus（曲霉）and mucor（毛霉）.

10. 2. Clinical uses Deep mycosis(深部真菌病) iv Amphotercin B
candidiasis(念珠菌病 )
Histoplasm caspsulatum (组织胞浆菌 )
Cryptococcal meningitis(隐球菌性脑膜炎 )
Coccidioidomycosis(球孢子菌病)
aspergillus infections(曲霉菌感染 ).

11. Pharmacokinetics Amphotercin B
Poorly absorbed from the gastrointestinal tract.Oral amphotericin B cannot be used for treatment of systemic disease.
>90% bound by serum proteins
Excreted slowly in the urine over a period of several days.
The serum t1/2 is approximately 15 days.
Hepatic impairment, renal impairment, and dialysis have little impact on drug concentrations, and therefore no dose adjustment is required.
The drug is widely distributed in most tissues, but only 2–3% of the blood level is reached in cerebrospinal fluid, thus occasionally necessitating intrathecal therapy for certain types of fungal meningitis.

12. Adverse Effects Amphotercin B INFUSION-RELATED TOXICITY (输液相关性毒性)
Fever, chills, muscle spasms, vomiting, headache, and hypotension.
Prevention :
(1)They can be ameliorated by slowing the infusion rate or decreasing the daily dose.
(2)Pretreatment with oral acetaminophen(醋氨酚), or use of intravenous hydrocortisone hemisuccinate (氢化可的松半琥酯) at the start of the infusion decreases reaction;
(3)Supplemental K+ is required;
CUMULATIVE TOXICITY(蓄积毒性)
Renal damage: the most significant toxic reaction.
Abnormalities of liver function.
serious neurologic sequelae,seizures, chemical arachnoiditis(蛛网膜炎): After intrathecal therapy (鞘内注射 )
Hematological toxicity: hypochromic(低血红蛋白性) and normocytic(正常细胞) anemia, etc.

13. 5. New formulations of amphotercin B
(1)Liposomal Amphotercin B(L-AMPH B, 两性霉素B脂质体);
(2)Amphotercin B lipid complex(ABLC, 两性霉素B脂质复合体);
(3)Amphotercin B collcodal dispersion (ABCD, 两性霉素B胶质分散体).

14. Nystatin（制霉菌素）
Nystatin is a polyene macrolide much like amphotericin B. It is too toxic for parenteral administration（肠外给药 ） and is only used topically.
Formulation: creams, ointments, suppositories
Pharmacokinetics:
Poorly absorbed from the gastrointestinal tract.
It is not absorbed to a significant degree from skin, mucous membranes.
Spectrum: most Candida sp(念珠菌属).
Cinical indications:
oropharyngeal thrush（鹅口疮）
vaginal candidiasis
intertriginous candidal infections.

15. Griseofulvin(灰黄霉素)
(1) Mechanism of action : Mitotic inhibitors
Binds to microtubules and prevents mitosis in fungi.
It is deposited in newly forming skin where it binds to keratin（角质 ）, protecting the skin from new infection. Because its action is to prevent infection of these new skin structures,
Administered for 2–6 weeks for skin and hair infections
Nail infections may require therapy for months .
It is a cytochrome p450 enzyme inducer
(2) Clinical uses:
Oral long-term therapy for dermatophyte, hair and nail infections
（3）Adverse effects
An allergic syndrome much like serum sickness(血清病 ), hepatitis,
Drug interactions with warfarin and phenobarbital.

16. 2、Azoles（唑类） Imidazoles （咪唑类）: Triazoles（三唑类）: ketoconazole(酮康唑),
Miconazole(咪康唑),
clotrimazole (克霉唑)
Triazoles（三唑类）:
Itraconazole(伊曲康唑),
Fluconazole(氟康唑),
Voriconazole(伏立康唑),
Posaconazole(泊沙康唑 ).

17. Mechanism of action 4.嘧啶类 3.丙烯胺类 1.抗生素类 2.唑类 5.棘白菌素类 壳多糖 葡聚糖合成酶 麦角固醇
角鲨烯环氧化酶
羊毛甾醇
5.棘白菌素类

18. Azoles
Mechanism of Action
Inhibition of Lanosterol 14alpha-demethylase ( 羊毛甾醇14 -脱甲基酶)--> Inhibition of fungal cytochrome P450 enzymes--> Reduction of ergosterol synthesis .
The selective toxicity of azole drugs results from their greater affinity for fungal than for human cytochrome P450 enzymes.
Imidazoles exhibit a lesser degree of selectivity than the triazoles, accounting for their higher incidence of drug interactions and side effects.
Resistance to azoles occurs via multiple mechanisms.
The spectrum of action of azole is broad

19. Azoles
Clinical Use
Many candida species(念珠菌 ), C neoformans(新型隐球菌), the endemic mycoses (地方性真菌病 ), blastomycosis(芽生菌 ), coccidioidomycosis(球孢子菌病 ), histoplasmosis(组织胞浆菌病 ), the dermatophytes(皮肤癣菌 ), and, in the case of itraconazole and voriconazole, even aspergillus infections(曲霉菌感染 ).
They are also useful in the treatment of intrinsically amphotericin-resistant organisms such as P boydii(波氏假霉样真菌).

20. Azoles
Adverse Effects
The most common adverse reaction is relatively minor gastrointestinal upset.
All azoles have been reported to cause abnormalities in liver enzymes and, very rarely, clinical hepatitis.
All azole drugs affect the mammalian cytochrome P450 system of enzymes to some extent, and consequently they are prone to drug interactions.

21. Ketoconazole(酮康唑) Clinical Uses:
Azoles
Ketoconazole(酮康唑)
Ketoconazole was the first oral azole introduced into clinical use.
Less selective for fungal P450 than newer azoles.
Greater propensity to inhibit mammalian cytochrome P450 enzymes, block both testicular and adrenal androgen biosynthesis, and compete with androgens such as testosterone and DHT for androgen receptor binding.
Clinical Uses:
1. Cutaneous candidiasis(皮肤念珠菌病 ): vaginal
2. Dermatophytosis(皮肤癣菌病 )
3. Histoplasmosis(组织胞浆菌病 )

22. Clinical uses Itraconazole(伊曲康唑)
Azoles
Itraconazole(伊曲康唑)
Oral and intravenous formulations. Drug absorption is increased by food and by low gastric pH.
Penetrates poorly into the cerebrospinal fluid.
Clinical uses
Dermatophytoses(皮肤癣菌)and onychomycosis(甲癣).
Dimorphic fungi histoplasma(组织胞浆菌), Blastomyces(芽生菌 ), and sporothrix(孢子丝菌).
Aspergillosis(曲霉菌病): but it has been replaced by voriconazole

23. Fluconazole(氟康唑) Azoles
Fluconazole displays a high degree of water solubility and good cerebrospinal fluid penetration, its oral bioavailability is high.
The drug is available in oral and intravenous formulations.
Drug interactions are also less common because fluconazole has the least effect of all the azoles on hepatic microsomal enzymes. Because of fewer hepatic enzyme interactions and better gastrointestinal tolerance, fluconazole has the widest therapeutic index of the azoles, permitting more aggressive dosing in a variety of fungal infections.
Fluconazole displays no activity against aspergillus(曲霉菌 ) or other filamentous fungi(丝状真菌).
Clinical use
cryptococcal meningitis(隐球菌性脑膜炎).
Mucocutaneous candidiasis(皮肤粘膜念珠菌病).
Coccidioidal disease(球孢子菌病)

24. Voriconazole(伏立康唑) Azoles
Voriconazole is available in intravenous and oral formulations. The drug is well absorbed orally, with a bioavailability exceeding 90%, and it exhibits less protein binding than itraconazole.
Metabolism is predominantly hepatic. Voriconazole is a clinically relevant inhibitor of mammalian CYP3A4.
Adverse Effects
Observed toxicities include rash and elevated hepatic enzymes.
Visual disturbances are common, occurring in up to 30% of patients receiving intravenous voriconazole, and include blurring and changes in color vision or brightness. These visual changes usually occur immediately after a dose of voriconazole and resolve within 30 minutes.
Photosensitivity dermatitis is commonly observed in patients receiving chronic oral therapy.
spectrum of action
Excellent activity against Candida sp（假丝菌）(including fluconazole-resistant species such as C krusei) and the dimorphic fungi（双相真菌）。

25. Posaconazole(泊沙康唑 ) Azoles
Posaconazole is the newest triazole to be licensed in the USA. It is available only in a liquid oral formulation.
Posaconazole is rapidly distributed to the tissues, resulting in high tissue levels but relatively low blood levels.
Posaconazole is the broadest spectrum member of the azole family, with activity against most species of candida (念珠菌)and aspergillus(曲霉菌).
It is the only azole with significant activity against the agents of zygomycosis and mucormycosis(毛霉菌病).
Clinical use
Prophylaxis of invasive aspergillosis(侵袭性曲霉病),
Prophylaxis of fungal infections during induction chemotherapy for leukemia, allogeneic bone marrow transplant patients with graft-versus-host disease(异基因骨髓移植患者的移植物抗宿主病).

26. Azoles
Pharmacokinetics

27. Triazole
CYP3A4
CYP2C9
CYP2C19
Fluconazole
Moderate
Strong
Itraconazole -
Voriconazole
Weak
Posaconazole
- = no inhibition.

28. 3、Allylamine（丙烯胺类） (squalene monooxygenase inhibitors角鲨烯环氧化酶抑制剂)
Terbinafine （特比萘芬）
Terbinafine is a synthetic allylamine that is available in an oral formulation.
It is used in the treatment of dermatophytoses, especially onychomycosis (灰指甲). it is fungicidal.
It interferes with ergosterol biosynthesis, but rather than interacting with the P450 system, terbinafine inhibits the fungal enzyme squalene epoxidase (角鲨烯环氧化酶). This leads to the accumulation of the sterol squalene（甾醇角鲨烯）, which is toxic to the organism.
Adverse effects ： rare
Primarily of gastrointestinal upset and headache.
Terbinafine does not seem to affect the P450 system and has demonstrated no significant drug interactions to date.

29. Mechanism of action 4.嘧啶类 3.丙烯胺类 1.抗生素类 2.唑类 5.棘白菌素类 壳多糖 葡聚糖合成酶 麦角固醇
角鲨烯环氧化酶
羊毛甾醇
5.棘白菌素类

30. Flucytosine
4、Flucytosine (氟胞嘧啶) Pyrimidine analogues/Thymidylate synthase inhibitors
Mechanism of Action
Flucytosine is taken up by fungal cells via the enzyme--cytosine permease(胞嘧啶渗透酶). It is converted intracellularly first to 5-FU and then to 5-fluorodeoxyuridine monophosphate (FdUMP) and fluorouridine triphosphate (FUTP), which inhibit DNA and RNA synthesis, respectively.

31. Mechanism of antifungal action:
Flucytosine
Mechanism of antifungal action:
胸腺嘧啶核苷合成酶

32. Flucytosine Clinical uses:
Flucytosine is a narrow-spectrum anti-fungal drug.
Drug resistance occurs rapidly when flucytosine is used alone.
So, flucytosine is used predominantly in combination with amphotericin B for thearpy of crypotococcal meningitis in AIDS patient, etc.
Adverse reactions:
Depressing the function of bone marrow(leading to leukopenia and thrombocytopenia, etc.).
Plasma levels of hepatic transminase are elevated(reversible).
Other reaction: including rash, nausea, vomiting, diarrhea, etc.

33. 5、Echinocandins（棘白菌素类） （β-glucan synthase inhibitors β葡聚糖合成酶抑制剂）
Caspofungin(卡泊芬净)
Micafungin(米卡芬净)
Anidulafungin（阿尼芬净）
Echinocandins are available only in intravenous formulations.
Mechanism of Action
Act at the level of the fungal cell wall by inhibiting the synthesis of (1–3)-glucan（葡聚糖）.

34. Spectrum of action Adverse Effects
Echinocandins
Spectrum of action
Active : candida(念珠菌)and aspergillus(曲霉菌)
not Active : C neoformans (新型隐球菌) or the agents of zygomycosis(接合菌) and mucormycosis(毛霉菌病).
Adverse Effects
Echinocandin agents are extremely well tolerated, with minor gastrointestinal side effects and flushing reported infrequently.

35. Pharmacokinetics Echinocandins
Caspofungin（卡泊芬净） is water-soluble and highly protein-bound. The half-life is 9–11 hours, and the metabolites are excreted by the kidneys and gastrointestinal tract. Dosage adjustments are required only in the presence of severe hepatic insufficiency.
Micafungin （米卡芬净）displays similar properties with a half-life of 11–15 hours for treatment of candida esophagitis（念珠菌食管炎）, candidemia, and prophylaxis of fungal infections.
Anidulafungin （阿尼芬净）has a half-life of 24–48 hours. For esophageal candidiasis, it is administered intravenously at 100 mg on the first day and 50 mg/d thereafter for 14 days. For candidemia, a loading dose of 200 mg is recommended with 100 mg/d thereafter for at least 14 days after the last positive blood culture.

36. Echinocandins
Clinical Use
Caspofungin is currently licensed for disseminated and mucocutaneous candida infections（侵袭性和皮肤粘膜念珠菌病）
Note：caspofungin is licensed for use in invasive aspergillosis（侵袭性曲霉病） only as salvage therapy（抢救治疗）in patients who have failed to respond to amphotericin B, and not as primary therapy.
Micafungin is licensed for mucocutaneous candidiasis, candidemia, and prophylaxis of candida infections in bone marrow transplant patients.
Anidulafungin is approved for use in esophageal candidiasis and invasive candidiasis, including candidemia.

38. Part 2 Antiviral drugs Anti-influenza virus agent Antiherpes agents
Anti-HIV agents
Entry inhibitors(入胞抑制药)
Reverse transcriptase inhibitor(逆转录酶抑制剂)
Nonnucleoside reverse transcriptase inhibitor(非核苷逆转录酶抑制剂 , NNRTI);
Nucleoside reverse transcriptase inhibitor(核苷逆转录酶抑制剂 , NRTI);
Protease inhibitor(蛋白酶抑制剂,PI)
Integrase Inhibitors （整合酶抑制药）

39. Antiviral therapy Influenza—RNA virus herpesviruses (HSV)—DNA virus
Antiviral drugs
Antiviral therapy
肝炎病毒
艾滋病毒
疱疹病毒
流感病毒
Influenza—RNA virus
herpesviruses (HSV)—DNA virus
human immunodeficiency virus (HIV)- RNA Reverse transcript virus

40. 1 Anti-influenza virus agents
Antiviral drugs1
1 Anti-influenza virus agents
M2蛋白抑制剂--influenza A
Amantadine(金刚烷胺)
Neuraminidase(神经氨酸酶,NA) inhibitors
--influenza A &B
Oseltamivir(奥司他韦)；
zanamivir（扎那米韦）
广谱抗病毒药--DNA &RNA viurs
Ribavirin(利巴韦林, virazole病毒唑）

41. Replicative cycles of DNA viruses
A. Replicative cycles of herpes simplex virus, a DNA virus, and the probable sites of action of antiviral agents. Herpesvirus replication is a regulated multistep process. After infection, a small number of immediate-early genes are transcribed; these genes encode proteins that regulate their own synthesis and are responsible for synthesis of early genes involved in genome replication, such as thymidine kinases, DNA polymerases, etc. After DNA replication, the bulk of the herpesvirus genes (called late genes) are expressed and encode proteins that either are incorporated into or aid in the assembly of progeny virions.

42. Replicative cycles of RNA viruses
B. Replicative cycles of influenza, an RNA virus, and the loci for effects of antiviral agents. The mammalian cell shown is an airway epithelial cell. The M2 protein of influenza virus allows an influx of hydrogen ions into the virion interior, which in turn promotes dissociation of the RNP (ribonuclear protein) segments and release into the cytoplasm (uncoating). Influenza virus mRNA synthesis requires a primer cleared from cellular mRNA and used by the viral RNAp complex. The neuraminidase inhibitors zanamivir and oseltamivir specifically inhibit release of progeny virus. Small capitals indicate virus proteins.

43. Amantadine(金刚烷胺) Antiviral drugs1
The mechanism of Amantadine's antiviral activity involves interference with a viral protein, M2 (an ion channel), which is required for the viral particle to become "uncoated" once taken inside a cell by endocytosis.
The mechanism of its antiparkinsonian effect is poorly understood. The drug has many effects in the brain, including release of dopamine and norepinephrine from nerve endings. It appears to be a weak NMDA receptor antagonist as well as an anticholinergic.
Clinical use
(1) For 100% of seasonal H3N2 and 2009 pandemic flu samples tested have shown resistance to adamantanes, Amantadine is no longer recommended for treatment of influenza A infection.
(2) Parkinson's disease

44. Side effects: Antiviral drugs1
(1)CNS side effects include nervousness, anxiety, agitation, insomnia, difficulty in concentrating, and exacerbations of pre-existing seizure disorders and psychiatric symptoms in patients with schizophrenia or Parkinson's disease.
(2)Rare cases of severe skin rashes such as Stevens Johnson Syndrome(皮肤黏膜眼综合征) and suicidal ideation.
(3) Livedo reticularis (网状青斑) is a possible side effect of amantadine use for Parkinson's disease.

45. Rimantadine(金刚乙胺) Antiviral drugs1
Rimantadine is four to ten times more active than amantadine in vitro.
Amantadine is well absorbed and 67% protein-bound. Its plasma half-life is 12–18 hours and varies by creatinine clearance.
Rimantidine is about 40% protein-bound and has a half-life of 24–36 hours. Nasal secretion and salivary levels approximate those in the serum, and cerebrospinal fluid levels are 52–96% of those in the serum; nasal mucus concentrations of rimantidine average 50% higher than those in plasma.
Amantadine is excreted unchanged in the urine, whereas rimantadine undergoes extensive metabolism by hydroxylation, conjugation, and glucuronidation before urinary excretion.

46. Neuraminidase(神经氨酸酶,NA) inhibitors
Oseltamivir(奥司他韦)；
Zanamivir（扎那米韦）
Both influenza A and influenza B viruses.
analogs of sialic acid
Mechanism:
Interfere with release of progeny influenza virus from infected to new host cells, thus halting the spread of infection within the respiratory tract.
Destroy the receptors recognized by viral hemagglutinin(血凝素) on cells, newly released virions, and respiratory tract mucins.
Early administration is crucial because replication of influenza virus peaks at 24–72 hours after the onset of illness.

47. Oseltamivir(奥司他韦)
Oseltamivir is FDA-approved for patients 1 year and older,
Oseltamivir is an orally administered prodrug that is activated by hepatic esterases and widely distributed throughout the body.
Oral bioavailability is approximately 80%, plasma protein binding is low, and concentrations in the middle ear and sinus fluid are similar to those in plasma.
The half-life of oseltamivir is 6–10 hours,
Excretion is by glomerular filtration and tubular secretion in the urine.
Potential adverse effects include nausea, vomiting, and abdominal pain, which occur in 5–10% of patients early in therapy but tend to resolve spontaneously.

48. Zanamivir（扎那米韦） zanamivir is approved in patients 7 years or older.
Zanamivir is delivered directly to the respiratory tract via inhalation. 10%-20% of the active compound reaches the lungs, and the remainder is deposited in the oropharynx.
The concentration of the drug in the respiratory tract is estimated to be more than 1000 times the 50% inhibitory concentration for neuraminidase, and the pulmonary half-life is 2.8 hours.
5%-15% of the total dose (10 mg twice daily for 5 days for treatment and 10 mg once daily for prevention) is absorbed and excreted in the urine with minimal metabolism.
Potential adverse effects include cough, bronchospasm (occasionally severe), reversible decrease in pulmonary function, and transient nasal and throat discomfort.
zanamivir is approved in patients 7 years or older.

49. Ribavirin（利巴韦林） Antiviral drugs1 Mechanism of action
Ribavirin is a guanosine analog (鸟苷类似物) that is phosphorylated intracellularly by host cell enzymes.
interfere with the synthesis of guanosine triphosphate,
inhibit capping of viral messenger RNA,
inhibit the viral RNA-dependent polymerase of certain viruses.
Action: It is effective against a broad spectrum of RNA and DNA viruses.
Influenza A and B,
parainfluenza(副流感病毒)
respiratory syncytial virus(呼吸道合胞体病毒)
paramyxoviruses(副粘病毒)
HCV
HIV-1.

50. In addition to oral administration for hepatitis C infection in combination with interferon alfa,
Aerosolized ribavirin is administered by nebulizer (20 mg/mL for 12–18 hours per day) to children and infants with severe respiratory syncytial virus (RSV) bronchiolitis or pneumonia to reduce the severity and duration of illness.
Aerosolized ribavirin has also been used to treat influenza A and B infections but has not gained widespread use.
Aerosolized ribavirin is generally well tolerated but may cause conjunctival or bronchial irritation.

51. 2、Antiherpes agents Herpessimplexvirus（疱疹病毒，HSV）
Varicella-zoster virus (水痘/带状疱疹病毒，VZV)
Cytomegalovirus(巨细胞病毒CMV)
Epstein-Barrvirus(EB病毒，EBV）
idoxuridine(碘苷) -- HSV, VZV
Vidarabine(阿糖腺苷)—HSV,VZV,HBV,CMV
acyclovir（阿昔洛韦）; Valacyclovir(伐阿昔洛韦)--HSV、VZV
ganciclovir(更昔洛韦) ; valacyclovir(伐昔洛韦)--HSV、VZV、CMV
foscarnet (磷甲酸盐）--HSV, influenza ,CMV, HIV
cidofovir (西多福韦)—HSV,VZV,CMV
Trifluridine(屈氟尿苷)--HSV-1和HSV-2,CMV

52. Mechanism of action of antiherpes agents

53. Acyclic guanosine derivative （无环鸟苷衍生物）
Antiviral drugs2
Acyclic guanosine derivative （无环鸟苷衍生物）
更昔洛韦
阿昔洛韦
缬阿昔洛韦
缬更昔洛韦

54. Acyclic guanosine derivative
Antiviral drugs2
Acyclic guanosine derivative
胸苷激酶

55. Acyclovir(阿昔洛韦,无环鸟苷) Antiviral drugs2 Valganciclovir
1. Mechanism of action
It inhibits viral DNA-polymerase, terminating the DNA- chain.
Clinical activity --HSV-1, HSV-2, and VZV, but it is approximately 10 times more potent against HSV-1 and HSV-2 than against VZV.
In vitro activity -- Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus-6 (HHV-6) is present but weaker.
2. Clinical use:
The bioavailability of oral acyclovir is low (15–20%) and is unaffected by food. An intravenous formulation is available.
It is used to treat herps simplex viruses, varicella-zoster viruses.
First choice --Herpes simplex viruses infection.

56. Antiviral drugs2
Valganciclovir
Ganciclovir(更昔洛韦)
Initial phosphorylation is catalyzed by the virus-specified protein kinase phosphotransferase UL97 in CMV-infected cells.
The activated compound competitively inhibits viral DNA polymerase and causes termination of viral DNA elongation.
Ganciclovir has in vitro activity against CMV, HSV, VZV, EBV, HHV-6, and HHV-8.
Its activity against CMV is up to 100 times greater than that of acyclovir.

57. Adverse effect Antiviral drugs2 Myelosuppression.
nausea, diarrhea, fever, rash, headache, insomnia, and peripheral neuropathy.
Central nervous system toxicity (confusion, seizures, psychiatric disturbance) and hepatotoxicity have been rarely reported.
Ganciclovir is mutagenic in mammalian cells and carcinogenic and embryotoxic at high doses in animals and causes aspermatogenesis;

58. Valganciclovir(缬更昔洛韦)
Antiviral drugs2
Valganciclovir
Valganciclovir(缬更昔洛韦)
After oral administration, both diastereomers are rapidly hydrolyzed to ganciclovir by intestinal and hepatic esterases.
Valganciclovir is well absorbed and rapidly metabolized in the intestinal wall and liver to ganciclovir;
The absolute bioavailability of oral valganciclovir is 60%. The AUC0–24h resulting from valganciclovir (900 mg once daily) is similar to that after 5 mg/kg once daily of intravenous ganciclovir and approximately 1.65 times that of oral ganciclovir.
The major route of elimination is renal, through glomerular filtration and active tubular secretion.
Clinical use
Cytomegalovirus(CMV) retinitis in patients with AIDS
Prevention of CMV disease in high-risk kidney, heart, and kidney-pancreas transplant patients.

59. Foscarnet(磷甲酸盐) Foscarnet
It has in vitro activity against HSV, VZV, CMV, EBV, HHV-6(人类疱疹病毒), HHV-8, and HIV-1.
inhibits viral DNA polymerase,
inhibits RNA polymerase,
inhibits HIV reverse transcriptase
Foscarnet blocks the pyrophosphate（焦磷酸） binding site of these enzymes and inhibits cleavage of pyrophosphate from deoxynucleotide triphosphates.
Foscarnet is available in an intravenous formulation only;

60. Foscarnet
Adverse effects
Renal impairment, hypo- or hypercalcemia, hypo- or hyperphosphatemia, hypokalemia, and hypomagnesemia.
Nausea, vomiting, anemia, elevation of liver enzymes, and fatigue
The risk of anemia may be additive in patients receiving concurrent zidovudine.
Central nervous system toxicities include headache, hallucinations, and seizures;
Foscarnet caused chromosomal damage in preclinical studies.

61. Cidofovir（西多福韦） Antiviral drugs2
Cidofovir is an acyclic cytosine nucleotide （无环胞嘧啶核苷酸）analog with in vitro activity against CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, HHV-8, adenovirus, poxviruses（痘病毒）, polyomaviruses, and human papillomavirus（人乳头状瘤病毒）.
In contrast to ganciclovir, phosphorylation of cidofovir to the active diphosphate is independent of viral enzymes ; thus activity is maintained against thymidine kinase-deficient or -altered strains of CMV or HSV.
Cidofovir-resistant isolates tend to be crossresistant with ganciclovir but retain susceptibility to foscarnet.
Adverse effects：a dose-dependent proximal tubular nephrotoxicity

62. Anti-HIV agents Entry inhibitors(入胞抑制药)
Reverse transcriptase inhibitor(逆转录酶抑制剂)
Nonnucleoside reverse transcriptase inhibitor(非核苷逆转录酶抑制剂 , NNRTI);
Nucleoside reverse transcriptase inhibitor(核苷逆转录酶抑制剂 , NRTI);
Protease inhibitor(蛋白酶抑制剂,PI)
Integrase Inhibitors （整合酶抑制药）

63. Anti-HIV agents summary
马拉韦罗（maraviroc）
Entry inhibitors(入胞抑制药)
恩夫韦地（enfuvrtide）
西夫韦肽（sifuvirtide）
Integrase Inhibitors （整合酶抑制药）:雷特格韦（raltegravir）
NNRTI:
地拉韦定(delavirdine)
奈韦拉平(nevirapine)
依法韦恩茨(efavirenz)
NRTI:
齐多夫定(zidovudine，AZT)
扎西他宾(zalcitabine，ddC)
司他夫定(stavudine，d4T)
拉米夫定(lamivudine，3TC)
去羟肌苷(didanosine，ddI)
阿巴卡韦(abacavir，ABC)
Protease inhibitor
(蛋白酶抑制剂,PI)
利托那韦(ritonavir)
奈非那韦(nelfinavir)
沙奎那韦(saquinavir)
英地那韦(indinavir)
安谱那韦(amprenavir)

64. Nucleoside reverse transcriptase inhibitor--Zidovudine(齐多夫定,zdv,azt)
Zidovudine (azidothymidine; AZT) is a deoxythymidine（脱氧胸苷） analog
Zidovudine was the first antiretroviral agent to be approved and has been well studied. The drug has been shown to decrease the rate of clinical disease progression and prolong survival in HIV-infected individuals.
Efficacy has also been demonstrated in the treatment of HIV-associated dementia and thrombocytopenia.

65. Pharmakinetic Well absorbed (63%)
Zidovudine
Pharmakinetic
Well absorbed (63%)
Distributed to most body tissues and fluids, including the cerebrospinal fluid, where drug levels are 53% of those in serum.
The serum half-life averages 1.1 hours,
Eliminated primarily by renal excretion following glucuronidation in the liver.

66. Zidovudine
Clinical use
Zidovudine is often co-administered with lamivudine, and a combination formulation is available.
In pregnancy, a regimen of oral zidovudine beginning between 14 and 34 weeks of gestation, intravenous zidovudine during labor, and zidovudine syrup to the neonate from birth through 6 weeks of age has been shown to reduce the rate of vertical (mother-to-newborn) transmission of HIV by up to 23%.

67. Adverse effect Zidovudine
Myelosuppression, resulting in macrocytic anemia (巨细胞性贫血)(1–4%) or neutropenia (2–8%)，thrombocytopenia,
Gastrointestinal intolerance, headaches, and insomnia may occur but tend to resolve during therapy.
Extremity fat loss
Hyperpigmentation of the nails
Myopathy.
High doses can cause anxiety, confusion, and tremulousness.
Vaginal neoplasms caused in mice; however, no human cases of genital neoplasms have been reported to date. Short-term safety has been demonstrated for both mother and infant.
Hematologic toxicity may be increased during co-administration of other myelosuppressive drugs such as ganciclovir, ribavirin, and cytotoxic agents.

68. The End