ANTIVIRAL DRUGS DR. SOE AUNG MYINT Monday

Classification Purine and Pyrimidine Nucleoside Analogues (Resp. Syncitial,HBV,Herpes,CMV,HIV) Non-nucleoside inhibitors of reverse transcriptase (HIV) Direct inhibitor of DNA polymerase and RT – Foscarnet(Herpes,HIV) Protease Inhibitors (HIV) Interferon-alpha 2b (Hep. B&C) Others: Amantadine, Rimantadine (Influenza)

Nucleoside Analogues General Mechanism of Action 1.Taken up by cells 2.Converted by viral and cellualr enzymes to the triphosphate form 3.The triphosphate form inhibits: 1.DNA polymerase 2.Reverse transcriptase 3.RNA polymerase 4.Or it may get incorporated into growing DNA leading to abnormal proteins or breakage.

OVERVIEW Virus is an ifective agent that typically cosists of nucleic acid molecule in a protein coat Drugs prevent viral replication without injury to host Symptomatic stage of viral infection,administration of drugs block viral replication Some antiviral agents r useful as prophylactic agents

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A(H1N1)A(H2N2)A(H3N2) 1918: “Spanish Flu” 1957: “Asian Flu” 1968: “Hong Kong Flu” million deaths 1-4 million deaths Influenza Pandemics in the history historically resulted in highly lethal pandemics, because of “Antigenic shift”

TREATMENT OF RESPIRATORY VIRUS INFECTION Influenza A n B n respiratory syncytial virus(RSV) Outbreak due to virus not covered by vaccines Outbreaks occur among unvaccinated individuals at risk n in closed settings(Nursing homes)

(A)Neuraminidase inhibitors Orthomyxoviruses that cause influenza contain enzyme neuraminidase which is essential to life cycle of virus Enzyme can be blocked by sialic acid analogs, oseltamivir n zanamivir(Drugs) prevent release of new virions effective against both type A n type B influenza viruses

MOA Influenza virus inserted into host cell membrane for releasing newly formed virions Oseltamivir n zanamivir serves as inhibitors of enzyme activity

Pharmacokinetics Oseltimivir is an orally active prodrug that is rapidly hydrolyzed by liver to its active form Zanamivir is not active orally but inhalation Both drugs are eliminated unchanged in urine

Adverse effects GI discomfort,nausea (oseltimivir) Irritation of respiratory tract(Zanamivir should be avoided in individuals with severe reactive asthma or COPD → bronchospasm will occur)

RESISTANCE Mutations of neuraminidase have been indentified in adults treated with neuraminidase inhibitors Mutants r less infective n virulent

(B)Inhibitors of viral uncoating Amantadine n rimantadine r limited to influenza A infections Equally effective in both Tx n Prevention Both drugs reduce the severity of systemic symptoms Tx is useful in high risk patients who have not been vaccinated n during epidemics

Amantidine Oseltamivir (Tamiflu) Zanamivir (Relenza) 75 mg capsule Treatment – 1 capsule twice a day for 5 days Prophylaxis – 1 capsule/day 5 mg per inhalation Treatment – 2 inhalations twice a day for 5 days Prophylaxis – 2 inhalations/day

MOA Primary antiviral mechanism of amantidine n rimantadine is to block the viral membrane matrix protein which as a channel for hydrogen ion,required for fusion of viral membrane with host cell Interfere with release of new virions

PHARMACOKINETICS Well absorbed orally (both drugs) Amantidine distributes throughout body n readily penetrates into CNS Rimantadine does not across the blood brain barrier

ADVERSE EFFECTS Amantadine r associated with CNS..insomnia,dizziness, and ataxia n more serious effects (hallucinations n seizures) Rimantadine causes fewer CNS reactions Both drugs cause GI intolerance n used with caution in pregnant n nursing mothers Embryotoxic n teratogenic in rats

RESISTANCE Rapidly in up to 50% of treated individuals Resistsnce strains can be readily transmitted to close contacts Cross resistance occurs b/t 2 drugs

(C)RIBAVIRIN Synthetic guanosine analog(nucleoside analog) Effective against a broad spectrum of RNA n DNA viruses Used in treating infants n young children with severe RSV infections(not for adults) Also effect in chronic hepatitis C when used in combination with interferon- α-2b.

MOA Ribavirin-triphosphate which exerts antiviral action by inhibiting guanosine triphosphate formation, preventing viral mRNA capping,and blocking RNA- depedent RNA polymerase.

PHARMACOKINETICS Effective orally n intravenously Increase absorption when taken with fatty meal An aerosol is used in certain respiratory conditions,RSV infections Drug n its metabolites r eleminated in urine

ADVERSE EFFECT Dose dependent transient anemia(oral n parenteral) Elevated bilirubin reported Aerosol is safer CI in pregnancy

TREATMENT OF HEPATIC VIRAL INFECTIONS Hepatitis viruses identified A,B,C,D n E Replication n destruction of hepatocytes Hepatitis B n C r most common causes of chronic hepatitis, cirrhosis n hepatocellular carcinoma n r the only hepatic viral infections for which therapy is currently available. Hepatitis A is commonly encountered infection but not chronic disease

Chronic hepatitis B is usually treated with peginterferon- α-2a, SC,once weekly(interferon-α-2b IM or SC 3-times weekly is also useful) Oral therapy includes lamivudine, adefovir,enetecavir or telbivudine Combination therapy of interferon +lamivudine is more effective than monotherapy AIDS patients with hepatitis B r poor responders to interferon therapy Chronic hepatitis C is treated with combination of peginterferon- α -2a or peginterferon- α-2b+ ribavirin

(A)Interferon Naturally occuring inducible glycoproteins that interfere with ability of viruses to infect cells Synthesized by recombinant DNA technology 3 types of interferon alpha,beta n gamma. Interferon alpha 2 b has ben approved for treatment hepatitis B n C

MOA Inhibit viral RNA translation, ultimately leading to degradation of viral mRNA n tRNA

Pharmacokinetics Is not active orally May be administered intralesionally, subcutaneously or intravenously Metabolised by liver n kidney

ADVERSE EFFECTS On injection flu-like symptoms,such as fever, chills, myalgias,arthralgias n GI disturbances. Fatigue n mental depression r common these symptoms r subsided by subsequent administration Bone marrow suppression including granulocytopenia,neurotoxicity characterized by somnolence n behavioral disturbances, severe fatigue n wt loss, autoimmune disorder such as thyroiditis CHF, actue hypersensitivity n hepatic failure r rare

DRUG INTERACTION Interferes with hepatic drug metabolism n toxic accumulations of theophylline Potentiate the myelosupression caused by other bone marrow- depression agents,such as zidovudine

(B)LAMIVUDINE Nucleoside analog is an inhibitor of both hepatitis B virus(HBV) DNA polymerase n human immunodeficiency virus(HIV) reverse transcriptase Reduce hepatic inflammation Must be phosphorylated by host cellular enz to triphosphate active form Absorbed orally widely distributed,plasma half life is 9hrs,70% is excreted unchanged in urine Rarely occur headache n dizziness

(c)ADEFOVIR Adefovir dipivoxil is a nucleotide analog that is phosphorylated to adefovir diphosphate Termination of viral DNA synthesis n prevent viral replication Once a day,excreted in urine Decreased viral load n improved liver function Caution with existing renal dysfunction

(D)Entecavir Guanosine analog approved for treatment of HBV infections Has been shown to be effective against lamivudine-resistant strains of HBV Liver inflammation n scarring r improved

(E)TELBIVUDINE Thymidine analog used in treatment of HBV Unlike lamivudine n adefovir,telbivudine is not effective against HIV or other viruses

TREATMENT OF HERPESVIRUS INFECTIONS Herpesvirus r associated with broad spectrum of diseases ex,cold sores,viral encephalitis, n genital infections(the latter being a hazard to newborn during parturition) Effective against at acute phase but without effect at latent phase Except for foscarnet n fomivirsen, all r purine or pyrimidine nucleotide analogs that inhibit viral DNA synthesis

Antiherpes virus agents - Acyclovir- Ganciclovir - Valacyclovir- Idoxuridine - Famciclovir- Sorivudine - Penciclovir- Trifluridine - Foscarnet- Vidarabine

(A) ACYCLOVIR Prototypic antiherpetic therapeutic agent Herpes simplex virus(HSV) type 1 n 2,varicella-zoster virus (VZV) n some Epstein-Barr virus-mediated infections r sensitive to acyclovir It is treatment of choice in HSV encephalitis n more efficacious than vidarabine Most common use of acyclovir is therapy for genital herpes infections Can be given prophylactically

ACYCLOVIR ACYCLOVIR (Acycloguanosine) synthetic purine nucleotide analog MOA: Acyclovir viral thymidine kinase monophosphate  diphosphate  active triphosphate  incorporated into viral DNA & ▼ herpes viral DNA (selective for infected cell) polymerase (selective for infected cell)

Pharmacokinetics -oral bioavailability % -well distributed -can be given orally, intravenously or topically - -can be given orally, intravenously or topically -peak hr -excreted by kidney, partly by GFR & partly by tubular secretionUses - chronic & recurrent mucocutaneous Herpes (esply in immunocompromised patients) - neonatal herpes - Herpes simplex encephalitis - Varicella Zoster infection Untoward effects -minimal -IV - local inflammation if extravasation -nausea, headache, diarrhoea -rarely encephalopathy renal dysfunction when acyclovir is given IV; slow infusion reduces the risk

Valacyclovir ( prodrug ) -converted to acyclovir -use for genital herpes and herpes zoster Famciclovir, Penciclovir -effective against HSV, VZV, EBV, HBV MOA- competitive inhibitor of viral DNA polymerase

Ganciclovir Ganciclovir -similar to acyclovir -100 times more active against HSV, CMV in vitro -drug of choice for CMV infection Pharmacokinetics given by IV route -low oral bioavailability, given by IV route, well distributed, -excreted unchanged in urine Most common adverse effect: bone marrow suppression (leukopenia 40%, thrombocytopenia (20%) and CNS effects (headache, behavioral, psychosis, coma, ocnvulsions).

Foscarnet (Trisodium phosphonoformate) -inhibits viral DNA polymerase, RNA polymerase -also inhibits HIV reverse transcriptase -effective against HSV, CMV, VZV, EBV, HHV-6, HHV-8, & HIV Uses -retinitisCMV -retinitis (CMV in HIV patients) -acyclovir resistant HSV -HIV patients (Zidovudine + Foscarnet) -prophylaxis & treatment of CMV infection in transplant patients Untoward effects - serious nephrotoxicity -hypo or hypercalcaemia, hypo- or hyperphosphatemia -HA, tremors, seizures, hallucinations, fever, N, V serious serious unwanted actions including bone marrow depression & potential carcinogenicity

Other Nucleoside Analogues Vidarabine Poor solubility, give i.v. with big volume of fluids (2.5 L) ⇒ risk of fluid overload Toxicity: GI; Bone marrow; Hypokalemia; inappropriate ADH secretion; (psychosis; painful neuropathy; Not a drug of choice for anything. Replaced by Acyclovir because of toxicity and problems in administration. Idoxuridine and Trifluridine Topical agents for Herpes keratitis Trifluridine also for CMV and others Trifluridine better for H. simplex II keratoconjuctivitis

Antiretroviral agents 1. Nucleoside reverse tran­scriptase inhibitors: -zidovudine*, lamivudine*, emtricitabine, stavudine*, didanosine*, abacavir*, tenofovir* 2. Non-nucleoside reverse transcriptase inhibitors: -Efavirenz*, nevirapine* 3. Protease inhibitors: -Indinavir*, Lopinavir*, Ritonovir*, Amprenavir, Atazanavir, Saquinavir 4. Inhibitors of HIV fusion with host cells: -Enfuvirtide(Fuzeon) 5. Entry inhibitors (CCR5 co-receptor antagonist) : -Maraviroc 6. HIV integrase inhibitor: -Raltegravir(N.B.* locally available agents)

A ‘little’ HIV treatment is very dangerous Treatment needs to be ‘all or nothing’ Weak treatment (less than 3 drugs) or missing doses (even one dose a week) will lead to resistance, and the combination will fail Once resistance develops it never reverses Resistance will make the next combination less likely to succeed - because there is cross-resistance between most drugs in each class How to get treatment right

Anti-retroviral Agents(Nu Ana) Zidovudine (AZT) Cellular enzyme phosphorylate to the triphosphate form which inhibits RT and causes chain termination Adverse effect: – Granulocytopenia and anemia: 45% in AIDS but 5% if asymptomatic HIV – Severe headache, nausea, insomnia, myalgias ↓mortality & opportunistic infections, weight gain, better quality of life, delays signs and symptoms of AIDS

Other Retroviral RT Inhibitors Other nucleoside analogs: didanosine, stavudine, zalcitabine: same as AZT but can cause peripheral neuropathy and pancreatitis. Can be used with AZT for enhanced effect and less toxicity. Non-nucleoside RT inhibitors: e.g. neviparine. Noncompetitive binding to RT and direct inhibition at a site different from AZT and others. May be active against AZT-resistant strains. Can be used in combination. Main adverse effect is rash

Protease Inhibitors Produce non-infectious particles or virions Reduces the number of new rounds of infection in susceptible cells To be effective must be prolonged, profound and constant. Pharmacokinetics important to maintain constant concentrations within the effective range. Metabolic adverse effects (DM, hyperglycemia) and GI (diarrhea, pain vomiting).

Fig. 3. HIV-1 virion forms. (a) Particles assembling and budding at the cell membrane. (b) An immature virus particle. (c) Mature forms of HIV-1.

Prevention of Mother to Child Transmission (PMCT ) during pregnancy initiated at weeks up to onset of labour – oral AZT 600 mg/day in divided dose During labour IV. AZT 2mg/kg in 1 hr followed by 1 mg/kg/hr till delivery Infant AZT 2mg/kg 6 hrly up to 6 weeks Transmission rate decreased (9% compared to 19% for control) Nevirapine 200 mg single oral dose at onset of labour and 2mg/kg single oral dose at hrs after delivery (47%  )

Nucleoside reverse transcriptase inhibitors include -----a. Nevirapine -----b. Zidovudine -----c. Ritonavir -----d. Didanosine -----e. Abacavir N Y N Y Y

Check: a. Amantadine is used in influenza A -----b. Acyclovir is used in herpes simplex -----c. Acyclovir selectively inhibit viral DNA synthesis -----d. Interferon  2b is contraindicated in HBV -----e. Lamivudine is useful in treatment of HBV Y Y Y N Y

Check the following statements: a. Amnatidine interfere with uncoating and release of release of viral gene into the host cell b. Zidovudine is contraindicated in AIDS related complex c. Acyclovir is guanine derivative d. Interferon act indirectly by stimulating immune system e. Vidarabine can inhibit nucleic acid synthase Y N Y Y Y

Check the following statements: a. Amantadine is used in influenza A b. Acyclovir is used in herpes simplex c. Gamma globulin may attenuate hepatitis by neutralizing virus d. Interferons act directly on uninfected cells to induce enzyme that degrade viral RNA e. Interferon alpha 2b is contraindicated in HBV Y Y Y Y N