ANTI VIRAL ANDANTIRETROVIRAL DRUGSPresented By-Krushangi Shah,Nirma University.
Viruses• Viruses are the smallest infective agents, consisting essentially ofnucleic acid (either RNA or DNA) enclosed in a protein coat orcapsid.• A virus cannot replicate on its own. It must attach to and enter ahost cell. It then uses the host cell’s energy to synthesize protein,DNA, and RNA. Viruses are difficult to kill because they live insidethe cells. Any drug that kills a virus may also kill cells
Some important examples of viruses and the diseases theycause are as follows:DNA viruses• Pox viruses (smallpox)• Herpes viruses (chickenpox,herpes etc.)• Adenoviruses (sore throat,conjunctivitis)• Hepadnaviruses (serumhepatitis)• Papillomaviruses (warts)RNA viruses•Orthomyxoviruses (influenza)•Paramyxoviruses (measles, mumps)•Rubella virus (German measles)•Rhabdoviruses (rabies)•Picornaviruses(colds, meningitis, poliomyelitis)•Retroviruses (AIDS, T-cellleukaemia)•Arenaviruses (meningitis, Lassafever)•Arboviruses (arthropod-borneencephalitis, yellow fever)
Replication in viruses• Replication in DNA virusesViral DNA enters the host cell nucleus, where transcription into mRNAby the host cell RNA polymerase occurs. Translation of the mRNA intovirus-specific proteins takes place. These proteins are enzymes thatthen synthesise more viral DNA, as well as proteins for the viral coatand envelope. After assembly of coat proteins around the viral DNA,complete virions are released by budding or after host cell lysis.• Replication in RNA virusesEnzymes within the virion synthesise its mRNA from the viral RNAtemplate, or sometimes the viral RNA serves as its own mRNA. This istranslated by the host cell into various enzymes, including RNApolymerase and also into structural proteins of the virion. Assembly andrelease of virions occurs as explained above. With these viruses, thehost cell nucleus is usually not involved in viral replication, althoughsome RNA viruses (e.g. orthomyxoviruses) replicate exclusively withinthe host nuclear compartment.
• Replication in retrovirusesThe virion in retroviruses contains a reverse transcriptase enzyme(virus RNA-dependent DNA polymerase), which makes a DNA copy ofthe viral RNA. This DNA copy is integrated into the genome of the hostcell, and it is then termed a provirus. The provirus DNA is transcribedinto both new viral genome RNA as well as mRNA for translation in thehost into viral proteins, and the completed viruses are released bybudding. Many retroviruses can replicate without killing the host cell.
CLASSIFICATION OF ANTIVIRAL DRUGS ACCORDING TO THE MECHANISM OF ACTIONThe viral growth cycle Selective inhibitors1) Attachment2) Penetration- Antiviral antibodies(gamma globulin)3) Uncoating - Amantadine, Rimantadine - Interferon4) Early translation(early mRNA and protein synthesis)- fomivirsen5) Transcription(viral genome replication)Inhibitors of DNA-polymerase-Acyclovir, Gancyclovir, Famcyclovir, Cidofovir- Vidarabine, Idoxuridine -FoscarnetInhibitors of RNA-dependant DNA-polymerase(reverse transcriptase inhibitors)-Zidovudine, Stavudine, Lamivudine- Didanosine, Zelcitabine6) Late translation(late mRNA an protein synthesis)- Ribavirin -Interferons7) Posttranslational modifications(proteolytic cleavage)Protease inhibitors- Saquinavir, Indinavir, Ritonavir8) Assembly(packaging of viral nucleic acids)-Interferons -Rifampin9) Release(virion is releasing from cell) (budding)-Antiviral antibodies- Cytotoxic T lymphocytesNeuraminidase Inhibitors-Zanamivir, Oseltamivir
Mechanism of action of antiviral drugsInhibition of penetration of host cell• Amantadine and also Rimantadineinhibit uncoating and are effectiveagainst influenza A virus.• AmantadineCNS effects: insomnia, nervousness,lightheadedness.GI effects: anorexia, nausea, others.• RimantadineSame spectrum of activity,mechanism of action, andindications as amantadine. FewerCNS adverse effects. Causes GIupset.• Gammaglobulins neutralizeviruses.
Antiviral mechanism of action: Inhibitionof nucleic acid synthesis I• Acyclovir a guanosine derivative selectively inhibits viral DNApolymerase; minimal unwanted effects. Used to suppress replication of:– HSV-1(oral herpes), HSV-2(genital herpes), VZV (chickenpox orshingles), To some extend EBV and CMV.• Gancyclovir, also a guanosine derivative is phosphorylated and thenincorporated into viral DNA, suppressing its replication; used incytomegalovirus infections; especiallyCMV retinitis in AIDS patients.CMV retinitis– Ophthalmic form surgicallyimplanted.– Ocular injection (fomivirsen).Dose-Limiting Toxicities• Gancyclovir and zidovudine– Bone marrow toxicity.• Foscarnet and cidofovir– Renal toxicity.
Antiviral mechanism of action: Inhibitionof nucleic acid synthesis II• Vidarabine, an adenosinederivative, is a relatively selectiveinhibitor of viral DNA polymerase;effective against Herpes simplexand Varicella zoster; can haveserious unwanted effects.• Ribavirin is similar to guanosineand is thought to interfere withsynthesis of viral DNA; can inhibitmany DNA and RNA viruses.Given orally, or oral or nasalinhalation.Inhalation form (Virazole) used forhospitalized infants with RSV(respiratory syncytial virus)infections.
Antiviral mechanism of action: Inhibitionof nucleic acid synthesis III• Foscarnet inhibits viral DNA polymerase by attaching to thepyrophosphate binding site; approved for CMV infections.• Zidovudine, an analogue of thymidine, inhibits reversetranscriptase and is relatively effective in HIV infection.• Zalcitabine and didanosine are reverse transcriptaseinhibitors used in HIV infection.
Neuraminidaseinhibitors• Zanamivir and oseltamivirinhibits neuraminidasewhich is essential for virusreplication. They are usedagainst influenza A and B.They are for avian and swineinfluenza (H5N1 and H1N1respectively) which areinfluenza A subtypes.Zanamivir is used byinhalation; oseltamivirorally.• oseltamivir: causes nausea& vomiting• Zanamivir: causes diarrhea,nausea, sinusitis
Immunomodulators• Interferons induce, in the host cells’ ribosomes, enzymes whichinhibit viral mRNA; Interferon has broad spectrum anti-viral activityHSV 1 & 2, HZV, HPV (DNA viruses), influenza, chronic hepatitis,common cold, breast cancer, lung cancer, Karposi’s sarcoma (cancerassociated with AIDS) (RNA viruses).• ADRs: Flue like symptoms, neurotoxicity, myelosuppression etc.• Pavilizumab is a monoclonalantibody against fusion proteinsof respiratory syncytial virus.• Imiquimod is an immune responsemodulator used topically againstgenital and perianal warts.
The human immunodeficiency virus (HIV)and AIDS• Infection with HIV results in the acquired immune deficiencysyndrome (AIDS). In 1997 it was estimated that nearly 30 millionadults world-wide were infected with HIV, with the number ofHIV infections increasing by five every minute. The epidemic isoverwhelmingly centred on sub-Saharan Africa, where about7% of the population is infected.
The interaction of HIV with the hostsimmune system• The interaction of HIV with the hosts immune system iscomplex. Cells of the immune system have the equivalent of“name badges” that identify them. The surface glycoproteinCD4 is the name badge of a particular group of helper Tlymphocytes; it also occurs on macrophages and dendriticcells.
Highly active antiretroviral therapy• The advent of highly active antiretroviral therapy (HAART) haschanged the prognosis, in countries that can afford it. HAARTis a combination of three antiviral drugs including at leastone protease inhibitor. There are 20anti-HIV drugs available;six nucleoside reverse transcriptase inhibitors, four non-nucleoside reverse transcriptase inhibitors, one nucleotidereverse transcriptase inhibitor, eight protease inhibitors,and one fusion inhibitor. Most are discussed below.• With a HAART regime, HIV replication is inhibited -itspresence in the plasma being reduced to undetectable levels-and patient survival is prolonged; but the regime is complex,difficult to adhere to and may well have to be lifelong. It isalso extremely expensive-which effectively prevents its use indeveloping countries. In any case, with the high mutation rateof the virus, resistance is an important problem. HIV hascertainly not yet been outsmarted.
Zidovudine (Azidothymidine, AZT)• Zidovudine is an analogue ofthymidine. In retroviruses-such as theHIV virus-it is an active inhibitor ofreverse transcriptase. It isphosphorylated by cellular enzymes tothe triphosphate form, in which itcompetes with equivalent cellulartriphosphates which are essentialsubstrates for the formation of proviralDNA by viral reverse transcriptase(viral RNA-dependent DNApolymerase); its incorporation into thegrowing viral DNA strand results inchain termination.• Mammalian alpha DNA polymerase isrelatively resistant to the effect.However, gamma DNA polymerase inthe host cell mitochondria is fairlysensitive to the compound and thismay be the basis of unwanted effects.
Pharmacokinetic aspects of zidovudine• Given orally, the bioavailabilityof zidovudine is 60-80% and thepeak plasma concentration occursat 30 minutes. It can also be givenintravenously. Its half-life is 1 hour,and the intracellular half-life of theactive triphosphate is 3 hours.• Zidovudine enters mammalian cells by passive diffusion and inthis is unlike most other nucleosides which require activeuptake. The drug passes into the CSF and brain. Most of thedrug is metabolized to inactive glucuronide in the liver, only20% of the active form being excreted in the urine.
Unwanted effects of zidovudine• Anaemia and neutropenia are common, particularlywith long-term administration. Administration oferythropoietin and GM-CSF may alleviate theseproblems.• Other unwanted effects include gastrointestinaldisturbances, paraesthesia, skin rash, insomnia,fever, headaches, abnormalities of liver function and,more particularly, myopathy. Confusion, anxiety,depression and a flu-like syndrome are also reported.The prophylactic use of the drug, short-term, in fitindividuals, after specific exposure to the virus, isassociated with only minor, reversible unwantedeffects.
Resistance to the antiviral action ofzidovudine• Because of rapid mutation the virus is a constantlymoving target, thus the therapeutic response waneswith long-term use, particularly in late-stage disease.Furthermore, resistant strains can be transferredbetween individuals. Other factors which underliethe loss of efficacy of the drug are decreasedactivation of zidovudine to the triphosphate andincreased virus load due to reduction in immunemechanisms.
Didanosine(dideoxyinosine, ddl)• Didanosine is a synthetic purine dideoxynucleosideanalogue. It is phosphorylated in the host cell to thetriphosphate, dideoxyadenosine, in which form it acts asa chain terminator and inhibitor of the viral reversetranscriptase. It is used to treat AIDS.• Pharmacokinetic aspects of didanosineDidanosine is given orally, rapidly absorbed and isactively secreted by the kidney tubules. The plasma half-life is 30 minutes but the intracellular half-life is morethan 12 hours. The cerebrospinal fluid/plasma ratio is0.2.
Unwanted effects of didanosine• The main unwanted effect -occurring in >30% of patients-isdose-related pain and sensoryloss in the feet. Dose-relatedpancreatitis occurs in 5-10% ofpatients and has been fatal in afew cases. Headache andgastrointestinal disturbance arealso common and insomnia, skinrashes, bone marrow depression(less marked than with AZT) andalterations of liver function havebeen reported.
Zalcitabine(dideoxycytidine, ddC)• Zalcitabine, a synthetic nucleoside analogue, is used incombination with zidovudine for the therapy of AIDS. It is areverse transcriptase inhibitor and it is activated in the T cellby a different phosphorylation pathway from zidovudine. It isgiven orally, its plasma half-life is 20 minutes, its intracellularhalf-life is nearly 3 hours and its cerebrospinal fluid/plasmaratio is ~0.2.• Unwanted effects of zalcitabineThe most important unwanted effect is a dose-relatedneuropathy (which can increase for several weeks after thedrug has been stopped). Other unwanted effects includegastrointestinal disturbances, headache, mouth ulcers, nailchanges, edema of the lower limbs and general malaise. Skinrashes occur but may resolve spontaneously. Pancreatitis hasbeen reported.
Nevirapine• Mechanism Of Action:– Direct inhibitor of reverse transcriptase without intracellularphosphorylation.– NNRTIs bind to the Reverse transcriptase near the catalytic siteand cause its denaturation.– More potent on HIV-1 than Zidovudine but not HIV-2.– Cross resistance among themselves but not with others.• Kinetics:– Administered Orally. Plasma half-life – 20 min. Conc. in CSF –45% of that in plasma. Metabolism – Metabolized in the liverand metabolite is excreted in the urine (CYP3A4).– Nevirapine can prevent mother-to-baby transmission of HIV ifgiven to the parturient mother and the neonate• Unwanted effects:– Skin rash(17%), Fever, Headaches, Lethargy.– If not monitored carefully: Stevens-Johnson syndrome or Toxicepidermal necrosis.– Fulminant hepatitis (occasionally)• Dose: 200 mg/day
Other reverse transcriptase inhibitors• New nucleoside reverse transcriptaseinhibitors now in use include Lamivudine andStavudine. Non-nucleoside reversetranscriptase inhibitors now in use includenevirapine and delavirdine. All are givenorally.
Protease inhibitors• Host mRNAs code directly for functional proteins, but in HIV, theRNA is translated into biochemically inert polyproteins. A virus-specific protease then converts the polyprotein into variousstructural and functional proteins by cleavage at the appropriatepositions. Since this protease does not occur in the host, it is a goodtarget for chemotherapeutic intervention.• Several protease inhibitors have now been developed, and theiruse, in combination with reverse transcriptase inhibitors, hastransformed the therapy of AIDS. Examples of current proteaseinhibitors are: amprenavir, atazanavir, indinavir, fosemprenavir,nelfinavir, ritonavir and saquinavir.• They are all given orally and all can cause gastrointestinal disorders:nausea, vomiting and diarrhoea. Raised concentrations of liverenzymes in the blood are reported with ritonavir and indinavir.Ritonavir can cause paraesthesia around the mouth, and in thehands and feet, and patients on indinavir may develop kidneystones.
Protease inhibitors(continued)• All inhibit the cytochrome P450 enzymes (indinavir and saquinavirto a lesser extent than ritonavir) and can interact with other drugshandled by this system, and all can increase the plasmaconcentration of benzodiazepines. Preliminary evidence suggeststhat long-term use may lead to an unusual redistribution ofcutaneous fat.• Class-Specific Toxicities:NRTI Mitochondrial DNA toxicityNtRTI Proximal renal tubular dysfunctionNNRTI Hypersensitivity, RashPI Metabolic disorders
Fusion inhibitors• Enfuvirtide inhibits the entrance of HIV virus intohost cells. It is applied subcutaneously incombination with other anti-AIDS drugs.
Principles of HIV/AIDS therapy• Monitor plasma viral load and CD4 count.• Start treatment before immunodeficiencybecomes evident.• Aim to reduce plasma viral concentration asmuch as possible for as long as possible.• Use combinations of at least three drugs, e.g. tworeverse transcriptase inhibitors and one proteaseinhibitor.• Change to a new regime if plasma viralconcentration increases.
New Agents to Treat HIV InfectionPhaseReverseTranscriptaseInhibitorsProteaseInhibitorsEntryInhibitorsIntegrase/MaturationInhibitors;Immunologics2/3 Etravirine(TMC 125)Darunavir MaravirocVicrivirocMK-05182 BILR 355 BS TNX-355 GS-91371/2 AmdoxovirApricitabineRilpivirine(TMC 278)Brecanavir AMD 070PRO 542BevirimatCTLA4-mAb1 Fosalvudine PPL-100 PRO 140TAK 652Pre-clinical 22 7 21 11
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