Anti-viral drug comparison; tinable ko lng ang drugs dun sa Cor tranx, double checked na din with Katzung

11th ed
Drug Acyclovir Characteristics A cyclic guanosine derivative High specificity to HSV-1 and HSV-2 and VZV DNA Polymerase Inhibitors Against HSV & VSV MOA Activated and converted by thymidine kinase to monophosphate converted by host kinase to diphosphate triphosphate inhibits viral DNA polymerase by: Pharmacokinetic Absorption Formulation: Oral, intravenous, topical Oral: 20-30% bioavailability; Unaffected by food Pharmacokinetic Distribution Well distributed even to CSF; CSF concentration is 50% of serum level Pharmacokinetic Metabolism T : 3-4 hrs if normal renal function; T1/2: 20 hrs if anuric patient Pharmacokinetic Excretion Glomerular filtration & tubular secretion Probenecid and cimetidine dec acy clearance and inc exposure

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Adverse Effect Generally well tolerated Nausea, diarrhea and headache have occasionally been reported (katzung) Principal dose-limiting; renal insufficiency If IV admin: - Reversible renal dysfunction - Neurologic toxicity such as tremors, delirium, serizures High doses: Chromosomomal dagae and testicular atrophy in rats

Resist thru: a) Absence or partial a.) Competition production of viral with thymidine kinase deoxyGTP for b) Atletered thymidine the viral DNA kinase substrate polymerase specificity binding to c) Altered viral DNA DNA polymerase template as d) Clinically resistant an infection have been irreversible reposted in comlex immunocompromise b.) Chain d host termination ff incorporatio n to viral DNA Anti-Retrovirals A. Nucleosid/tide Reverse Transcriptase Inhibitors (NRTI) B. Non-NRTI

Anti-viral drug comparison; tinable ko lng ang drugs dun sa Cor tranx, double checked na din with Katzung 11th ed
A. zidovudine NRTIs Competitive o inhibition of Incorporated into HIV-1 growing viral DNA reverse chain to cause transcriptase o termination (RNAdependent Requires DNA intracytoplasmic Polymerase) o activation via PO4rylation by cellular enzyme to the triPO4 form. Deoxythymidine analog Well absorbed 63% Usually coadmin with lamivudine Increase serum levels with the ff by inhibiting the first pass effect or dec clearance: Probenicid Phenytoin Methadone Fluconazole Atovaquone Valproic aid Lamvudin Zidovudine decreases phenytoin level naman hahaha Well distributed to most body trissues and fluids including the CSF: 60-65% of serum level T = 1 hr Intracellular half-life of the PO4 compound = 3-7 hrs Glucoronidation in the liver metab into inactive glucoronide toxicity may incrase in patients with advance hepatic insufficiency Renal excretion 20% active form excreted in the urine Cleance is reduced by 50% in uremic patients Adverse effect (cont) sorry d n kaxa sa kabila eh hahaha. 1. Myelosuppression resulting in macrocytic anemia (1-4%) or neutropenia (2-8%) 2. GIT intolerance 3. Headache 4. Insomnia 5. Thrombocytopenia 6. Hyperpigmentation of nails 7. myopathy Urine

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Should be suspended int the setting of: Rapidly rising aminotransferase levels Progressive hepatomegaly Metabolic acidosis of uknown cause May be assoc with mitochondrial toxicity probably due to inhibition of mitochondrial DNA polymerase gamma resulting to: - Increased risk of lactic acidosis with hepatic steatosis fatal - Disorders of lipid metab Hematologic toxicity may be increased when given with other myelosupp like ganciclovir and cytotoxic agents Severe life threatening skin rashes o Steven Johnson o Toxic epidermal necrolysis

Resistance: Generally seen in strains with three or more of the five most common mutation: 1. M41L 2. D67N 3. K70R 4. T215F 5. K219Q

o o o o o o o o

B1. Nevirapine

- Non-NRTI - Compete with nucleoside triPO4 - Doesnt require PO4 to be active

Binds directly to o 90% the enzymes bioavailability (HIV-reverse o Not food transcriptase) dependent active site o Highly blocking RNA lipophilic

60% protein bound T : 25-30 hrs

Metab by CYP450 and CYP3A Induces CYP3A4 thus decreases some antiviral

Anti-viral drug comparison; tinable ko lng ang drugs dun sa Cor tranx, double checked na din with Katzung 11th ed
and DNA dependent DNA Polymerase activity agents Lets clear things out katzung 11th ed Page 861, a further limitation to use of NNRTI agent as a component of HAART is their metab by CYP450 system. Same page all NNRTI agents are substrates for CYP3A4 and can act as inducer (nevirapine) Page 862, extensive metabolized by the CYP3A isoform to hydroxylated metabolites Same page moderate inducer of CYP3a4 metabolism, resulting in dec levels. Protease Inhibitor 1. Saquinavir 2. Ritonavir Effective against HIV-1 and HIV2 and does not need intracellular activation

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Hepatoxicity: - Occur more frequently in those with higher pretherapy CD4 cell counts, in women and in patients with Hepatitis B or C co-infection Fulmitant hepatitis rare Fever, nausea, headache, somnolence

Resistance: Occurs rapidly with monotherapy and can be due to single mutation of: - K103N - T181C Drug interaction with niverapine, maxado mahaba. Tignan nio n lng sa tranx ni kate. Thank you!

Anti-viral drug comparison; tinable ko lng ang drugs dun sa Cor tranx, double checked na din with Katzung 11th ed
1. Saquinavir Drug interaction: Pls refer to kates tranx nhibited cleavage of the translated protein (Gag and Gag-pol polyproteins) into func and structural protein production of immature and non-infectious viral particles Block viral maturalation therefore active in both acutely and chronically infected cells Inhibitor of HIV1-HIV2 proteases Formulation: Hard gel capsule (originally) but has poor bioavail of 4% and should be taken within 2 hrs after fatty meal Now: Soft gel capsule with 3x better absorption, increases when taken with food 98% protein bound Large vol distribution CSF penetration is negligible Extensive 1 pass metabolism CYP3A4 and func as inhibitor too and substrate.
st

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1. GIT discomfort (common in soft gel) Nausea Diarrhea Abdo discomfort Dyspepsia Rhinitis

feces

2.

Ritonavir

High bioavail og 75% and increases when taken with food

98% protein bound T1/2: 3-5 hours

CYP3A4 and CYP2D6 isoforms

Feces

o o o o o o o o

GIT disturbances Parathesias Elevated serum aminotransferases Altered taste Headache Hypertriglyceridemi a Hyperchole Elevation in serum creatine kinase (katzung)

During 1st few wks of therapy: 1. Nausea 2. Vomiting 3. Diarrhea

Anti-viral drug comparison; tinable ko lng ang drugs dun sa Cor tranx, double checked na din with Katzung 11th ed

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4. Abdominal pain

Entry Inhibitors

1. Enfurvitide

Integrase Inhibitors

Fusion inhibitors that blocks the entry of the virus into the cell Formerly called as T-20 Binds to gp41 subunit of viral Synthetic 36 amino acid envelope peptide fusion inhibitor glycoprotein, preventing the Only effective for HIV-1 conformational changes Resistance: required for the 1. Mutation to gp41 fusion of the viral and cellular membranes 1. Raltegravir Combination of 2. Elvitegravir multiple agents is recommended for HIV infected individuals to a. Inc potency b. Delay emergence of resistance E.g Elvucitabine (NRTI) + Vicriviroc (entry inhibitor) +

1. 2. 3.

Enfuvirtide Maraviroc Vicriviro

Subcutaneously

Proteolytic hydrolysis w.o involvement of CYP450

T : 3.8 hrs

From katzung (but not discussed by doc) 1. 2. Local injection site rxn Eosinophilia

Anti-viral drug comparison; tinable ko lng ang drugs dun sa Cor tranx, double checked na din with Katzung 11th ed
Elvitegravir (integrase inhibitor)

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AntiCytomegalovirus

A. B. C. D.

Ganiciclovir Valganciclovir Foscarnet Cidofivir

Cmv infection occur primarily in the setting of advanced immunosuppres sion and are typically due to reactivation of latent infection

Antihepatitis

1.

Anti-HepaB

Effective against HBV and HCV; More of suppressive rather than curative o IFN-a2b o Pegylated IFN-a2b

Enhance specific T-cell mediated immune response Direct antiviral effect: Degredation of viral mRNA Inhibition of proteinsynth esis iii.Prevents infection of new cell same

2.

AntiHepa C

o o o o

IFN-a2b Pegylated IFN-a2a Pegylated IFN-a2b IFN-alfacon-1

Anti-viral drug comparison; tinable ko lng ang drugs dun sa Cor tranx, double checked na din with Katzung 11th ed Antiinfluenza agents a. amantidine
a. Amantidine b. Rimantidine c. Oseltamivir d. zanamivir Approved by DA in o inhibits the 1976 to treat uncoating of Influenza A the viral Targets early stages genome of infection o specifically 1-aminoadamante targets a HCL protein called Alpha-methyl M2 (an ion derivative of channel) rimantidine, thereby Tricyclick amins of inhibiting the adamantane family uncoating of the viral DNA o infective to influenza B because it lacks M2 Same with amantidine Same with amantidine

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Well absorbed orally and crosses BBB

67% protein bound

T : 12-18 hours and varies by creatinine clearance

90% excreted unchanged w.o metabolic products

1. Low toxicity at therapeutic levels 2. GIT - Nausea - Anorexia 3. CNS - Nervousness - Diffutly in concentrating - Insomnia - Lightheadedness

b. rimantidine

Same with amantidine

40% protein bound

T : 24-36 hours Undergoes extensive metabolism by hydroxylation, conjugation and glucoronidation

Urinary excretion

Same but CNS toxicity is less frequent

Immunoglobulin Therapy
1. Normal Ig

1. 2. 3.

normal Ig prophylaxis hyper-Ig serum

Pooled product from serum of normal donorsl contain low titers of Ab to a wide range of human viruses

Anti-viral drug comparison; tinable ko lng ang drugs dun sa Cor tranx, double checked na din with Katzung 11th ed
2. Prophylaxis Vs: Heap-B Parovirus e.g zoster immune globulin human rabies Ig Hepa-B Ig

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3. Hyper-Ig serum of selected individuals with high titers of Ab to a particular dse Viral vaccine

Vaccination- most cost effective method of prevention of serious viral infection

a. Killed virus vaccine (influenza, rabies b. Attenuated live vaccine (MMR( c. Future genetic manipulation (?)
th

Warning: 1) table form lng po ito but na-double checked ko na using katzung 11 ed 2) for drug interaction, pls refer to cors tranx. Kasi kung lalagay ko ditto maxado na mahaba 3) pls pls refer to cors tranx explanation for viral replication, kasi ung mga drugs will act on certain phase of viral replication, like acyclovir sa DNA polymerase inhibitor halt DNA synthesis, etc I STRONGLY SUGGEST TO READ YOUR BOOKS AND NEXT TIME PAG C DOC DEO NAGLLECTURE, SUNDAN NIO LNG SIYA SA BOOK, KATZUNG LNG LAGI ANG REFERENCE NIA HAPPY CRAMMING! 2014

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