Antivirals UPDATE PDF

Pharmacology 3 Anti-Viral Drugs Dr. Lina Tamimi Background viruses may be regarded as: 1. exceptionally complex aggregations of nonliving chemicals or 2. exceptionally simple living microbes  Viruses are obligate intracellular parasites their replication depends primaril...

Pharmacology 3 Anti-Viral Drugs Dr. Lina Tamimi Background viruses may be regarded as: 1. exceptionally complex aggregations of nonliving chemicals or 2. exceptionally simple living microbes  Viruses are obligate intracellular parasites their replication depends primarily on synthetic processes of the host cell. to be effective, antiviral agents must either: 1- block viral entry into or exit from the cell or 2- be active inside the host cell Non-selective inhibitors of virus replication : may interfere with host cell function and result in toxicity. Treatment periods Monotherapy for brief periods of time (eg, acyclovir for herpes simplex virus) Dual therapy for prolonged periods of time (interferon alfa/ribavirin) for HCV Multiple drug therapy for indefinite periods (HIV). RSV: Respiratory Syncytial Virus HIV : human immunodeficiency virus HSV: herpes simplex virus HCV: Hepatitis C virus HBV: Hepatitis B virus CMV: Cytomegalovirus HHV8: Human herpesvirus-8  Structure of virus 1- envelope as their outmost layer, composed of elements of the host cell membrane, endoplasmic reticulum, or nuclear envelope. 2- This layer covers the capsid, a shell/coat composed of identical building blocks of capsomeres. 3- The capsid protects the viral nucleic acid, which is either DNA or RNA but not both. Adsorption and Uncoating of 1. Synthesis of Assembly of Release penetration viral nucleic regulatory proteins : viral particles from host into cell acid 2. Synthesis of RNA or cell DNA 3. Synthesis of structural proteins Steps for Viral Replication RSV: Respiratory Syncytial Virus HIV : human immunodeficiency virus HSV: herpes simplex virus HCV: Hepatitis C virus HBV: Hepatitis B virus CMV: Cytomegalovirus 1- Anti-Herpes Simplex Virus and Varicella-Zoster Virus Agents Acyclovir Valcyclovir -clovir Famciclovir Penciclovir Docosanol Trifluridine 1- Anti-Herpes Simplex Virus and Varicella-Zoster Virus Agents 1- Anti-Herpes Simplex Virus and Varicella-Zoster Virus Agents 2- Anti-cytomegalovirus (CMV) Agents  Acyclovir Is an acyclic guanosine derivative Available as prodrug Selectivity of acyclovir and related drugs Against: 1. Herpes Simplex Virus (HSV-1) gingivostomatitis 2. HSV-2 3. Varicella Zoster Virus (VZV) Shingles, also known as herpes zoster, is an infection of a nerve and the skin around it. MOA Gingivostomatitis: are self-limiting illnesses, severe infection can lead to significant oral pain and dehydration. Early antiviral therapy within 72 hours of symptom onset leads to earlier healing of lesions, decreased pain, and a shorter duration of fever.  Pharmacokinetics: Oral : poorly absorbed …… bioavailability is 15–20% and is unaffected by food Cmax: 1.5–2 hours after dosing Orally: five times daily valacyclovir and famciclovir :pro-drugs absorbed better and can be administered less frequently IV: choice for serious HSV infections such as encephalitis.  excretion primarily by: glomerular filtration tubular secretion. The half-life is approximately: 3 hours in patients with normal renal function 20 hours in patients with anuria  Topicals: produce high local concentrations in herpetic lesions, but systemic concentrations are undetectable. Acyclovir diffuses into most tissues and body fluids to produce concentrations that are 50–100% of those in serum. CSF : 50% of serum values Clinical Administration Resistance can develop in HSV or VZV through: alteration in either: Viral thymidine kinase Viral DNA polymerase Agents such as: foscarnet Cidofovir trifluridine do not require activation by viral thymidine kinase and thus have preserved activity against the most prevalent acyclovir-resistant strains  Prodrugs Valacyclovir is a pro-drug of acyclovir with: advantages: improved bioavailability and less-frequent dosing. Disadvantage: higher cost. Famciclovir is a pro-drug of penciclovir only as a topical preparation Adverse effects The most concerning adverse effect is nephrotoxicity through : 1. crystallization 2. acute interstitial nephritis (AIN) most commonly associated with IV acyclovir in higher doses. Crystallization is preventable through hydration and correct dosing in renally impaired patients. Acyclovir is most nephrotoxic in combination with diuretics or other nephrotoxins. Keep your patients hydrated during acyclovir therapy, particularly if it is given in higher IV doses.  Seizures, tremors, or other CNS effects can also occur. Nausea, diarrhea, and rash are more common. Thrombotic thrombocytopenic purpura has been reported with valacyclovir in HIV patients.  Clinical uses Acyclovir is the drug of choice for: severe or difficult-to-treat HSV infections, such as: encephalitis or severe HSV outbreaks among HIV patients. Any of these agents can be used to treat HSV-2 infections (genital herpes) to prevent outbreaks or decrease symptom duration. They are all also effective in treating VZV infection.  2- Anti-cytomegalovirus (CMV) Agents infection results in end-organ disease including: retinitis, colitis, esophagitis, CNS disease, and pneumonitis Mechanism of action preventing viral replication. They also all have appreciable toxicity that must be respected and monitored. Cytomegalovirus (CMV) is a common virus. Once infected, your body retains the virus for life. Most people don't know they have CMV because it rarely causes problems in healthy people. If you're pregnant or if your immune system is weakened, CMV is cause for concern. Women who develop an active CMV (Cytomegalovirus) infection during pregnancy can pass the virus to their babies, who might then experience symptoms. For people who have weakened immune systems, especially people who have had an organ, stem cell or bone marrow transplant (immunosuppression) , CMV infection can be fatal. Agents 2.1. Ganciclovir Ganciclovir is a nucleoside analogue that, after phosphorylation, is integrated into viral DNA or inhibiting DNA polymerase competitively, halting viral replication. Valganciclovir is a pro-drug of ganciclovir. Cidofovir is a nucleotide analogue that has a similar mechanism to ganciclovir Ganciclovir Valganciclovir  PK Its activity against CMV is up to 100 times greater than that of acyclovir. Ganciclovir may be administered : IV, orally, or via intraocular implant. Oral: The bioavailability is poor. CSF concentrations are approximately 50% of serum concentrations The T1/2 is 4 hours intracellular half-life is prolonged at 16–24 hours. Clearance of the drug is linearly related to creatinine clearance  IV ganciclovir has been shown to delay progression of CMV retinitis in patients with AIDS……. Better when combined with foscarnet Pneumonitis : ganciclovir is combined with IV cytomegalovirus immunoglobulin IV ganciclovir, followed by oral ganciclovir reduces the risk of CMV infection in transplant recipients Oral ganciclovir is indicated for prevention of end-organ CMV disease in AIDS patients and as maintenance therapy of CMV retinitis after induction The risk of Kaposi’s sarcoma is reduced in AIDS patients receiving long-term ganciclovir, presumably because of activity against HHV-8 Adverse effects 1- The most common adverse effect of systemic ganciclovir treatment, particularly after intravenous administration, is myelosuppression. Myelosuppression may be additive in patients receiving concurrent: zidovudine, azathioprine, or mycophenolate mofetil. 2- Other potential adverse effects are: nausea, diarrhea, fever, rash, headache, insomnia, and peripheral neuropathy. 3- CNS toxicity (confusion, seizures, psychiatric disturbance) 4- hepatotoxicity have been rarely reported. 2.2. VALGANCICLOVIR ester pro-drug of ganciclovir After oral administration rapidly hydrolyzed to ganciclovir by esterase's in the intestinal wall and liver. 2.3. Foscarnet Is a pyrophosphate analogue that acts as a noncompetitive inhibitor of the DNA and RNA polymerases of multiple viruses. inhibits herpesvirus DNA polymerase, RNA polymerase, and HIV reverse transcriptase directly without requiring activation by phosphorylation. 1- Anti-Herpes Simplex Virus and Varicella-Zoster Virus Agents 1- Anti-Herpes Simplex Virus and Varicella-Zoster Virus Agents 2- Anti-cytomegalovirus (CMV) Agents  PK available in an IV formulation only Why not oral? Poor oral bioavailability and gastrointestinal intolerance T1/2 : is 3–7 hours up to 30% of foscarnet may be deposited in bone, with a half-life of several months. Clearance of foscarnet is primarily renal and is directly proportional to creatinine clearance.  As with ganciclovir, a decrease in the incidence of Kaposi’s sarcoma has been observed in patients who have received long term foscarnet Foscarnet is effective in the treatment of: CMV retinitis CMV colitis CMV esophagitis acyclovir-resistant HSV infection acyclovir-resistant VZV infection.  Adverse effects renal impairment Nephrotoxicity hypo- or hypercalcemia hypo- or hyperphosphatemia Hypokalemia hypomagnesemia. prevent nephrotoxicity: 1. Saline preloading 2. avoidance of concomitant administration of drugs with nephrotoxic potential (e.g. amphotericin B, pentamidine, aminoglycosides). The risk of severe hypocalcemia, caused by: chelation of divalent cations, is increased with concomitant use of pentamidine (Pneumocystis jiroveci (carinii)).  Genital ulcerations associated with foscarnet therapy may be due to high levels of ionized drug in the urine. Nausea, vomiting, anemia, elevation of liver enzymes, and fatigue have been reported the risk of anemia may be additive in patients receiving concurrent zidovudine. CNS toxicity includes headache, hallucinations, and seizures the risk of seizures may be increased with concurrent use of imipenem.  2.4. CIDOFOVIR Cidofovir is a cytosine nucleotide analog. In contrast to ganciclovir, phosphorylation of Cidofovir to the active diphosphate is independent of viral enzymes thus activity is maintained against thymidine kinase-deficient or -altered strains of CMV or HSV. IV cidofovir must be administered with high-dose probenecid (2 g at 3 hours before the infusion and 1 g at 2 and 8 hours after). Concomitant oral probenecid decreases both the renal clearance of cidofovir and the incidence of nephrotoxicity Initiation of cidofovir therapy is contraindicated in patients with existing renal insufficiency. 1- Anti-Herpes Simplex Virus and Varicella-Zoster Virus Agents 1- Anti-Herpes Simplex Virus and Varicella-Zoster Virus Agents 2- Anti-cytomegalovirus (CMV) Agents 2.4.5 LETERMOVIR CMV prophylaxis in adult hematopoietic stem cell transplant. It is available in both oral and intravenous formulations. moderate CYP3A4 inhibitor, an inducer of CYP2C9 2.4.6 MARIBAVIR treatment of post transplant CMV infection The most commonly reported side effect: dysgeusia requires activation by the CMV UL97 protein kinase concurrent use of maribavir results in antagonism of ganciclovir or valganciclovir  3- ANTIRETROVIRAL AGENTS Greater knowledge of viral dynamics through the use of viral load and resistance testing has made it clear that combination therapy with maximally potent agents will: reduce viral replication to the lowest possible level decrease the likelihood of emergence of resistance. Administration of combination antiretroviral therapy, typically comprising at least three antiretroviral agents  Retrovirus The retroviral genomic RNA serves as the template for synthesis of a double-stranded DNA copy, the provirus Synthesis of the provirus is mediated by: a virus-encoded RNA dependent DNA polymerase “reverse transcriptase.” The provirus is translocated to the nucleus and integrated into host DNA. Transcription Translation  Classes of antiretroviral agents 3.1. nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) 3.2. nonnucleoside reverse transcriptase inhibitors (NNRTIs) 3.3. Protease inhibitors (PIs) 3.4. entry and fusion inhibitors (CCR5 receptor antagonists) 3.5. integrase inhibitors  3.1- Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs) Oldest class A combination of two of these drugs typically forms the “backbone” of most anti-HIV regimens Hepatitis B virus  Agents Tenofovir disoproxil fumarate (TDF) Tenofovir alafenamide (TAF) Emtricitabine (FTC) Lamivudine (3TC) thiacytidine Abacavir (ABC) Zidovudine (ZDV, AZT) Stavudine (d4t) thymidine Didanosine (ddi)  Combinations 1. Emtricitabine/ tenofovir disoproxil Fumarate (truvada) 2. Abacavir/ lamivudine (Epzicom) 3. Emtricitabine/ tenofovir alafenamide (Descovy) 4. lamivudine/ zidovudine (combivir) 5. Abacavir/ lamivudine/zidovudine (trizivir) For most treatment-naïve patients, we recommend a regimen that contains two different NRTIs plus an INSTI (Integrase Strand Transfer Inhibitor) (Grade 1B). We typically suggest: INSTI NRTIs dolutegravir plus tenofovir alafenamide /emtricitabine (TAF/FTC) Bictegravir plus emtricitabine-tenofovir alafenamide (TAF/FTC)  MOA The NRTIs inhibit the action of the virally encoded protein reverse transcriptase by: taking the place of nucleotides in the elongating strand of viral DNA, leading to early termination of the viral DNA strain. Most of the NRTIs require dosage adjustment in renal dysfunction. This may require avoiding the fixed-dose combination preparations to give more dose flexibility  3.2- Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Agents: -efavirenz (EFV) -etravirine (ETR) -rilpivirine (RPV) -nevirapine (NVP) NNRTIs NRTIs efavirenz/ tenofovir/ emtricitabine: initial treatment of treatment- naive patients with HIV rilpivirine/ tenofovir/ emtricitabine (Complera) MOA Instead of inhibiting the action of reverse transcriptase by being similar to nucleosides, NNRTIs bind to a different part of the enzyme. The binding of the NNRTI causes a change in the conformation of the enzyme that interferes with its ability to form the viral DNA chain  Adverse effects Metabolic: Lipohypertrophy, manifesting as a gradual accumulation of fat in the abdomen, chest, and neck (as a “buffalo hump”), may occur with the NNRTIs. Efavirenz and Nevirapine have also been linked to hyperlipidemia. Compared to Efavirenz, rilpivirine showed less of an effect on lipid profiles  Efavirenz can cause a broad spectrum of CNS effects; common effects include dizziness, drowsiness or sometimes insomnia and abnormal especially vivid dreams Rashes can occur with all NNRTIs Hepatotoxicity in all NNRTIs  Resistance A key limitation of NNRTIs has been the low “genetic barrier” to resistance. A single point mutation can lead to high-level resistance to the entire class of drugs. Thus, even stricter adherence may be necessary to NNRTI- based regimens to prevent the emergence of resistance. The advanced-generation agents: etravirine and rilpivirine possess activity against viruses with some NNRTI mutations have roles for patients who have failed either efavirenz or nevirapine  Drug interaction NNRTIs have a much broader drug interaction profile than the NRTIs Nevirapine: an inducer of drug metabolism efavirenz and etravirine : mixed inducing and inhibitory properties rilpivirine does not as yet appear to have significant effects on metabolism of other drugs. 3.3. Protease inhibitors 2 types: Anti HIV Anti HEPATITS C 1- Combination regimens with PIs were the beginning of the era of “highly active antiretroviral therapy” (HAART) and have had a major impact on prolonging lifespan among HIV- infected individuals. 2- Protease inhibitors that treat hepatitis C virus (HCV) are different drugs and are not active against HIV, and vice versa Protease Inhibitors agents: Atazanavir (ATV) Darunavir (DRV) Atazanavir (ATV) Ritonavir (RTV) Fosamprenavir (FPV) Saquinavir (SQV) Indinavir (IDV) Nelfinavir (NFV) Tipranavir (TPV) Boosting: all Protease Inhibitors agents must be boosted by either PI’s with boosting effect agent or booster agent alone 1- PI’s with boosting effect agent: potent inhibition of drug- metabolizing enzymes displayed by the antiretroviral ritonavir or 2- booster agent only: the pharmacokinetic booster cobicistat (CYP3A inhibitor) to increase the serum concentrations and half-lives of other PIs Only atazanavir can be used unboosted (and this is recommended only for selected patients). If there’s not a little ritonavir or cobicistat in the regimen, something is probably wrong.  Boosting Combinations: Darunavir/cobicistat (DRV/c,Prezcobix) Atazanavir/cobicistat (ATV/c, evotaz) Lopinavir/ritonavir (LPV/r, kaletra) A variety of PIs combinations are used in salvage regimens for patients with resistant virus.  MOA During the later stages of the HIV growth cycle: the gag and gag - pol gene products are translated into polyproteins become immature budding particles. The HIV protease cleaving these precursor molecules To produce the final structural proteins of the mature virion core. PIs inhibit HIV protease Adverse effects (particularly cardiovascular effects), and patients should be prepared to make appropriate lifestyle changes.  3.4. Entry and Fusion Inhibitors Agents (CCR5 receptor antagonistes) Maraviroc (MVC): entry inhibitor Enfuvirtide (T20): fusion inhibitor block HIV from infecting a cell.  MOA The process of HIV binding to and entering the cell involves binding between viral proteins and proteins on the host cell target. This binding to the chemokine receptors CCR5 or CXCR4 induces conformational changes in gp120 allowing exposure to gp41 leading to fusion of the viral envelope with the host cell membrane entry of the viral core into the cellular cytoplasm.  Maraviroc targets a human protein (CCR5) that serves as a coreceptor for the virus entry Clinical experience with the use of maraviroc in treatment- naive patients is limited Tropism testing should be performed before initiating treatment with maraviroc. Enfuvirtide binds to a viral protein (gp41) subunit ….. preventing the conformational changes required for the fusion  Tropism testing Maraviroc Enfuvirtide: entry inh. fusion inh.  Black box warning Maraviroc : has a black box warning regarding hepatotoxicity based on case reports from healthy subjects who received the drug in early clinical trials. The effect seems to be rare in patients treated with maraviroc.  3.5. Integrase Inhibitors Agents: Raltegravir Bictegravir Dolutegravir Elvitegravir Cabotegravir Combinations: 1. Elvitegravir/cobicistat/Emtricitabine/Tenofovir disoproxil fumarate (EVG/c/FTC/TDF, Stribild): Elvitegravir: HIV Integrase Inhibitor Cobicistat: Pharmacokinetic Enhancer Emtricitabine, Tenofovir DF: Nucleoside Reverse Transcriptase Inhibitor NRTIs 2. Elvitegravir/cobicistat/ Emtricitabine/Tenofovir alafenamide (EVG/c/FTC/TAF, Genvoya): Elvitegravir: HIV Integrase Inhibitor Cobicistat: Pharmacokinetic Enhancer Emtricitabine, Tenofovir AF: Nucleoside Reverse Transcriptase Inhibitor NRTIs 3. Dolutegravir/Abacavir/Lamivudine (Triumeq): Dolutegravir: HIV integrase inhibitors Abacavir, Lamivudine: Nucleoside reverse-transcriptase inhibitors NRTIs Spectrum Only current clinical use is for HIV. MOA After the HIV reverse transcriptase enzyme creates a strand of viral DNA A viral protein called integrase facilitates the transfer of the HIV DNA into the host cell’s genome. The INSTIs inhibit this enzyme, preventing the viral DNA from becoming a part of the host cell enzyme, an important step in HIV replication.  Anti Flu: 1. Adamantines 2. inhibitors of neuraminidases  introduction Influenza virus strains are classified by: - Core proteins (A, B,or C) - Species of origin (eg, avian, swine) - Geographic site of isolation. Influenza A, the only strain that causes pandemics classified into: subtypes based on surface protein: 16 H (hemagglutinin) 9 N (neuraminidase) Current influenza A subtypes that are circulating among worldwide populations include H1N1, H1N2, and H3N2 influenza A viruses can infect a variety of animal hosts Influenza B viruses usually infect only people 1. Adamantines: 1.1. Amantadine 1.2. Rimantadine  MOA inhibit an early step in replication of the influenza A (but not influenza B) virus. They prevent un-coating Adamantines-resistant influenza A virus mutants are now common. Prevents uncoating CLINICAL USES AND TOXICITY These drugs are prophylactic against influenza A virus infection can reduce the duration of symptoms if given within 48 h after contact. The H1N1 strain responsible for the recent pandemic that contain genes derived from both avian and porcine Resistant to Adamantines.  Minimal cross-resistance to the neuraminidase inhibitors. Toxic effects of these agents include: 1. GI irritation 2. Dizziness 3. Ataxia 4. slurred speech. Rimantadine NOT greater than that of Amantadine it has a longer half-life NO dosage adjustment in renal failure 2. Neuraminidase inhibitors  MOA 2.1. Oseltamivir 2.2. Zanamivir These drugs are inhibitors of neuraminidases produced by influenza A and B active against both H3N2 and H1N1 strains. Decreased susceptibility to the drugs is associated with mutations in viral neuraminidase worldwide resistance remains rare.  viral neuraminidase enzymes cleave sialic acid residues from viral proteins and surface proteins of infected cells. They function to promote virion release and to prevent clumping of newly released virions. By interfering with these actions, neuraminidase inhibitors impede viral spread.  CLINICAL USES AND TOXICITY Oseltamivir a prodrug used orally activated in the gut and the liver. Prophylactically: significantly decreases the incidence of influenza. Zanamivir administered as inhalers Both drugs decrease the duration of influenza symptoms more effective if used within 24 h after onset of symptoms. GI symptoms may occur may cause: 1. cough 2. throat discomfort 3. bronchospasm in asthmatic patients.  Anti Hepatitis B hepatitis B virus (HBV) : The agents available for use in the treatment of infections caused by are suppressive rather than curative.  Agents 1. interferon-α (IFN-α) 2. Lamivudine NRTIs 3. adefovir dipivoxil 4. Entecavir 5. Telbivudine 6. Tenofovir NRTIs 7. Ribavirin 8. Sofosbuvir  MOA IFN-α cytokine that acts through host cell surface receptors increasing the activity of Janus kinases (JAKS). JAKS phosphorylate signal transducers and activators of transcription (STATS) increase the formation of antiviral proteins. SELECTIVITY: activation of a host cell ribonuclease that preferentially antiviral degrades viral proteins mRNA. promotes formation of natural killer cells that destroy infected liver cells. Adefovir Dipivoxil prodrug of adefovir competitively inhibits (HBV) DNA polymerase chain termination after incorporation into the viral DNA  Anti Hepatitis C hepatitis C virus (HCV) The primary goal of drugs is viral eradication The main targets of the DAAs are the HCV-encoded proteins that are vital to the replication of the virus There are four current classes of direct-acting antiviral agents (DAAs): 1. Nonstructural protein (NS) 3/4A protease inhibitors 2. NS5B nucleoside polymerase inhibitors 3. NS5B non-nucleoside polymerase inhibitors 4. NS5A inhibitors. The safety profiles of all the combination regimens are generally excellent mainstays of chronic hepatitis C treatment: 1. Peg-interferon alpha-2a : Peginterferon 2. Peg-interferon alpha-2b : Peginterferon 3. Ribavirin  Case study A 43-year-old man with HIV disease presents to the emergency room with blurry vision and eye pain for the past 3 days. His symptoms began in the left eye and now the right eye is involved. His CD4 count is found to be 43. Funduscopic exam confirms the most likely cause for the patients’ symptoms is CMV retinitis. What is the most appropriate treatment for CMV retinitis? (A) Acyclovir (B) Ganciclovir (C) Nevirapine (D) Ribavirin (E) Ritonavir