ANTI VIRAL Agents
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Transcript of ANTI VIRAL Agents
ANTI VIRAL Agents
Kaukab Azim, MBBS, PhD
Viruses
Features of Antiviral Drugs•Purine or pyrimidine analogs•Prodrugs must be phosphorylated•Antivirals have a narrow spectrum of action•Inhibit active replication; do not kill latent viruses, need host immune response •Resistance is common•Synergistic effects when given together•Efficacy relates to con. in infected cells •Start therapy early for optimal efficacy
A good antiviral drug will
Interfere with a viral specific function
Only kill virus-infected cells
Prevent viral replication
Sites Of Anti Viral Drug ActionEnfuvirtide, maraviroc
Indinavir
Oseltamivir
Reltegravir
B
C
D
Classes
• Class I Antinfluenza agents• Class II Antiherpetic agents• Class III Antiviral for HBV & HCV• Class IV Antiretroviral therapy (ART)• Class V Agents against human Papiloma
virus and RSV
Viruses susceptible to drug therapy
• DNA Viruses1. Herpes virus (HSV 1 & HSV 2)2. Varicella Zoster (VZV)3. Cytomegalovirus (CMV)4. Hepatitis B virus
• RNA Viruses 1. Hepatitis C 2. HIV (Retro virus) 3. Respiratory syncytial virus 4. Influenza A & infl. B viruses
Treatment of Influenza AAMANTADINE
• MOA: Inhibits uncoating no penetration
• Uses: Prophylaxis & treatment, • S/E: CNS: insomnia & restlessness
Livedo reticularis• dose in renal dysfunction• Good alternative to a vaccine in the elderly or in
immuno compromised patients
OSELTAMIVIR: Tamiflu
• Prophylaxis and treatment of Influenza A and B
• Neuraminidase inhibitor
OSELTAMIVIR: Tamiflu• Flu virus attaches to host cell membrane –
hemagglutinin on viral envelope binds to sialic acid moiety in glycoprotein of cell membranes
• Neuraminidase enzyme cleaves viral attachment
• Neuraminidase inhibitor keep the virus tethered to the host cell membrane; prevent it from being released and thus spreading to other cells
Treatment of HSV, VZV and CMV
• ACYCLOVIR• GANCICLOVIR• FOSCARNET • Compete with dGTP for viral DNA-
polymerase & inhibit viral DNA synthesis • 1st two are purine analogs• Acyclovir and Ganciclovir are prodrugs• Foscarnet acts directly on DNA
polymerase
ACYCLOVIR: guanine analogMOA: Inhibits HSV replication
Acyclovir
Acyclo-MP
Acyclo-DP
Acyclo-TP(ACTIVE DRUG)
Viral thymidine kinase
Cell kinase
Cell kinase
Incorporated into growing DNA strand
Chain termination
Stops viral replication
Competes with dGTP for viral
polymerase
USES of ACYCLOVIR
• Genital Herpes: 1st episode viral shedding,
duration of symptoms• Orolabial herpes: Topical/ oral acyclovir
(penciclovir)• Herpes encephalitis: Acyclovir I/V• Varicella zoster: Oral, till all lesions
encrusted I/V in disseminated CNS
or Visceral infection• Cytomegalovirus: Prophylaxis only (prevent
CMV infection in transplant patients)
Use in pregnancy: for 1st episode of genital H. to prevent neonatal herpes (H.pneumonia)
Side effects: NEPHROTOXIC (reversible crystalline nephropathy) Encephalopathy (rare)Resistance:Mutations occur in the thymidine kinase gene causing an enzyme that does not phosphorylate acyclovir
Occurs more in HIV+ive people
A 23-year-old man had recurrent genital herpes which was effectively treated each time by acyclovir. The patient asked his physician why the treatment was not able to prevent recurrence. Which of the following was most likely the answer of the physician?
A) Acyclovir has a very short duration of actionB) Recurrence is due to a new contact with infected partnersC) Antiviral drugs have no effect on the latent state of viral diseasesD) Recurrence is due to a hypersensitivity reaction to viral proteinsE) Resistant to acyclovir is the rule after one cycle of therapy
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GANCICLOVIR1st drug effective against CMV
Uses: Cytomegalovirus (CMV):
Acute infection (retinitis, pneumonia in AIDS)
Prophylactic (in transplant patients, AIDS)
S/E: Bone marrow toxicity (granulocytopenia & thrombocytopenia)
Drug Interactions:DO NOT give with ZIDOVUDINE (overlapping myelosuppression toxicities)
A 31-year-old man with AIDS was recently diagnosed with cytomegalovirus pneumonia. The patient’s current medications included zidovudine, didanosine and saquinavir. An IV therapy with ganciclovir was started. Which of the following adverse effects could be most likely predicted from the concurrent administration of ganciclovir and the antiretroviral drugs?
A) Anemia and neutropeniaB) Retinal detachmentC) CataractD)Sexual dysfunctionE) HyperglycemiaF) Lactic acidosis
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FOSCARNET (alternate to Ganciclovir for CMV)
Not a prodrug!
Uses: CMV infections Acyclovir-resistant HSV encephalitis
MOA: Directly inhibits DNA polymerase
S. Effect: Decrease in Renal function, hypocalcaemia, teratogenic, mutagenic & carcinogenic drugDrug Interactions:Cyclosporine (renal toxicity), Pentamidine (hypocalcaemia), Imipenem (seizures)
Wide Spectrum anti viral RIBAVIRIN: Respiratory Syncytial Virus (given by aerosol only)
Hepatitis C
MOA: Synthetic analogue of nucleoside; inhibits GTP synthesis & , inhibits 5 ̀ capping of viral mRNA, RNA-dependant RNA polymerase (MAO not known exactly)S/ E: Headache, insomnia, anemia, teratogenesisUses: Severe RSV infection with serious underlying respiratory, CV problems or immuno compromisedC.I: Pregnancy
HEPATITIS B: Lamivudine (ARV drug) • Inhibits HBV-DNA polymerase & HIV- reverse-
transcriptase by competing with dCTP • Uses:
1. Chronic Hepatitis B infection with evidence of active viral replication
• 2. HIV infectionSE: N/V, headache, insomnia, fatigue
HEPATITIS B: INTERFERONs
• Interferon -2b & INF- : CytokineBroad spectrum antivirals, Immuno modulator activity, Antiproliferative actions; progression of liverDz in HBVS/E: Many, Flu-like syndrome, Bone marrow suppression
A 10-days old baby girl/ an AIDS pt. e low CD+4/ or bone marrow transplant pt. is suffering from RSV pneumonitis,
what is the treatment of choice?
1. Lamivudine2. Ribavirin3. Oseltamivir
HEPATITIS C: Peg-interferon Ribavirin
PAPILLOMAVIRUS: Imiquimod For topical treatment of perianal & external genital warts (cream)
Stages in Retrovirus development
Anti retroviral agents• 4-5 big classes
1) Protease Inhibitors 2) Nucleoside reverse transcriptase Inhibitors 3) Non-nucleoside reverse transcriptase inhibitors 4) Fusion Inhibitors
5) Integrase inhibitors
Retrovirus & Anti retroviral agents
Drugs in different classes
NRTIs Non NRTIS Protease inhibitors
Zidovidine NEVIRAPINE SAQUINAVIR
Didanosine DELAVIRDINE INDINAVIR
Stavudine EFAVIRENZ RITONAVIR
Lamivudine ATAZANAVIR
ART• Antiretroviral therapy (ART) is begun when:
Symptomatic disease is present, regardless of CD+4 count and viral load OR
• Patient has CD+4 < 350 cells/mm3 with any value of RNA copies per milliliter– OR
• Plasma HIV RNA viral load>10,000-20,000/ml • HIV infection assoc with lots of symptoms
Malaise, fever, blood disorders, neurological, opportunistic infections etc. difficult to separate these effects from the side effects of the drugs
Zidovudine (NRTIS)• Inhibit reverse transcriptase – prevent conversion of
viral RNA to DNA• All NRTIs nucleoside analogs e.g. Zidovudine
(azidothymidine- AZT) a thymidine analog• NRTIs: narrow therapeutic window, dose limiting
toxicities (mainly due to mitochondrial toxicity and inhibition of cellular DNA polymerases)
• In toxicity– withdraw drug until symptoms clear or become tolerable OR the drug has to be discontinued
AZT
AZTmonophosphate
AZT diphosphate
AZT triphosphate
Thymidine kinase (host)
Thymidylate kinase
Cell Kinase
Incorporated into
Viral DNA strand
Chain elongation is terminated at thymidine residues
(lack of 3’-OH group)
No viral DNA formed
Resistance• Major cause of treatment failure• Likelihood of resistance:
duration of therapy Advancing disease
• Due to point mutations in reverse transcriptase enzyme
• 33% patients on monotherapy with AZT become resistant within a year
• Use a combination of NRTIs so that there are different point mutations
• R5 viral strains & Maraviroc (new; fusion inhibitor)
Maraviroc is a:
1. Reverse T. Inhibitor2. CCR5 inhibitor3. Protease inhibitor
NRTIs MAJOR TOXIC EFFECT
ZIDOVUDINE Bone marrow suppression, myopathy & lactic acidosis (LA)
LAMIVUDINE LESS TOXIC THAN ABOVE
DIDANOSINE NEUROPATHY, Hepatitis (LA), PANCREATITIS
ABACAVIR HYPERSENSITIVITYREACTIONS, MYOPATHY
STAVUDINE NEUROPATHY, Hepatitis (LA)PANCREATITIS (no myopathy)
Maykota, a 42 year old company executive visited his physician complaining of mouth sores. On questioning he stated that he had been feeling unwell for the past couple of weeks. He felt tired and had lost his appetite. On examination, the physician noted white plaques in his mouth and a generalised lymphadenopathy. ResultsELISA: HIV positiveCD4+ count: 350 mm3
mouth swab positive for Candida albicans
The physician decided to prescribe antiretroviral drugs for him and clotrimazole or nystatin for the Candida infection.The antiretroviral drugs he was prescribed were a combination of efavirenz, lamivudine and abacavir (treatment naive patient)
These 3 drugs are typical of the HAART regimen. 2 NRTIs together are synergistic.HAART: Highly Active Anti Retroviral TherapyNow called ART: Antiretroviral Therapy (ART)
NON NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs)
•NEVIRAPINE•Delavirdine•Efavirenz
MOA: Bind directly to reverse transcriptase
Allosteric inhibition of enzyme function
Blocks transcription of viral RNA to DNA
Note: They are NOT pro drugs!
Pharmacokinetics Of NNRTIsWell absorbed orally
Enter CNS (nevirapine more than the others)
Metabolized in the liver by cytochrome P450 enzymes
Excreted by the kidney
Lot of potential (cyp450) for drug interactions
Toxicity: Relatively low toxicity, also effect lipid profileToxicities do not overlap with NRTIsMajor toxicity: Skin rashes
Drug InteractionsNevirapine INDUCES enzymes: P.Is (protease inhibitors)
(saquinavir, ritonavir, indinavir, nelfinavir, amprenavir)
Contraceptives
Efavirenz……………. Zidovudine
Indinavir
Antiepileptics level
Delavirdine INHIBITS enzymes: P.Is
An HIV positive female developed rash after 3 Months of treatment with efavirenz & switched
to nevirapine. She is expected to have:
1. Impaired lipid profile2. Decreased OCP levels3. Increased biliary excretion
Protease Inhibitors (Do not need to be prodrugs)• SAQUINAVIR• Indinavir• Ritonavir
MOA: Blocks the protease enzyme
Prevent the cleavage of the gag and gag-pol protein precursors causing the formation of immature, non-infectious particles.
Can inhibit cell to cell spread of the virus
Gag is a polyprotein and is an acronym for Group Antigens (ag).Pol is the reverse transcriptase.Env in the envelope protein.
ToxicitySaquinavir: GIT disturbances
Indinavir: “trunkal obesity” (Cushing-like syndrome)
Nephrolithiasis (kidney stones)
Hemolytic anemia
Ritonavir: Paresthesias
Drug Interactions
All INHIBIT cytochrome P450 enzymes
High potential for drug interactions!
Ketoconazole: toxicity of saquinavir
Delavirdine: toxicity of saquinavir and indinavir
Rifampin: efficacy of all P.Is
Ritonavir: rifampin toxicity
FUSION INHIBITORS ENFUVIRTIDE, Maraviroc
MOA: Prevents the fusion of HIV with the host cell membrane
Uses: To treat AIDS which is progressing despite HAART
Integrase inhibitor
• Integration of viral DNA into host DNA• First approved HIV-integrase inhibit. • Raltegravir - integrase inhibitor• Use: Detectable viremia & treatment failure in
pt e triple class experience• Short term efficacy
Adherence
• A major determinant of degree and duration of viral suppression
• Poor adherence associated with virologic failure
• Optimal suppression requires 90-95% adherence
• Suboptimal adherence is common
Antiretroviral Medications: Should not be offered at any
time • Regimens not recommended:
– Monotherapy (except possibly zidovudine to prevent perinatal HIV transmission)
3-NRTI regimen (except abacavir/lamivudine/ zidovudine and possibly lamivudine/zidovudine + tenofovir
– NRTI-sparing regimens
A 43-year-old man with AIDS presented to his physician with a complaint of multiple painful ulcers in tongue and palate. Exfoliative cytology was done which led to the diagnosis of herpes simplex infection, and a therapy with oral acyclovir was initiated. Two weeks later no improvement was seen and the dose of the drug was increased but without success. Which of the following was most likely the cause of failure of acyclovir therapy?
A) Mutation of aspartate proteaseB) Viral transpeptidase deficiencyC) Viral thymidine kinase deficiencyD) Viral neuraminidase deficiencyE) Mutation of reverse transcriptase
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