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Antifungal Drugs These are drugs used for superficial and deep (systemic) fungal infections. Fungal infections are mostly associated with the use of broad-spectrum antibiotics, corticosteroids, anticancer/immunosuppressant drugs, dentures, indwelling catheters and implants, and emergence of AIDS. As a result of breakdown of host defence mechanisms by the above agents, saprophytic fungi easily invade living tissue. CLASSIFICATION 1. Antibiotics Polyenes: Amphotericin B (AMB), Nystatin, Hamycin Heterocyclic benzofuran: Griseofulvin 2. Azoles Topical: Clotrimazole, Econazole, Miconazole, Oxiconazole Systemic: Ketoconazole,Fluconazole,Itraconazole, Voriconazole, Posaconazole 3. Allylamine Terbinafine 4. Other topical agents Benzoic acid, Quiniodochlor, Ciclopirox olamine, Butenafine, Sod. thiosulfate. POLYENE ANTIBIOTICS Amphotericin B (AMB) Action: fungicidal Antifungal spectrum: AMB is active against a wide range of yeasts and fungi—Candida albicans, Histoplasma capsulatum, Cryptococcus neoformans, Blastomyces dermatitidis, Coccidioides immitis, Torulopsis, hodotorula, Aspergillus, Sporothrix, etc. Uses It is the most effective drug for various types of systemic mycoses and is the gold standard of antifungal therapy. Because of higher toxicity of AMB, the azole antifungals are now preferred in conditions where their efficacy approaches that of AMB Leishmaniasis: AMB is the most effective drug for resistant cases of kala azar and mucocutaneous leishmaniasis. Amphotericin B Adverse effects The toxicity of AMB is high. Acute reaction -This occurs with every infusion: Chills, fever, aches and pain all over, nausea, vomiting and dyspnoea lasting for 2–5 hour. Thrombophlebitis of the injected vein can occur Nephrotoxicity Anaemia(bone marrow depression) CNS toxicity (headache, vomiting, nerve palsies) Nystatin It is similar to AMB in antifungal action and other properties. However, because of higher systemic toxicity, it is used only locally in superficial candidiasis. Corticosteroid aerosols (e.g. beclomethasone) can cause oral candidiasis: nystatin is effective in preventing as well as treating it. HETEROCYCLIC BENZOFURAN Griseofulvin Action: fungistatic effect Antifungal spectrum: most dermatophytes, including Epidermophyton, Trichophyton, Microsporum, etc., but not against Candida Mechanism of action: inhibition of the mitotic activity of fungal cells in metaphase and impaired DNA synthesis. Selectively accumulate in the cells of the skin, hair, fingernails → newly formed keratin is resistant to fungal disease. Recovery occurs after complete replacement of infected keratin, therefore, the clinical effect develops slowly. Uses: only for dermatophytosis: tinea, trichophytia, microsporia. Fungal infection of the scalp. Onychomycosis Adverse reactions: Gastrointestinal: abdominal pain, nausea, vomiting, diarrhea. Nervous system: peripheral neuritis. Skin: photodermatitis. Hematologic reactions: granulocytopenia, leukopenia. Liver: jaundice, hepatitis. AZOLES Azoles are the most representative group of synthetic antimycotics that includes drugs for: systemic (ketoconazole, fluconazole, Itraconazole) and local (bifonazole, isoconazole, clotrimazole, miconazole, oxiconazole, econazole) applications. Mechanism of action The azoles have predominantly fungistatic effect, which is associated with the inhibition of fungal cytochrome P450 enzyme → violation of the synthesis of fungal membrane. Antifungal spectrum: Broad spectrum of antifungal activity(Candida, Aspergillus spp., dermatophytosis (Epidermophyton spp. Trichophyton spp. Microsporum spp.)) AZOLES Use Dermatophytosis. It is an alternative to griseofulvin. Effective in seborrhoea of scalp and dandruff (used as a lotion or shampoo) Systemic and mucosal candidiasis in both normal and immunocompromised patients Adverse reactions: Gastrointestinal: nausea, vomiting, diarrhea, constipation. CNS: headache, dizziness, drowsiness, blurred vision, paresthesia, tremor, convulsions. Allergic reactions: syndrome Stevens–Johnson (often with the use of fluconazole). Hematologic reactions: thrombocytopenia, agranulocytosis. Additionally for Itraconazole Cardiovascular system: congestive heart failure, arterial hypertension. Liver: hepatotoxic reactions Additionally for ketoconazole Liver: severe hepatotoxic reactions, until the development of hepatitis. Endocrine system: impaired production of testosterone and corticosteroids, accompanied by gynecomastia, oligospermia, impotence, female menstrual cycle. ALLYLAMINE Terbinafine This orally and topically active drug against dermatophytes and Candida Action: Fungicidal Use: Dermatophytosis Onychomycosis. Efficacy in nail infection is ~80%, which is higher than griseofulvin and itraconazole. Terbinafine is less effective against cutaneous and mucosal candidiasis: may be used as an alternative to fluconazole. ADR: gastric upset, rashes, taste disturbance. erythema, itching, dryness, irritation, urticaria and rashes. CLASSIFICATION 1. Anti-Herpes virus drugs Acyclovir, Valacyclovir, Famciclovir, Ganciclovir, Valganciclovir, Foscarnet 2. Anti-Influenza virus drugs Amantadine, Rimantadine, Oseltamivir, Zanamivir 3. Anti-Hepatitis virus drugs hepatitis B: Lamivudine,Tenofovir, Interferon α hepatitis C: Ribavirin, Interferon α 4. Anti-Retrovirus drugs Nucleoside reverse transcriptase inhibitors (NRTIs): Zidovudine, Stavudine, Lamivudine, Abacavir, Tenofovir Nonnucleoside reverse transcriptase inhibitors (NNRTIs): Nevirapine, Efavirenz Protease inhibitors: Ritonavir, Indinavir, Nelfinavir, Saquinavir Anti-Influenza virus drugs In severe cases there may be hemorrhagic bronchitis, pneumonia; can be fatal. Anti-Influenza virus drugs Treatment should begin within 2 days from the onset of the first clinical symptoms and continue for 5 days. Chemoprophylaxis is effective in 70-90% of cases in influenza virus type A. Chemoprophylaxis does not replace vaccination, which is the most important preventive measure. In patients from high-risk groups recommended a combination of preventive reception of anti-influenza drugs and vaccines. Blockers of M2-channels Amantadine ,Rimantadine Mechanism of action Antiviral effect of is realized by blocking of a special M2 ion–channel of influenza A virus → its ability to penetrate into cells decreased → inhibition of the replication of influenza A virus. Spectrum of activity Amantadine and rimantadine are active only against influenza A virus. Influenza B is not affected. Adverse reactions GIT: abdominal pain, loss of appetite, nausea. CNS: drowsiness, insomnia, headache, dizziness, blurred vision, irritability, paresthesia, tremor, convulsions. Indications: Treatment of seasonal influenza A, H5N1 (bird flu), H1N1 (swine flu) strains of influenza A. Prophylaxis of influenza A2 during an epidemic or seasonal influenza, especially in high risk patients. The efficiency of 70-90%. Amantadine has dopaminergic effect, through which can be used in Parkinson's disease. Neuraminidase inhibitors Neuroaminidase is one of the key enzymes involved in replication of influenza viruses A and B. Mechanism of action disrupting of the virus ability to penetrate healthy cells → inhibition of the virion release from infected cells → inhibited further spread of the virus in the body. In addition, neuraminidase inhibitors reduce the production of cytokines, preventing the development of local inflammatory response and attenuating systemic appearance of viral infection (fever, etc.). Indication Treatment of influenza A, swine flu, bird flu and influenza B. Prophylaxis of influenza A and B (oseltamivir only). Side effects: nausea and abdominal pain due to gastric irritation, headache, weakness, sadness, diarrhoea, cough and insomnia. ANTI-HERPES VIRUS DRUGS These are drugs active against the Herpes group of DNA viruses which include: Herpes simplex virus-1 (HSV-1) is the most commonly causes lesions on the mucous membrane of the mouth, eyes and skin (Orofacial herpes, its recurrent form - herpes labialis) Herpes simplex virus-2 (HSV2)- often a lesion of genitals Varicella-Zoster virus (VZV)-causes chicken pox and shingles; Epstein-Barr virus (EBV)- causes infectious mononucleosis, Burkitt's lymphoma Cytomegalovirus (CMV). ANTI-HERPES VIRUS DRUGS Basic antiherpetic drugs with proved efficacy – acyclovir, valacyclovir, penciclovir famciclovir. Mechanism of action Inhibition of viral DNA polymerase → Blocking of the synthesis of DNA in multiplying herpes-viruses, but do not act on viruses in the latent state. No effect on DNA polymerase of human cells and inactive in the healthy cells. Acyclovir Acyclovir is active only against herpes group of viruses; HSV-1 is most sensitive followed by HSV-2 > VZV=EBV, while CMV is practically not affected. Uses: Genital Herpes simplex (type-2) Mucocutaneous H. simplex (type-1) H. simplex encephalitis H. simplex (type I) keratitis Herpes zoster Chickenpox- is the drug of choice: reduces fever, eruptions,hastens healing and prevents visceral complications. Adverse effects Topical: Stinging and burning sensation after each application. Oral: Headache , nausea, malaise Intravenous: Rashes, sweating, emesis and fall in BP Reversible neurological manifestations (tremors, lethargy, disorientation, hallucinations, convulsions and coma) No teratogenic potential has been noted. Antiherpetic drugs Valacyclovir Differences from acyclovir: - a prodrug of acyclovir, is converted into acyclovir; - only per os; - has higher bioavailability and more long T½; Penciclovir similar to acyclovir. Differences from acyclovir: - effective in the later stages of Herpes labialis (papule, vesicle); - used only topically; - has a longer T ½ Famciclovir - prodrug of penciclovir - only per os; - It has narrower indications: - genital herpes - shingles (Herpes zoster) in patients without immunodeficiency CMV INFECTION CMV infection in adults: syndrome of infectious mononucleosis interstitial pneumonia. Guillain-Barre syndrome (polyneuropathy) meningoencephalitis, myocarditis, thrombocytopenia, etc. CMV INFECTION IN NEWBORN: jaundice, hepatosplenomegaly, petechiae, microcephaly, chorioretinitis, brain calcifications, etc. The consequences of CMV infection are neurologic complications, microcephaly and mental retardations. Anti-CMV Ganciclovir It is an analogue of acyclovir which is most active against CMV. The precursor cells in bone marrow are also quite sensitive to ganciclovir, and this may account for its bone marrow toxicity. Due to poor oral absorption, bioavailability of ganciclovir is low (<10%) → i.v. infusion Valganciclovir Prodrug which in the body turns into ganciclovir has ~ 8 times higher bioavailability, Oral valganciclovir has replaced i.v. ganciclovir for long-term therapy. ADR: Systemic toxicity of ganciclovir is high (bone marrow depression, rash, fever, vomiting, neuropsychiatric disturbances). Uses : prophylaxis and treatment of severe CMV infections (pneumonia/colitis/retinitis) in immunocompromised (AIDS, transplant recipient) patients. Anti-CMV Foscarnet It is a simple straight chain phosphonate which inhibits viral DNA polymerase and reverse transcriptase. It is active against H. simplex (including strains resistant to acyclovir), CMV (including ganciclovirresistant ones). ADR. Toxicity of foscarnet is high: Kidney damages—renal diabetes-like condition, acute renal Anaemia, phlebitis, tremor, convulsions Neurological as well as constitutional symptoms due to hypocalcaemia ANTI-RETROVIRUS DRUGS These are drugs active against human immunodeficiency virus (HIV) which is a retrovirus. They are useful in prolonging and improving the quality of life and postponing complications of acquired immunodeficiency syndrome (AIDS), but do not cure the infection. Anti-retrovirus (ARV) drugs The aim of anti-HIV therapy is to cause maximal suppression of viral replication for the maximal period of time that is possible. Nucleoside reverse transcriptase inhibitors (NRTIs): Zidovudine, Stavudine, Lamivudine, Abacavir, Tenofovir Nonnucleoside reverse transcriptase inhibitors (NNRTIs): Nevirapine, Efavirenz Protease inhibitors: Ritonavir, Indinavir, Nelfinavir, Saquinavir Nucleoside reverse transcriptase inhibitors (NRTIs) Zidovudine, Stavudine, Lamivudine, Abacavir, Tenofovir Mechanism of action blocking of reverse transcriptase of HIV → selectively inhibition of the replication of viral DNA. Use In HIV infected patients (inhibit HIV-1 and HIV-2) First line drug for chronic hepatitis B (Lamivudine, Tenofovir) Adverse reactions Gastrointestinal: nausea,vomiting, abdominal pain, diarrhea, anorexia, hepatotoxicity Hematologic reactions: anaemia, neutropenia, leukopenia, thrombocytopenia. CNS: weakness, fatigue, headache, insomnia, asthenia, drowsiness, depression, peripheral neuropathy, paresthesia. Other: lactic acidosis, myopathy (due to mitochondrial toxicity), fever, chills, frequent urination, pancreatitis. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Nevirapine, Efavirenz Mechanism of action Directly inhibit HIV reverse transcriptase → selectively inhibition of the replication of viral DNA. Use In HIV infected patients (inhibit only HIV-1) Adverse reactions rash, fever, arthralgia, myalgia. toxic epidermal necrolysis Gastrointestinal: nausea, stomatitis. CNS: headache, fatigue, drowsiness. Hematologic reactions: granulocytopenia. Liver: hepatitis Retroviral protease inhibitors Ritonavir, Indinavir, Nelfinavir, Saquinavir Mechanism of action HIV protease is an enzyme required for the production of structural proteins and enzymes (including reverse transcriptase and integrase) of the virus. Blocking the active site of the enzyme → inhibit the replication of HIV → HIV-infected cells produce immature noninfectious viral progeny → prevent further rounds of infection. Use In HIV infected patients (inhibit HIV-1 and HIV-2) Adverse reactions GI: diarrhea, abdominal pain, nausea. The oral cavity: mucosal ulceration, pharyngitis. Blood: haemolytic anaemia. CNS: headache, confusion, ataxia, weakness, dizziness, asthenia, convulsions, peripheral neuropathy, numbness of the limbs. Skin: rash, pruritus, Stevens–Johnson syndrome. Musculoskeletal system: pain in muscles and joints, osteoporosis. Other: avascular necrosis (rare). ANTI-HEPATITIS VIRUS Hepatitis B virus (HBV) is a DNA virus which, like retroviruses, can integrate into host chromosomal DNA to establish permanent infection Hepatitis C virus (HCV) is a RNA virus, which does not integrate into chromosomal DNA, does not establish noncurable infection, but frequently causes chronic hepatitis. Hepatitis B: Lamivudine, Tenofovir, Interferon α Hepatitis C: Ribavirin, Interferon α Ribavirin This purine nucleoside analogue has broad-spectrum antiviral activity against: influenza A and B, respiratory syncytial virus many other DNA and double stranded RNA viruses. Inhibit GTP and viral RNA synthesis Accumulates in the body on daily dosing and persists months after discontinuation; t½ is > 10 days. Administered orally or i.v. Uses Chronic hepatitis C (the first line treatment + combined with injected peginterferon ) severe influenza A/B and measles in immunosuppressed patients not a first Herpes virus infections, Acute hepatitis C line drug respiratory syncytial virus bronchiolitis in infants and children ADR: anaemia, bone marrow depression, haemolysis, CNS and g.i. symptoms. It is also teratogenic. The aerosol can cause irritation of mucosae and bronchospasm. Interferon α Interferons (IFNs) have nonspecific antiviral as well as other complex effects on immunity and cell proliferation. Three types of human IFNs (α, β and γ) are known to have antiviral activity. Only IFNα2A and IFNα2B produced by recombinant technology are available and are clinically used. Administered by i.m. or s.c. injection Complexed with polyethylene glycol (peginterferon), it is absorbed more slowly— more effective and induce longer lasting effects Pegylated forms are meant for s.c. injection at weekly intervals. Plasma levels of pegIFNα2A are sustained twice longer than those of pegIFNα2B. Interferon α Uses Chronic hepatitis B Chronic hepatitis C (in combination with ribavirin) Viral infections in immunocompromised patients Adverse effects Flu-like symptoms—fatigue, aches and pains, malaise, fever, dizziness, anorexia, nausea, taste and visual disturbances develop few hours after each injection, but become milder later. Neurotoxicity—numbness, neuropathy, altered behaviour, mental depression, tremor, sleepiness, convulsions. Myelosuppression: dose dependent neutropenia, thrombocytopenia. Thyroid dysfunction (hypo as well as hyper). Hypotension, transient arrhythmias, alopecia and liver dysfunction.