Antiviral Antifungal and Antiparasitic Drugs Nursing 3703 Pharmacology

Antiviral, Antifungal and Antiparasitic Drugs Nursing 3703 Pharmacology By Linda Self

Viruses • Intracellular parasites • Enter host, bind to receptors on cell membranes • Use cellular metabolic activities for replication • May be DNA or RNA viruses

Viruses • DNA viruses incorporate into chromosomal DNA, produce new viruses • RNA viruses must be converted to DNA by reverse transcriptase in order to replicate

Viruses • Induce antibodies and immunity • Protein coat allows host recognition as foreign vs. self • Exception is influenza

Viral illnesses • • • Herpes Simplex 1 and 2 Cytomegalovirus Influenza RSV Rotavirus HIV and AIDS

Antiviral Drugs • Catalyst was AIDS • Both for Tx of AIDS and for opportunistic infections

Viral Vaccines • • • Poliomyelitis Measles Rubella Varicella RSV HPV Herpes Zoster Yellow Fever others

Viral Vaccines • Attenuated vaccines generally safe • Do not use in patients who are: pregnant, on steroids, receiving immunosuppressants or antineoplastiacs, undergoing radiation Tx or who are immunodeficient

Drugs for Herpes Virus Infections • Zovirax (acyclovir) for herpes labialis, varicella, herpes zoster, genital herpes • Famvir (famciclovir) for zoster and genital herpes • Valtrex (valacyclovir) for herpes labialis, zoster, recurrent genital herpes • Famvir and Valtrex need titration in renally impaired

Influenza H=hemagglutinin N=neuramidase April 2009 Quadruple reassortment Tx—Tamiflu (oseltamivir) or Relenza (zanamivir) or Flumadine (rimantadine) • Tx for 5 days • Relenza can cause bronchospasm • • •

Influenza • To short course of infection, must be started within 48 h • Thereafter, ? may decrease severity

RSV • Virazole (ribavirin) • Administered by inhalation • Can cause bronchospasm

Viral hepatitis • Hepatitis B—Hepsera (adefovir), Epivir (lamivudine) • Hepatitis C—peginterferon alfa 2 a and Virazole (ribavirin)

HIV • Unique features • 2 proteins on surface of virus bind with 2 sites on CD 4+ cell • Virus infiltrates into genetic material • Reverse transcriptase enzyme enables virus to become double stranded DNA

HIV • Once double-stranded DNA, like the host cell, HIV can infiltrate cell nucleus of target cell • Gains entry into target cell nucleus with aid of Integrase • Following integration and replication, long protein chain is cleaved. Pieces then form into new viral particle

HIV • Cleavage is accomplished with aid of protease • See page 568

Drugs for HIV Infection • Nucleoside reverse transcriptase inhibitors • Nucleotide reverse transcriptase inhibitors • Non-nucleoside reverse transcriptase inhibitors • Protease inhibitors • Entry inhibitors

Antiretrovirals • Always used in combination • Target enzymes or receptor sites • Specific guidelines for pregnancy

Nucleoside Reverse Transcriptase Inhibitors • Prototype is AZT • Similar structurally to DNA components (adenosine, guanosine, cytosine or thymidine) • Affect thymidine, thus inhibit reverse transcriptase • Slow progression but do not cure • Didanosine, Ziagen (abacavir), AZT (zidovudine), Epivir (lamivudine)

Nucleotide Reverse Transcriptase Inhibitors • Also inhibit reverse transcriptase • Differ structurally from nucleoside RTI so circumvent resistance • Viread (tenofovir) • Used to Tx hep B as well

Non-nucleoside Reverse Transcriptase Inhibitors • Directly bind with reverse transcriptase • Used in combination with NRTIs • Viramune (nevirapine) and Sustiva (efavirenz)

Protease Inhibitors • Inhibit action of protease • Most protease inhibitors metabolized by cytochrome p 450 system • Many drug interactions • Liver toxicities • Lipid abnormalities • Hyperglycemia • lipodystrophies

Protease Inhibitors • Prezista (darunavir), Crixivan (indinavir), Viracept (nelfinavir), Norvir (ritonavir), Invirase (saquinavir)

Combination Antiretrovirals • Combovir (stavudine and zidovudine) • Trizivir (abacavir, lamivudine and zidovudine) • Decrease pill burden

Entry Inhibitors • Fuzeon (enfuvirtide) • Selzentry (maraviroc) • Do not act on enzymes but rather affect glycoproteins that allow binding and fusion of the virus to the CD 4+ cell

Integrase inhibitors • Still in clinical trials

Fungi (mycoses) • Mild or life threatening • Widely present in environment • Dermatophytes—tinea capitis, tinea pedis, tinea cruris, tinea corporis • Examples: Candida, Aspergillosis, Cryptococcus, Histoplasmosis, B

Antifungal Drugs • Development of antifungals difficult because fungal cells closely resemble human cells • Polyenes—Amphotericin B, Nystatin • Azoles—Sporonox (itraconazole), Nizoral (ketoconazole), Diflucan (fluconazole) • Echinocandins—Eraxis (anidulafungin), Cancidas (caspofungin)

Fungizone (amphotericin B) • Give in D 5 W • Use separate line • In line filter depending on formulation • Adverse effects: Infusion reaction with chills, fever, tachypnea Treat with Benadryl, Tylenol or steroids • Nephrotoxicity most serious SE

Amphotericin B • Indicated for life-threatening fungal infections such as aspergillosis, blastomycosis, candidiasis, coccinioidomycosis, crytococcis and histoplasmosis • Drug concentrations are highest in inflamed tissues

Miscellaneous Antifungals • Lamisil (terbinafine) • griseofulvin

Mycostatin (nystatin) • Same mechanism of action as Amphotericin B • Too toxic for systemic use

Azoles • • Largest group of commonly used antifungals Can be used topically or systemically Prototype is Nizoral (ketoconazole 0 All azoles are contraindicated in pregnancy

Azoles • • • Less toxic than ampho Many drug interactions Poor absorption if achlorhydric Some hepatotoxicity Can be given orally

Diflucan (fluconazole) • Synthetic, broad spectrum against candidiasis, cryptococcis, coccidioidomycosis • Not effective against aspergillosis • PO or IV • Fewer side effects than ketoconazole • Does not require gastric acidity, does not cross blood-brain barrier • Reduce dosage in renal failure

Sporanox (itraconazole) • Similar to Diflucan • Drug of choice for blastomycosis, histoplasmosis and sporotrichosis • Good for suppressive Tx in AIDS patients w/histo • Contraindicated for dermatophytic infections and onychomycoses in heart failure patients • IV or PO • Many drug interactions

Cancidas (caspofungin) • First chicocandin antifungal • Affects glucan in fungal cell wall leading to leakage of cellular contents • Indicated for Tx of invasive aspergillosis who cannot take or do not respond to Fungizone or Sporanox

Cancidas • • • Can cause thrombophlebitis Abnormalities in blood count Liver impairment Drug interactions Mix only with normal saline, infuse over at least one hour

Fulvicin (griseofulvin) • For dermatophyte infections of the scalp and nails and for extensive skin eruptions • Drug binds to keratin, over time the infected tissues are shed and replaced by uninfected tissues • Need 3 -8 weeks to Tx ringworm • Up to one year for onychomycoses

Fulvicin • Side effects: GI upset, skin rash, insomnia, fatigue, hepatotoxicity, blood dyscrasias and peripheral neuritis • Take with fatty meal • May affect efficacy of OCP • Coumadin may warrant adjustment

Lamisil (terbinafine) • Synthetic with broad spectrum of activity • Inhibits an enzyme needed for synthesis of ergosterol, a structural component of fungal cell membranes • Good for Tx of ringworm, nails • hepatotoxic

Drug Treatment for Specific Infections • Aspergillosis—Sporonox, Amphotericin B • Blastomycosis—Sporonox, Amphotericin B • Candidiasis—varies r/t area of infection Oral Cutaneous Vaginal Systemic

Drug Treatment for Fungal Infections • • Histoplasmosis—Sporanox PCP—Bactrim, pentamidine, dapsone, others Cryptococcis-Amphotericin B Coccidioidomycosis- azole to Amphotericin B

Aspergillosis • Found in soil, decaying plant matter, cellars • May be found in cereals, powdered milk, peanuts, cashews, coffee beans • Characterized by granulomatous lesions of lungs, skin, eyes, nose, urethra and may infiltrate to vital organs • Occurs in debilitated and immunocompromised • Tx w/ Amphotericin or Sporonox

Histoplasmosis • Found in soil, organic debris around chicken houses, bird roosts and caves inhabited by bats • Develops when spores are inhaled • Tx with Sporanox, possibly Ampho

Candidiasis • Yeast infection commonly affects those on abx therapy, inhaled steroids, diabetics, those on antineoplastic Tx or on steroids or who have AIDS • Presents as: vaginal candidiasis, skin candidiasis, oral candidiasis or systemic disease

Tx for Candidiasis • Systemically—Amphotericin B • Vaginally-Lotrimin (clotrimazole), Diflucan • Oropharyngeal, esophageal, vaginal and systemic—Diflucan PO or IV

Parasites • Organisms that live within, upon or at expense of another organism to survive • Include protozoa, helminths, scabies and pediculi

Protozoa • Include amebiasis, giardiasis, malaria, toxoplasmosis and trichomoniasis • Single celled, may be saprophytes. Usually contracted by oral-fecal route, by contaminated water or by bite of an insect.

Amebiasis • Common in Africa, Asia and Latin America • In US, more likely in homosexuals and bisexual men and in those who travel to areas with poor sanitation

Amebiasis • Drugs used are classified according to site of action • Extraintestinal e. g. liver—use Aralen (chloroquine) • For Intestinal use Yodoxin (lodoquinol) • Flagyl is effective for intestinal and extraintestinal amebiasis • May also use tetracycline or doxycycline as they alter bacterial flora

Giardiasis • Caused by Giardia lamblia • Spread by food or water contaminated with feces with encysted forms of organism • Also can contract by person to person transmission in day cares, institutions and in homosexual or bisexual men

Giardiasis • Seen in campers who drink water • Causes diarrhea • Can progress to chronic condition with malabsorption, wt. loss, anorexia • Can result in B 12 deficiency • Tx is Flagyl

Malaria • Seen in tropics • Rare in US • Caused by four species of protozoa of genus Plasmodium-vivax, malariae, ovale and falciparum • Transmitted by the Anopholes mosquito • Antimalarials act at different stages in life cycle

Malaria • Chloroquine with primaquine is used for prophylaxis • Lariam (mefloquine) for prevention and Tx, better in more resistant forms • Plaquenil (hydroxychloroquine) used to Tx erythrocytic malaria • Daraprim (pyrimethamine) folic acid antagonist also used in prevention

Malaria • • Quinamm (quinine) prototype Derived from bark of cinchona tree Sometimes still used for leg cramps Replaced by agents with fewer SE

Trichomoniasis • Vaginal infection caused by Trichomonas vaginalis • Contracted sexually • Treat both partners • Flagyl is Tx

Helminthiasis • Infestation with parasitic worms • Some types of worms penetrate body tissues or produce larvae that migrate to blood, lymph, lungs, liver or other sites • Some anthelminthics act locally, some systemically

Vermox (mebendazole) • Effective for hookworms, pinworms, roundworms, whipworms • May be useful with tapeworms • Prevents uptake of glucose necessary for parasitic metabolism • Only 10% is absorbed systemically

Stromectrol (vermectin) • Used for various parasitic infections, most useful in stronguloidiasis • Also used for resistant lice

Scabies and Pediculosis • Parasitic infestations of the skin • Scabies by the itch mite called the Sarcoptes scabeii • Scabies caused by one of three types of lice: pediculosis capitis, pediculosis corporis and pediculosis pubis

Scabicides and Pediculocides • • • Permethrins drug of choice for both Two applications recommended Pediculosis is a 1% preparation (Nix) Scabies used a 5% cream (Elimite) Permethrins safest Second line use Lindane (gamma benzene hexachloride)

Scabicides and Pediculosis • Ovide (malathion) is a pediculicide for head lice • Rid (pyrethrin) for pediculosis