Antiviral pharmacology OT 628:Pharmacology in Rehabilitation

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Anti-viral pharmacologyOT 628Pharmacology in
Rehabilitation

• Kim Benner, Pharm.D.
• Samford University McWhorter School of Pharmacy
• March 26, 2003

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Background

• Common viruses
• DNA viruses (adenovirus, hepatitis,
  cytomegalovirus, Epstein-Barr, Herpes, Varicella)
• RNA viruses (hepatitis, flu, measles/mumps, RSV,
  polio, rhinovirus, HIV, rabies, rubella)
• Viral replication
• Adsorption
• Penetration/uncoating
• Biosynthesis
• Virus takes over to make more viral RNA/DNA
• Maturation and release
• Mature viruses are released from host cell

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Non-HIV antivirals

• For Herpes family viruses such as simplex (HSV),
  zoster, varicella (VZV), Epstein-Barr virus
  (EBV)
• acyclovir (Zovirax)
• valacyclovir (Valtrex) prodrug of acyclovir
• famciclovir (Famvir)
• penciclovir (Denavir) topical for cold sores
• vidarabine (Vira-A) opth. ointment for HSV

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Herpes anti-virals

• These drugs work by inhibiting viral DNA
  synthesis and viral replication. Must be
  phosphorylated, then incorporated into viral DNA
• acyclovir can be given orally, intravenously, or
  topically
• valacyclovir and famciclovir are oral meds
• penciclovir is topical only

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Adverse effects of acyclovir, etc.

• Oral meds
• CNS dizziness, lethargy, headache, insomnia,
  hallucinations
• See more when used with zidovudine
• GI nausea/vomiting/diarrhea
• Derm rash, alopecia
• Muscular myalgias, parasthesia, tremors
• Topical meds
• Locally pain and stinging

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Anti-virals for Influenza A

• amantadine (Symmetrel)
• Also treats Parkinson disease
• rimantadine (Flumadine)
• Block uncoating of virus/prevent release of viral
  DNA
• Useful for prophylaxis of flu
• Limited use for treatment as they only decrease
  the severity and length of symptoms and

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Adverse effects of amantadine, etc

• CNS dizziness, confusion, insomnia, difficulty
  concentrating, restlessness
• Can administer several hours before bedtime
• Especially problematic in elderly
• Large doses may increase severity
• Pts should avoid alcohol
• amantadine gt rimantadine
• Urinary retention

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Newer agents for the fluNeuraminidase
inhibitors

• Inhibit influenza neuraminidase enzyme which
  prevents virus aggregation and release
• Being studied to prevent influenza
• zanamivir (Relenza)
• uses inhalation device for 5 days
• oseltamivir (Tamiflu)
• Available as a capsule/suspension
• Must use within 48 hrs of symptoms
• bronchospasms are rare side effects also
  dizziness, drowsiness

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Cytomegalovirus (CMV)

• Can affect many organs (eyes, colon, esophagus,
  brain)
• Spread through blood or secretions
• Commonly affects immunosupressed pts.
• CMV retinitis is a common manifestation in AIDS
  patients
• Can also be congenital, perinatal or cause
  mononucleosis

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Treatment options for CMV

• ganciclovir (Cytovene) 1st line
• Inhibits viral DNA replication
• Primarily hematologic side effects
• Also mood changes, tremor, visual disturbances
• foscarnet (Foscavir) 2nd line
• Also inhibits viral replication but does not
  require phosphorylation
• Lip tingling, numbness, parasthesias may occur
• Can be toxic to kidneys
• Confusion, dizziness, fatigue common also may
  see amnesia and hallucinations
• May affect bone growth
• cidofovir (Vistide) newer agent
• also nephrotoxic
• Affects blood counts and may cause fever, chills,
  sore throat

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Other antivirals

• Ribavirin (Virazole) for RSV, influenza A/B?
• Impairs RNA synthesis
• Administered via nebulizer
• Teratogenic caregivers need to take precautions
• Interferons a, ß, or ?
• for cancer, MS, hepatitis
• Adverse effects
• Flu-like symptoms
• Depression New Psychiatric Warnings out!

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Human Immunodeficiency virus (HIV)

• Two human retroviruses (HIV-1 or-2) cause the
  syndrome of AIDS
• RNA virus uses reverse transcriptase to produce
  viral DNA and replicate
• Profound immunodeficiency due to helper T
  cells
• Progression dictated by falling CD4 counts and
  increasing viral load
• Susceptible to many opportunistic infections such
  as Pneumocystis carinii pneumonia (PCP),
  tuberculosis (TB), CMV and Cryptococcal infections

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Antiretrovirals for HIV

• Three classes of agents inhibit reverse
  transcriptase (RTIs)
• Either purine or pyrimidine based nucleoside or
  nucleotides (NRTIs or NtRTIs)
• Must be converted to metabolite
• Non-nucleoside or nucleotide based (NNRTIs)
• After transcription and translation occur, viral
  assembly occurs with the help of protease
• Protease inhibitors (PIs) reversibly bind to
  viral protease which prevents assembly and
  therefore production of new virus particles

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Anti-retrovirals for HIV

• Reverse transcriptase inhibitors
• Nucleoside reverse transcriptase inhibitors
  (NRTIs)
• zidovudine (Retrovir )
• didanosine (Videx )
• lamivudine (Epivir )
• stavudine (Zerit )
• zalcitabine (Hivid )
• abacavir (Ziagen )
• Nucleotide reverse transcriptase inhibitor
  (NtRTI) tenofovir (Viread)

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Adverse effects of NRTIs

• nausea/vomiting
• CNS excessive fatigue, HA, dizziness, insomnia
• myopathy (weakness, tenderness)
• peripheral neuropathies common with this class of
  agents (esp. with higher doses)
• abacavir has been associated with a
  hypersensitivity reaction

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Non-nucleoside reverse transcriptase inhibitors
(NNRTIS)

• delavirdine (Rescriptor )
• efavirenz (Sustiva)
• nevirapine (Viramune)
• Adverse effects
• CNS headaches, dizziness, insomnia
• Hallucinations common with efavirenz
• GI N/V, GI upset
• Rashes may resolve
• Can use Benadryl for itching
• More common with nevirapine/efavirenz
• Liver dysfunction

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Protease inhibitors (PIs)

• amprenavir (Agenerase )
• indinavir (Crixivan )
• nelfinavir (Viracept )
• ritonavir (Norvir )
• saquinavir (Fortovase , Invirase )
• Adverse effects
• Nausea/vomiting/diarrhea
• Alteration in fat deposition
• Fatigue, depression, confusion
• Arthralgias, paresthesias, weakness
• Many can crystallize in kidneys

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Combination anti-retrovirals

• Combivir (zidovudine lamivudine)
• Trizivir (zidovudine lamivudine abacavir)
• Kaletra (lopinavir ritonavir)

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Typical anti-retroviral regimen

• All HIV pts who meet criteria for therapy should
  be on HAART (Highly active anti-retroviral
  therapy)
• Utilizes at least three agents
• DHHS guidelines recommend for initial therapy
• 2 NRTIs 1 PI OR
• 2 NRTIs 1 NNRTI OR
• 2 NRTIs 2 PIs

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Anti-retroviral regimens

• May not work in all patients
• Limitations
• Side effects
• Resistance
• Drug interactions
• Almost all agents metabolized in liver by
  cytochrome p450 enzymes
• Majority inhibit metabolism of other medications
• Logistics some may be on mega-HAART and may take
  up to 20 pills a day!

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AIDS manifestations affecting ADL

• Neurological (dementia)
• Neuromuscular neuropathic pain due to
• Peripheral neuropathies
• Myopathies
• Opportunistic Infections
• Viral infections can cause a variety of pain
• Bacterial infections TB is most common
• Fungal infections
• Protozoal infections PCP is most common

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Questions and Case Discussion