Antimicrobial part 4 Flashcards

Question

NS3/NS4A Protease Inhibitors

Answer 1

 Viral NS3/NS4A serine protease needed to process single polyprotein encoded by Hep C RNA into active proteins  Without these serine proteins, RNA replication does not occur and the Hep C life cycle is stalled

Answer 2

```  Paritaprevir + Ritonavir boost  Grazoprevir  Voxilaprevir  Glecaprevir  ADEs—rash, itching, nausea, fatigue, anemia ```

Answer 3

NS5B is only RNA polymerase responsible for Hep V replication and is processed with other Hep C proteins into an individual polypeptide by the viral NS3/NS4A serine protease; these drugs inhibit NS5B

Answer 4

Sofosbuvir Dasabuvir ADEs—few; well tolerated

Answer 5

``` ♦ NS5A is a viral protein necessary for Hep B RNA replication and assembly ↓ This protein forms a membranous web [along with NS4B]— and this web is the platform for virus replication ↓ Ledipasvir ↓ Ombitasvir ↓ Elbasvir ↓ Velpatasvir ↓ Pribrentasvir ↓ Daclatasvir ↓ Many drug interactions due to their metabolism by CYP 450 and pglycoprotein inhibition ```

Answer 6

 Approved for the treatment of chronic Hep C when used in combination with standard pegylated interferon or with DDAs  Guanosine analogue, improves viral clearance, decreases relapses rates and improves rates of SVR  Adding Ribavirin to a DDA backed regimen is based on Hep C genotype, cirrhosis status, presence of mutation and treatment history  MOA is unknown  This drug is given BID with food, and it is weight based

Answer 7

♦Elbasvir/grazoprevir [Zepatier] ♦Glecaprevir/pibrentasvir [Mavyret] ♦Paritaprevirritonavir/ombitasvir [Technivie] ♦Pariaprevier/rtionavir/ombitasvir+dasabuvir [Viekira park, Viekira XR] ♦Sofosbuvir + daclatasvir [Sovaldi + Daklinza] ♦Sofosbuvir/ledipasvir [Harvoni] ♦Sofosbuvir/velpatasvir [Epclusa] ♦Sofasbuvir/velpatasvir/voxilaprevir [Vosevi]

Answer 8

``` Zovirax is the prototype antiherpetic drug It covers HSV1, HSV2, VZV and some strains of Epstein-Barr virus DOC in treating HSV encephalitis Most common use is for genital herpes Used to prevent disease to seropositive patients before BMT and post-cardiac transplant patients ```

Answer 9

• Guanosine analog; monophosphorylated in the cell the HSV-encoded enzymes • Monophosphate analog is converted to triphosphate with competes as a substrate for viral DNA and incorporates in the viral DNA, causing the DNA chain to terminate

Answer 10

* Iv, oral, topical routes * Topical form has questionable efficacy * Distributes well throughout the body, including CSF * Partially metabolized to an inactive product * Excretion is via the urine from glomerular filtration and tubular secretion * The drug accumulates in those with CKD * The valyl ester, Valacyclovir, has better bioavailability—it is rapidly hydrolyzed to Acyclovir and achieves level comparable to giving IV Acyclovir

Answer 11

* Depends on route of administration * Local irritation from topical use * Headache, diarrhea, nausea and vomiting can be seen with oral dosing * Transient renal dysfunction can be seen with high doses or in a dehydrated patient getting the drug IV

Answer 12

• Altered or deficient thymidine kinase and DNA polymerases found in some resistance— especially in the immunocompromised • Cross resistance to other agents in the family does occur

Answer 13

Vistide—indicated for CMV retinitis in patients with AIDS Nucleotide analog of cytosine—inhibits viral DNA synthesis Slow elimination of the active intracellular metabolite allows prolonged dosing intervals Given IV—causes renal toxicity; contraindicated in those with pre-existing renal problems and in those on other nephrotoxic drugs Neutropenia and metabolic acidosis occur Oral Probenecid and IV NS are given with Cidofovir to mute the nephrotoxic effect With the introduction of HAART, the incidence of CMV in the immunosuppressed patient has declined as has the use of this drug

Answer 14

It is a pyrophosphate derivative, and does not need activation by viral or cell kinases Used for CMV retinitis in the immunosuppressed and or Acyclovir resistant HSV Works by reversibly inhibiting viral DNA and RNA polymerases Mutation of the polymerase structure is responsible for resistance Poorly absorbed after oral dose; must be given IV Must be given frequently to avoid relapse when plasma levels fall Dispersed throughout the body, >10 % enters the bone matrix, where it slowly disperses ``` ADEs—nephrotoxicity, anemia, nausea, fever; low Ca++ and Mg+ because of chelation; low K+, phosphate abnormalities, seizures, arrhythmias ``` Parent drug is eliminated by glomerular filtration and tubular excretion

Answer 15

``` Cytovene—analog of Acyclovir that has greater activity for CMV; used in the treatment of CMV retinitis in the immunosuppressed and to prevent CMV in the transplant patient ```

Answer 16

``` • Activated through conversion to the nucleoside triphosphate by viral and cell enzymes • Nucleotide inhibits viral DNA polymerase and can be incorporated into the DNA causing chain termination ```

Answer 17

``` • Given IV and distributes throughout the body and CSF • Excretion into urine through glomerular filtration and tubular secretion • Accumulates in those with CKD • Valganciclovir, an oral agents—is the valyl ester of Ganciclovir • Valganciclovir [Valcyte] has high oral bioavailability; it hydrolyses rapidly in the liver and intestine after oral dose and obtains high levels of Ganciclovir ```

Answer 18

``` • Severe dose dependent neutropenia • Carcinogenic and teratogenic • BB warning for use in pregnancy ```

Answer 19

``` • Resistant strains of CMV have been seen with low levels of Ganciclovir triphosphate ```

Answer 20

``` Penciclovir [Denivir]— acyclic guanosine nucleotide derivative active against HSV-1, HSV-2, VZV ``` ``` Given topically; monophosphorylated by viral thymidine kinase and enzymes from nucleoside triphosphate that inhibits HSV DNA polymerase ``` Intracellular ½ life longer than Acyclovir Minimally absorbed after topical use; well tolerated ``` Famciclovir [Famvir]— cyclic analog of 2’- deoxyguaosine is a prodrug that is metabolized to the active Peniciclovir ``` ``` Antiviral spectrum is similar to that of Ganciclovir, and it is approved to treat acute Herpes Zoster, genital HSV infection, and recurrent Herpes labialis ``` Effective orally; ADEs are headache and nausea

Answer 21

Viroptic—fluorinated pyrimidine nucleoside analog that is structurally similar to thymidine ``` Once converted to triphosphate, inhibits the incorporation of thymidine triphosphate into viral DNA and leads to synthesis of defective DNA that causes the virus to stop replicating ``` Active against HSV1, HSV-2, vaccinia Indicated to treat HSV keratoconjunctivitis and recurrent epithelial keratitis Too toxic to use systemically; use is restricted to ophthalmic drops Short ½ mandates frequent administration ADEs—transient irritation of eye; eyelid edema

Answer 22