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MOD 10 am June 9, 2003 Dr. Luedtke Ryann McClennen Page 1 of 10 ANTIVIRAL DRUGS I. Background A. Viruses are consisting of a. Nucleic acid (RNA or DNA) b. Protein coat or capsid B. Some Viruses may also contain a. Antigenic viral glycoproteins b. enzymes for replication c. single or double stranded nucleic acid “Built for speed NOT comfort” C. Examples a. DNA viruses poxvirus (small pox), Herpesvirus (chicken pox, shingles, herpes), adenovirus (sore throat, conjunctivitis), papillomavirus (warts) b. RNA viruses orthomyxoviruses (influenza), paramyxoviruses (measles, mumps), rubella virus (german measles, rhabdoviruses (rabies), retrovirus (AIDS, T-cell Leukemia), arenavirus (meningitis, Lassa fever), hepadnavirus (serum hepatitis), arbovirus (arthropod-borne encephalitis) D. General Viral life cycle represents certain points for antiviral therapy II. Antiviral Drugs A. General a. Viruses share the metabolic processes of host cells, therefore, difficult to find selective antiviral drugs. b. Generally, by the time viral infection becomes diagnosed viral replication is advanced and chemotherapy is difficult. c. For many life-threatening viral infections, there is no cure and the antiviral drugs simply improve quality of life (AIDS and Herpes) d. Best strategy is prevention B. Purine and Pyrimidine Analogues –Commonn Mechanism of action that inhibits viral nucleic acid synthesis. C. HIV and AIDS a. 1st figure 10 yo from 1995 b. WHO estimated that in 1993 13 million individuals would be infected with HIV. In 2000 36.1 million people world wide were infected and living with AIDS world wide 3 million people died of AIDS in 2000 21.8 million people have died of AIDS 2 >750,000 total AIDS cases had been reported in the USA 82% males 17% females 1% children c. Course of HIV Infection 1. virus interacts with CD4 and chemokine receptors 2. Symptoms: fever, headache, swollen lymph, rash 3. increase in number of viral particles in the blood 4. wide spread dissemination of viral particles in the body 5. after several weeks, viremia is reduced 6. after clinical latency symptoms of AIDS appears, including: a. opportunistic infection b. neurological disease c. bone marrow depression d. cancer e. chronic GI infections/severe weight loss f. cardiovascular and kidney damage g. death d. RNA retrovirus replication 1. virion contains reverse transcriptase, 2. viral encoded DNA integrates into the host genome a as provirus 3. virally coded DNA is transcribed into genomic RNA and mRNA 4. translation of viral proteins 5. virus is released by budding 6. virus can replicate without killing the host cell 7. some RNA retroviruses transform normal cells to malignant cells Anti-AIDS Drugs (know generic name NOT common name i.e. Know Zidovudine not just AZT) Nucleoside Reverse Transcriptase Inhibitors (NRTI) 1. Zidovudine (AZT) - azido (N3) thymidine analogue (nucleotide analogue) Clinical Use i. reduces the incidence of opportunistic infections stabilizes weight, reverses HIV-associated dementia and reduces viral burden ii. delays the onset of AIDS in HIV-positive patients. AZT alone delays the progression of the disease, but does not alter the median survival time. Poorly tolerated by patients and ineffective in late stage of AIDS iii. reduces the risk of transmission of the virus from HIV mothers to fetus (66% reduction of risk). iv. After specific exposures to the HIV virus (i.e., after accidental needle-stick injury) 3 AZT given as prophylactic therapy with lamivudine (3TC) and a protease inhibitor. The effectiveness of this strategy in preventing HIV transmission is unclear. Mechanism i. analogue of the pyrimidine thymidine ii. phosphorylated by cellular enzymes to the triphosphate derivative (Must be modified to be activated) iii. inhibitor of reverse transcriptase. iv. mammalian alpha DNA polymerase is not effected however mitochondria gamma DNA is effected. Administration i. i.v and oral (60-80% bioavailability) ii. Glucuronidation in the liver causes inactivation. iii. Probenecid inhibits hepatic inactivation/ renal excretion. iv. Agents which undergo glucuronidation may alter AZT metabolism (i.e. St. John’s Whart enhances the metabolism of AZT) Side Affects anemia, neutropenia (agranulocytosis)/ long term administration GI disturbances, paresthesia, skin rash, insomnia, fever, headache abnormalities of liver function and myopathy Resistance The therapeutic response to AZT wanes with long-term use. Viral resistance due to mutation of reverse transcriptase. Increasing viral load due to immunosuppression 2. Zalcitabine (ddC) - synthetic cytosine nucleoside analogue. Used in combination with AZT. Mechanism i. inhibitor of reverse transcriptase. ii. activated in T cells by a different phosphorylation pathway than AZT (Selectively unique to T-cells) Administration oral Side affects i. dose-related neuropathy ii. GI disturbances, headache, mouth ulcers, nail changes, edema of lower limbs and general malaise. 3. Lamivudine (3TC)-2'-deoxy-3'-thiacytidine (3TC) Clinical Use AIDS in combination with zidovudine (AZT). Mechanism i. a dideoxynucloside terminates the synthesis of the proviral DNA ii. inhibiting reverse transcriptase Administration oral Side Affects pancreatitis can develop in pediatric patients Resistance 4 resistance to AZT develops more slowly when given in combination with 3TC (decrease rate of mutations) 4. Didanosine (ddI) – purine dideoxynucleotide ananlogue Clinical Use Switching to didanosine after AZT therapy has been shown to be beneficial in AIDS therapy. Mechanism i. phosphorylated in the host to a triphosphate ii. chain terminator and inhibitor of viral reverse transcriptase Administration Oral- rapidly adsorbed (even better with antacids) Increased Bioavailability Side Affects i. dose-related peripheral neuropathy and pancreatitis ii. headache and GI disturbances, insomnia, skin rash,bone marrow depression and alteration of liver function Resistance After prolonged therapy, but is less than AZT NonNucleoside Reverse Transcriptase Inhibitors (NNRTI) 1. Nevirapine (BI-RG-587; Viramune) Clinical Use i. Treatment of AIDS and AIDS related symptoms ii. Prevention of transmission of HIV virus from infected mothers to newborns A study of African HIV compared the effects of AZT and Nevirapin on the ability to prevent HIV-1 transmission for mothers to newborns during birth. AZT Nevirapine Infection % 25% 13% Cost $1,000 $4 Mechanism i. Binds to the lipohilic pocket of RT to allosterically distort the polymerase active site. ii. Acts synergistically with NRTIs Side Effects Rash (16%) within 6 weeks of treatment on trunk, face and Extremities, fever, fatigue headach nausea Resistance Rapid if given alone, Decreased rate of resistance if given with NRTIs 2.Delavirdine (BHAP U-90152) Mechanism i. Binds to the lipohilic pocket of RT to allosterically distort the polymerase active site. ii. Acts synergistically with NRTIs iii. Inhibits the P-450 system, so decreases the metabolism of protease inhibitors. (Don’t worry about this, but it effects any other drugs in 5 system) Side Effects Rash (not as sever as with Nevirapine) Resistance Rapid if given alone, Decreased rate of resistance if given with NRTIs Second Generation NNRTI currently approved by the FDA. Experimental evidence indicates that the resistance to second generation NNRTIs may occur less rapidly. (Second generation NNRTI – Efavirenz) (NOT on Drug List) Protease Inhibitors (First to extend life span) Clinical Use Treatment of HIV Mechanism i. Inhibition of HIV-1 protease. HIV-1 protease is an member of the aspartyl class of proteases and is essential for the final stage of viral formation. ii. Gag-pol 160-kDA precursor protein undergoes autocatalytic cleavage to form HIV-1 proteases. The active enzyme then hydrolyses the precursor protein to generate the proteins required for viral formation. The proteases inhibitors interfere with this viral formation leading to immature, noninfectious virions. (Inhibits large protein therefore non-infective viron) In vitro studies indicate that the combination of reverse transcriptase inhibitors and protease inhibitors is at least additive and usually synergistic. 1. Indinavir (Crixivan) Side Effects increase bilirubin without other hepatic abnormalities and nephrolithiasis due to crystallization of drug in urine Resistance resistance emerges rapidly at suboptimal doses. essential to administer the protease inhibitors at maximum tolerated doses and in combination with reverse transcriptase inhibitors. 2. Nelfinavir (Viracept) Side Effects diarrhea, asthenia, headache and moderate hypertension 3. Ritonavir (Norvir) Side Effects nausea, vomiting and diarrhea elevated hepatic aminotransferase and triglyceride levels 4. Saquinavir (Invirase) Side Effects mild diarrhea, abdominal discomfort and nausea low bioavailability (4-5%)/ metabolized by P-450 co-administration with rifamycin or cabamazepine can further decrease plasma concentrations Resistance 6 resistant variants emerge in 45% of patients after 1 yr appears to be due to a single amino acid mutation at either position 48 or 90. Cross Resistance- to indinavir and ritonavir can also occur, but requires 3 to 11 amino acid changes AIDS Drugs are given in combination 1st choice 2 NRTIs + Protease Inhibitor 2nd choice 2 NRTIs + NNRTI 3rd choice NTRI + NNRTI + PI E. Herpes Simplex Virus a. General 1. HSV-1 and HSV-2 2. DNA virus. 3. Humans are the only host 4. A sexually transmitted disease generally not seen before puberty. 5. 500,000 cases per year b. HSV-1 1. Oral involvement HSV-1 is found in oral mucosa and oral cavity; Found in sensory neurons causes recurrent lesions known as cold sore or fever blisters 2. Ocular involvment can infect cornea of the eye immune response leads to scarring, clouding and blindness; Antibodydependent complement-medicated lysis of infected cells of the cornea c. HSV-2 1. Genital Herpes -- both HSV-1 and HSV-2 are sexually transmitted HSV-2 is the major cause of genital herpes 2. Maternal – fetal transmission HSV-2 can be spread to fetus during delivery resulting in encephalitis and disseminated herpes infections [ 6% of children become infected; 60% of infected newborns will die likely due to an immature immune system] d. Pathogenesis of Genital HSV 1. Initial infection Onset 5 days after sexual contact First episode ends 20-30 days Initial symptoms generally more severe than recurrent episodes 2. Recurrence pain and itching 4-5 days lesions 10-14 days Reoccurring lesions 4-5/ year Anti-Herpes Drugs 7 1. Acyclovir (Zovirax) Clinical Use a. varicella-zoster (VZV) infections (shingles) i. orally if immunocompotent ii. i.v. for immunocompromised patients b. herpes simplex infection (genital herpes, mucocutaneous herpes and herpes encephalitis) i. prophylactic treatment in immunocompromised patients ii. prophylactic treatment in patient with recurring genital infection with herpes virus. c. varicella (chicken pox) in immunocompromised hosts Mechanism i. Acyclovir is converted to the monophosphate by thymidine kinase (viral enzyme) ii. The monophosphate is converted to the triphosphate by mammalian kinases. iii. Acyclovir-triphosphate inhibits viral DNA-polymerase (30x more selective at herpes virus enzymes than at host enzymes) Side Affects i. local inflammation during i.v injection ii. renal dysfunction if given i.v. too rapidly iii. nausea and headache Resistance Herpes simplex virus isolates that are resistant to acyclovir have been obtained from immunocompromised patients. Mutations in the viral genes for thymidine kinase or DNA polymerase 2. Valacyclovir (Valtrex) Clinical Use similar to acyclovir Mechanism i. an L-valyl ester of acyclovir. (PRO DRUG) ii. almost completely metabolized to acyclovir. iii. higher bioavailability than acyclovir. (More efficient at getting the drug into the system) Administration Oral Side Affects Generally well tolerated. Side effects are generally similar to acyclovir. 3. Vidarabine (Vira-A) - adenine arabinoside purine nucleotide (alanine perinucleotide analogue) Clinical Use i. herpes simplex virus in neonates ii. Herpes associated encephalitis iii. varicella-zoster virus infections in AIDS patients iv.* second-line drug after Acyclovir.* With Resistance to Acyclovir 8 Mechanism i. phosphorylated by cellular kinases to a triphosphate ii. The triphosphate inhibits of viral DNA polymerase. Administration slow i.v. administration or topically Side Affects i. nausea, vomiting and diarrhea ii. neurotoxicity late in therapy with high doses/reversible iii. bone marrow disturbances have been reported iv. can be carcinogenic (Acyclovir is generally more effective for herpes with less toxicity, therefore it is the first choice. However, Vidarabine is a second choice drug for HSV resistant to acyclovir. Foscarnate is also used and is more effective and less toxic) 4. Idoxuridine (Herplex) - pyrimidine analogue of thymidine Clinical Use herpes simplex and varicella-zoster infections in eye Mechanism i. idoxuridine is phosphorylated by cellular kinases ii. the triphosphate derivative is incorporated into both viral and host DNA. Administration topically dissolve in dimethylsulfoxide (DMSO) [Solvent very toxic therefore only used as topical] Side Affects i. irritation (due to DMSO)/ contact dermatitis ii. used topically only it is a mutagen and too toxic for systemic use F. Cytomegalovirus a. Ubiquitous DNA herpesvirus b. Most infections during normal childhood and adulthood are asymptomatic. c. Immunosuppressed patients, such as organ or bone marrow transplant patients or patients on cancer chemotherapy, CMV may be reactivated resulting in interstitial pneumonia. d. AIDS patients, CMV often disseminates to visceral organs causing chorioretinitis (inflammation of the choriod and retina), gastroenteritis and neurological disorders 1. Ganciclovir (Cytovene) - synthetic guanosine nucleoside purine analogue. It is structurally similar to Acyclovir. Clinical Use a. 100 x more active than acyclovir for cytomegalovirus (CMV) b. life-threatening or sight-threatening CMV infections in immunocompromised patients. c. prevent CMV infection in transplantation patients *In AIDS patients* It is difficult to administer ganciclovir and AZT simultaneously 9 because they both cause granulocytopenia. Mechanism i. initial phosphorylation of ganciclovir is performed by a protein kinase encoded by CMV ii. Ganciclovir is converted to the triphosphate iii. The triphosphate competes with guanosine triphosphate for incorporation into viral DNA Not broken down rapidly, persists in cell for 18-20 hours. Administration i.v. Side Affects i. bone marrow suppression ii. severe myelosuppressive if given with zidovudine iii. potentially carcinogenic and teratogenic 2. Foscarnet (Foscavir) - a non-nucleoside analogue, an inorganic pyrophosphate analogue Clinical Use Second-line drug for CMV eye infection in immunocompromised patients Mechanism i. inhibits viral DNA polymerase ii. binds to the pyrophosphate-binding site Administration i.v. Side Affects serious nephrotoxicity/ reversible/ kidney dialysis. Resistance CMV strains resistant to foscarnet reported G. Lassa Fever a. West African arenovirus hemorrhagic fever transmitted from rodents to humans. b. Symptoms are fever associated with hemorrhagic manifestations, shock, neurological disturbances and bradycardia. c. Diagnosis is suggested by recent travel to West Africa and clinical symptoms. Any patient suspected of being infected should be isolated/public health authorities notified. d.Due to high risk of the spread of infection from fluids and excreta, routine laboratory studies are best deferred until diagnosis and specimen disposition is resolved 1.Ribavirin (Virazole) - adenosine/guanosine analogue. Clinical Use (DRAMATIC advance in treatment) i. Used to treat viral respiratory infections including influenza, respiratory syncytial virus (RNA paramyxovirus) ii. Used to treat early stages of Lassa fever, an arenovirus infection. Reduces to 9% a case-fatality; rate previously at 76%. Mechanism alters both viral DNA and viral mRNA synthesis. 10 Administration i.oral ii.aerosol (influenza and respiratory infections) iii.i.v. for Lassa fever Side Affects (Very Toxic) i.teratogenic, embryotoxic and oncogenic ii.anemia ( dose-related and reversible) H. Hepatitis Virus - hepatitis means inflammation of the liver a. Hepatitis A: self-limiting/ asymptomatic b. Hepatitis B: 1. acute -fatigue and nausea 2. increasing liver involvement 3. jaundice/ darkening of urine 4. chronic hepatitis leading to liver failure c.Hepatitis C: 1. mild symptoms at onset 2. longterm infection can lead to chronic liver disease 3. most common reason for liver transplantation in the USA Hepatitis C risk factors 1. injection of illicit drugs 2. sexual partners with HCV 3. living in prison or juvenile detention centers 4. body-piercing or tattoos 5. health care workers exposed to infected blood 6. newborns of HCV-infected mothers Anti-Hepatitis Drugs HBV interferon α2b HCV interferon α2b & Ribavirin 1. Interferon (IFN) (α, β and γ interferon) are inducible proteins synthesized by mammalian cells. 2. Interferons are involved in cell growth, regulation and modulation of the immune response. Clinical Usage α-2b-IFN - hepatitis B and C, Kaposi sarcomas & hairy cell leukemia Mechanism i. Thought to induce host enzymes that inhibit the translation of viral mRNA. ii. Receptors of IFN may be cell surface gangliosides, which cause inhibition of viral replication. Side Affects i. Common fever, lassitude, headache and myalgia (muscle pain). ii. bone marrow suppression, cardiovascular changes, rashes, alopecia, alter thyroid & renal function. iii. exacerbate autoimmune diseases such as thyroiditis iv. acute, reversible hearing loss and/or tinnitus.