antiviral presentation.pdf

PHARMACOLOGY _ ANTIVRALS A Virus is an obligate intracellular parasite that contain either double- or single-stranded DNA or RNA enclosed in a protein coat (called a capsid). Outside of a host, a virus exist as a particle. Some viruses also poss...

PHARMACOLOGY _ ANTIVRALS A Virus is an obligate intracellular parasite that contain either double- or single-stranded DNA or RNA enclosed in a protein coat (called a capsid). Outside of a host, a virus exist as a particle. Some viruses also possess a lipid envelope that, like the capsid, may contain antigenic glycoproteins. Note that: Viruses Lack both cell wall and cell membrane They do not carry out metabolic processes. Most viruses contain or encode enzymes essential for viral replication inside a host cell → they usurp the metabolic machinery of their host cell Structure of a typical viruses Replicative cycle of a DNA and RNA virus 1) Attachment of the virus to the host cell 2) Entry of the virus through the host cell membrane 3) Uncoating of viral nucleic acid 4) Synthesis of early regulatory proteins, e.g., nucleic acid polymerases 5) Synthesis of RNA or DNA 6) Synthesis of late, structural proteins 7) Assembly (maturation) of viral particles 8) Release from the host cell The process above leads to the lysis of the host cells. DNA viruses are transcribed in the host cell nucleus. Most RNA viruses complete their replication in the cytoplasm, some viruses such as influenza are transcribed in the nucleus Below is a table containing different types of viruses  ANTIVIRAL AGENTS Act by: 1) Block viral entry into host cell 2) Block viral exit from the host cell 3) Active inside the host cell Few drugs are selective enough to prevent viral replication without injury to the host cell Nonselective inhibitors of virus replication may interfere with host cell function and lead to toxicity Effective agents:  Have a restricted spectrum of antiviral activity  Target a specific viral protein, most often an enzyme involved in viral nucleic acid synthesis (polymerase or transcriptase) or a viral processing protein (protease)  Most agents inhibit active replication virus.  Effective host immune responses are essential for recovery from infection  Not eliminate non- replicating or latent virus  Clinical efficacy requires inhibitory concentrations at the site of infection (within infected cells)  Most drug-resistant viruses are recovered from immunocompromised patient or those with chronic infections (e.g., HBV) with high viral loads and repeated or prolonged courses of antiviral treatment. TREATMENT OF RESPIRATORY VIRUS INFECTIONS Respiratory virus infections include:  Influenza (type A and B)  Respiratory syncytial virus (RSV) Immunization against influenza A is the preferred approach. Antiviral agents is indicated when: 1) Patients are allergic to vaccine 2) The outbreak is due to an immunologic variant of virus not covered by vaccines 3) The outbreaks occur among unvaccinated individuals who are at risk and in closed settings.  A. ANTI-INFLUENZA VIRUS DRUGS I. NEURAMINIDASE INHIBITORS:  Neuraminidase enzyme:  Present in the orthomyxoviruses  Essential for life cycle of the virus  Inserted into the host cell membrane → releasing newly formed virions  Include: OSELTAMIVIR (TAMIFLU®) and ZANAMIVIR (RELENZA®) These agents have a broader-spectrum activity covering influenza A, B and avian-influenza (bird flu) and other strains. When they are administered prior to exposure, they prevent infection. When they are given within the first 24- 48 hrs after the onset of infection they produce modest effect on the intensity and duration of symptoms Contraindication May include; hypersensitivity to zanamivir or lactose Mechanism of action: They inhibit influenza virus neuraminidase enzyme thus, the virions accumulate at the internal infected cell surface preventing the release of new virions and their spread from cell to cell. Resistance: result from mutation of the neuraminidase Pharmacokinetics (Oseltamivir)  Administered. orally  Prodrug hydrolyzed in the liver to its active form (oseltamivir carboxylate).  Excreted by the kidney with a t½ of 6- 10 hrs. Pharmacokinetics (zanamivir)  Administered as an inhaled powder due to very low oral bioavailability or intranasally  Excreted by the kidney with a t½: 2-5 hrs. Adverse effects Bronchospasm, Cough, headace, dizziness, rash, delirium, hallucination, seizure. Nausea, diarrhea and abdominal can also be seen in Oseltamivir Nursing responsibilities 1. Be alert for seizures especially at the onset of the drug treatment and report findings to the physician immediately.  2. Monitor for signs of allergic reaction including pulmonary symptoms( tightness in the chest and throat, wheezing, cough, dyspnea or skin reaction e.g rash (especially with zanamivir) and notify physician immediately 3. Be alert for delirium, hallucination, agitation or other abnormal behaviour. 4. Give Oseltamivir with food in order to reduce G.I disturbances 5. When administering zanamivir, assess any breathing problem and report signs of brochospam. 6. Instructs patient and family or caregiver to report other troublesome side effects such as nightmares. II. INHIBITORS OF VIRAL UNCOATING Examples: Adamantine derivatives: amantadine and rimantadine These agents effective only against type A influenza.  Effective in both treatment and prevention  If treatment is begun at the time of – or prior to exposure to the virus, they are 70-90% effective in preventing infection  If started within the first 48 hrs after exposure to virus it reduces the duration and severity of systemic symptoms  Support the immune response to influenza A administered as a supplement to vaccination Clinical Use Prophylaxis of influenza A during an epidemic or seasonal, esp. in high risk patient Treatment of influenza (A) illness reducing fever, congestion and cough (A 5 day treatment is advised). Amantadine: also use in the treatment Parkinsonism Contraindications: Epilepsy and other CNS disease; gastric ulcer, pregnancy. Mechanism of action: The primary mechanism is by blocking the viral membrane matrix protein, M2, which function as an ion channel for hydrogen ion, this channel is required for the fusion of viral membrane with the cell membrane that ultimately which forms the endosome (the acidic environment of endosome is required for viral uncoating). Resistance:  Develops by mutation causing amino acid substitutions in the M2 protein.  Cross – resistance occurs between the two drugs Pharmacokinetics (Amantadine)   Well absorbed orally  Distributes throughout the body  Readily penetrates into the CNS  Not extensively metabolized  Excreted unchanged in urine (t½ 16 hrs) and can accumulate to toxic levels in patients with renal failure Pharmacokinetics (Rimantadine)  Well absorbed orally  Not cross the BBB to the same extent  Extensively metabolized by the liver  Long-acting (½ 30 hr)  Eliminated by kidney Adverse effects GI tract intolerance, nausea, anorexia, Minor (insomnia, dizziness, ataxia, nightmares) and serious (hallucination and seizures) Nursing Responsibilities 1.Monitor patients who have a history of psychiatric illness or substance abuse because amantadine may worsen these conditions. Some patients taking amantadine have attempted suicide or had suicidal ideation. 2. If patient has a history of heart failure or peripheral edema, monitor for weight gain and edema because drug may cause redistribution of body fluid. Instruct patient to take amantadine exactly as prescribed and not to stop abruptly. Advise patient to notify prescriber if drug becomes less effective. 3. Tell patient to notify prescriber if influenza symptoms don’t improve after 2 to 3 days. iii. RIBAVIRIN It is a synthetic guanosine analog. It has broad-spectrum antiviral activity, including that against influenza A and B, RSV and many other DNA and double stranded RNA viruses. Uses: 1) As nebulized for severe RSV bronchiolitis in infants and children, particularly those with congenital heart disease, prematurity or other high risk conditions. 2) Chronic Hepatitis C (HCV) infection (+ interferon –α- 2b) 3) Lassa fever (Reduce mortality and viraemia) 4) Influenza A/B, measles, and herpes virus infections Mechanism of action: First, the drug is converted to ribavirin – triphosphate which inhibits GTP formation, thus preventing viral mRNA coping by blocking RNA-dependent RNA polymerase, finally inhibiting viral RNA synthesis Note: Rhinoviruses and enteroviruse are relatively resistant to ribavirin (because they contain preformed mRNA Adverse effects: 1) Parenteral use: dose – dependent transient anemia, haemolysis, CNS and GI symptoms (prominent toxic effects) 2) Aerosol treatment: irritation of mucosa and bronchospasm in infants. 3) Teratogenic in animals → contraindicated in pregnancy Nursing Responsibilities  Be alert for signs of cardiac arrest, and seek immediate medical assistance if the patient collapses, loses consciousness, stops breathing, and lacks a pulse.  Monitor signs of hemolytic anemia, including unusual weakness and fatigue, dizziness, jaundice, and abdominal pain. Report these signs to the physician immediately.  Assess blood pressure periodically and compare to normal values Report low blood pressure (hypotension), especially if patient experiences dizziness or faintness.  Assess any breathing problems, and report difficult or labored breathing (dyspnea).  Assess any joint pain to rule out musculoskeletal pathology; that is, try to determine if pain is drug induced rather than caused by anatomic or biomechanical problems.