Antiviral Drugs PDF

Antiviral Drugs Prepared by, Dr. Rani J. Qasem, PhD College of Pharmacy Middle East University (MEU) Amman- Jordan 1  Viruses- Introduction Obligate intracellular parasites lack a cell wall & membrane, and do not ca...

Antiviral Drugs Prepared by, Dr. Rani J. Qasem, PhD College of Pharmacy Middle East University (MEU) Amman- Jordan 1  Viruses- Introduction Obligate intracellular parasites lack a cell wall & membrane, and do not carry out metabolic processes.. Consists of nucleic acid (DNA or RNA) enclosed in a protein coat (capsid) – Some have a lipoprotein envelope- contains antigenic glycoproteins. Treatment is difficult because:  Use host metabolic machinery  few drugs selective enough to prevent viral replication without injuring the infected host cells.  Unlike bacterial infections, clinical symptoms appear late in the course of the disease when most virus particles have replicated. Research is focused on identifying agents with greater selectivity, higher potency, in vivo stability, and reduced toxicity. Antiviral drugs share the common property of being virustatic; are active only against replicating viruses and do not affect latent virus. Antiviral drugs- 2 Prepared By Dr. Rani J. Qasem  Examples of DNA & RNA Viruses DNA viruses and the diseases that they produce include: Adenoviruses (colds, conjunctivitis) Hepadnaviruses (hepatitis B) Herpesviruses (cytomegalovirus, chickenpox, shingles) Papillomaviruses (genital warts) Chickenpox Shingles Poxviruses (smallpox) Pathogenic RNA viruses and their diseases include: Arborviruses (tick-borne encephalitis, yellow fever) Arenaviruses (Lassa fever, meningitis) Smallpox Orthomyxoviruses (influenza) Measles Paramyxoviruses (measles, mumps) Picornaviruses (polio, meningitis, colds) Rhabdoviruses (rabies); rubella virus (German measles) Retroviruses (AIDS). Antiviral drugs- 3 Prepared By Dr. Rani J. Qasem Polio Mumps Rabies  Treatment Approaches to Viral Infections Three basic approaches used to control viral diseases: Vaccination Antiviral chemotherapy Stimulation of host resistance mechanisms (least used strategy- is gaining more interest lately). Chemotherapy of viral infections  involve interference with any or all steps of the viral replication cycle. Because viral replication and host cell processes are so intimately linked  the main problem is finding a drug that is selectively toxic to the virus. Current chemotherapy is used to control: Herpes viruses, Cytomegalovirus (CMV), Influenza viruses (the “flu”), Respiratory syncytial virus (RSV), Hepatitis viruses, Human Immunodeficiency virus (HIV). Antiviral drugs- 4 Prepared By Dr. Rani J. Qasem  Viral Replication Cycle & Major Sites of Antiviral Drug Action Note: Interferon alfas are speculated to have Integrase strand multiple sites of action. transfer inhibitors (INSTIs) Antiviral drugs- 5 Prepared By Dr. Rani J. Qasem  I. Treatment of Respiratory Viral Infections Treatments available for the following respiratory viruses: Influenza A and B (Single-stranded RNA viruses) Immunization preferred approach. Antiviral agents are used when patients are allergic to the vaccine or outbreaks occur. Respiratory syncytial virus (RSV) (Single-stranded RNA viruses) Infections of the respiratory tracts and lungs. So common that most children get infected with the virus by age 2. Also infects adults. Antiviral drugs- 6 Prepared By Dr. Rani J. Qasem  A. Neuroaminidase inhibitors Neuraminidases, also called sialidases, catalyze the hydrolysis of terminal sialic acid residues from the newly formed virions and from the host cell receptors. Agents: Oseltamivir & Zanamivir (both sialic acid analogs) Active against both type A & type B influenza viruses. Can prevent infection, if administered prior to exposure. Cause a modest decrease in the intensity and duration of symptoms if given within 24 to 48hrs after the onset of symptoms. Antiviral drugs- 7 Prepared By Dr. Rani J. Qasem  Neuroaminidase inhibitors Oseltamivir Prodrug  taken orally, activated by hepatic esterases  eliminated in urine. Side effects: GI discomfort (Nausea) and abdominal pain in 5-10% patients  alleviated by taking the drug with food. Zanamivir Inactive orally inhaled or administered intra-nasally  eliminated in urine. Side effects: Irritation of respiratory tract, transient nasal and throat discomfort, cough, bronchospasm (severe), reversible decrease in pulmonary function. Should be avoided in patients with severe asthma & COPD. Antiviral drugs- 8 Prepared By Dr. Rani J. Qasem  Resistance to neuroaminidase inhibitors Mutations in the neuraminidase enzyme have been identified in adults when treated with either of the neuraminidase inhibitors. Mutants are often less infective and virulent than the wild type. Antiviral drugs- 9 Prepared By Dr. Rani J. Qasem  B. Inhibitors of Viral Uncoating -adamantanes- Agents: Amantadine & Rimantadine Block viral membrane matrix protein (M2) which functions as a channel for hydrogen ion. Effective for prevention and treatment of influenza A virus infections… Are 70% - 90% effective in preventing infection if treatment is begun at the time of—or prior to— exposure to the virus. Due to widespread resistance, the adamantanes are not recommended in the United States for the treatment or prophylaxis of influenza A. Antiviral drugs- 10 Prepared By Dr. Rani J. Qasem  Inhibitors of Viral Uncoating -Mechanism of Action of Adamantanes- Amantadine's antiviral activity was first and generally described in 1964. Target the M2 influenza A viral protein. Resistant influenza A isolates result from a single amino acid change in the M2 protein. The M2 protein plays a crucial role in the release of viral ribonucleoprotein complexes into the cytoplasm. Involves influenza A virus uncoating  defined by the fusion of viral and endosomal membranes. Two viral proteins, M1 and M2, are important in this process. M1 is a structural protein in the viral membrane and appears to link the viral membrane containing essential glycoproteins with viral ribonucleoproteins. During uncoating, this linkage must be disrupted to for complete uncoating and transport of ribonucleoprotein to the nucleus. This disruption catalyzed via the viral M2 protein. Antiviral drugs- 11 Prepared By Dr. Rani J. Qasem  Inhibitors of Viral Uncoating -Mechanism of Action of Adamantanes- The M2 protein is an ion channel, the activity of which is pH dependent. At lower pH the ion channel activity is enhanced; upon endosomal acidification, increased M2-dependent proton (H+) translocation from the endosome into the virion occurs. This proton movement results in acidifying the internal of the virus particle (decrease in pH) promoting the dissociation between M1 and viral ribonucleoproteins. This releases the viral ribonucleoprotein complexes into the cytoplasm. Antiviral drugs- 12 Prepared By Dr. Rani J. Qasem Schematic of the mechanism of adamantane drug inhibition. The drugs interact with specific residues of the influenza A virus M2 transmembrane protein. This protein forms a channel for the influx of protons into the virion. Only two of the four M2 subunits that form the channel are shown. Binding of amantadine or rimantadine blocks the channel, preventing intra-virion acidification Antiviral drugs- 13 Prepared By Dr. Rani J. Qasem  Inhibitors of Viral Uncoating -Adverse Drug Events of Adamantanes- 1. GIT (nausea, anorexia). 2. CNS toxicity… Occur in approximately 5% - 33% of patients treated with amantadine, significantly less frequent with rimantadine (less entrance into the CNS). Nervousness, difficulty concentrating, insomnia, light- headedness. Underlying cause: alteration in dopamine neurotransmission. Used cautiously in patients with psychiatric problems ,epilepsy, cerebral atherosclerosis & renal impairment. 3. Both drugs should be used with caution in pregnant & nursing mothers. Antiviral drugs- 14 Prepared By Dr. Rani J. Qasem  C. Ribavirin Synthetic guanosine analog. Effective against a broad spectrum of RNA and DNA viruses. Treatment of immunosuppressed infants & young children with severe RSV infections (bronchiolitis or pneumonia)- Aerosol formulation. Effective in chronic hepatitis C infections in combination with other direct-acting antivirals (DAAs). Effective by inhalation & orally  Absorption increased with a fatty meal. The drug and its metabolites are eliminated in urine. Side effects: Dose-dependent transient anemia, and elevated bilirubin… Respiratory function in infants can deteriorate quickly after initiation of aerosol treatment  monitoring is essential. Contraindicated in pregnancy. Antiviral drugs- 15 Prepared By Dr. Rani J. Qasem  Phosphoribosylamine Putative antiviral mechanisms of action of Ribavirin during the treatment of HCV infection. Taken up into hepatocytes through the ENT1 transporter, Ribvirin is modified by cellular kinases to RMP and RTP- 1. RTP enhances HCV mutagenesis due to erroneous integration of RTP into newly synthesized viral RNA and may also directly inhibit HCV replication by blocking RNA-dependent RNA polymerase.. 2. RMP inhibits IMPDH which converts IMP to GTP, effectively depleting the intracellular GTP pool required for viral replication. 3. Ribavirin treatment may enhance the antiviral T cell function. TH, T helper cells; RdRp, RNA-dependent RNA polymerase. 16 Antiviral drugs- Prepared By Dr. Rani J. Qasem II. Treatment of Hepatic Viral Infections Hepatitis viruses currently identified (A, B, C, D, and E). Pathogenesis involves replication in and destruction of hepatocytes. Hepatitis B (DNA virus) & hepatitis C (RNA virus) are the most common causes of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Hepatitis A  commonly encountered infection, but it is not chronic. Chronic hepatitis B  treated with peginterferon-α-2a SC 1 q week. Oral therapy: Lamivudine, Entecavir, Adefovir & Tenofovir. Chronic hepatitis C  Treated with a combination of Direct Acting Antivirals (DAAs)  selection is based on the hepatitis C genotype. Ribavirin added in some cases to regimen to enhance virologic response. Pegylated interferon-α no longer used for HCV & is not recommended in current guidelines after the advent of new DAAs  it has inferior efficacy & poor tolerability. Antiviral drugs- 17 Prepared By Dr. Rani J. Qasem  Schematic representation of the HBV viral replication cycle Attachment to the sodium taurocholate co-transporting polypeptide (NTCP) receptor, and possibly other receptors too, is the initiating event of infection (1); After uncoating and nuclear translocation of the capsid, relaxed circular DNA (rcDNA) is delivered to the nucleus (2); rcDNA is then repaired to form covalently closed circular DNA (cccDNA) (3); which is the template for transcription of viral RNA (4); Viral mRNA is translated………….. (5); The pre-genomic RNA (pgRNA) is then packaged into capsid particles together with the viral Pol (6); The pgRNA is reverse transcribed in the nucleocapsid (7); And the viral particles are secreted via the endoplasmic reticulum (8). Sites of action of licensed and potentially therapeutic agents are indicated in red text. Viral cccDNA may be disabled by methods that employ gene editing. Exogenous activators of the RNA interference (RNAi) pathway may be employed to inactivate viral RNA. Nucleoside and nucleotide analogues, which are currently licensed drugs, may be used to inhibit reverse transcription of pgRNA. Antiviral drugs- Prepared 18 By Dr. Rani J. Qasem  Treatments for hepatitis B viral (HBV) infections A. Interferons Naturally occurring, inducible cytokines - glycoprotein in nature. Interfere with the ability of viruses to infect cells. Synthesized by recombinant DNA technology. At least- three types of interferons exist-α, β & γ. “Pegylated“ formulations bis-monomethoxy polyethylene glycol covalently attached to interferon-α to increase size of the molecule. Larger molecular size  Delays absorption from the injection site Lengthens the duration of action of the drug Decreases its clearance Antiviral drugs- 19 Prepared By Dr. Rani J. Qasem  Interferons- Mechanism of Action Antiviral mechanism of action is incompletely understood. Appears to involve induction of host cellular enzymes that inhibit viral RNA translation, ultimately leading to the degradation of viral mRNA and tRNA. Interferon (IFN)-alfa also appears to function by: Induction of intracellular signals resulting in inhibition of viral penetration, transcription, translation, protein processing, maturation, and release… Increased expression of major histocompatibility complex antigens… Enhanced phagocytic activity of macrophages. Enhanced proliferation and survival of cytotoxic T cells. Antiviral drugs- 20 Prepared By Dr. Rani J. Qasem  Interferons- Therapeutic uses Peg-interferon alfa-2α is approved for the treatment of chronic HBV infection. Indicated for the treatment of HCV in combination with other agents Use is becoming uncommon due to availability of more effective DAA agents. Antiviral drugs- 21 Prepared By Dr. Rani J. Qasem  Interferons- Adverse effects These include flu-like symptoms  fever, chills, myalgias, arthralgias, and Gl disturbances- Occur within 6 hours after dosing in more than 30% of patients during the first week of therapy. Tends to resolve upon continued administration. Transient hepatic enzyme elevations  First 8-12 weeks of therapy- more common in responders Fatigue and mental depression are common. Principal dose-limiting toxicities: bone marrow suppression, severe fatigue and weight loss, neurotoxicity characterized by somnolence and behavioral disturbances, autoimmune disorders (induction of auto-antibodies) such as thyroiditis and, rarely, cardiovascular problems such as heart failure. Antiviral drugs- 22 Prepared By Dr. Rani J. Qasem  B. Lamivudine Known as 3TC (2′-deoxy-3′-thiacytidine). A nucleoside analogue of cytidine. Must be phosphorylated by host cellular enzymes to the triphosphate (active) form… Mechanism of Action: Converted intracellularly to its triphosphate form. Competes with deoxycytidine triphosphate (dCTP) for incorporation into the developing viral DNA strand. Results in chain termination & ceases viral DNA replication. Competitively inhibits HBV DNA polymerase at concentrations of negligible effects on host DNA polymerase. Adverse Drug Events: well tolerated, rare cases of headache & dizziness… High rates of HBV resistance with long-term therapy  no longer recommended in current hepatitis B guidelines. Antiviral drugs- 23 Prepared By Dr. Rani J. Qasem  C. Entecavir A deoxyguanosine analogue. Requires intracellular phosphorylation to the triphosphate Competes with the natural substrate, deoxyguanosine triphosphate (dGTP) for viral reverse transcriptase… Inhibits reverse transcription, DNA replication and transcription in the viral replication process. Effective against lamivudine-resistant strains of HBV… Undergoes glomerular filtration and tubular secretion. Renal function must be assessed periodically, and drugs that have renal toxicity should be avoided… Antiviral drugs- 24 Prepared By Dr. Rani J. Qasem  D. Adefovir Nucleotide analog  phosphorylated by cellular kinases to adefovir diphosphate  incorporated into viral DNA  termination of chain elongation  prevents viral replication. Administered once daily  renally excreted via glomerular filtration and tubular secretion. Nephrotoxicity occurs with chronic use  used cautiously in cases of existing renal dysfunction. Discontinuation may result in severe exacerbation of hepatitis. No longer recommended in current hepatitis B guidelines due to lower efficacy compared to other agents. Antiviral drugs- 25 Prepared By Dr. Rani J. Qasem  E. Telbivudine Synthetic thymidine β-L-nucleoside analogue. L-isomer of thymidine (differs from the natural nucleotide in the spatial location of the sugar and base moieties, taking on an levorotatory configuration versus a dextrorotatory configuration as do the natural deoxynucleosides). Phosphorylated intracellularly to the triphosphate- impairs hepatitis B virus (HBV) DNA replication by leading to chain termination. Administered orally, once a day, with or without food. Eliminated by glomerular filtration as the unchanged drug Antiviral drugs- 26 Prepared By Dr. Rani J. Qasem  Treatments for Hepatitis C Infection Schematic representation of the HCV viral life cycle & targets of direct acting antivirals (DAAs) The life cycle of hepatitis C virus and targets for antiviral therapy. Major steps of the HCV life cycle are shown schematically. The viral particles associated with lipoproteins enter into host cells via (co)receptor binding and clathrin-mediated endocytosis. The known entry (co)receptors, tetraspanin CD81, the scavenger receptor class B member I (SR-BI), Claudin 1 (CLDN1), Occludin (OCLN), glycosaminoglycans (GAG), the low-density lipoprotein receptor (LDLR), epidermal growth factor receptor (EGFR), ephrin receptor A2 (EphA2), and Niemann-Pick C1-like L1 (NPC1L1). After uncoating process, the positive-stranded viral RNA is released and translated into a polyprotein which is processed into different structural and nonstructural viral proteins. The NS viral proteins mediate the replication of positive-stranded viral RNA within a membranous structure, called membranous web. The infectious viral particles containing the newly-synthesized viral RNA and structural proteins are assembled and egressed via the secretory pathway. HCV polyprotein procession is targeted by NS3-4A inhibitors. HCV RNA replication is targeted by NS5B polymerase inhibitors, NS5A inhibitors, and cyclophilin A inhibitors. Note that HCV proteins interact throughout the HCV life cycle, and DAAs therefore impact on multiple steps in the HCV life cycle. This was shown for example for NS5A inhibitors, which affect HCV replication, assembly and release. Specific inhibitors of viral entry or assembly and release are in preclinical or early clinical development. 27 Antiviral drugs- Prepared By Dr. Rani J. Qasem Combination therapy of -Direct Acting Antiviral- (DAA) drugs DAA combination therapy is necessary to optimize HCV treatment response rates  each DAA targets different stages of the HCV life cycle. Combination therapy can suppress wild-type & drug-resistant viral populations. Certain combinations may have different efficacy based on HCV genotype. Antiviral drugs- 28 Prepared By Dr. Rani J. Qasem  A. NS3/NS4A protease inhibitors Viral NS3/NS4A serine protease is crucial for processing the single polyprotein encoded by HCV RNA into individually active proteins  NS4A, NS4B, NS5A and NS5B. Without these serine proteins RNA replication does not occur  HCV life cycle is effectively disrupted. DAAs that inhibit NS3/NS4A proteases as the primary mechanism of action: Paritaprevir (which requires ritonavir boosting) Grazoprevir Note: HCV protease Glecaprevir inhibitors often have the Voxilaprevir ending “previr” Have a lower barrier to resistance than other agents, such as sofosbuvir. Metabolism by CYP3A enzymes  Significant potential for drug-drug interactions. Adverse effects: rash, pruritus, nausea, fatigue and anemia. Antiviral drugs- 29 Prepared By Dr. Rani J. Qasem  B. NS5B polymerase inhibitors NS5B is the sole RNA polymerase responsible for HCV replication  processed along with other HCV proteins into an individual polypeptide by the viral NS3/NS4A serine protease. Two types of NS5B RNA polymerase inhibitors (often end in "buvir"): Nucleoside/nucleotide analogues- compete for enzyme active site Sofosbuvir is the only NS5B nucleotide polymerase inhibitor for HCV infection. Non-nucleoside analogues- that target allosteric sites Dasabuvir is the only nonnucleoside analogue. NS5B polymerase inhibitors are well tolerated with few adverse effects. Antiviral drugs- 30 Prepared By Dr. Rani J. Qasem  C. NS5A replication complex inhibitors NS5A is essential for HCV RNA replication & assembly. Its role in replication appears to be the formation of a membranous web along with viral protein NS4B, which provides a platform for replication. The currently available NS5A inhibitors include (often in "asvir“): Ledipasvir Elbasvir Pibrentasvir Ombitasvir Velpatasvir Daclatasvir All co-formulated with other direct-acting antivirals (Except for daclatasvir). Have a number of clinically significant drug interactions due to their metabolism by hepatic CYP450 isoenzymes & inhibition of P-glycoprotein (P-gp). Daclatasvir is extensively metabolized via hepatic CYP3A4 enzymes, and is contraindicated in combination with strong CYP3A4 inducers because of the potential for reduced efficacy. Absorption of ledipasvir is reduced when gastric pH is increased. Antiviral drugs- 31 Prepared By Dr. Rani J. Qasem  D. Ribavirin Approved for chronic HCV in combination- with standard or pegylated interferon or with DAAs. Improves viral clearance Decreases relapse rates Improves rates of sustained virologic response with other agents. Addition of ribavirin to DAA-based regimens is based on: HCV genotype/ subtype Cirrhosis status Mutational status Treatment history Despite its use in patients with HCV for more than 20 years, the precise mechanism(s) how it improves outcomes is unknown. Ribavirin remains an important component of HCV therapy, even in the age of DAA therapy. Dose of ribavirin is always weight-based and it is administered in two daily divided doses with food. Antiviral drugs- 32 Prepared By Dr. Rani J. Qasem  III. TREATMENT OF INFECTIONS BY HERPESVIRUSES Family of double-stranded DNA viruses. Associated with a large number of human diseases. Examples: Herpes simplex virus (HSV) type1 (oral herpes/cold sores) & type 2 (genital herpes), Varicella zoster virus (VZV) the cause of chickenpox and shingles, Epstein-Barr virus (EBV) the cause of mononucleosis and some cancers, & human cytomegalovirus (HCMV) which causes infectious mononucleosis and retinitis & Kaposi’s sarcoma associated herpes virus (KSHV) which causes Kaposi’s sarcoma.... Herpes zoster blisters on the neck and shoulder Antiviral drugs- 33 Prepared By Dr. Rani J. Qasem  A. Acyclovir (Zovirax®) Prototypic antiherpetic agent. Used in treating infections causes by herpes simplex virus (HSV) types 1 and 2, varicella-zoster virus (VZV) and some Epstein-Barr virus-mediated infections are sensitive to acyclovir. It is the treatment of choice in HSV encephalitis. Most common use of acyclovir is in therapy for genital herpes infections. Given prophylactically to seropositive patients before bone marrow transplant and post-heart transplant to protect such individuals from herpetic infections. Antiviral drugs- 34 Prepared By Dr. Rani J. Qasem  Acyclovir Mechanism of Action Acyclovir is a guanosine analog. Requires three phosphorylation steps for activation. It is first monophosphorylated in the cell by the herpesvirus-encoded enzyme thymidine kinase  Therefore, virus-infected cells are most susceptible. The monophosphate analog is converted to the di- and triphosphate forms by the host cell kinases. Acyclovir triphosphate competes with deoxyguanosine triphosphate as a substrate for viral DNA polymerase and is itself incorporated into the viral DNA, causing premature DNA chain (chain termination). Antiviral drugs- 35 Prepared By Dr. Rani J. Qasem  Acyclovir- Pharmacokinetics Given topically (efficacy questionable), orally & IV. Distributes well throughout the body, including the cerebrospinal fluid (CSF). Partially metabolized to an inactive product. Excreted into urine both by glomerular filtration & tubular secretion. Acyclovir accumulates in patients with renal failure. The valyl ester, valacyclovir has greater oral bioavailability (3-5x greater) than oral acyclovir -- the ester is rapidly hydrolyzed to acyclovir and achieves levels of the latter comparable to those of acyclovir following IV administration. High doses effective for adults (shingles) herpes zoster & children (chicken pox) if begun within 24 hours of rash… IV acyclovir treatment of choice for herpes simplex encephalitis, neonatal HSV infection, and serious HSV or VZV infections…. In the immunocompromised with VZV infection, IV acyclovir reduces incidence of cutaneous and visceral dissemination… Antiviral drugs- 36 Prepared By Dr. Rani J. Qasem  Acyclovir- Adverse Drug Events (ADEs) Generally well tolerated. ADEs depends on the route of administration: Oral administration: NVD and headache. Topical administration: local irritation. Reversible (transient) renal dysfunction (azotemia) & neurotoxicity (tremor, seizure, delirium) are dose limiting toxicities of high intravenous acyclovir, or in dehydrated patients. Adequate hydration and slow drug infusion can minimize the risk of renal toxicity. Acyclovir- Resistance Altered or deficient viral thymidine kinase and DNA polymerases have been found in some resistant viral strains and are most commonly isolated from immunocompromised patients. Cross-resistance to the other agents in this family occurs. Antiviral drugs- 37 Prepared By Dr. Rani J. Qasem  B. Ganciclovir An analog of acyclovir that is of greater activity against CMV. Used to treat CMV retinitis in immunocompromised patients and for CMV prophylaxis in transplant patients. Mechanism of action: Like acyclovir, is converted to nucleoside triphosphate by viral and cellular enzymes, which inhibits viral DNA polymerase and can be incorporated into the DNA resulting in chain termination. Pharmacokinetics: given IV, distributes throughout the body including the CSF. Excreted into the urine occurs through glomerular filtration and tubular secretion. Like acyclovir, ganciclovir accumulates in patients with renal failure. Valganciclovir an oral drug, is the valyl ester of ganciclovir. Like valacyclovir, it has high oral bioavailability, because rapid hydrolysis in the intestine and liver after oral administration leads to high levels of ganciclovir. Adverse effects: Severe, dose-dependent neutropenia. Carcinogenic & teratogenic  carries a boxed warning for use in pregnancy. Resistance: Resistant CMV strains detected of low levels of ganciclovir triphosphate. Antiviral drugs- 38 Prepared By Dr. Rani J. Qasem  C. Cidofovir A “nucleotide” analog of cytosine. A nucleotide  phosphorylation is not dependent on viral or cellular enzymes  the drug inhibits viral DNA synthesis. Indicated to treat cytomegalovirus (CMV) retinitis in patients with AIDS (given intravitreally  injected into the vitreous humor between the lens and retina). Cidofovir is given IV for HSV-1 & 2, EBV, and VZV. Slow elimination of active intracellular metabolite allows for prolonged dosage intervals & eliminates need for permanent venous access with ganciclovir therapy. Produces significant renal toxicity  contraindicated in preexisting renal impairment and those taking nephrotoxic drugs. Oral probenecid and IV normal saline are coadministered to reduce the risk of nephrotoxicity. Neutropenia and metabolic acidosis also occur. Since the introduction of highly active antiretroviral therapy, prevalence of CMV infections in immunocompromised hosts markedly declined, as the importance of cidofovir in treating these patients. Antiviral drugs- 39 Prepared By Dr. Rani J. Qasem  D. Foscarnet Not a purine or pyrimidine analog  a pyrophosphate derivative -- does not require activation by viral (or cellular) kinases. Reversibly inhibits viral DNA and RNA polymerases  interferes in viral DNA and RNA synthesis. Approved for: CMV retinitis in immunocompromised hosts & Acyclovir-resistant HSV infections. Effectiveness comparable to ganciclovir  synergistic against refractory retinitis. Mutation of the polymerase structure is responsible for resistant viruses. Pharmacokinitcs: Poorly absorbed orally  must be injected intravenously. Must be given frequently to avoid relapse when plasma levels fall. It is dispersed throughout the body greater than 10% enters the bone matrix, from which it slowly disperses. The parent drug is eliminated by glomerular filtration and tubular secretion. Adverse effects: nephrotoxicity, anemia, nausea, and fever. Chelates with divalent cations  hypocalcemia & hypomagnesemia seen. Hypokalemia, hypo/hyperphosphatemia, seizures & arrhythmias reported. Antiviral drugs- 40 Prepared By Dr. Rani J. Qasem E. Penciclovir & Famciclovir Penciclovir - acyclic guanosine nucleoside active against HSV-1 & 2 and VZV. Monophosphorylated by viral thymidine kinase, and cellular enzymes form the nucleoside triphosphate, which inhibits HSV DNA polymerase. Administered topically -the triphosphate form has an intracellular half-life much longer than acyclovir triphosphate. Negligibly absorbed upon topical application and is well tolerated. Famciclovir- an acyclic analog of 2'-deoxyguanosine  a prodrug that is metabolized to the active penciclovir. The drug is effective orally. Antiviral spectrum similar to ganciclovir  approved for acute herpes zoster, genital HSV infection, and recurrent herpes labialis. Adverse effects include headache and nausea. Antiviral drugs- 41 Prepared By Dr. Rani J. Qasem  F. Trifluridine A fluorinated pyrimidine nucleoside analog  structurally similar to thymidine. Converted to the triphosphate  inhibits incorporation of thymidine triphosphate into viral DNA and leads to synthesis of defective DNA  renders the virus unable to replicate. Active against HSV-1 & 2, and vaccinia virus. Also indicated for treatment of HSV keratoconjunctivitis and recurrent epithelial keratitis. Effective in patients unresponsive or intolerant to topical idoxuridine or vidarabine. The triphosphate form can also incorporate into cellular DNA  drug is too toxic for systemic use. Use restricted to a topical ophthalmic preparation. A short half-life necessitates that the drug be applied frequently. Adverse effects: transient irritation to the eye & palpebral (eyelid) edema. Antiviral drugs- 42 Prepared By Dr. Rani J. Qasem  G. Idoxuridine Converted to the triphosphate  incorporated into viral DNA leading to incorrect base pairing  renders the virus unable to replicate. Only FDA-approved in the treatment of HSV infections of the eyelid, conjunctiva, and cornea. Originally developed as an anticancer drug- can cause cardiotoxicity. Became the 1st antiviral in 1962. Marketed strictly for topical ophthalmic use  systemic exposure is insignificant. Antiviral drugs- 43 Prepared By Dr. Rani J. Qasem  H. Docosanol 1-Docosanol, also known as behenyl alcohol, is a saturated fatty alcohol containing 22 carbon atoms, used traditionally as an emollient, emulsifier, and thickener in cosmetics. Docosanol (Abreva®) cream is clinically effective against HSV. Approved for the OTC treatment of herpes labialis (cold sores). Shortens the duration of symptoms of cold sores and fever blisters but does not provide symptomatic relief. Not directly virucidal; it blocks the entry of the virion into the host cell by inhibiting the fusion of the viral envelope with the host plasma membrane. Less susceptible to the development of resistance than other antiviral drugs  because it does not affect viral replication or protein production. Antiviral drugs- 44 Prepared By Dr. Rani J. Qasem  I. Fomivirsen First FDA approved antisense antiviral drug 21 member oligonucleotide with phospho-orthotiolate linkages to resist degradation by nucleases. Binds to complementary sequence of viral mRNA  blocks translation of viral gene UL123 of CMV. Treatment of CMV retinitis in patients with AIDS  who do not respond to other treatments or are contraindicated. Administered via intraocular injection. CMV retinitis often associated with CMV infection elsewhere in the body  patients undergoing treatment with fomivirsen should be monitored for extra-ocular CMV disease. Iritis  affects up to 25% of patients undergoing fomivirsen therapy  managed with topical corticosteroids. Vitritis  increased intra-ocular pressure also result from fomivirsen administration. Antiviral drugs- 45 Prepared By Dr. Rani J. Qasem I. Fomivirsen Antiviral drugs- 46 Prepared By Dr. Rani J. Qasem  J. Vidarabine Nucleoside analog  9-β-D- arabinofuranosyladenine (ara-A). Phosphorylated to the active ara-ATP  a substrate (competitive inhibition of dATP incorporation into viral DNA  leads to faulty DNA) It is also an inhibitor of viral DNA polymerase -- > Interfers in viral DNA synthesis. ara-ADP also inhibits ribonucleotide reductase  decreases reduction of ribonucleotide diphosphates. Principal use in the treatment of HSV keratoconjunctivitis. Also used to treat superficial keratitis in patients unresponsive or hypersensitive to topical idoxuridine. Most commonly observed side effects: lacrimation, burning, irritation, pain, photophobia. Antiviral drugs- 47 Prepared By Dr. Rani J. Qasem Summary of selected antiviral agents. Antiviral drugs- 48 Prepared By Dr. Rani J. Qasem  IV. TREATMENT OF HIV INFECTION Treatment of HIV initially focused on decreasing opportunistic infections that caused high degrees of morbidity & mortality in AIDS patients. Today, a combination of drugs is used to suppress replication of HIV and restore the number of CD4 cells and immunocompetence to the host. The multidrug regimen is commonly known as antiretroviral therapy, or ART. There are five classes of ART drugs, each targets 1 of the 4 viral processes. Nucleoside & nucleotide reverse transcriptase inhibitors (NRTis), Non-nucleoside reverse transcriptase inhibitors (NNRTis), Protease inhibitors (Pis) Entry inhibitors Integrase inhibitors. Two pharmacokinetic enhancers, also known as "boosters:‘  serve to increase drug levels of concomitantly administered ARTs  less frequent dosing and less variation in drug levels. Antiviral drugs- 49 Prepared By Dr. Rani J. Qasem  Antiretroviral Therapies (ARTs) and their mechanism of action Antiviral drugs- 50 Prepared By Dr. Rani J. Qasem