Antiviral drugs -- pharm exam 2.pdf

Antiviral drugs Antiviral drugs ○ Antibacterial and antifungal drugs have little to no effect on viral infections ○ Compounds have been developed to treat some viral infections (e.g., HIV, influenza, and hepatitis) ○ Work in a variety of ways (e.g.,...

Antiviral drugs Antiviral drugs ○ Antibacterial and antifungal drugs have little to no effect on viral infections ○ Compounds have been developed to treat some viral infections (e.g., HIV, influenza, and hepatitis) ○ Work in a variety of ways (e.g., prevent replication of viral nucleic acid; inhibit entry, uncoating, or release of virus) Drugs for influenza Influenza ○ One of the most common causes of infectious disease-related deaths ○ Vaccines are primary means of prevention ○ Neuraminidase inhibitors are useful for ppx, during outbreaks, can shorten duration of illness in infected persons and prevent complications Neuraminidase ○ These drugs inhibit the enzyme neuraminidase in influenza A and B viruses ○ Neuraminidase catalyzes reactions that promote viral spreading and infection Enables release of virions from surface of infected cells Inactivates RT mucous that would prevent spreading of virions Neuraminidase inhibitors ○ Reduce complications including OM and PNA; drug therapy should be started as early as possible for any patient with confirmed or suspected influenza who is hospitalized, has severe illness, or is at higher risk of complications ○ Most beneficial in reducing symptom severity and duration of illness if given < 3 days after onset, preferable within 48 hours. ○ May still provide benefit in reducing respiratory failure and death in pregnant woman if started 3-4 days after onset Prophylaxis ○ 70-90% effective in preventing influenza, useful adjuncts to vaccines ○ CDC recommended against prophylaxis because of risk of resistance ○ Only ppx, populations at risk of complications and control institutional outbreaks Baloxavir Marboxil (Xofluza) ○ Single dose PO treatment for influenza A and B ○ First-in-class medication ○ Unique MOA→ prodrug gets converted to baloxavir acid (BXA) targets ribonuclease activity that affects transcription of viral RNA ○ Approved in US in 2018 ○ Potentially less side effects vs oseltamivir. Drugs for herpesvirus infections Cytomegalovirus (CMV) ○ Infections in immunocompetent are usually asymptomatic  ○ CMV retinitis, esophagitis, and colitis usually seen in immunocompromised patients Drugs for herpesviruses ○ Nucleoside analogues Acyclovir aka Zovirax IV acyclovir most effective for serious herpesvirus infections, including encephalitis and infections in immunocompromised patients Topical acyclovir can be used to treat genital herpes and mild mucocutaneous infections ○ Topical treatment is less effective than oral treatment Ganciclovir aka Cytovene Trifluridine aka Viroptic Valacyclovir aka valtrex Acyclovir has a low oral bioavailability (22%) Valacyclovir is a prodrug that gets rapidly converted to acyclovir by intestinal and hepatic enzymes, more completely absorbed (55%) Required less frequent administration Famciclovir aka Famvir has greatest bioavailability (80%), gets rapidly hydrolyzed to penciclovir after absorption ○ Other drugs Foscarney aka Foscavir ○ Treating genital herpes When either 3 drugs is given orally for genital herpes, prevents replication of HSV and reduces pain and other symptoms of acute infection Shortens time to healing of lesions, reduced amount of viral shedding Does NOT eliminate the virus, recurrent episodes are common (can be treated with lesser doses) ○ Treating shingles When either 3 drugs is given orally for shingles, shortens duration of acute illness and pain and lowers incidence of postherpetic pain Famciclovir and valacyclovir are more effective than acyclovir Newer drugs have less frequent administration, higher serum levels A vaccine is now available (Zostavaz) that reduces the incidence and severity of herpes zoster infections in older adults. ○ Treating CMV Nucleoside analogues that have been used to prevent and treat CMV disease including retinitis, esophagitis, and colitis Ganciclovir is 100x more active against CMV than acyclovir  ○ Routes and uses Cidofovir and ganciclovir are available for IV use Ganciclovir also has oral formulation Low bioavailability, only used for long-term suppression of CNV retinitis Also available as ophthalmic gel to treat acute epithelial hepatitis (infection of corneal epithelium) caused by HSV-1 and HSV-2 ○ Trifluridine ava Viprotic Given topically to treat ocular herpesvirus infections Primarily used for herpetic epithelial keratitis and keratoconjunctivitis Generally well tolerated, can cause superficial irritation and hyperemia ○ Foscarnet aka Foscavir Active against CNV, VZV and HSV Must be given IV, used to treat CMV retinitis in AIDS patients and acyclovir-resistant HSV infections and shingles Can be combined with ganciclovir to treat infections resistant to either drug alone Adverse reactions include, renal impairment and failure, hematologic deficiencies, cardiac arrhythmias, heart failure, seizures and pancreatitis. Drugs for HIV Human immunodeficiency virus (HIV) infection ○ Many remarkable advancements have been made in treating HIV infection and AIDs ○ Combined use of 2 or more drugs from different classes have been shown to markedly reduce viral load and improve survival ○ Multidrug treatment called highly active antiretroviral therapy (HAART) HAART ○ Initially were complicated regiments requiring multiple doses of several drugs every day ○ Recent emphasis on developing drug regimens that require only a few doses each day or even a single pill (like atripla) ○ Guidelines continue to evolve as new regimens are developed and testing Pathophysiology of HIV ○ Enters CD4 cells, viral RNA produced double-stranded DNA via reverse transcriptase ○ Viral DNA enters host cell nucleus and gets incorporated into host genome via HIV integrase ○ Eventually the viral DNA gets transcribed/translated to produce polyproteins that get packed into immature virions  ○ HIV protease cleaves polyproteins into smaller functional proteins during viral maturation where virions get released into plasma Drug classes 1. Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) 2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) 3. Protease inhibitors (PIs) 4. Fusion and entry inhibitors 5. Integrase strand transfer inhibitors Reverse Transcriptase inhibitors ○ Nucleoside reverse transcriptase inhibitors (NRTIs) ○ Non-nucleoside reverse transcriptase inhibitors (NNRTIs) ○ Small amounts of NRTIs are converted to active triphosphate metabolites by host cell kinases ○ Metabolites compete with corresponding endogenous nucleoside triphosphate for incorporation into DNA ○ Once incorporated into DNA, cause chain termination ○ Also inhibit host cell DNA polymerase to varying degrees, accounting for toxic effects (e.g., anemia) Nucleoside vs nucleotide ○ Tenofovir disoproxil fumarate (TDF) is classified as a nucleoTIDE RTI ○ Gets hydrolyzed in the body to form tenofovir Nucleoside transcriptase inhibitors (NRTIs) ○ First class of drugs developed for treating HIV + individuals ○ Included in almost all regimens ○ Have some basic MOA, but serve as antimetabolites for different purine and pyrimidine bases of DNA ○ Therefore, NRTIs are often more effective when combined with other NRTIs ○ Two NRTIs are usually combined with an NNRTI or a protease inhibitor (PI) ○ Zidovudine [AZT, ZDV] aka Retrovie (also called azidothymidine [AZT]) ○ Lamivudine [3TC] aka epivir ○ Emtricitabine [FTC] aka Emtriva ○ Tenofovir disoproxil [TDF] aka Viread ○ Chemistry and kinetics Synthetic derivatives of naturally occurring nucleosides All can be given orally, AZT can also be given IV Cross the BBB and are distributed to CSF Renal excretion so impairment will prolong half-life ○ Adverse effects All NRTIs can cause lactic acidosis, hepatic steatosis and lipodystrophy AZT causes bone marrow suppression, anemia and neutropenia  Didanosine can cause peripheral neuropathy; both didanosine and stavudine can cause pancreatitis Abacavir [ABC] aka Ziagen is more likely to cause hypersensitivity reaction Tenofovir causes renal impairment in some people AZT/ZDV ○ First NRTI to be developed, still one of the most widely used drugs in this class ○ Always combined with other drugs… Zidovudine/Lamivudine aka Combivir Zidovudine/Lamivudine/abacavir aka Trizivir ○ In utero transmission Studies found that AZT treatment significantly reduced in utero transmission of HIV from infected pregnant woman to their offspring Given from 14th to 34rh week of gestation Combo therapy now recommended for most pregnant woman with HIV Initial treatment of HIV ○ Newer NRTIs are now recommended for initial treatment of HIV… Tenofovir disoproxil fumarate [TDF] Emtreicitabine also called fluorothia cytidine [FTC] ○ Combo drug containing TDF, FTC, and efavirenz called Atripla is now available, once a day therapy with a single pill. Non-nucleoside RTIs (NNRTIs) ○ Unlike NRTIs, NNRTIs do not require metabolic activation and are not incorporated into viral DNA ○ Efavirenz is the most potent NNRTI available, preferred for initial treatment of people with HIV because it can be taken qd ○ Nevirapine is used in combo with two NRTIs ○ Delaviridine, not recommended for most patients, has lower antiviral activity compared to others in this class. ○ Kinetics Given orally and have good bioavailability Highly lipophilic, reach the CNS Extensively metabolized before undergoing fecal and renal excretion ○ Adverse effects Moderately well-tolerated Rash is the most common side effect, drug can usually be continued or restarted Can lead to SJS so be careful Efavirenz is teratogenic, avoid in pregnancy and woman who can become pregnant; can cause neuropsychiatric reactions  Nevirapine has many drug interactions, can cause hepatotoxicity Protease inhibitors (PIs) ○ HIV protease is responsible for maturation of the virus ○ Protease inhibitors bind to the active site of the enzyme and inhibits its activity, resulting in production of immature, non-infectious virus particles ○ First PI introduced in 1995, ushered in a new era of HIV treatment ○ Newer PIs like atazanavir are better tolerated and have improved pharmacokinetic properties ○ Atazanavir and darunavir are the preferred PIs for treating HIV today Ritonavir inhibits metabolism of other PIs, so it is combined with them to increase their plasma levels and duration. This is called boosted therapy. Combo ○ Combo drug products containing ritonavir and another PI are available ○ Standard mode of PI administration with HIV ○ Lopinavir/ritonavir combo known as Kaletra Fusion and entry inhibitors ○ Enfuvirtide aka Fuzeon [T-20] Large peptide that binds to HIV glycoprotein 41 and blocks fusion process Not active when given orally, must be injected sq bid Often causes ISRs, so change the injection site Well tolerated, approved for use in children and adults ○ Maraviroc aka Selzentry ○ Newer drugs that inhibit fusion and entry of HIV ○ Active against HIV strains resistant to RTIs and PIs ○ Approved to treat HIV infection caused by drug resistant strains ○ Decrease viral loads, increase CD4 cells and improve symptoms Integrase inhibitors ○ Integrase incorporates viral DNA formed by reverse transcriptase into DNA of CD4 cells ○ Raltegravir aka Isentress is the first integrase strand inhibitor approved to treat HIV ○ Works by preventing DNA strand transfer ○ Potent in vitro activity against wild-type and MDR HIV strains ○ Recent recommendations for initial treatment include a regimen containing raltegravir