Chapter 8: Antifungal and Antiviral Agents Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

Outline Antifungals Antiviral: Herpes Antiviral: HIV Antiviral: Chronic Hepatitis

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Antifungals Nystatin(Mycostatin) Imidazoles Amphotericin B

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Antifungal Agents Caused by molds, yeasts, fungi Candida ▫Normal flora of mouth & other areas of body ▫Over-growth caused by Superinfection or immunocompromised patients (HIV) Fungal infections (mycosis) classified into 3 groups 1.Systemic (common in HIV) 2.Superficial or mucocutaneous: dental  TX: topical (most common), systemic (severe cases) 3.Subcutaneous

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

Antifungal Agents Nystatin(Mycostatin) Usual: oral suspension liquid rinse, lozenge, cream Mechanism of action: binds to sterols in the fungal cell membrane & causes lysis ▫Bacteria do not contain sterols in their cell membrane  Reason nystatin is not effective against bacteria

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

Antifungal Agents : Imidazoles Used in dentistry 1)Clotrimazole(Mycelex) Lozenge for oral use (contains sugar) Do NOT use in pt with HIGH caries risk 2)Ketoconazole(Nizoral)  Systemic fungal infections, used after oral meds not worked 3)Fluconazole(Diflucan)  Severe, extensive oropharyngeal candida  Can be used as preventive in HIV patients Drug Interactions Warfarin CCB Erythromycin

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

Antifungal Agents: Amphotericin B Used in the tx of many serious systemic fungal infections Nickname: “amphoterrible” due to side effects

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. NBQ Which of the following drugs interacts with systemic fluconazole(Diflucan)? a.Erythromycin b.Penicillin c.Acetaminophen d.Ibuprofen

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. NBQ Which of the following drugs interacts with systemic fluconazole(Diflucan)? a.Erythromycin b.Penicillin c.Acetaminophen d.Ibuprofen

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. NBQ Which of the following drugs is the treatment of choice in the therapy of oral candidiasis? a.Nystatin rinse b.Ketoconazole tablets c.Fluconazole tablets d.Miconazole ointment

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. NBQ Which of the following drugs is the treatment of choice in the therapy of oral candidiasis? a.Nystatin rinse b.Ketoconazole tablets c.Fluconazole tablets d.Miconazole ointment

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Antiviral Agents

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Antiviral Agents Tx of viral infections extremely difficult ▫They are obligate intracellular organisms that require cooperation from the host ▫To kill virus = also kill host ▫Viruses are smaller then bacteria, fungus, protozoa ▫All virus’s have genetic info: RNA or DNA, surrounded by protected PRO coat ▫Virus invades host cell-injected its genetic material

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

Antiviral Agent Outline Herpes simplex Acquired immunodeficiency syndrome (AIDS) ANTIHERPETIC DRUGS Acyclovir sodium(Zovirax) Docosanol cream(Abreva) Penciclovir(Denavir) Famciclovir(Famvir) Valacyclovir(Valtrex) ANTIRETROVIRAL DRUGS Nucleoside reverse transcriptase inhibitors (NRTIs) Nonnucleoside reverse transcriptase inhibitors (NNRTI) Protease inhibitors(PIs) Fusion (Entry) Inhibitors

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Herpes Simplex ANTIHERPETIC DRUGSNotations Acyclovir sodium(Zovirax)Inhibit DNA synthesis Penciclovir(Denavir)Inhibit DNA synthesis Docosanol cream(Abreva)Inhibit fusion of virus to cells Famciclovir(Famvir) Ganciclovir injectable(Cytovene)

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Herpes Simplex HSV-1: oropharyngeal, lips, vermillion border HSV-2: genital Primary herpectic gingivostomatitis: 1 st exposure Early tx with Zovirax or Famvir can shorten duration

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Spectrum ▫HSV 1 & 2 ▫Varicella zoster: herpes 3 ▫Epstein-Barr: herpes 4 Application  5x/day for 4 days Uses  HIV: HSV1&2  Immune competent: HSV2 ONLY Herpes Simplex: ACYCLOVIR (ZOVIRAX)

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

Topical Use during prodromal stage Immuno-competent patients Herpes Simplex: Penciclovir(Denavir)

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. OTC (combo petroleum + cocoa butter) Topical applied 5x/day Inhibits fusion virus to cell membranes – blocks more viral replication ↓ healing time by ½ day Have to start med w/in 12 hours of prodromal symptoms Herpes Simplex : Docosanol(Abreva)

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Which of the following antiherpetic drugs is recommended for herpes labialis? a.Ganciclovir b.Famciclovir c.Valacyclovir d.Penciclovir Review Question

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Which of the following antiherpetic drugs is recommended for herpes labialis? a.Ganciclovir b.Famciclovir c.Valacyclovir d.Penciclovir NBQ

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Which of the following drugs is contraindicated for the treatment of herpes labialis? a.Penicillin b.Docosanol c.Acyclovir d.Penciclovir NBQ

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Which of the following drugs is contraindicated for the treatment of herpes labialis? a.Penicillin b.Docosanol c.Acyclovir d.Penciclovir NBQ

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Which of the following drugs is available OTC for the treatment of herpes labialis? a.Valacyclovir b.Docosanol c.Acyclovir d.Penciclovir NBQ

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Which of the following drugs is available OTC for the treatment of herpes labialis? a.Valacyclovir b.Docosanol c.Acyclovir d.Penciclovir NBQ

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. AIDS ANTIRETROVIRAL DRUGS Nucleoside reverse transcriptase inhibitors (NRTIs) Nonnucleoside reverse transcriptase inhibitors (NNRTI) Protease inhibitors(PIs) Fusion (Entry) Inhibitors Integrase inhibitors

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. HIV General Info  HIV type 1: RNA retrovirus  HIV type 2: Western Africa, rare to USA  Single strand RNA virus that converts to a double-stranded DNA to make more retroviruses through a specific enzyme: reverse transcriptase  Newly produced viral DNA enters the host cell nuclei and is incorporated into the host chromosome through a special HIV enzyme: integrase  Now only new virus cell replication occurs

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. HIV TX  Objective antiretroviral therapy is to reduce viral load = improve survival  Decision for start of drug therapy o CD4 count = 500mm 3 o Viral load = 30,000 copies per mL blood plasma  HAART therapy (Highly Active AntiRetroviral Therapy) o Preferred initial regime o Uses 3-4 drugs to suppress viral replication, prevent opportunistic infections o 20 drugs approved in US o 78% patient become resistant least 1 drug

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. HIV TX HAART TX COMBO 2 NRTI + NNRTI + PIPreferred method 2 NRTI + NNRTIAlternative 2 NRTI + PIAlternative

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. AIDS Nucleoside reverse transcriptase inhibitors (NRTIs) Abacavir(Ziagen) Didansosine(Videx) Emtricitabine(Emtriva) Lamivudine(Epivir) Stavudine zidovudine(Retrovir) Tenofovir disoproxil fumarate(Viread) Zalcitabine-HIVID 1 st drugs on the market in USA in 1980s

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

Embed themselves into viral DNA ↓ Inhibit conversion of RNA to DNA by binding to reverse transcriptase enzyme ↓ Virus replication decreased Many adverse effects Enlarged liver Life-threatening lactic acidosis Neuropathy Oral: xerostomia, oral ulcers, stomatitis NRTI

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

AIDS Nonnucleoside reverse transcriptase inhibitors (NNRTI) Efavirenz(Sustiva) Nevirapine(Viramune) Delavirdine(Rescriptor)

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Same action as NRTIs on virus (just a different receptor) When used alone = resistance quickly occurs Adverse effects Fatal liver damage NNRTI

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

AIDS Protease inhibitors(PIs) ~avir ending for all! Amprevavir(Agenerase) Atazanavir(Reyataz) Fosamprenavir(Lexiva) Indinavir(Crixivan) Lopinavir+Ritonavir(Kaletra) Nelfinavir(Viracept) Ritonavir(Norvir) Saquinavir(Fortovase, formerly Invirase)

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. MOST POTENT of all HIV drugs! Action ▫Prevent breakdown of PRO produced by virus into infectious mature viruses ▫Advantage: new viruses cannot be released to infect more cells Only class metabolized by P450 liver enzymes: many drug interactions Side effects ▫Oral paresthesia, dental pain, taste changes, metallic taste in mouth, taste impairment ▫Liver damage Protease Inhibitors (PI)

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

AIDS Fusion (Entry) Inhibitors Enfuvirtide(Fuzeon) Integrase Inhibitors Raltegravir(Isentress)

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Interfere with entry of HIV-1 into host cells Inhibit fusion of the virus and cell membrane Integrase Inhibitors Fusion (Entry) Inhibitors Inhibit action of integrase

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. All of the following drugs are nucleoside reverse transcriptase inhibitors used to treat AIDS EXCEPT one. Which one is the EXCEPTION? a.Didanosine b.Zidovudine c.Ritonavir d.Abacavir e.Lamivudine NBQ

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. All of the following drugs are nucleoside reverse transcriptase inhibitors used to treat AIDS EXCEPT one. Which one is the EXCEPTION? a.Didanosine b.Zidovudine c.Ritonavir d.Abacavir e.Lamivudine NBQ

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Which of the following drugs could cause metallic taste in mouth? a.Didanososine(Videx) b.Delavirdine(Rescriptor) c.Indinavir(Crixivan) d.Enfuvirtide(Fuzeon) NBQ

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Which of the following drugs could cause metallic taste in mouth? a.Didanososine(Videx)NRTI b.Delavirdine(Rescriptor)NNRTI c.Indinavir(Crixivan)PI d.Enfuvirtide(Fuzeon)Fusion Inhibitor NBQ

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Chronic Hepatitis B & C Inteferons: inhibit cell growth & expression Protease Inhibitors