Antimicrobial part 4 Flashcards
Antiviral Drugs
♦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
Treating Viral Respiratory Infections
♦Viral URIs that can be treated are Influenza A,
influenza B, and RSV
♦Flu vaccine is more effective than trying to treat
the patient after they are infected
♦Antivirals can be helpful when the patient
cannot be immunized OR when there is an
outbreak
Neuraminidase Inhibitors examples
Oseltamivir—Tamiflu prototype drug
Zanamivir—Relenza
Neuraminidase Inhibitors
Effective against flu A and B; they do not interfere with
immune response to the flu vaccines
Given prior to exposure, these agents prevent
infections and when given 24-48 hours after the
symptoms occur, they modestly decrease the intensity
and duration of the illness
Neuraminidase Inhibitors: MOA
• 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
Neuraminidase Inhibitors: Pharmacokinetics
• 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
Neuraminidase Inhibitors: ADEs
• 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
Neuraminidase Inhibitors: Resistance
• 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
Amantadine Antivirals examples
♦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]
Ribavirin: MOA
• Inhibits replication of RNA and DNA viruses
Ribavirin: Pharmacokinetics
- Effective orally and by inhalation
- Aerosol is used to treat RSV
- Absorption is increased if the oral drug is taken with a fatty meal
- Drugs and metabolites are eliminated in the urine
Ribavirin: ADEs
- Ribavirin—dose dependent transient amnesia, elevated bilirubin
- Aerosol can be safer, but respiratory function in babies can deteriorate quickly after aerosol treatment is started— close monitoring is mandatory
- Ribavirin is contraindicated in pregnancy
Treating Hepatic Viral Infections
vMany different types of viral hepatitis—Hep B [DNA
virus] and Hep C [RNA virus] are the most
common cause of chronic Hep, cirrhosis and hepatocellular cancer
♦In 2019, we only have therapy for these two viral
hepatitis viruses
How is chronic Hep B treated
♦Chronic Hep B can be treated with Peginterferon-α-2a injected SQ weekly
♦Oral therapy for chronic Hep B can be with Lamivudine, Adefovir and Tenofovir
How is chronic hep C 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
Treating Hepatis B—Interferons
-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
• Incompletely understood
• Involves the induction of host cell enzymes that inhibit viral RNA translation—leading to the breakdown of
viral RNAs
Hepatitis B—Interferons: USES
• 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]
Hepatitis B—Interferons: ADEs
• 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
Hepatitis B—Lamivudine
♦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—Adenovir
♦Hepsera is a nucleotide analog that is phosphorylated by cellular kinases to adefovir diphosphate, which is
incorporated into viral DNA
♦This causes termination of chain elongation and prevents replicationof Hep B virus
♦Given once daily; renally excreted via glomerular filtration and tubular secretion
♦Stopping the drug may result in an exacerbation of Hep B
♦Nephrotoxicity can occur with chronic use
♦Use with caution in those with CKD
♦No longer 1st line in treatment of Hep B—as it has lower efficacy than other agents
Hepatitis B—Entecavir
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
♦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
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
NS3/NS4A Protease Inhibitors examples
Paritaprevir + Ritonavir boost Grazoprevir Voxilaprevir Glecaprevir ADEs—rash, itching, nausea, fatigue, anemia
NS5B Polymerase Inhibitors
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
NS5B Polymerase Inhibitors examples
Sofosbuvir
Dasabuvir
ADEs—few; well tolerated
NS5A Replication Complex Inhibitors
♦ 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
Ribavirin Pearls
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
Options for Hepatitis C
♦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]
Acyclovir
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
Acyclovir: MOA
• 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
Acyclovir: Pharmacokinetics
- 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
Acyclovir: ADEs
- 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
Acyclovir: Resistance
• 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
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
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
Foscarnet
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
Ganciclovir
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
Ganciclovir: MOA
• 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
Ganciclovir: Pharmacokinetics
• 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
Ganciclovir: ADEs
• Severe dose dependent neutropenia • Carcinogenic and teratogenic • BB warning for use in pregnancy
Ganciclovir: Resistance
• Resistant strains of CMV have been seen with low levels of Ganciclovir triphosphate
Penciclovir and Famciclovir
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
Trifluridine
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
Acyclovir
slide 42
MOA:
Virsuses or diseases affected:
Amantadine
MOA:
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Cidofovir
MOA:
Virsuses or diseases affected:
Famciclovir
MOA:
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Forcarnet
MOA:
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