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33 Cards in this Set
- Front
- Back
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Five Clinical Principles of Antiviral Use:
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1. Make a diagnosis accurately and promptly
2. Know the natural history of the disease 3. Evaluate (and alter, if possible) immune status 4. Early intervention 5. Assess risk/benefit ratio for each intervention |
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How do we make diagnoses accurately and promptly?
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-use clinical clues
rash, hepatitis, encephalitis, retinitis immune status - normal host vs AIDS vs transplant -rapid diagnostic tests 1993 viral culture - days, low sensitivity 2003 direct fluorescent antibody (DFA) tests - 1/2 day 2013 PCR or nucleic acid amplification tests (NAAT) – hours * "this is the future" * -imaging – e.g., characteristic appearance of Herpes simplex encephalitis on MRI |
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What things do you keep in mind when considering the natural history of the disease?
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-are you fairly certain of the diagnosis and will it resolve uneventfully without treatment? (common cold, Herpes labialis, chickenpox in a normal child).
-or is there a viral disease in your differential diagnosis that you need to treat early and aggressively with antiviral therapy? |
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Why is it important to treat flu and shingles as quickly as possible?
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*influenza --> antivirals are less effective with each passing day
*herpes zoster (shingles) --> reduced incidence of post-herpetic neuralgia if treated within 72 hours of rash onset. |
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Why is it important to consider the pt's immune status when considering antiviral use??
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-You may need to make a new diagnosis of an immunocompromising condition (which you may suspect based on the disease)
-Transplants, chronic immunosuppressants: stop or decrease immunosuppressants -AIDS: start antiretroviral therapy |
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Why do you want to do early intervention in starting antiviral therapy?
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-Viral burden is low
-Host damage is minimal early (think inflammation) -If immune response is weak, you definitely want to intervene early. |
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What kind of things do you consider when weighing risks/benefits of anti-viral therapy?
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-low morbidity disease (herpes labialis = cold sore) --> not willing to accept toxic or expensive therapy for a disease that will resolve without sequelae.
-high morbidity or mortality disease *CMV retinitis in AIDS --> blindness *CMV pneumonitis in BMT --> death *accept much higher toxicity (renal or bone marrow) to provide sight- or life-saving therapy |
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Virologic Principles of Antiviral Use:
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-Viruses are intracellular pathogens which utilize host cell functions for replication; inhibition of these functions cause toxicity in the host.
-Choose virus-encoded (virus-specific) functions for selective inhibition and less host toxicity. |
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Possible anti-viral targets based on characteristics of the virus life cycle?
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-You CANNOT inhibit DNA-DNA enzymes or DNA-RNA enzymes, because WE NEED these enzymes.
-Therefore, target RNA-DNA enzymes! |
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What Pharmacologic Principles of Antiviral Use should you keep in mind? 5
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1. mechanism of action
2. pharmacokinetics -dosage forms: intravenous, subcutaneous, oral, inhalation, topical -bioavailability: drugs and prodrugs -tissue distribution -metabolism and dose adjustment 3. side effects 4. drug interactions, including “boosting” 5. combination strategies (fixed dose combinations) *Bioavailability extremely important. *Tissue distro is important *Keep in mind adjustments may be needed accounting for renal insufficiency. |
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What are the ADMEs of antiviral meds?
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-Absorption – may be affected by acid, food, fat content. *Some pts may need to take drug with food for fat solubility purposes.
-Distribution – may be poor into fat, brain, prostate. Protein binding. -Metabolism – hepatic cytochrome P450, glucuronidation. -Elimination – renal excretion and/or hepatic metabolism and excretion into bile |
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Blood levels of a drug in the body over time.
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Blood levels of a drug in the body over time with multiple doses:
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-Trough concentration very important in HIB, bone marrow transplant patients, and other immunocompromised patients.
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What's the tgt in herpesviruses?
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viral DNA polymerase
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Drugs to treat herpesviruses:
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HSV/VZV: Acyclovir, Valacyclovir, Famciclovir
*common infections, commonly used drugs CMV: Ganciclovir, Valganciclovir, Foscarnet, Cidofovir *uncommon infections, uncommonly used drugs |
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nucleoside:
nucleoside analogue: nucleotide analogue: |
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Two mechanisms of action for Nucleoside and Nucleotide analogue antiviral drugs:
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-Competitive inhibition: e.g., azidothymidine (as AZT-TP) competes with dTTP.
-Chain termination: once AZT-TP is incorporated into the growing DNA chain, natural dNTP cannot be added. |
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How does Acyclovir work?
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-Mechanism of action: it's a nucleoside analogue.
selective uptake by virus infected cells vs uninfected cells (no toxicity) selective phosphorylation by viral thymidine kinase vs host thymidine kinase selective affinity for viral DNA polymerase vs host DNA polymerase |
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Pharmacologic properties of Acyclovir:
-how do we become resistant to it? -what kind of infections can you treat? -cleared by? |
-mechanism of resistance: absent or altered viral thymidine kinase, altered viral DNA polymerase
-clinical spectrum: Herpes simplex, Varicella zoster. 10 x more active against HSV 1 and 2 than against VZV -clinical pharmacology: oral, intravenous (topical) -cleared by the kidneys (so consider renal insufficiency) -side effects - uncommon -clinical use: oral/genital/perianal HSV, HSV encephalitis, neonatal HSV, Herpes zoster (shingles), chickenpox in high risk patients |
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What are disadvantages of Acyclovir?
How might we make a better drug? |
-LOW oral bioavailability -- 10-20%, must give lots
*SHORT half-life -- 3 hours, must be given 5x/d *HSV 200 mg 5x/day (1 g) *VZV 800 mg 5x/day (4 g) -PRODRUGS provide increased bioavailability, allow twice (HSV) or thrice (VZV) daily dosing. *Valacyclovir *Famciclovir |
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Why is Valacyclovir so great?
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-It's a prodrug: the L-valyl ester of acyclovir
-three to five times greater bioavailability than oral acyclovir -rapidly converted to acyclovir after oral administration -metabolism, distribution, elimination, toxicity same as acyclovir. |
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When would Famciclovir be useful?
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*Oral drug for herpes simplex and for varicella zoster.*
-It's a prodrug converted to active metabolite (penciclovir) by the liver -high oral bioavailability and prolonged intracellular half-life -70% excreted unchanged by the kidneys -also active against HBV and some ACV-resistant HSV -Penciclovir is available as topical preparation (Denavir) |
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Discuss Ganciclovir in all its enthralling nuances:
-mech of action- -what infections is it good for? -when can we become resistant to it? |
-Mechanism of action: nucleoside analogue
selective phosphorylation selective affinity -10 to > 50 fold more active against CMV than is acyclovir; also active against HSV -monophosphorylated by CMV protein kinase or HSV Thymidine Kinase; resistance is due to mutations in CMV protein kinase (UL97) or DNA polymerase (UL54) |
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Pharmacologic properties of Ganciclovir:
-clinical pharmacology -side effects -clinical use |
-clinical pharmacology:
not metabolized; adjust dose for renal insufficiency low oral bioavailability (<5%) (3000 mg = 12 pills/day) -side effects: granulocytopenia, thrombocytopenia -clinical use: *IV: CMV retinitis, colitis, esophagitis, polyradiculopathy in AIDS; CMV pneumonia in transplant patients *oral: maintenance/prophylaxis of CMV disease – now supplanted by oral valganciclovir *intraocular implant, intravitreal injections |
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How do we get ganciclovir in to the blood more efficiently?
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-Use a prodrug, fool. --> VALGANCICLOVIR
-prodrug: L-valyl ester of ganciclovir -60% oral bioavailability, rapidly converted to ganciclovir after oral administration -side effects: similar to IV ganciclovir -oral: induction and maintenance of CMV disease |
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What if you want to treat CMV but your first two choice drugs (what are they, btw?) don't work?
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-First try ganciclovir/VALGANCICLOVIR. If resistant, try Foscarnet.
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Foscarnet:
-structure/function: -when do you use it? -admin route? -problems with it? -conditions it treats? |
-pyrophosphate analogue: directly inhibits herpesvirus DNA polymerase by blocking the pyrophosphate binding site
-active against TK-deficient (ACV-resistant) HSV and VZV and GCV-resistant CMV -intravenous only -nephrotoxicity: dose-related, reversible, dose-limiting; anemia, not granulocytopenia -CMV retinitis, esophagitis, colitis, HIV-associated CMV myelopathy/polyradiculitis, Acyclovir-resistant HSV or VZV disease |
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Categories of agents for treating flu and examples of drugs in each:
-what does each do to the virus? |
1) M2 protein inhibitors – inhibit viral uncoating
*amantidine *rimantidine *You can't use these with H3N2 and that's what we've had recently* 2) Neuraminidase inhibitors – inhibit viral release *oseltamivir *zanamivir |
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How do M2 protein inhibitors work?
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-blocks ion movement into endocytotic vesicle through M2 protein (on influenza A only), thereby inhibits fusion of virus HA protein with endosome membrane, prevents viral uncoating and entry into cytoplasm
-mechanism of resistance: mutation in HA protein gene, allows virus to uncoat at higher pH -Amantadine: renal excretion -Rimantidine: hepatic metabolism, better tolerated -clinical spectrum: influenza A not B !!!!!!!!!!!!!!!!lol -since 2005-2006 >90% of H3N2 isolates resistant |
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Neuraminidase Inhibitors:
-what do you use them against? |
-active against influenza A & B and amantidine- and rimantidine-resistant viruses
-1.3 day reduction in time to clinical improvement |
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Discuss Oseltamivir:
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-IT's a Neuraminidase Inhibitor.
-high oral bioavailability -not metabolized by P450 enzymes -99% excreted by the kidneys; dose reduce for renal insufficiency -mild GI side effects (take with food) |
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Zanamivir:
-problems with it? |
-administered as a dry powder inhalation with low oral and systemic bioavailability
-<3% side effects in healthy adults -do not use in pregnancy -may cause bronchospasm in patient with COPD or asthma – not recommended -active vs oseltamivir-resistant seasonal, avian and 2009 H1N1 (swine) flu *this worked for Oseltamivir-resistant flu in 2009, so use in cases of resistance* |
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Discuss Ribavirin:
-moa? -form of intake? -uses? -risks? |
-mechanism of action: hypermutation and inhibition of RNA polymerase
-inhaled aerosol used for acute respiratory syncytial virus (RSV) pneumonia in children *may cause bronchospasm, complications of drug precipitation in mechanical ventilator tubing; *teratogenic to exposed health care workers -oral form used in combination with interferon for hepatitis C causes dose-related hemolytic anemia, teratogenic |
