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PHRM 865 > Clinical Pharmacology and Therapeutics of Antivirals > Flashcards

Clinical Pharmacology and Therapeutics of Antivirals Flashcards

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1
Q

What are herpes simplex viruses?

A

HSV1 and HSV2
* A double stranded DNA virus that can cause several different types of infections
* The virus can be active/lytic (producing new virus) or latent (dormant)
* Dormant virus is often activated in response to stress or declining immune response
* HSV is uncurable but can be managed with medication

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2
Q

Where is HSV1 most commonly found in?

A

oral mucosa

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3
Q

Where is HSV2 most commonly found in?

A

genital mucosa

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4
Q

Where are HSV1/2 commonly found in?

A

CNS, eye, skin, visceral organs (last 3 really only in immunocompromised)

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5
Q

What are signs/symptoms of HSV1 in oral mucosa?

A
  • Blisters or ulcers around the mouth (cold sore) or in the mouth
  • Transferred via infected oral secretions
  • First episode can experience fever, body aches, sore throat, headache, swollen lymph nodes
  • Reoccurrence can start with a tingling or burning sensation where the sore will form (prodrome)
  • The virus establishes chronic infection in the sensory ganglia
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6
Q

What is the diagnosis of HSV1?

A

diagnosis via swab and PCR testing

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7
Q

What are signs/symptoms of HSV2 in genital mucosa?

A
  • Bumps, blisters, or ulcers around the genitals or anus
  • Transferred via infected secretions
  • Reoccurrence can start with a tingling or burning sensation where the sore will form or can feel pain down the leg or buttock (prodrome)
  • Reoccurrence are often shorter and less severe than the initial outbreak
  • The virus establishes chronic infection in the sacral ganglia
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8
Q

What is the diagnosis of HSV2?

A

diagnosis via swab and PCR testing

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9
Q

What are signs/symptoms of HSV1/HSV2 in the CNS?

A
  • Fever (80%)
  • Confusion (72%)
  • Abnormal behavior / personality changes (59%)
  • Headache (58%)
  • Seizures (54%)
  • Focal neurological deficits (41%)
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10
Q

What is HSV encephalitis caused by? What is the diagnosis?

A

mostly caused by HSV1 (90% of cases) but can be caused by HSV2
* Can see changes on imaging
* Diagnosis via lumbar puncture and PCR testing for virus

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11
Q

What is the MOA of acyclovir?

A

A Prodrug that is converted to active form acyclovir triphosphate via triphosphoylation
* Acyclovir-TP competitively inhibits viral DNA polymerase to inhibit viral replication
* Acyclovir-TP can be incorporated into viral DNA causing premature chain termination

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12
Q

What is the oral bioavailability of acyclovir? Does it need dose adjusted?

A

oral bioavailability 10-20% (not affected by food)
Renally eliminated by glomular filtration and tubular secretion
* Renally dose adjusted
* Removed by hemodialysis (10% per hour)
dose adjust in obesity (use ABW)

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13
Q

What are the adverse effects of acyclovir?

A

Nausea / vomiting / diarrhea
Rash
Headache (oral formulation only)
Nephrotoxicity!! (crystalline nephropathy)
Neurotoxicity
Thrombophlebitis (IV formulation is alkaline)

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14
Q

What is acyclovir used for?

A

genital HSV - primary infection, recurrent infection, or supression
oral HSV
HSV encephalitis
varicella (chickenpox)
zoster (shingles)
severe disseminated disease or VZV encephalitis

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15
Q

What is the MOA of valacyclovir?

A

A prodrug of acyclovir (same MOA)
Rapidly absorbed and completely converted to acyclovir by intestinal and hepatic metabolism following oral absorption

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16
Q

What is the bioavailability of valacyclovir? Does it need dose adjusted?

A

Bioavliability of acyclovir is 3-5 greater with valacyvlovir (55%) formulation
Renally eliminated
* Renally dose adjusted
* Removed by hemodialysis

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17
Q

What is valacyclovir used for?

A

oral herpes
genital herpes - primary infection, recurrent infection, or suppression
varicella (chickenpox)
zoster (shingles)
disseminated zoster

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18
Q

What is the MOA of famciclovir?

A

Prodrug of penciclovir converted to active form via triphosphorylation
Concentration increase proportional to drug given (linear kinetics)

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19
Q

What is the bioavailability of famciclovir? Does it need dose adjusted?

A

Food slows absorption but overall does not affect concentration of drug (can be given without regards to food)
Penciclovir is 77% bioavailable when given as famciclovir (well absorbed)
90% of penciclovir is excreted unchanged in urine
*Excreted by tubular secretion and glomerular filtration
*Dose reduce in renal dysfunction

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20
Q

What are the drug interactions of famciclovir?

A

probenecid + famciclovir decreases renal clearance, increases serum concentrations

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21
Q

What are the adverse effects of famciclovir?

A

Generally well tolerated
Headache
Nausea / vomiting / diarrhea
Acute renal failure

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22
Q

What is famciclovir used for?

A

oral herpes
genital herpes - primary infection, recurrent infection, or suppression
zoster (shingles)

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23
Q

What is varicella zoster virus (VZV)?

A
  • A DNA virus that causes the infections commonly referred to as chickenpox and shingles; After the initial infection (chickenpox) the virus stays in the body by becoming dormant in the sensory nerve ganglia as a latent infection
  • Reactivation of virus is what causes the infection known as shingles
  • Reactivation is commonly caused by stress or decreasing immune function
  • A highly contagious virus that is spread by direct contact or inhalation
  • Patients are considered contagious until lesions have crusted
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24
Q

What is cytomegalovirus?

A
  • Common virus found in people of all ages
  • An opportunistic infection – most healthy people’s immune system can keep the virus from causing illness
  • In those with weak immune systems can cause serious infections most commonly in the eyes and can even cause end organ damage
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25
What is the MOA of ganciclovir in HSV/VZV?
the drug is a prodrug turned into the active form by viral thymidine kinase
26
What is the MOA of ganciclovir in CMV?
ganciclovir is a pro drug converted to its active form mono-phosphorylated by a CMV-encoded protein kinase (UL97 gene), then to di- and triphosphate forms by cellular kinases (triphosphorylation) GCV triphosphate inhibits viral DNA polymerase and/or incorporation into viral DNA which inhibits viral replication
27
How does resistance develop in ganciclovir?
Resistance can develop via a UL97 gene mutation which leads to viral kinase deficiency or altered viral DNA polymerase
28
What is the oral bioavailability of ganciclovir? Does it need dose adjusted?
Low oral bioavailability (~5%), food helps increase absorption (up to ~9%) Adequate concentrations in CSF, brain tissue, and eye >90% is eliminated unchanged by glomerular filtration and tubular secretion * Renally dose adjusted * HD removes ~50%
29
What are the drug interactions with ganciclovir?
avoid other cytotoxic drugs with risk of BM suppression, probenecid
30
What are the adverse effects of ganciclovir?
* Bone marrow suppression!!: neutropenia, thrombocytopenia; stop drug if ANC < 500mm# or platelet <25,000/mm3 * Phlebitis * Headache, confusion, psychosis * Rash * Fever * Nausea/vomiting
31
What is ganciclovir used for?
CMV retinits - induction and maintenance CMV esophagitis, colitis, pneumonitis, neurologic disease prevention and treatment of CMV in bone marrow and organ transplant recipients
32
What is the MOA of valganciclovir?
Prodrug of ganciclovir (rapidly converted to ganciclovir by intestinal and hepatic esterases) MOA and adverse effects same as ganciclovir (hematologic toxicity!)
33
What is the bioavailability of valganciclovir? Does it need dose adjusted?
Bioavailability of ganciclovir ~ 60% when administered as valganciclovir (with food) AUC can increase 30% when administered with high fat meal – so counsel to take with food Renally eliminated * Renally dose adjust * HD removes 50%
34
What is valganciclovir used for?
CMV retinitis - induction or maintenance Prevention of CMV disease in transplant patients at high risk (based on seropositivity of donor and recipient)
35
What is the MOA of letermovir?
Inhibits the pUL56 subunit of the viral terminase complex of cytomegalovirus (CMV) --> Prevents cleavage of concatemeric DNA into monomeric genome length DNA, interfering with viral DNA processing and packaging into procapsids --> End result – inhibition of CMV replication and prevention of CMV infection
36
What is the oral bioavailability of letermovir? Does is need dose adjusted?
Well absorbed orally ~94% Maybe given with or without food Highly protein bound ~99% No dosage adjustment for creatinine clearances > 10 ml/min; if creatinine clearance < 50 ml/min, monitor serum creatinine due to potential accumulation of the IV vehicle
37
What does the IV formulation of letermovir contain?
hydroxypropyl betadex (mainly eliminated by glomerular filtration) this is very nephrotoxic, give fluids
38
What are the drug interactions of letermovir?
Lots!! Letermovir – CYP 3A4 inhibitor; substrate and inhibitor of organic aniontransporting polypeptide 1B1/3 (OATP1B1/3) transporters
39
What are the adverse effects of letermovir?
Nausea/Vomiting/Diarrhea Peripheral edema Cough Headache Fatigue Abdominal pain
40
What is letermovir used for?
Prophylaxis of CMV infection and disease in adult CMV- seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT)
41
What is the MOA of foscarnet?
Directly inhibits viral DNA polymerase (does not require phosphorylation by thymidine kinase or other kinases)
42
What is the oral bioavailability of foscarnet? Does is need dose adjusted?
Only available IV due to poor oral absorption Moderate CNS concentration Bone sequesters 10-20% of dose >80% excreted unchanged by glomerular filtration * Adjust for renal dysfunction * Hemodialysis removes ~ 50%
43
What is foscarnet used for?
Commonly used as a last line in drug resistant HSV, VZV, and CMV
44
What are the drug interactions of foscarnet?
nephrotoxic drugs; pentamidine
45
What are the adverse effects of foscarnet?
nephrotoxicity!!! - major dose-limiting adverse effect * Risk factors: high doses, rapid infusion, dehydration, preexisting renal dysfunction, concomitant nephrotoxic agents Hydrate with 0.75-1 liter of normal saline or D5W prior to first infusion; For subsequent infusions, hydrate with 0.75-1 L for doses of 90-120 mg/kg and 0.5 L for doses of 40-60 mg/kg (administer concurrently with each infusion) metabolic CNS, GI, hematologic
46
What are the symptoms of influenza?
fever/chills, cough, sore throat, congestion, muscle aches, headaches, fatigue The most important step in preventing influenza is widespread vaccination
47
What are the neuraminidase inhibitors?
zanamivir: Dry powder administered by inhalation via proprietary Diskhaler device; Breath-activated - requires cooperative, trained patient with adequate lung function oseltamivir: Ethyl ester prodrug of oseltamivir carboxylate; capsule or powder for oral suspension peramivir: IV formulation
48
What is the MOA of oseltamivir?
Rapidly absorbed, metabolized by esterases in GI tract, liver, and blood to active carboxylate Linear pharmacokinetics; low protein binding (<3%) for oseltamivir carboxylate Prodrug and carboxylate excreted unchanged by glomerular filtration and tubular secretion (probenecid decreases renal clearance by ~50%)
49
What is the oral bioavailability of oseltamivir? Does is need dose adjusted?
Well absorbed when administered through NG tube Ingestion with food delays absorption but no change in bioavailability Half-life ~22 hours in patients with CrCl < 30 mL/min * Renal dose adjustment No dose adjustment required in morbid obesity (obesity associated with poor outcomes) Oseltamivir carboxylate removed by dialysis and CRRT
50
What are the adverse effects of oseltamivir?
nausea, vomiting, diarrhea, abdominal pain, transient neuropsychiatric events (self injury or delirium) mainly reported among Japanese adolescents and adults.
51
What is oseltamivir used for?
Treatment of influenza infection in patients ≥ 2 weeks of age who have been symptomatic for no more than 2 days (not approved for < 1 year old) Prophylaxis of influenza in patients ≥ 1 year of age Do not administer the live attenuated influenza vaccine (intranasal) within 2 weeks before or 48 hours after administration of oseltamivir Inactivated influenza vaccine can be administered at any time
52
What are the adverse effects of zanamivir?
bronchospasm!, worsening COPD, allergic reactions (oropharyngeal or facial edema), neuropsychiatric events (seizures, hallucinations, delirium), headache, nausea, sinusitis, nasal signs and symptoms, bronchitis, cough, dizziness
53
What is zanamivir used for?
* Treatment of influenza infection in patients ≥ 7 years of age who have been symptomatic for no more than 2 days * Prophylaxis of influenza in patients ≥ 5 years of age * Do not administer the live attenuated influenza vaccine (intranasal) until 48 hours after cessation of zanamivir * Do not administer zanamivir until 2 weeks following administration of the live attenuated influenza vaccine
54
What patient population should you not use zanamivir in?
Not recommended in patients with underlying respiratory disease (e.g., asthma, COPD)
55
What is unique about peramivir?
First parenterally available neuraminidase inhibitor (oral bioavailability ~ 2%) Potent inhibitor of both influenza A and B; structurally different than oseltamivir and zanamivir less cross resistance
56
What are the adverse effects of peramivir?
diarrhea, serious skin/hypersensitivity reactions (rare)
57
What are the drug interactions of peramivir?
avoid use of live attenuated influenza vaccine (intranasal) within 2 weeks before or 48 hours after administration of peramivir
58
What is peramivir used for?
Indicated for treatment of acute uncomplicated influenza in patients 18 years or older who have been symptomatic for no more than 2 days need to dose adjust for renal dysfunction
59
What is the MOA of baloxavir marboxil?
inhibits polymerase acidic (PA) endonuclease (influenza specific enzyme in the viral DNA polymerase complex required for viral gene transcription) -> inhibition of mRNA synthesis and viral replication Prodrug completely converted to active baloxavir by hydrolysis
60
With baloxavir marboxil, what should you avoid with co-administration?
Avoid co-administration with dairy products, calcium-fortified beverages, polyvalent cation-containing laxatives, antacids, or oral supplements (e.g., calcium, magnesium, aluminum, iron, selenium, zinc) Do not administer with live attenuated influenza vaccine
61
What are the adverse effects of baloxavir marboxil?
* Well tolerated * Diarrhea (3%), headache (1%), nausea (1%) * No effect on QTc
62
What is baloxavir marboxil used for?
Acute uncomplicated influenza in patients >12 years of age who have been symptomatic for no more than 48 hours
63
What NOT to use in influenza?
Amantadine + Rimantadine – not used in clinical practice due to high resistance rates among FluA viruses
64
What are the drugs of choice for HSV 1/2?
acyclovir valacyclovir
65
What are the drugs of choice for VZV?
acyclovir valacyclovir
66
What are the drugs of choice of CMV?
ganciclovir valganciclovir

PHRM 865 (61 decks)

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