Antiviral drugs – Flashcards
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Define virus.
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A virus is an obligate intracellular parasite; its metabolic processes, such as synthesis of proteins and DNA, depend on the host cell.
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Can all viruses be pharmacologically treated?
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No. Most drugs cannot distinguish between host cell functions and viral functions. Therefore, the drugs would cause significant toxicity to both.
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List the steps in viral replication.
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1. Absorption and penetration of host cells. 2. Synthesis of early nonstructural proteins, such as nucleic acid polymerases 3. Synthesis of RNA and DNA 4. Synthesis of late structural proteins 5. Assembly of virus particles Antiviral drugs usually inhibit one of these steps.
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What is the easiest way to remember the antiviral drugs?
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By classifying them according to which virus they attack.
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Drugs Used to Treat Herpes Virus Infection: Name five drugs used to treat the herpes virus infection.
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1. Foscarnet 2. Ganciclovir 3. Idoxuridine 4. Vidarabine 5. Acyclovir "For herpes, GIV acyclovir".
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What pathogens are included in the herpes virus family?
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- Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) - Varicella-zoster virus - Cytomegalovirus (CMV) - Epstein- Barr virus
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Acyclovir (Zovirax): What is it?
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Acyclovir is a guanine analog.
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What is its mechanism of action?
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Acyclovir is monophosphorylated by a herpes enzyme called thymidine kinase. Later, it is di- and triphosphorylated by the host cell. The active triphosphate form of acyclovir is then incorporated into viral DNA, which causes premature DNA-chain termination.
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For what would you prescribe acyclovir?
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* HSV-1, which causes diseases of the mouth, face, skin, esophagus and brain. * HSV-2, which causes infections of the genitals, rectum, skin, hands or meninges. * Varicella-zoster virus
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What is the route of administration?
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Intravenous, topical, or oral
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What is its metabolism?
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Acyclovir is partially metabolized to 9-carboxyl methylguanide and excreted by the kidneys.
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What are acyclovir's adverse effects?
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This drug's adverse effects depend on the route of administration: * Intravenous: renal dysfunction and neurotoxicity (delirium, tremor, seizures) * Oral: diarrhea and headache * Topical: local irritation
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Ganciclovir (Cytovene): What is it?
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Ganciclovir is a guanine analog similar to acyclovir. Ganciclovir- Guanine analog
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How does ganciclovir work?
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Ganciclovir works very similarly to acyclovir. It is triphosphorylated and then inhibits viral DNA polymerase. It is also incorporated into DNA, decreasing chain elongation.
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What are ganciclovir's clinical indications?
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It is the drug of choice for treating CMV, retinitis, pneumonia, and esophagitis.
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How is it given to patients?
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Orally and IV. It absorbs well into the CNS.
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How is ganciclovir metabolized?
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By renal excretion.
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What are ganciclovir's adverse effects?
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- Bone marrow suppression - Renal dysfunction - Seizures - Fever - GI disturbances
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Idoxuridine (Stoxil) and Trifluridine (Viroptic): What is idoxuridine?
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A thymidine analog.
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What is its mechanism of action?
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Idoxuridine is converted into an active triphosphate form by cellular enzymes and is incorporated into DNA, making it more susceptible to breakage.
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What are idoxuridine's clinical uses?
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Treatment of herpes simplex keratitis and vaccinia virus keratitis.
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What is the route of administration?
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Idoxuridine is administered only by ophthalmic solution or ointment.
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What is trifluridine?
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A newer ophthalmic drug similar to idoxuridine but even more effective against herpes simplex keratitis.
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What are the adverse effects of idoxuridine?
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Conjunctival irritation and photophobia.
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Vidarabine (Vira-A): What is it?
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Vidarabine is an adenosine analog.
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What is its mechanism of action?
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Like acyclovir, vidarabine is converted into an active triphosphate form within the host cells and then inhibits viral DNA synthesis.
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What is its clinical use?
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Vidarabine is used to treat HSV-1 encephalitis and keratitis. It is also used against varicella zoster in immuno-compromised patients. It is not effective against HSV-2.
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What is the route of administration?
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Vidarabine is given parentally or topically (ophthalmic).
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What is its metabolism?
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Vidarabine is excreted by the kidneys.
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Describe vidarabine's adverse effects.
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* Gastrointestinal (GI) effects: anorexia, nausea * CNS effects: paresthesias, tremor * Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) * Hypokalemia * Hepatic dysfunction
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Foscarnet (Foscavir): What type of drug is it?
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Foscarnet is not a nucleoside analog; it is a phosphonate analog that does not rely on phosphorylation for activation.
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What is foscarnet's mechanism of action?
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It inhibits replication by blocking the pyrophosphate binding site of viral DNA polymerase.
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How is foscarnet administered?
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Only by the intravenous route.
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What is its clinical use?
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Foscarnet is used in the treatment of CMV infections (retinitis).
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How is foscarnet metabolized?
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It is excreted through the kidneys.
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What are foscarnet's adverse effects?
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- Nephrotoxicity - Electrolyte abnormalities such as hypocalcemia and hypomagnesemia - Seizures
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Other Agents: Name three other newer agents used to treat herpes virus.
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1. Sorivudine 2. Trifluridine 3. Famciclovir
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What is their mechanism of action?
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These drugs also work by inhibiting viral DNA synthesis. NOTE: (They are not discussed in detail here because they have not yet been tested in USMLE Step 1).
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Drugs Used to Treat Respiratory Viruses: Which drugs are used in the treatment of respiratory viruses?
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Amantadine, rimantadine, and ribavirin.
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Amantadine and Rimantadine: What are amantadine and rimantadine?
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Amantadine and its derivative rimantadine are uniquely configured tricyclic amines.
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What is their mechanisms of action?
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Amantadine and rimantadine inhibit viral uncoating.
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What is viral uncoating?
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Viruses enter cells through endosomes, which are membrane-bound vacuoles that surround the virus particle. Acidification of the endosome is needed for the virus to uncoat and transfer its genetic material to the cytoplasm.
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What is the action of these drugs on the viral endosome?
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Amantadine and rimantadine act as weak bases to prevent acidification of the endosome.
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What is their therapeutic use?
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Amantadine and rimantadine are used mainly for influenza A prophylaxis in elderly and immunosuppressed populations.
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What is the route of administration?
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Amantadine and rimantadine are well absorbed orally.
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What is their metabolism?
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They are excreted by the kidneys.
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What are their adverse effects?
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Insomnia, dizziness, and ataxia. These symptoms are less common with rimantadine because it does not cross the blood-brain barrier.
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Ribavirin: Describe this drug.
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Ribavirin is a synthetic gaunosine analog.
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What is ribavirin's mechanism of action?
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The mechanism of action is not completely clear, but it is thought to decrease synthesis of guanosine triphosphate, inhibit 5' capping of viral mRNA, and interfere with viral RNA-dependent RNA polymerase of certain viruses.
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What ribavirin's major therapeutic use?
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Treatment of infants and young children who are suffering from respiratory syncytial virus bronchiolitis and pneumonia.
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What other clinical uses does this drug have?
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Ribavirin is also used occassionally for treating influenza A and B and Lassa fever.
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How is this drug administered?
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Ribavirin is effective when administered orally, intravenously and by aerosol methods.
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What is ribavirin's toxicity?
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Dose-dependent transient hemolytic anemia and elevated bilirubin levels.
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Should this drug be used in pregnant women?
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No! It is teratogenic.
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Interferons: What are they?
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Interferons are a family of naturally existing glycoproteins or cytokines that possess antiviral actions.
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What are the therapeutic uses for interferons?
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- Condyloma acuminatum - Chronic hepatitis B and C - Kaposi's sarcoma - Hairy cell leukemia
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What are the adverse effects of interferons?
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An acute flulike syndrome including headache, fever, chills, and muscle aches is the most common adverse effect. However, interferons may also cause neurotoxicity, cardiotoxicity, thyroid dysfunction, and bone marrow depression.
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Drugs Used to Treat HIV Infection and AIDS: Define acquired immuno-deficiency syndrome (AIDS).
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AIDS, caused by the human immunodeficiency virus (HIV), is characterized by a CD4 count of less than 200 and the presence of opportunistic infections.
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How is the CD4 count calculated?
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White blood cells (WBCs) x % lymphocytes x % CD4 cells
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How does HIV differ from other viruses?
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HIV is a retrovirus. After entering the host cell, it undergoes reverse transcription and is then incorporated into the host cell's DNA.
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List two surrogate markers that help to predict the risk of progression from HIV positive to AIDS.
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The CD4 count and HIV RNA PCR (polymerase chain reaction), which is commonly called the viral load.
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What are some uses of the viral load test?
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It can predict progression to AIDS, and it is also used for therapeutic monitoring.
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Which two viral enzymes do anti-retroviral medications inhibit?
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1. Reverse transcriptase 2. Protease
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What is the action of reverse transcriptase?
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It converts viral RNA into DNA.
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What is the action of viral protease?
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It cleaves viral protein into infectious virions.
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What are the two types of reverse transcriptase inhibitors (RTIs)?
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1. Nucleoside analogs 2. Non-nucleoside analogs
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Give four examples of nucleoside analog RTIs.
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1. Zidovudine (AZT) 2. Didanosine (ddI) 3. Zalcitabine (ddC) 4. Stavudine (d4T)
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What is zidovudine?
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A structural analog of thymidine.
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Describe didanosine.
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It is a structural analog of adenosine.
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What is zalcitabine?
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A structural analog of cytosine.
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Describe stavudine.
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It is a structural analog of thymidine.
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What is the mechanism of action of these drugs?
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They are phosphorylated and incorporated into viral DNA by reverse transcriptase. They, then, terminate chain elongation once they are incorporated into the viral DNA.
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What are the side effects of AZT?
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- Anemia - Neutropenia - Headache - Fatigue - Myalgia
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What are the side effects of ddI?
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Acute pancreatitis, painful peripheral neuropathy, nausea, and vomiting.
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What are the side effects of ddC?
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Peripheral neuropathy, GI effects and arthralgia.
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What are the side effects of zalcitabine and stavudine?
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Painful sensory peripheral neuropathy.
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Give some examples of non-nucleoside analog reverse transcriptase inhibitors (NNRTIs).
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Nevirapine (Viramune) and delavirdine (Rescriptor).
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Give examples of protease inhibitors.
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- Saquinavir (Invirase) - Ritonavir (Norvir) - Indinavir (Crixivan) - Nelfinavir (Viracept)
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What are the side effects of saquinavir?
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Diarrhea, abdominal discomfort, and nausea
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What are the side effects of ritonavir?
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Nausea, abdominal pain, vomiting, circumoral paresthesias, abnormal elevations in liver function tests and increased cholesterol levels.
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What are the side effects of indinavir?
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Nausea, vomiting, increased bilirubin levels, abdominal pain and nephrolithiasis.
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What are the side effects of nelfinavir?
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Diarrhea and flatulence
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Drugs Used to Prevent Infection in Patients with HIV: Which vaccines should be given to patients who have HIV?
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Pneumococcal, hepatitis and influenza vaccines.
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Which vaccines should not be given to patients with HIV?
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Live vaccines such as the oral polio vaccine and varicella vaccine.
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Medications are used for primary prophylaxis of which infections?
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- Pneumocytosis carinii pneumonia (PCP) - Mycobacterium avium- complex (MAC) - Mycobacterial tuberculosis (TB)
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What are the indications for PCP prophylaxis?
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* Prior PCP infection * CD4 count of less than 200 cells per cubic millimeter * HIV- associated thrush * Unexplained fevers over 100° F for more than 2 weeks
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Which medications are used for PCP prophylaxis?
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Bactrim, dapsone, and aerosolized pentamidine.
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What are the indications for MAC prophylaxis?
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CD4 count less than 50 and prior diagnosis of MAC.
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Which medications are used for MAC prophylaxis?
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Clarithromycin, azithromycin, and rifabutin.
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What are the indications for TB prophylaxis?
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- Tuberculin skin test (TST) ≧ 5mm - Prior positive TST results without treatment - Contact with active case of TB
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Which medications are used for TB prophylaxis?
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Isoniazid and rifampin
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What are the side effects of isoniazid?
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Hepatitis, rash, and peripheral neuropathy
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What are the side effects of rifampin?
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Hepatitis and GI upset.
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Drug Therapy for Opportunistic Infections in Patients with HIV: What medications are used to treat PCP?
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- Bactrim - Pentamidine - Atovaquone
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What medications are used to treat Toxoplasma infection?
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- A combination of pyrimethamine and sulfadiazine - A combination of pyrimethamine and clindamycin
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What medications are used to treat esophageal Candida albicans?
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Fluconazole, Ketoconazole and amphotericin B
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What medications are used to treat MAC?
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Macrolides (clarithromycin or azithromycin), plus one of the following: - Ethambutol - Ciprofloxacin - Amikacin
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What medications are used to treat Cryptococcus infection?
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Amphotericin, fluconazole and itraconazole.
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What medications are used to treat Cytomegalovirus?
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Ganciclovir and foscarnet
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HIV Post-Exposure Prophylactic Medications: Which body fluids have been documented to carry HIV?
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Blood, semen, vaginal secretions, cerebrospinal fluid, synovial fluid, pleural fluid, peritoneal fluid, pericardial fluid, and amniotic fluid.
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Which body fluids have not been documented to carry HIV?
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Feces, nasa secretions, sputum, saliva, sweat, tears, urine and vomitus.
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Which medication has established efficacy when used for post-exposure prophylaxis?
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AZT
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Which medications should be prescribed for the recipient of a deeply penetrating hollow-bore needle stick injury from a host who has HIV?
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- AZT - Lamivudine (a new nucleoside analog RTI) - Indinavir
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How soon after exposure should these medications be started.
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As soon as possible- preferably within 1 to 2 hours.
