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Acyclovir is most effective for what virus?
Less effective for?
- Most effective= replicating HSV
- Less effective= VZV, EBV
-
Why is CMV resistant to Acyclovir?
- It either
- 1) Lacks a thymidine kinase gene OR
- 2) Viral encoded thymidine kinase is unable to phosphorylated acyclovir
-
Used in prophylaxis of recurrent genital herpes
Acyclovir
*Oral therapy is also effectie in treating primary genital HSV infxn
-
3 uses of Acyclovir (other than HSV prophylaxis)
- Can be given IV to manage:
- 1) Severe genital herpes
- 2) Herpes Encephalitis
- 3) VZV infxn in immune compromised and burn patients
-
3 Acyclovir Prodrugs
- Valacyclovir
- Penciclovir
- Famciclovir
-
Acyclovir molecules entering the cell are converted to acyclovir monophosphate by
virus-induced thymidine kinase
*host cell enzymes then add two more phosphates to form acyclovir triphosphate which is transported to the nucleus
-
Inserts acyclovir monophosphate rather than 2'-deoxyguanosine monophosphate into the viral DNA
Viral DNA Polymerase
-
Adverse Effects of Acyclovir
- Minor- nausea, diarrhea, headache
- Major- Reversible renal toxicity, neurologic effects
-
Acyclovir Resistance
- Long term use of acyclovir can cause resistant types of HSV and VZV.
- These types lack thymidine kinase or have an altered DNA Pol.
- Mutants are sensitive to foscarnet
-
Ganciclovir has 100x more activity than acyclovir against this virus
CMV
-
Acyclovir treats
Gancyclovir treats
-
Adverse Effects of Ganciclovir
- Myelosuppression
- CNS and hepato- toxicity
-
Ganciclovir myelosuppression can be additive when taking
- Zidovudine
- Azathiprine
- Mycophenolate mofetil
-
Amantadine and Remantadine prevent
Uncoating of M2 viral protein
-
Prevent uncoating of M2 viral protein in RNA viruses
-
Treats Influenza A
Amantadine, Rimantidine
-
Treats influenza A and B
Oseltamivir (tamiflu)
-
Adverse Effects of Amantadine and Rimantadine
- More common w/ Amantadine
- Marked behavioral changes, delirium, hallucinations (due to dopamine neurotransmission)
-
Adverse effects of amantadine/rimantadine may increase w/
concomitant antihistamines, anticholinergic agents, hydrochlorothiazide, and TMP/SMX
-
Tx of Influenza A and B
Oseltamivir, Zanamivir
-
Oseltamivir/ Zanamivir MoA
- Interfere w/ release of progeny influenza virus from host infected cells
- Halt spread of infxn in the respiratory tract
-
Neuraminidase Inhibitors (Analogs of sialic acid)
Oseltamivir, Zanamivir
-
Adverse Effects of Oseltamivir
- Minor: Nausea (resolves spontaneously)
- Major: Neuropsychiatric events (self-injury or delirium in adolescents or Japanese adults)
-
Not recommended for pts. w/ underlying airway disease
Zanamivir
-
Oseltamivir resistance
Associated w/ point mutations in viral HA/NA genes
-
Goal of chronic HBV therapy?
Goal of HCV infxn?
- HBV- Sustain suppression of HBV replication
- Slow progression of hepatic disease
- Prevent complications
- Reduce need for liver transplantation
- HCV- Eradication
-
Most powerful tx against HBV, HCV
IFN-a
-
Major MoA of IFN-a
Inhibition of translation
- Activates methylase, thereby reducing mRNA cap mythylation
- Activates 2'5' oligoadenylate synthetase -> inhibits mRNA splicing and inactives RNase I -> cleaves viral RNA
- Activates protein kinase P1 -> blocks eIL-2afunction -> inhibits initiation of mRNA translation
- Activates phosphodiesterase -> blocks tRNA function
-
IFN-a Contraindications
- Pts. w/:
- Hepatic decompensation
- Autoimmune disease
- Hx of cardiac arrhythmia
-
IFN-a: Potential drug-drug interactions
- Theophylline
- Methadone
- Didanosone (Increases risk of hepatic failure)
- Zidovudine (Exacerbates cytopenias)
-
Used in combination with IFN-a to treat HBV, HCV
- Lamviudine (HBV)
- Ribavirin (HCV)
-
Treats HCV
IFN-a, Lamivudine
-
Treats HCV
IFN-a, Ribavirin
-
Lamivudine inhibits
- HBV- DNA Polymerase
- HIV- Reverse Transcriptase
-
Lamivudine use w/ co-infxn of HIV can increase risk of
Pancreatitis
-
Adverse Effects of Ribavirin
Dose-dependent hemolytic anemia
-
Contraindications for Ribavirin use
- Anemia
- End-stage Renal Disease
- Ischemic vascular disease
- Pregnancy
-
Binds CCR5 receptor and prevents gp120 from binding and entering cells
Maraviroc
-
Maraviroc binds
host CCR5 receptors (prevents gp120 from binding)
-
Adverse Effects/ Contraindications of Miraviroc
AE= Myocardial ischemia and infarction
- Contraindicated in pts. w/:
- Increase cardiovascular risk
- End-stage renal empairment who are taking concurrent CYP3A inhibitors or inducers
- Preexisting hepatic impairment
- Co-infxn w/ HBC or HCV
-
Miraviroc resistance is mediated by
Mutations in the V3 loop of gp120
-
Associated w/ mutations in V3 loop of gp120
Resistance to maraviroc
-
MoA of Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (e.g. Zidovudine)
Triphosphate competes w/ native nucleotides -> loss of 3' OH -> chain termination
-
Found in CSF at levels of 60-65% that of serum
Zidovudine (AZT)
-
Adverse Effects of Zidovudine
Myelosuppression (macrocytic anemia, neutropenia)
-
Zidovudine: Drug-Drug Interactions
- Ganciclovir, Ribavirin = Increased hematologic toxicity
- Stavudine (in vitro antagonism)
-
Zidovudine resistance
- Involves at least 3 or more of the following mutations:
- M41L
- D67N
- K7OR
- T215F
- K219Q Reverse Transcriptase
-
NNRTIs
Efavirenz, Delavirdine, Etravirine
-
NNRTI MoA
- Binds to a nonessential site distant from enzyme catalytic site
- *Doesn't compete w/ nucleotide triphosphates
- *Doesn't require phosphorylation to be active
-
Adverse Reaction of Delavirdine
- Skin rash, increased AST
- *Avoid in pregnant
-
Inhibits CYP3A4, 2C9
Extensively metabolized by
-
A single dose prevents spread of HIV from mother to fetus
Neviparen
-
Adverse Effects of Etravirin
Skin rash, increased serum cholesterol/triglyceride/glucose
-
Substrate and inducer of CYP3A4
Inhibits CYP2C9
Etravirine
-
Binds to HIV integrase, prevents DNA strand transfer
Raltegravir (integrase inhibitor)
-
Metabolized by glucuronidation (does not interact with CYP450 system)
What drug interacts with this? How do you combat it?
Raltegravir
Rifampin interacts with this because it is a strong inducer of UGT1A1. Dose of raltegravir should be doubled.
-
Integrase enzyme is essential for replication of
HIV-1 and -2
-
Adverse Effect of Raltegravir
Increased serum creatine kinase
-
Increased serum AST
Increased serum cholesterol/ triglyceride/ glucose
Increased serum creatine kinase
- AST= Delavirdine
- C/T/G= Etravirin
- CK= Raltegravir
-
Prevents post-translational cleavage of Gag-Pol polyprotein, thus prevents viral proteins from becoming functional
Indinavir
-
Do NOT administer Indinavir with
Etravirine
-
Contraindicated w/ Protease Inhibitors
Ant-Eaters Are Big 'In Hairy Herbivore Nomnoms
- A= Antiarrhythmics (Quinidine)
- E= Ergot Derivatives (Ergotamine)
- A= Antimycobacterial Drugs (Rifampin)
- B= Benzodiazepines (Triazolam)
- I= Inhaled Steroids (Fluticasone)
- H= Herbal Supplements (St. John's Wort)
- H= HMG CoA Reductase Inhibitors (Lovastatin, Simvastatin)
- N= Narcotics (Fentanyl)
-
Antiretroviral Agents for use in Pregnancy
- NRTIs: Lamivudine, Zidovudine
- NNRTIs: Nevirapine
- PIs: Lopinavir/Ritonavir
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