Antimicrobials study guide, Summaries of Pharmacology

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Antimicrobial Therapy

Patti Parker, PhD, RN, A/GNP

1

Part Four

Antiviral Drugs / Antiprotozoal Drugs / Anthelmintic Drugs Lippincott [7th^ Edition] Chapters 34, 46, 47 2

Antiviral Drugs 3 Let’s Begin 4 Viruses are intracellular parasites The do not have a cell wall or cell membrane and do not carry out metabolic processes They use much of the metabolic processes of the host— very few drugs are selective enough to prevent viral replication without injuring the infected individual Treating viral illness is further complicated by the fact that symptoms appear late in the course of illness—after the virus has replicated—so drugs that prevent replication are not helpful

Neuraminidase Inhibitors MOA Pharmacokinetics

• Flu viruses use a certain neuraminidase that it slotted into the host cell membrane to release newly formed viruses; this enzyme is critical for the virus to live
• These drugs selectively inhibit neuraminidase—this prevents new virions from being made and prevents the virus from spreading - Oseltamivir is dosed orally as a prodrug that is hydrolyzed by the liver into active form - Zanamivir is not active orally and is given via inhalation - Both are eliminated unchanged in the urine 7 Neuraminidase Inhibitors ADEs Resistance
• GI discomfort and nausea
• Symptoms are lessened if taken with food
• Irritation of the respiratory tract from Zanamivir—use with caution in those with asthma or COPD— because it can cause bronchospasm
• Mutations of the neuraminidase enzyme have been identified in adults with either of the neuraminidase inhibitors
• These mutants are usually less infective and less virulent than the wild type influenza 8

Amantadine Antivirals 9 Amantadine—Symmetrel [prototype] Rimantadine—Lumazine Spectrum is only Influenza A Due to resistance—Amantadine is not recommended in the US Ribavirin Virazole; synthetic guanosine analog Effective against a broad spectrum of RNA and DNA viruses Used in treatment of immunosuppressed children with RSV Also effective in chronic Hepatitis C infections when used with other direct acting antivirals [DAAs] 10

Treating Hepatic Viral Infections 13 Chronic Hep C is treated with a combination of direct acting antivirals [DAAs]—based on the genotype of the virus that patient has Ribavirin can be added to the DDAs to boost the viral response Pegylated interferon is no longer commonly used for chronic Hep C Oral therapy for chronic Hep B can be with Lamivudine, Adefovir and Tenofovir Chronic Hep B can be treated with Peginterferon-α-2a injected SQ weekly Treating Hepatis B—Interferons 14 Naturally occurring inducible glycoproteins that interfere with virus to infect the host cells Interferons are synthesized by recombinant DNA technology—α [alpha], ß [beta] and γ [gamma] In pegylated formulations—polyethylene glycol has been attached to interferon-α to increase the size of the molecule, and lengthens duration of action and reduces clearance

Hepatitis B—Interferons MOA Uses ADEs

• Incompletely understood
• Involves the induction of host cell enzymes that inhibit viral RNA translation—leading to the breakdown of viral RNA - Peginterferon alfa-2a is approved for chronic Hep B - Also indicated for treatment of Hep C in combination with other drugs [but no longer common] - Flu like sx—fever, chills, myalgias, arthralgias, Gi distress - Fatigue and mental depression is common - Dose limiting BM toxicity, severe fatigue, weight loss, somnolence, thyroiditis often curbs the use of this agent - HF has been reported 15 Hepatitis B—Lamivudine 16 Epivir-HBV is a cytosine analog is an inhibitor of both Hep B and HIV reverse transcriptase Must be phosphorylated by host enzymes to active form Competitively inhibits Hep B RNA-dependent DNA polymerase Intracellular half-life of the triphosphate is much longer than its ½ life Rate of HBV resistance is high after long term use— therefore it is no longer 1st^ line in treating chronic Hep B

Hepatitis B— Entecavir 19  Baraclude is a guanosine nucleoside analog for the treatment of Hep B  After intracellular phosphorylation to triphosphate, it competes with natural substrate, deoxyguanosine triphosphate, for viral reverse transcriptase  Effective against lamivudine-resistant strains of Hep B; it is dosed once a day  Excreted unchanged in the urine; adjustments are needed in those with CKD  Avoid use of other agents with renal toxicity Treatment of Hepatitis C 20 Once Hep C is inside the cell, a viral genome is released from the nucleocapsid and a Hep C viral polyprotein is translated using the internal ribosome entry site Core NS3 and NS5a proteins form the replication complex on fat drops and serve as a scaffold for RNA polymerase to reproduce the viral genome— which is then packed in an envelope of glycoproteins before noncytolytic secretion of mature virions DAAs– target NS3/NS4A protease, NS5B polymerase and NS5A involved in Hep C replication

Treatment of Hepatitis C 21 Combination DDAs is needed to optimize Hep C therapy Drug selection is given in detail in www.hcvguidelines.org NS3/NS4A Protease Inhibitors  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

 Paritaprevir + Ritonavir boost  Grazoprevir  Voxilaprevir  Glecaprevir  ADEs—rash, itching, nausea, fatigue, anemia 22

Ribavirin  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 25 Options for Hepatitis C 26

Treating Herpes Virus Infections 27 These viruses are associated with many diseases Agents effective against these viruses work in the action phase of viral infections and are without effect during the latent phase Acyclovir 28

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

Cidofovir 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 31 Cidofovir 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 32

Foscarnet 33 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 Foscarnet 34

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

Ganciclovir MOA Pharmacokinetics ADEs Resistance

• 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 - 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 - Severe dose dependent neutropenia - Carcinogenic and teratogenic - BB warning for use in pregnancy - Resistant strains of CMV have been seen with low levels of Ganciclovir triphosphate 37 Penciclovir and Famciclovir 38 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

Penciclovir and Famciclovir 39 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 Trifluridine 40 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