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Pharm-Y2S1B2
Antivirals
| Drug | Features |
|---|---|
| Antiviral agents | fewer options, limited MOAs, ideally works to inhibit viral-specific fxns and causes minimal host cell metabolic disturbances; target depends on type of virus |
| Most viruses are obligate intracellular parasites | require host mechanisms for replication; difficult to design drugs to target viral replication w/o damaging host |
| Non-HIV viral infections | herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), influenza A & B, hepatitis B & C, papillomavirus, respiratory syncytial virus (RSV) |
| Herpes simplex virus | dsDNA virus; skin/mucous membranes; vesicles; common STD; recurrent; a/w immunocompromised; |
| HSV-1 | localized mainly around oral region |
| HSV-2 | mainly localized around genital region |
| Varicella-zoster virus | belongs to a group of herpes viruses including: HSV-1, HSV-2, VZV, CMV, EBV, HHV-6, HHV-7 |
| VZV disease manifestations: Varicella | "chicken pox" - 75-95% of cases occurs in kids <10yo |
| VZV disease manifestations: Herpes Zoster | "shingles" - virus becomes active after bein latent usu face/trunk; occurs in 10-20% of those who had chickenpox; uknown cause of reactivation (age, immunosuppression, cancer) |
| Antiviral Agents for HSV and VZV | nucleoside analogs (systemic) and topical/ocular agents |
| Nucleoside analogs (guanosine derivatives) | acyclovir (zovirax), famciclovir (famvir), valcyclovir (valtrex); all have similar MOA/indications/but different pharmokinetics |
| Drugs for HSV: Systemic Therapy - oral, genital, mucocutaneous HSV | acyclovir, famciclovir, valcyclovir |
| Drugs for HSV: Systemic Therapy - HSV encephalitis | acyclovir |
| Drugs for HSV: Systemic Therapy - Acyclovir-resistant HSV (severe infxn, immunocopromised) | Foscarnet (foscavir) |
| Drugs for VZV: Systemic Therapy - Varicella | Acyclovir |
| Drugs for VZV: Systemic Therapy - Herpes Zoster | acyclovir, famciclovir, valcyclovir |
| Drugs for VZV: Systemic Therapy - Acyclovir-resistant VZV | Foscarnet |
| Acyclovir | available topical, PO, IV (the ONLY IV in this class); primary use HSV1, HSV2, VZV, CNS, visceral, disseminated infxns; can dec risk of transmission to baby w/maternal genital herpes; Great data; |
| Acyclovir MOA | requires 3 steps to be activated; enter cell (convert to acyclovir monophosphate by thymidine kinase); Add 2Ps (forms acyclovir triphopshate); Competes w/dGTP for viral DNA polymerase; Incorporated into viral DNA & stops elongation |
| Acyclovir Pharmokinetics | oral dose 5x/day; short half-life; poor bioavailability (15-20%); renal clearance; large volume of distribution |
| Acyclovir: Topical | treats oral herpes outbreaks; reduces duration by 1/2 day (must apply 5x/day for 4 days) |
| Acyclovir: IV | encephalitis, disseminated disease |
| Acyclovir: PO | genital herpes initial/recurrent outbreak and daily suppressive; Oral herpes; Herpes Zoster; Varicella |
| Acyclovir: adverse effects | Oral (GI disturbances, headache); IV (phlebitis, renal dysfxn - crystalizes in kidney; make sure pt is hydrated; dose on IBW) |
| Famciclovir | PO only! Used for: HSV-1, HSV-2, VZV; if HSV and VZV are resistant to acyclovir that are usually resistant to this drug too |
| Famciclovir MOA | metabolized to penciclovir in the body, works in a similar manner to acyclovir |
| Famciclovir Pharmokinetics | extensive first-pass metabolism to penciclovir (PCV); nucleoside analog similar to acyclovir; Improved bioavailability (77%); Longer intracellular half-life in PCV triphosphate form (10-20hrs) drops dose to 3x/d |
| Famciclovir: PO | genital herpes initial outbreak/recurrent outbreak and daily suppressive; Oral herpes; Herpes Zoster |
| Famciclovir: adverse effects | headache, nausea, diarrhea |
| Valacyclovir | PO only! HSV-1, HSV-2, VZV (HSV and VZV acyclovir-resistant strains also resist this drug) |
| Valacyclovir: MOA and Pharmokinetics | same as acyclovir; Valine ester prodrug of acyclovir metabolized to acyclovir; Results in blood levels 3-5x higher than acyclovir; less frequent dosing |
| Valacyclovir: PO | genital herpes initial/recurrent oubreak and daily suppression (once daily dosing; reduces transmission risk); Oral herpes (once daily dose); Herpes zoster |
| Valacyclovir: Adverse Effects | GI disurbances, HA; TTP/HUS (thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in HIV pts w/high dose) |
| Topical Therapy for Orolabial HSV | acyclovir (zovirax), penciclovir (denavir), docosanol (abreva) |
| Ocular Therapy for Keratoconjunctivitis (ocular herpes) | Trifluridine (viroptic) |
| Zovirax | prescription only, similar to systemic product; apply 5x/day for 4 days |
| Denavir | prescription only, similar MOA to acyclovir; apply every 2hrs while awake for 4days; decresaes healing time by 0.7days |
| Abreva | available OTC; inhibits fusion btw HSV and plasma membrane preventing entry into cells; apply 5x/day ($16); if started w/in 12hrs it decreases healing time by 1/2day |
| Trifluridine | nucleoside analog; **active against Acyclovir-Resistant Strains of HSV;** irreversible inhibition of thymidylate synthetase (incorporates thymidine into viral DNA); incorporates into cellular DNA (precludes systemic use) |
| Acyclovir Resistance | mostly limited to immunocompromised (5-10% in AIDS pts; 18% in bone marrow transplants; 0.6% in immunocompetent); Mechanisms: Viruses deficient in TK/altered substrate specificity of TK (can't recognize ACV or ACV-3P/altered viral DNA polymerase enzymes |
| CMV | infects 50-85% of adults in US by age 40 (frequ transmitted to child b/f birth); more widespead in low class; some experience mono-like syndrome; virus stays dormant for life (recurs rarely unless immunocompromised) |
| Drugs for CMV | Systemic: ganciclovir (cytovene), valganiciclovir (valcyte), foscarnet (foscavir), cidofovir (visitide); Ocular: ganciclovir (vitrasert), fomivirsen (vitravene) |
| Ganciclovir | PO, IV, intra-ocular implant; Mostly used for CMV (also effective but toxic for resistant HSV, VZV but foscarnet is more active) |
| Ganciclovir MOA | similar to acyclovir, except it is initially phosphorylated by enzyme UL97 (NOT thymidine kinase (TK)) |
| Ganciclovir Pharmokinetics | poor oral bioavailability (5% inc to 9% w/food); Renal excretion; dose adjust |
| Ganciclovir Place in Therapy | Tx of systemic CMV (lungs, colon, esophagus); CMV retinitis; prevention of CMV in transplant, immunosuppressed pts |
| Ganciclovir Adverse Effects | teratogenic, carcinogenic, mutagenic; myelosuppression (esp. neutropenia 20-40%); fever, rash, HA; liver/kidney dysfxn |
| Valganciclovir | PO only!! Used for activity against CMV; MOA like ganciclovir |
| Valganciclovir: Pharmokinetics | oral prodrug of ganciclovir; converted in body to ganciclovir; improved bioavailability (61%); achieves concentrations similar to IV ganciclovir; dosed less frequently |
| Valganciclovir: Place in Therapy | mostly replaced oral ganciclovir; CMV retinitis; prevention of CMV in transplant/immunosuppressed pts; maintenance Tx of systemic CMV |
| Valganciclovir | same as ganciclover, except more anemia and diarrhea |
| Resistance to Ganciclovir | Mutation in UL97 (not x-resistant with cidofovir or foscavir); Mutation in DNA polymerase (may be x-resistant with cidofovir...use foscavir instead) |
| Foscavir | IV only!! Requires slow infusion and large fluid volume; Used for CMV (also good for non-resistant and resistant HSV & VZV); Toxicity prevents use as first-line for CMV; Toxicity limits use to resistant HSV, VZV only; Try cidofovir if foscavir-resistant |
| Foscavir MOA | pyrophoshate analog; doesn't require TK activation or phosphorylation; Inhibits DNA and RNA polymerase |
| Foscavir Pharmokinetics | poor bioavailability and GI intolerance prevent oral dosing; primarily renally cleared; can be deposited in bone |
| Foscavir Place in Therapy | 2nd line for CMV (retinitis, systemic infxn, ganciclovir-resistant CMV, prevention in transplant/immunosuppressed pts); Resisant HSV and VZV |
| Foscavir Adverse Effects | nephrotoxic, electrolyte disturbance (hypocalcemia, hypophosphatemia, hypokalemia, hypomagnesemia); GI effects; Bone marrow suppression (anemia, neutropenia; less than ganciclovir??) |
| Cidofovir | IV only!! cytosine nucleoside analog; used for CMV, resistant HSV/VZV, and rare viruses |
| Cidofovir MOA | 2 stages of phosphorylation (cellular enzymes: Monophosphate Kinase and Pyruvate Kinase; not TK); Forms cidofovir diphosphate; similar to nucleotides (competitive inhibitor of alternate substrate for CMV DNA polymerase) |
| Cidofovir Pharmokinetics | primarily renally excreted (plasma half-life 2.5hrs; clinical intracellular duration of action up to 60hrs); Given once a week for 2 weeks |
| Cidofovir Place in Therapy | Primarily used for CMV activity (also resistant HSV/VZV; adenoviruses, papillomaviruses, poxviruses); not available commercially, but compounded as topical cream for genital warts |
| Cidofovir Adverse Effects | Nephrotoxic (always give w/NS and probenecid to decrease nephrotoxicity; avoid use of nephrotoxic meds and pts w/renal insufficiency); Neutropenia; Metabolic acidosis |
| Fomivirisen (vitravene) | given intravitreally every 2-4wks (half-life 55hrs); used for CMV retinitis (for those unresponsive to other therapies); Unique MOA (binds to mRNA) |
| Ganciclovir (vitrasert) | small capsule-like device containing a drug core encased in permeable and impermeable polymer layers for surgical implantation in the back of the eye |
| Influenza virus nomenclature | type of nucleoprotein (virus type, geographic origin, strain number and year of isolation); Hemagglutinin and Neuraminidase indicates the virus subtype based on surface antigens |
| Drugs for Influenza: M2 Inhibitors | prevention and treatment of influenza A; Rimantadine (flumadine), Amantadine (symmetrel) |
| Amantadine & Rimantadine | prevents/treates influenza A; if Tx begins in 48hrs it decreases fever/symptoms by 1day; resistance develops in 3-5days |
| M2 Inhibitor MOA | blocks M2 protein channel in influenza A; disrupts H transport, viral uncoating in host cell and therefore viral RNA transcription |
| M2 Inhibitor Pharmokinetics | both are renal excretion (adjust dose); Rimantadine is hepatically metabolized before excretion (dose adjust) |
| M2 Inhibitor Place in Therapy | control institutional outbreaks, protect high risk pts immunized after epidemic begins; prophylactic for immunosuppressed/those at high risk for flu |
| M2 Inhibitor Adverse Effects | GI (anorexia, nausea); CNS effects (nervous/anxiety, confusion, concentration; Amantadine > Rimantadine dt release of DA; rarely use in Parkinsons Dx) |
| Drugs for Influenza: Neuraminidase Inhibitors | Prevention and Treatment of influenza A & B: Oseltamivir (tamiflu), Zanamivir (relenza) |
| Oseltamivir & Zanamivir | prevent/treat influenza A&B; Must Tx w/in 48hrs for Zanamivir, 36hrs for Oseltamivir to decrease sx by 1-2days; Decreases risk of complications (respiratory, hospitalization, antibiotic use); |
| Drugs for Influenza: Neuraminidase Inhibitors Resistance | Oseltamivir (1-9% emergence during therapy); Zanamivir (rare resistance; active agains strains resistant to other agents) |
| Neuraminidase Inhibitors MOA | virion has already infected host cell and looks to bud from infected cell; Surface of virus has neuramidase ptns (neuramidase breaks bonds holding viruses to outside of infected cells); If Neuramidase is inhibited ==> new virus insn't released/spread |
| Oseltamivir Pharmokinetics | PO only; pro-drug activated in body; renal excretion (dose adjust) |
| Zanamivir Pharmokinetics | Inhalation only! up to 25% bioavailable (17% is systemically absorbed) |
| Drugs for Influenza: Neuraminidase Inhibitors Place in Therapy | same pt population as M2 agents; prevention of complications; effective against most strains of influenza; less resistance; better tolerated |
| Oseltamivir Adverse Effects | nausea/vomiting (give w/food) |
| Zanamivir Adverse Effects | nasal/throat discomfort; bronchospasm (avoid in asthmatics) |
| HBV: Drugs for chronic hepatitis | Lamivudine (epivir HBV); Interferon alfa-2b (intron A); Peginterferon alfa-2a (pegasys); Adefovir (hepsera); Entecavir (baraclude) |
| HCV: Drugs for Chonic Hepatitis | Peginterferon alfa-2b (PEG-Intron) + Ribavirin (rebetol), Peginterferon alfa-2a (Pegasys) + Ribavirin (copegus) |
| HCV: Drugs for Acute Hepatitis | Interferon alfa-2b (intron A) |
| Hepatitis Drugs by Class: Interferons | Interferon alfa-2b (Intron A), Peginterferon alfa-2b (PEG-intron), Peginterferon alfa-2a (pegasys) |
| Hepatitis Drugs by Class: Ribavirin | rebetol, copegus |
| Interferons - just know they have various effects on body | ptns w/many actions: 1. Antiviral/immunomodul. effects RNA/ptn synth; 2. Binds membrane receptors/initiates cascade (enzyme induction, suppress cell prolif, inhibit viral replication, immunomodulate); 3. Given SC or IM; 4. w/Ribavirin for HCV |
| Interferons (IFN): Adverse Effects | Management of adverse effects/logistics (up to 66% of pts discontinue therapy b/c of "minor side effect hurdles"; some adverse effects can be managed while on therapy; Dr must play role in management/prevention of adverse effects |
| IFNs: flu-like symptoms | fever/chills, malaise/fatigue, muscle aches; occur in 75% of pts; usu occur 3-4hrs after injection and improve in 24hrs or in first 2-3months |
| IFN Management | start dose low and titrate slowly; temporarily reduce dose; give at bedtime w/ prophylactic ASA, APAP or NSAIDs; give w/low-dose glucocorticoid |
| IFN: Injection Site Reaction | 50% of pts given SC injections (erythema, skin lesions, atrophy/necrosis/secondary infxn (can require abx/surgery and d/c of drug)); Necrosis occus in 5% |
| IFNs: Management of Injection Site Rxns | proper technique (rotate sites, proper depth, massage); use autoinjectors for SC; pretreat w/ice; ensure drug is completely dissolved at room temp; avoid excess sunlight exposure |
| IFN Adverse Effects: Increased muscle spasticity | worsens during first months w/in 3-24hrs after injection lasting hrs-days); give NSAIDs or muscle relaxant (baclofen); reducing dose is not helpful |
| IFN Adverse Effects: Lab abnormalities | anemia, neutropenia, thrombocytopenia, LFT elevation (rarely persistant if d/c drug); get baseline LFT, CBC and repeat at 1 and 3 months of therapy) |
| IFN Adverse Effects: Depression | inc suicide risk? depression could be dt many mechanisms? trials show no added risk, but monitor and treat for depression as appropriate |
| Ribavirin | Nucleoside analog (inhibits synthesis of viral RNA or DNA); used in combo for HCV infxn (Primary, but never monotherapy for HCV); Also used nebulized as Tx for RSV (rarely); possibly for SARS/lassa fever; Primary toxicity: Hemolytic Anemia; Pregnancy X |
| Imiquimod (Aldara) | available as cream; use for HPV (regular and genital warts); actinic keratosis, superficial basal cell carcinoma; MOA unknown |
| Palivizumab (synagis) | monoclonal antibody; prevent RSV (respiratory syncytial virus - most common pneumonia in infants); NOT a vaccine; given to high-risk infants (lund Dx, premature) during RSV season to prevent infxn |
| HAART | combo HIV Tx - highly active antiretroviral therapy; must monitor CD4 cell count & HIV RNA levels (viral load); Inc in viral load or dec in CD4 may indicate drug resistance (susceptibility testing; change Tx regimen); different toxicity/efficacy |
| HIV Fusion Inhibitors: Enfuvirtide (fuzeon; aka T-20) | linear 36 amino acid synthetic peptide; only member in class; given as SC injection; not a first-line therapy (recommended in Tx experienced pts w/ongoing HIV replication despite current antiretroviral use) |
| Fusion Inhibitor MOA | after HIV binds to host surface a conformational change occurs in gp41; change allows fusion of membranes allowing entry into host cell; Fusion Inhibitors bind gp41 and block conformational change |
| Fusion of HIV virion w/ a host cell is a multi-step process | 1. HIV virion approaches CD4 cell w/gp41 and gp120 subunits in its glycoprotein spikes; 2. CD4 interacts w/gp120 for initial attachment; 3. When gp120 interacts w/CD4 receptors, a conformation allows interaction w/cell co-receptors CXCR4 or CCR5 |
| Conformational changes in gp120 following binding w/co-receptors causes: | gp41 to be exposed; fusion is mediated by gp41 (which contains 2 heptad repeat domains, HR1 and HR2) |
| As gp41 is exposed, a further structural change occurs in gp120 facilitatin insertion of gp41 into the: | Tcell membrane; HR2 domain begins to coild into the exposed grooves of the HR1 region; this zipping process destabilizes both Tcell and viral membranes allowing HIV RNA to pass into CD4 Tcell |
| Fuzeon | a peptide homolog of part of the HR2 region of gp41; it binds to portion of HR1 and blocks HR1-HR2 zipping interaction to prevent fusion |
| Fuzeon: Adverse Effects | injection site reactions (pain, induration, nodules, cysts); hypersensitivity |
| NRTIs "Nukes": NucleoSIDE reverse transcriptase inhibitors | Abacavir (ziagen, ABC), Didanosine (videx, videx EC, ddl), Emtricitabine (emtriva, FTC), Lamivudine (epivir, 3TC), Stavudine (zerit, d4T), Zalcitabine (hivid, ddC), Zidovudine (retrovir, AZT, ZDV) |
| NRTIs "Nukes": NucleoTIDE reverse transcriptase inhibitor | Tenofovir (viread, TDF) |
| NRTIs: Combination Products | Zidovudine/lamivudine (Combivir), Zidovudine/lamivudine/abacavir (trizivir), Abacavir/lamivudine (epzicom), Emtricitabine/tenofovir (truvada) |
| NRTI: MOA | reverse transcriptase converts HIV ssRNA into dsDNA; drugs competetively inhibits enzyme RT; synthetic analogs incorporated into viral DNA (viral DNA cannot produce fxnl DNA, elongation is stopped dt "dummy building blocks") |
| NRTI: Class Adverse Effects | 1. Mitochondrial Toxicity: lactic acidosis (never give stauv+dida), hepatic steatosis, peripheral neuropathy, pancreatitis (esp stauvudine/didanosine/zalcitabine/zidovudine); Lamivudine and Tenofovir are well tolerated; 2. Lipoatrophy: unnatural fat loss |
| NRTI: Points of Note | few drug interactions |
| NRTI: Points of Note - Didanosine | the only NRTI that must be taken w/regard to food (30min b/f, 2hr after) |
| NRTI: Points of Note - Abacavir | not toxic to mitochondria or causative of lipoatrophy (interacts w/alcohol); Hypersensitivity rxn in 3-9% (rash, fever, fatigue, respiratory/GI symptoms; can be fatal) |
| NRTI: Points of Note - Zalcitabine | rarely used |
| NNRTIs: "non-nukes" - Non-nucleoside reverse transcriptase inhibitors | Delavirdine (rescriptor, DLV), Efavirenz (sustiva, EFV), Nevirapine (viramune, NVP) |
| NNRTI: MOA | binds directly to enzyme RT (binds near active site; doesn't compete with viral nucleosides, alters active site and inactivates enzyme); viral RNA cannot produce any DNA |
| NNRTI: Adverse Effects | all can cause a serious rash |
| NNRTI: Adverse Effects - Efavirenz | CNS effects (dizziness, HA, insomnia, vivid dreams, nightmares, hallucinations w/in 3hrs of each dose and may stop in a few wks) |
| NNRTI: Adverse Effects - Nevirapine | severe hepatotoxicity (esp in pts w/liver probs at baseline); Highest incidence of rash |
| NNRTI: Points of note | more drug rxns than NRTIs; Cross-resistance w/in class is common (not across classes); Efavirenz and Nevirapine are used most commonly |
| Protease Inhibitors | Amprenavir (agenerase, APV), Atazanavir (reyataz, ATV), Fosamprenavir (lexiva), Indinavir (crixivan, IDV), Lipoinavir/ritonavir (kaletra, LPV/RTV), Nelfinavir (viracept, NFV), Ritonavir (norvir, RTV), Saquinavir hard/soft gel cap (invirase, SQV hgc/sgc) |
| Protease Inhibitor: MOI | protease enzymes cleave ptn into smaller functional mature virions; PIs inhibit this enzyme; ptn cannot be cleaved into fxnl ptn (cannot be assembled or released); cannot infect new cells or replicate further |
| Protease Inhibitor: Class Adverse Effects | inc serum glucose/cholesterol/TGs (inc risk of coronary artery disease); Lipodystrophy (inc fat deposition in back/abdomen and wasting in arms/face); Hepatotoxicity; GI side effects |
| Protease Inhibitors: Points of Note | class has revolutionized treatment; most drug interactions of HIV meds (substrates for CYP 3A4 except *Nelfinavir*); new regimens are combining 2 PIs together |
| PI: Nelfinavir | not a substrate for CYP 3A4 |
| PI: Atazanavir | lacks effect on cholesterol |
| HIV and Pregnancy: Best way to prevent perinatal transmission | Optimal Therapy: Nevirapine or Zidovudine + NRTI + PI |
| Single dose nevirapine | often used to prevent perinatal transmission in developing countries |
| Efavirenz | never use in pregnancy!!! |
| HAART: complicated therapy | drug interactions, resistance, additive toxicities from concomitant meds; guidelines continually updated |
| HAART: Initial Regimen - 2NRTIs + NNRTI | Zidovudine OR Tenofovir + Lamivudine OR Emtricitabine + Efavirenz |
| HAART: Initial Regimen - 2NRTIs + PI | Zidovudine OR Tenofovir + Lamivudine OR Emtricitabine + Lopinavir/Ritonavir |
| HAART: Build combinations with at least 3 medications | one of which is a NNRTI or PI! |
Created by:
bscaryp