ANTIVIRAL AGENTS

Drugs used in the treatment and prophylaxis of viral infections.

Viruses are obligate intracellular parasites and their replication depends on metabolic processes of the host cells a big disadvantage results: antiviral agents often interfere with host cell function and produce toxicity.

Therefore to be effective antiviral agents must either block viral entry into or viral exit from the cell or be active inside the cell.

1)TREATMENT OF HERPES SIMPLEX VIRUSE (HSV) and VARICELLA ZOSTER (VZV) INFECTIONS A)ACYCLOVIR(ZOVIRAX) -it is a synthetic purine nucleoside analog with an acyclic side chain. Pharmacokinetics: It can be administered orally(20 % is absorbed from the GI tract sufficient!), i.v. and locally. It is widely distributed including CSF, the brain, cornea and it is excreted in the urine both by glomerular filtration and tubular secretion.

Mechanism of action: It is phosphorylated by a virus specific enzymeacyclovir triphosphateinhibits viral DNA polymerase inhibits viral DNA synthesis.

Antiviral activity: H. simplex type I, H. simplex type II, varicella zoster virus, Epstein Barr virus, CMV weaker activity. Resistance may occur during therapy.

CLINICAL USES
By oral route(tablets or suspension) is effective in:
Mucocutaneous H. simplex-it is a type I virus disease and is localized to lips and gums ; Prophylactic oral therapy may prevent sun exposure related reccurences of mucocutaneous herpes simplex ( herpes labialis).
Disseminated disease in immunocompromised patients. Genital herpes simplex (generally caused by type II virus)-in late or severe cases in primary disease ;also in recurrent disease-but response is slow and incomplete. Herpes zoster-oral therapy may be benefical if started earlier.

Locally (cream, ointment):

genital herpes simplex, primary disease effective only if started earlier and in mild cases. Herpes simplex (type I) keratitis ; Herpes zoster the ointment may be applied on herpetic ulcers.

By i.v. route
H. simplex encephalitis (type I virus); Herpes zoster severe cases or in immunocompromised patients Genital herpes simplexsevere cases of recurrent disease; Chicken pox: in patients with immunodeficiency and in neonates.

Side effects: -orally: headache, nausea, malaise and some CNS effects; -i.v.: local phlebitis, rashes, nephrotoxicity, neuropsychiatric reactions. -topically: local discomfort, pruritus, burning sensation.

B) IDOXURIDINE
-it acts as a thymidine analogue; -it is a pyrimidine antimetabolite ; it competes with thymidine, gets incorporated in DNA this DNA directs the synthesis of wrong viral proteins; -the only indication for idoxuridine is H. simplex keratoconjunctivitis ; it is used as ophthalmological solution. -side effects are ocular irritation, edema of lids and photophobia.

C)VIDARABINE
-Herpes simplex keratitis -Herpes simplex encephalitis - Varicella zona zoster infections (all in immunocomprommised patients) It is administered i.v., locally (ointment).

D)TRIFLURIDINE
- It inhibits viral DNA synthesis; -It is used as solution in primary keratoconjunctivitis due to herpes simplex viruses 1 and 2 ( as 1% solution); - Alone / + Interferon alfa acyclovir resistant HSV infections.

C)FAMCICLOVIR
-it blocks viral DNA synthesis; -it is active against HSV1, HSV 2, CMV, HBV. -It is used in first and recurrent genital herpes, herpes labialis, and acute herpes zoster. It is given orally. -Side effects: headache, nausea, diarrhea; testicular toxicity in animals ( after repeated doses).

D) VALACYCLOVIR
-it is an ester of acyclovir rapidly converted to acyclovir after oral adm.; -it is used in genital herpes, orolabial herpes, herpes zoster. - It is generally well tolerated but nausea, vomiting, rash may occur.

E) PENCICLOVIR
- It is the metabolite of famciclovir; - Peniciclovir cream 1% is used for the treatment of recurrent herpes labilais.

F) DOCOSANOL
- It prevents viral entry into cells and subsequent viral replication; - It is active against HSV; - It is used in recurrent orolabial herpes as cream 10% .

2)TREATMENT OF CYTOMEGALOVIRUSES INFECTIONS

A) GANCYCLOVIR -it is an analog of acyclovir. -it has activity against CMV ( 100 times greater than that of acyclovir), HSV, VZV, EBV. -it inhibits viral DNA replication.

Clinical uses: -severe cytomegalovirus infections in immunocompromised patients (AIDS, transplant recipients); -patients with cytomegalovirus retinitis ( +foscarnet); - CMV colitis, esophagitis, pneumonia ; -prevention of CMV infection in patients receiving immunosuppressive therapy following organ transplantation. It is administered orally / i.v. / intraocularly ( in CMV retinitis)

Adverse effects: - The most common adverse effect of systemic gancyclovir( particularly after i.v. adm.) myelosuppression. -headache,insomnia, peripheral neuropathy; -fever, rash, GI disturbances; -teratogenic in animals.

B)FOSCARNET
- It inhibits viral DNA polymerase and HIV reverse transcriptase ( without activation by phosphorylation ); -It has activity against HSV (including strains resistant to acyclovir), VZV, CMV (including ganciclovir resistant ones), EBV and HIV. -it is avaiable only for i.v. adm.; -it is used in CMV retinitis, colitis, esophagitis, acyclovir resistant HSV anv VZV. -adverse effects : renal impairment, electrolytes disbalances.

C)VALGANCYCLOVIR D) CIDOFOVIR
- Prodrug of gancyclovir; - It is given orally with food; - It is used in CMV retinitis and prevention of CMV infection in patients with organ transplant. - It is used in CMV retinitis ( i.v.); - The primary adverse effect of i.v. cidofovir is dose dependent proximal tubule nephrotoxicity.

3)TREATMENT OF VIRAL RESPIRATORYINFECTIONS

a)AMANTADINE - is a synthetic tricyclic amine. - It is effective only against influenza A. Mechanism of action:it inhibits uncoating of the viral RNA within infected host cells thus preventing replication.

Clinical uses: It is administered orally. -prevention of influenza A virus infection during virus epidemias in debilitated persons, persons with respiratory disability, people with high risk ( before exposure); 100 mg twice daily or 200 mg once daily. - in shortening the fever and the duration of symptoms if administered at the onset of illness. -it is used in Parkinson. Side effects: -dose-related CNS effects (confusion, dizziness, insomnia, and even hallucinations, convulsions, in patients with impaired renal function) ; -nausea, anorexia ;- birth defects have been reported after exposure during pregnancy.

b)RIMANTADINE
It is a more potent( four to ten times) , long acting and better tolerated congener of amantadine. Oral bioavailability is higher and it is largely metabolized.Dose and clinical application is similar to amantadine and has a low risk of CNS effects. The marked increased in the prevalence of resistance to both agents over the last decades in infl .A, B, H1N1 as well as H3N2 has limited the usefulness of these agents for either the treatment or the prevntion of influenza.

c) OSELTAMIVIR and ZANAMIVIR

- They interfere with release of progeny influenza virus from infected to new host cells thus inhibiting the spread of the infection within the respiratory tract. - They are active against both influenza A and B. - Oseltamivir is given orally and Zanamivir by inhalation. - Early administration is crucial : 36-48 hours after the onset of symptoms ( because replication of influenza virus peaks at 24-72 hours after the onset of ilness) - they also are efective in preventing disease after exposure.

d) RIBAVIRIN:
It is a purine nucleoside analogue and acts against influenza A and B, respiratory syncytial virus and many other DNA and double stranded RNA viruses. Clinical uses: -nebulized ribavirin has been used for respiratory syncytial virus broncholitis or pneummonia in infants and children, particularly those with congenital heart disease, prematurity and other high risk conditions. - Orally, in combination with Interferon alfa in hepatitis C infection.

4)ANTIRETROVIRAL INFECTIONS
Anti-retrovirus drugs are active against HIV (human immunodeficiency virus). HIV (human immunodeficiency virus) is a retrovirus and member of Lentivirus family.It preferentially replicates in CD4 helper T lymphocytes. These drugs are useful in prolonging life and postponing complications AIDS but do not cure the infection.

Classes of antiretroviral agents:

1) Nucleoside /nucleotide reverse transcriptase inhibitors ( NRTIs) 2) Nonnucleoside reverse transcriptase inhibitors (NNRTIs); 3) Protease inhibitors (PIs); 4) Fusion inhibitors; 5) CCR5 receptor antagonists; 6) Integrase inhibitors. RESISTANCE OCCURS IN TIME

1)NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

- they act by competitive inhibition of HIV-1 reverse transcriptase incorporation into the growing viral DNA chain results in premature chain termination .

NAME

ADM.

SIDE EFFECTS

OBS.

ABACAVIR

orally

Within the first 6 weeks of therapy: fever , malaise, nausea, vomiting, diarrhea, respiratory symptoms, skin rashes, laboratory abnormatilities; risk of myocardial events!
Dose-dependent pacreatitis; Peripheral neuropathy, hepatitis, diarrhea, CNS toxicity etc. Headache, diarrhea, nausea, asthenia. Headache, dizziness, insomnia, fatigue, GI discomfort.

+ LAMIVUDINE

DIDANOSINE(ddl)

orally

EMTRICITABINE Once daily adm. LAMIVUDINE Synergy with zidovudine,stavudin e

Orally

It also acts against HBV no with zalcitabinne

orally

STAVUDINE

orally

Dose related peripheral neuropathy GI complaints

No with didanosinerisk of pancreatitis + EMTRICITABINE

TENOFOVIR

orally

ZALCITABINE

Orally but thrice daily dosing which limits its usefulness Orally

Dose dependent peripheral neuropathy Myelosuppression ( with macrocytic anemia) + LAMIVUDINE

ZIDOVUDINE - The first anti HIV agent -it decreases the rate of clinical disease progression and prolong survival in Hiv infected individuals.

b)NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

- They bind directly to HIV -1 reverse transcriptase and unlike the NRTIs they dont require phosphorylation to be active. - Resistance occurs rapidly with monotherapy; - As a class NNRTIs agents tend to cause GI intolerance, skin rash etc.

DELAVIRDINE EFAVIRENZ -it is given once daily on empty stomach; -the principal adverse effect is on CNS ( insomnia, headache, depression ); ETRAVIRINE - it may be effective against strains of HIV resistant to older NNRTIs; - the most common side effects: rash, nausea, diarrhea. NEVIRAPINE - Very well absorbed orally (90%); a single dose (200 mg) is effective in the prevention of the transmission of HIV from mother to newborn ( when administered at the onset of labour ) followed by administration to neonate ( 3 days); resistance may occur after a single dose !!!.

c)PROTEASE INHIBITORS
Protease is involved in synthesis of final structural proteins of the mature virion core; PIs prevent the processing of viral proteins resulting in the production of immature , noninfectious viral particles. PIs do not need intracelullar activation; They are given orally and they may be used in combination with reverse transcriptase inhibitors. The most prominent adverse effects are gastrointestinal intolerance, asthenia, headache, dizziness, rash, paresthesia etc.

ATAZANAVIR DARUNAVIR FOSAMPRENAVIR INDINAVIR LOPINAVIR RITONAVIR SAQUINAVIR TIPRANAVIR- in cases of resistance to other PIs

d) ENTRY INHIBITORS
MARAVIROC - It binds specifically and selectively to CCR5 , one of 2 coreceptors necessary for entrance of HIV into CD4+ cells , thus blocking the entry of HIV in these cells; - Adverse effects : cough, upper respiratory tract infections , muscle and joint pain, diarrhea, liver dysfunction. ENFUVIRTIDE

e)INTEGRASE INHIBITORS
RALTEGRAVIR - It binds integrase, a viral enzyme essential to replication of both HIV-1 and HIV-2 ; - It is effective in patients infected with HIV-1 resistant to multiple other agents. - It may cause diarrhea, nausea, dizziness, headache, laboratory abnormatilities.

5) ANTIHEPATITIS AGENTS
INTERFERON ALFA: *interferons are host cytokines with antiviral, immunomodulatory , antiproliferative actions; *injectable preparations of interferon alfa are available for treatment of both HBV and HCV infections ( i.m./ s.c.); *adverse side effects: flu-like syndrome ( within 6 h after dosing); chronic therapy: hepatic enzyme elevation, myelosuppression, CNS toxicity etc.

Drugs used in hepatitis B

- The goal of chronic HBV therapy is suppression of HBV replication, slowing of progression of disease, prevention of complications. - ADEFOVIR DIPIVOXIL- inhibits HBV DNA polymerase; it is given orally. - ENTECAVIR - LAMIVUDINE - TELBIVUDINE

Drugs used in hepatitis C

-the primary goal of treatment of patients with chronic HCV infection is viral eradication( absence of viremia) . RIBAVIRIN inhibits the replication of HCV

ANTIFUNGAL AGENTS
Drugs used for superficial and deep (systemic) fungal infections.

Mycotic infections may be: *superficial: they involve only the skin; *subcutaneous: fungi penetrate the skin; *disseminated fungal infections. Most fungi are resistant to antibiotics because of the structure of the cell wall. They are only a few drugs that inhibit fungi pathogenetic for humans and most of them are toxic.

a)Classification of antifungal drugs:

1) SYSTEMIC ANTIFUNGAL DRUGS 2)DRUGS FOR SUPERFICIAL FUNGAL INFECTIONS : *ORALLY DRUGS *TOPICAL DRUGS

b)Classification according to the chemical structure:

1)Antibiotics: *Polyenes: amphotericin B, Nystatin, Natamycin. *Heterocyclic benzofuran: Griseofulvin 2)Antimetabolites: Flucytosine 3)Azoles: * Imidazoles: -topical: clotrimazole, econazole, miconazole -systemic: Ketoconazole *Triazoles: -systemic: fluconazole, Itraconazole. 4) Allylamine: Terbinafine 5) Other topical agents: Tolnaftate, Undecylanic acid, benzoic acid, quiniodochlor etc.

1)SYSTEMIC ANTIFUNGAL DRUGS

*AMPHOTERICIN B -it is obtained from Streptomyces nodosus;

It is a polyene antibiotic ( macrocyclic ring - a large lactone ring of 12 or more atoms one side of which has several conjugated double bonds and is highly lipophilic, while the other side is hydrophilic with many OH groups.

Antifungal activity: Candida albicans, Cryptococcus neoformans, Aspergillus, Sporothrix, Blastomyces dermatitidis, Histoplasma capsulatum, Torulopsis, various species of leishmania.

Mechanism of action: It binds to ergosterol, a sterol specific to fungal cell membranes and changes the permeability and transport properties of the membranes.

Pharmacokinetics: It is not absorbed from the GI tract after oral administration; can be given orally for intestinal candidiasis without systemic toxicity. It is usually given by slow i.v. infusion. It is widely distributed into tissues, but penetration in cerebrospinal fluid is poor. It binds to sterols in tissues and to lipoproteins in plasma and stays in the body for long periods. It is metabolized in the liver and is excreted very slowly in the urine and bile.

Clinical uses: - systemic mycoses: disseminated fungal infections(with candida);fungal meningitis (candida, Cryptococcus) (i.v. infusion or as intrathecal injection ). !!!because of higher toxicity the azoles antifungals are now preffered in conditions where their efficacy approaches that of amphotericin B.

Side effects: -nephrotoxicity; -neurotoxicity; -cardiac toxicity; -hTA, electrolyte imbalance; -anaemia due to bone marrow depression ( reversible); -fever, chills, aches, pain all over, nausea, vomiting after i.v. infusion (probably due to release of cytokines).

*FLUCYTOSINE -is a synthetic compound. Mechanism of action: It is activated in fungal cells by cytosine deaminase-mediated conversion to 5fluorouracil, which when incorporated into RNA causes functional changes.

Antifungal activity: Narrow spectrum: Cryptococcus neoformans, few strains of candida, chromoblastomyces, torula. Clinical uses: It is used only in combination with Amphotericin B for the treatment of disseminated fungal infections and meningitis (with Candida or Cryptococcus).

Pharmacokinetics: It is administered by oral route.It is well absorbed from the GI tract. It penetrates well into CSF. It is eliminated by glomerular filtration. Side effects: -GI disturbances(diarrhoea); -hematologic toxicity; -reversible hepatic dysfunction with elevation of serum hepatic enzymes.

*AZOLES: KETOCONAZOLE (an imidazole), FLUCONAZOLE, ITRACONAZOLE (tryazoles).

KETOCONAZOLE (KTZ): Mechanism of action: -it decreases ergosterol formation by inhibiting an enzyme that catalyzes demethylation of lanosterol to ergosterol.

Clinical uses:It produces a slower response comparing with amphotericin but because of its lower toxicity it was preffered over amphotericin in less serious cases of systemic mycosis. -it is effective orally in disseminated infections caused by Histoplasma, Blastomyces.

Side effects: -GI irritation: nausea, vomiting (they can be reduced by giving the drug with meals); -fever, chills, rashes; - it decreases androgen production from testes(with gynecomastia, loss of hair and libido), suppression of estradiol synthesis (with menstrual irregularities).

FLUCONAZOLE:
-it is a newer water soluble triazole having a wider range of activity than KTZ; -it is very well absorbed from the GI tract; it is widely distributed in the body and has an excellent penetration into CSF. -it is used (especially in chronic ambulatory treatment) in cryptococcal meningitis, in systemic candidiasis, coccidioidal meningitis, histoplasmosis; it can be administerd orally as well as i.v. (in severe infections). -it has less side effects than ketoconazole : it has no endocrinological effects; it causes GI distress, rashes, it is a potent teratogenic agent.

ITRACONAZOLE: It is a new orally active triazole. It has a broader spectrum of activity than fluconazol and ketoconazol; includes some moulds like aspergillus. It is preffered over KTZ for most systemic mycosis (histoplasmosis, blastomycosis etc.).

2)) DRUGS FOR SUPERFICIAL FUNGAL INFECTIONS

A) ORALLY DRUGS
1) GRISEOFULVIN -it is extracted from Penicillium griseofulvum; -it is active against dermatophytes, including epidermophyton, microsporium, tricophyton; Mechanism of action: It interferes with mitosis and it also causes abnormal metaphase configurations.

 The mechanism of action at molecular level is unclear but it is deposited in newly forming skin where it binds to keratin protecting the skin from new infection. Because its action is to prevent infection of new skin structures it is administered for 2-6 weeks for skin and hair infections to allow the replacement of infected keratin by the resistant structures. Nails infections may require months of treatment.

Pharmacokinetics: It is administered orally. The absorbtion from gastrointestinal tract is somewhat irregular because of its very low water solubility. Absorbtion is improved taking it with fatty food. It is largely metabolized and excreted in the urine.

Clinical uses: Severe infections of the scalp, glabrous skin, of the hair and nails(finger and toe nails). Duration of treatment is variable: -body skin-3 weeks; -palm, soles- 4 to 6 weeks; -finger nails-4 to 6 months; -toe nails-8 to 12 months ;

Side effects: -headache, mental confusion, GI irritation, hepatitis; - Allergy. - Griseofulvin has been largely replaced by newer antifungal agents ( itraconazole, terbinafine).

2) KETOCONAZOLE It is effective orally in dermatophytosis because it is concentrated in the stratum corneum. 3) ALLYLAMINES: Terbinafine: -onychomycosis is treated by 3-12 months oral therapy; -efficacy higher than griseofulvin has been reported; terbinafine is now among the first line drugs for dermatophyte infections including onychomycosis. -it is less effective against cutaneous and mucosal candidiasis; 2-4 weeks oral therapy may be used as an alternative.

B)TOPICAL DRUGS FOR SUPERFICIAL INFECTION

NYSTATIN It is a polyene macrolide obtained from S. noursei. It is similar to amphotericine in antifungal action and other properties. It disrupts fungal membranes by binding to ergosterol.

However, because of higher systemic toxicity, it is used only locally.

Clinical uses: -it is used for corneal, conjunctival, cutaneous, vaginal, orally candidiasis as creams, ointments, powders, suppositories, vaginal tablets, orally suspension. -it has been combined with tetracyclines for the prevention of superinfection (due to candida) , diarrhoea (it is not absorbed from gastrointestinal tract and acts locally). -corticosteroids aerosols can cause oral candidiasis: nystatin is effective in preventing as well as treating it. Adverse effects: nausea, bad taste in mouth.

AZOLES: Clotrimazole, Econazole, Miconazole-they are imidazoles and they are entirely topically.Ketoconazol (also an imidazol)is used both orally and topically. Mechanism of action: like ketoconazole.

Clotrimazole: some clinical uses: -topical treatment of tinea infections; -otomycosis; - cutaneous, vaginal ,oropharyngeal candidiasis. -it is also effective in skin infections caused by corynebacteria; -it is well tolerated by most patients; local irritation with stinging and burning sensation occurs in some.

Econazole, Miconazole:
-effectively penetrate superficial layers of the skin and are highly effective in dermatophytosis, otomycosis, onychomycosis , cutaneous and vulvovaginal candidiasis;they also are effective for tinea, pityriasis versicolor -local irritation in few patients was reported. - available as gel, solution, powder, vaginal gel, ointment, lotion, ear drops, vaginal ovules.

ALLYLAMINES: Terbinafine: -it is a fungicidal agent; -applied topically as cream is indicated in tinea pedis/ corporis/cruris/capitis and pityriasis versicolor;2-6 weeks treatment is required according to the site.

OTHER TOPICAL ANTIFUNGALS: all these drugs are used for dermatophytosis. Tolnaftate (lotion and cream) -it is an effective drug for tinea cruris, tinea corporis. Ciclopirox olamine: -it is a newer drug effective in tinea infections, pityriasis versicolor and dermal candidiasis. Undecylanic acid: -it is a fungistatic used topically, generally in combination with its zinc salt; -it is still used for tinea pedis, tinea cruris but it is inferior to the drugs described above.