Antiviral Flashcards
(108 cards)
1
Q
challenges with antiviral therapy
A
for man infections viral replication peaks near the time slinical symptoms first appear
- drugs most effective if administered before onset of symptoms
- not true for herpesvirus, HIV, or hepatitis: replication continues over long periods
2
Q
Antiviral infections laten infections
A
therapy does not eliminate latent (dormant forms)
3
Q
are these drugs virustatic or virucidal
A
most are virustatic. so viral eradication requires competent host immune system
4
Q
Immunization
A
Active-vaccination
Passive-injection of immune globin (antibodies)
*Palivizumab: monoclonal Ab to prevent severe resspiratory synctial virus in high risk pediatric patients
5
Q
Palivizumab
- use
- mechanism
A
- humanized monoclonal Ab to prevent severe RSV in high risk pediatric patients
- binds to fusion protein of RSV to prevent fusion to host cells
6
Q
Infleunza A prophylaxis
A
-Amantadine
7
Q
Influenza A and B treatment/prophylaxis
A
Oseltamivir
8
Q
Amantadine
A
- prophylaxis against influenza A not influenza B (Best for prevention)
- therapy for infleunza A: reduces fever in 50% of patients and illness duration by 1-2 days if given within first 2 days
- resistance is now a common problem
9
Q
Amantadine
A
-blocks viral uncoating by interfering with influenza A M2 protein (an ion channel)
10
Q
Amantadine sie effects
A
- CNS effects
- slurred speech
- confusion, depression
- headaches, hallucinations
11
Q
Oseltamivir
A
- prodrug, given orally
- competitively inhibits influenza neuraminidases
- interferes with viral release and viral penetration
12
Q
approved uses for Oseltamivir
A
- treatment of uncomplicated influenza A and B in patients over one year old
- greatest benefit when given within 48 hours of symptom onset
- cinically it is less effective against influenza B than A
- influenza prophylaxis for people over 1 year old
13
Q
side effects for oseltamivir
A
- nausea, vomiting, diarrhea
- bronchitis
14
Q
Trifluridine
A
thymic analog
interferes with DNA synthesis
15
Q
Trifluridine
A
- ophthalmic use only
- treatment of HSV 1 and 2
16
Q
Acyclovir
A
- phosphorylated form is produced 40-100x faster in infected cells by herpes thymidine kinase
- inhibits herpes DNA polymerase 10-30x more effectively than host cell DNA polymerase
- competes with deoxy-GTP for DNa polymerase
- terminates DNA chain elongation
17
Q
Acyclovir IV use
A
- serious systemic herpes simplex virus
- HSV encephalitis
- disseminated neonatal HSV
- severe!! initial genital herpes
18
Q
Acyclovir oral use
A
- primary genital herpes
- primary herpetic gingivostomatitis
19
Q
Acyclovir topical uses
A
-primary genital herpes
may shorten healling time and pain when applied early
20
Q
Acyclovir side effects
A
- generally well-tolerated
- rash, itching
- nausea, vomiting, heaadache, fatugue
21
Q
Famciclovir
A
- prodrug activation
* active component is penciclovir-triP
22
Q
Famciclovir mechanism
A
-Penciclovir-triP inhibits viral DNA polymerase (similar mechanism to acyclovir)
23
Q
uses of famciclovir
A
- acute herpes zoster
- shingles latent chicken pox virus. localized and less than 3 days duration
- treatment and suppression of recurrent gential herpes
- oral administration and better absorbed than acyclovir
24
Q
what is the effect of Famciclovir daily
A
its a suppressive therapy that markedly reduces recurrent episodes of genital herpes
25
Side effects of famciclovir
similar to acyclovir
26
Penciclovir
MOA
Use
- mechanism similar to acyclovir
- recurrent herpes of the lips and face
- topical administration
27
Drug for CMV prophylaxis
-Acyclic nucleoside analogs
*Ganciclovir
Pyrophosphate analogs
*Foscarnet
28
Ganciclovir MOA
similar to acyclovir, except monophos by CMV protein kinase
29
why do we ever care about CMV virus if most of the population has it?
-in immunocompromised people like HIV positive or solid organ transplant
30
Uses of Ganciclovir
- CMV retinitis
* in aids patients. doesn't stop the retinitis completely
- CMV prophylaxis for transplant recipietns
31
side effects for Gangciclovir
- bone marrow suppression
| * leukopenia (less than 40%) thrombocytopenia, anemia
32
Foscarnet
- selectively inhibits CMV DNA polymerase by binding to its pyrophosphate-binding site
- does not require conversion to triphosphate form to be active
33
Foscarnet uses
- CMV retinitis
- acyclovir resistant herpes simplex
* eg those with thymidine kinase mutations
34
Foscarnet side effects
- renal damage
- electrolyte imbalances
- seizures
- compared to gancivlovir, higher percent of patients on foscarnet must be take off due to the side effects
35
so what is the real effect of an anti-CMV drug on retinitis
Anti-CMV drugs will slow the progression of CMV retinitis but not cure it
the best retinitis strategy is prevention, for HIV patients, effective anti-HIV drug regimens to keep CD4 counts elevated
36
Drugs for Hepatitis B
- Lamivudine
- Tenofovir
- Interferon-alpha
37
Hepatitis C drugs
- Ribavirin
- Interferon-alpha
- Simeprevir
- Sofosbuvir
- Ledipasvir
38
RSV-Repiratory syncytial virus
Ribavirin
39
Why is Hepatitis B difficult to cure
persistent HBV cccDNA in the nucleus
typically requires prolonged or lifelong therapy
40
Lamivudine
- nucleoside analog converted by cell enzymes to triphosphate form
- competitively inhibits the reverse transcriptase domain of the HBV polymerase
- causes DNA chain termination
41
Use of lamivudine
hepatitis B
42
side effect Lamivudine
nausea diarrhea
43
Tenofovir
- adenosine monophosphate prodrug that is phophorylated by cell enzymes to the triphosphate form
- competitively inhibits the reverse transcriptase domain of the HBV polymerase
- casues DNA chain termination
44
use of Tenofovir
approved fr hepatitis B
45
side effects for Tenofovir
GI upset
46
alpha interferons approved use
- condyloma acuminata (venereal warts)
- Hepatitis B and C given with other drugs Pegylation decreases IFN clearance
* better clearance and less frequent dosing
47
Side effects of interferon alpha
- flu-like syndrome
- leukopenia, bone marrow suppression
- neurotoxicity, myalgia
- side effects are the greatest limitation to long-term use of interferon alpha
48
Ribavirin MOA
- interferes with viral mRNA synthesis by
* mono-P form inhibits inosine-5'-P-dehydorgenase and thus GMP (and GTP) synthesis
* Tri-P form inhibits GTP-dependent capping of viral mRNA
49
Uses of RIbavirin
- aerosol use: subset of infants and young children with documented severe RSV infections. it is no longer commonly used
- oral capsules
* hepatitis C in combination with PEG interferon alpha and other drugs
50
Ribavirin side effects
- aerosol use:
* drugs may precipitate in and clog respiratory equipment
* pulmonary function deterioration; rash
- IV or oral use:
* anemia bone marrow suppression
51
Hepatitis C
RNA virus (ssRNA, + strand)
Does not integrate into host DNA
-theoretically curable
52
are there vaccines available for hepatitis
yes for hepatitis B no for hepatitis C
53
Drugs for Hepatitis C
* *Multidrug therapy**
- PEG-interferon alpha
- ribavirin
* *Ns3/Ns4 A protease inhibitors
- simeprevir
* *NS5B RNa polymerase inhibitors
- sofosbuvir
* *NS5A protein inhibitors
- ledipasvir
54
Simeprevir MOA
- reversible inhibitor of hepatitis C NS3/NS4A protease
| - blocks cleavage of polyprotein and thus formation of infectious virus
55
Approved use of simprevir
- hepatitis C genotype 1
| - In combo with other drugs for HCV
56
Adding simprevir does what to the outcomes for HCV genotype 1
Simprevir greatly improves the outcomes for HCV genotype 1
57
simprevir side effects
- rash (with r without photosensitivity)
- nausea, itching
- CYP3A interactions: SImprevir is metabolized by CYP3A
* avoid use with moderate or strong inducers or inhibitors of CYP3A they significantly alter simprevir levels
58
Sofosbuvir
- Nucleoside (uridine) analog prodrug
- active for is the triphosphate
* inhibits HCV NS5B RNA polymerase
* its incorporation causes chain termination
59
Sofobuvir uses
all hepatitis C drugs
| -give with other HCV drugs
60
Sofosbuvir adverse effects
avoid potent inducers of P-glycoprotein (Pgp)
| ex: rifampin, ST johns wart
61
Ledipasvir
MOA
use
adverse efects
- inhibits NS5A phosphoprotein
- given with sofosbuvir
* HCV genotypes 1,4,5,6
- SE: avoid potent inducers of P-glycoprotein
62
important properties of HCV drug combinations
- given 2 or more drugs with different mechanism
- avoid IFN-alpha when possible
- genotype appropriate therapy
- side effect tolerance (lengthy therapy, potential drug interactions, IFN alpha is the most difficult to tolerate overall)
63
HIV therapy
- multidrug
- Reverse transcriptase (RT) inhibitors
* Nucleoside analog (NRTIs)
* Non-nucleoside inhibitors (NNRTIs)
- protease inhibitors (PIs)
- Fusion inhibitors
- CCR5 antagonists
- integrase inhibitors
64
NRTIs
- Zidovudine (AZT)
- Lamivudine (3TC)
- Abacavir
- Tenofovir
- Emtricitabine (FTC)
65
NNRTIs
-Efavirenz
66
Protease Inhibitors
(navir)
- Lopinavir
- Ritonavir (booster)
67
Fusion Inhibitors
-Enfuvirtide
68
Zidovudine or AZT
-thymidine nucleoside analog phosphorylated by cell enzymes to AZT-triphosphate, which competitively inhibits RT and acts as a chain terminator
69
Zidovudine (AZT) side effects
- bone marrow suppression
* neutropenia, anemia
- avoid drugs which inhibit glucuronyltransferases
- myopathy
70
Why shouldn't you use a Glucuronyl Transferase with an AZT
-drugs that inhibit glucuronidation of AZT increase the hemolytic toxicity of AZT
so basically AZT can be metabolized in two ways, one is via glucuronyl transferases and the other is reduction by cytochrome P450s. The cytochrome pathway leads to a toxic amine production that causes bone marrow toxicity
so if you block glurcuronyl trasferase it all goes throught the path that causes bone amrorow toxicity
71
Mechanism fo NRTIs
- nucleoside analogs that must be phosphorylated to tri-phos form to be active
- competitive inhibitors of RT
- cause DNA chain termination when incorporated into DNA
72
Tenofovir
-adenosine monophosphate drug that is hydrolyzed to tenovir phosphonate, which is further phosphorylated by cellular enzymes to triphosphate form
73
similarities of Tenofovir and AZT
triphosphate form competitively inhibis RT causing DNA chain termination
74
Tenofovir uses
-combination therapy HIV
75
Side effects Tenofovir
overall well tolerated
76
Lamivudine
- nucleoside analog inhibitor of RT
* phosphorylated by cell enzymes to triphosphate form that competitively inhibits RT, causes DNA chain termination
* AZT resistant strains are 3C sensitive and
* 3TC resistant strains are AZT sensitive
-synergistic with AZT against HIV
77
side effects of Lamivudine
nausea, diarrhea, rash
78
Emtricitabine
- FLuortinated analog of lamivudine
| - same mechanism and resisitance as 3TC
79
Abacavir
- nucleoside analog
| * triphosphorylated form inhibits RT and causes DNA chain termination
80
adverse effects of abacavir
- HYPERSENSITIVITY
* associated with HLA-B*5701 allele
-If hypersensitivity occurs STOP drug immediately and never start again
81
other side effects associated with NRTIs as a group
- Lactic acidosis
| - Hepatic steatosis
82
Non-nucleoside inhibitors RT (NNRTIs)
efavirenz
**this is active as given it does not need to be phosphorylated to be active
83
Efavirenz
- non-nucleoside inhibitor RT
* binds at different site than NRTIs
* disrupts active site of RT
* active as given
- as part of a multi-drug therapy for HIV
* once per day dsingL 2005 #1 anti HIV drug in USA
84
side effects of Efavirenz
- rash
- CNS/psychiatric symptoms (various) nightmares, vivid dreams
* occurs in 50% of patients especially early in the treatment (first month, sometimes goes away after the first month)
these side effects are why it isn't being prescribed as much
85
Protease Inhibitors for HIV
- Lopinavir
- Ritonavir (used as a PI booster not as a PI)
- Ataznavir: less incidence of lipid abnormalities
- Darunavir: effective against many strains resisitant to other PIs
86
Use of protease inhibitors
- in combination with inhibitors of RT: for HIV-1 and HIV-2
| - significantly decrease viral blood level-often below detectable levels
87
Mechanism of Protease Inhibitors
- prevents viral aspartic protease from cleaving Gag-pol polypeptide into separate functional proteins
- competitive inhibitor of protease active site
- results in non-infectious viral particles
88
Toxicities common to a number of protease inhibitors including Lopinavir
- diabetes
- alterations in lipid metabolism: increase in triglycerides and cholesterol
- fat redistribution
- alters metabolism of many other drugs
* potent CYP3A inhibitors
89
Liponavir
protease inhibitor
90
Ritonavir
- used to boost levels of other protease inhibitors because it blocks their metabolism by CYP3A
- avoid other drugs metabolized by CYP3A
91
Retonavir as a PI booster
-Ritonavir boosts lopinavir levels by blocking the metabolism of lopinavir by CYP3A
92
Enfuvirtide
- used only for HIV-1 not HIv-2
| - HIV treatment experienced patients who have failed multiple regimens
93
MOA Enfuvirtide
- binds to gp41 subunit of HIV glycoprotein
| - block conformational changes required for membrane fusion to CD4 cells
94
side effects for Enfuvirtide
-local injection site reactions in 98% of people (pruritis, pain,, erythema, cysts, nodule formation can be very serious)
- diarrhea, nausea, fatigue
- used as a later option when other regimens have failed
95
Maraviroc-use
- treatments of CCR5-tropic HIV 1
- effective for strains resistant to other drugs
* CCR5 tropic strains tend to predominate early in infection
96
Maraviroc mechanism
- small molecule antagonist chemokine co-receptor CCR5 preventing interaction with HIV gp120
* the only anti HIV drug that targets a human protein
- blocks entry of HIV into cells
97
what is the only anti-HIV drug that targets a human protein
Maraviroc is targeting OUR CCR5 receptor, not HIV
98
Maraviroc side effects
possible hepatotoxicity
| -cardiovascular events
99
Inhibitors of HIV Integrase
raltegravir
100
Raltegravir- use
- treatment HIV-1 in new and treatment-experienced patients
- works on virus that is resisitant to other drugs
- as a part of multi drug therapy, common 1st like use
(teg in the name comes come inTEGrase)
101
Raltegravir
inhibits HIV-1 integrase activity
| -preventing integration of HIV-1 DNA into the genome
102
raltegrase
potential for severe/fatal skin and hypersensitivity reactions
103
Current reasons for HIV therapeutic failure
- failure to maintain adherence to rug regimens
- resistant stains emerge (replication not stopeed)
* test initially and when changing regimens
- the available drugs are very effective at suppressing viral replication when selected and used properly
- the best way to prevent opportunistic infection is anti-HIV therapy to stop HIV replication, keeping CD4 counts higher
104
Selection of drug combinations
- viral resistance profiles
- compliance
* ease of administration
* tolerance of side effects
* co-morbid conditions
105
Drug combination for treating HIV
3 or more drugs per patient ( more than two drug classes)
-YOU WANT TO KEEP REPLICATION AT ZERO TO PREVENT RESISTANCE
- HAART: Highly active anti-retroviral therapy
- combination of drugs of 2 or more classes
106
what is the current guideline to monitor therpy effectiveness
-current guidelines use viral load to monitor therapy effectiveness
107
indications for starting HAART DHHS Guidelines
- initiate treatment in all HIV infected individuals as soon as possible in order to:
* reduce risk of disease production
* reduce risk of HIV transmission
108
How soon after infection should you initiate anti-HIV drugs
ASAP!!!! even 24 hours-36 hours may be too late
