Transcript Antifungal Drugs

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,
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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
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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:
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tinea, trichophytia, microsporia.
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Fungal infection of the scalp.
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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
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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
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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
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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
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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
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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
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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
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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.