Pharmacology-Anti-HIV Agents Flashcards
1
Q
What are the fusion inhibitors?
A
Enfuviride
Maraviroc
2
Q
What are the nucleoside reverse transcriptase inhibitors?
A
zidovudin Didanosine Lamivudine Stavudine Abacavir
3
Q
What are the Nucleotide inhibitors?
A
Tenofovir
4
Q
What are the non-nucleoside reverse transcriptase inhibitors?
A
Nevirapine
Delavirdine
Efvirenz
5
Q
What are the integrase inhibitors?
A
Raltegravir
6
Q
What are the protease inhibitors??
A
Atazanavir Saquinavir Ritonavir Lopinavir Indinavir Nelfinavir
7
Q
What are the goals of therapy?
A
Improvement of quality of life
reduction of HIV related morbidity and morality
Restoration and or preservation of immunologic function
Maximal and durable suppression of Viral load
8
Q
What are the tools to achieve Goals?
A
Selection of ARV regimen
Preservation of future treatment options
Rational sequencing of therapy
Maximizing adherence
Use of resistance testing in selected clinical settings
9
Q
What are the parts of initiation?
A
attachment
penetration
uncoating
10
Q
What are the steps in Release?
A
assembly
maturation
exit from cell
11
Q
What is the mechanism of Enfuviritde adn what type of antiretroviral is it?
A
-increases the effectiveness of HAART in combo chemotherapy
-Binds ot GP41 of hte bviral envelope
-prevents conformational change and impedes the fusion of hte viral and host cell memranes
Fusion inhibitors
12
Q
What are the resistance mechanisms for Enfuviride?
A
pg41 mutations may develop when drug is given at suboptiaml doses as monotherapy
-No cross resistance with other HIV agents
13
Q
What are the ADMEs of Enfuvirtide?
A
- Subcu
- High protein binding
- Metabolized by proteolytic hydrolysis (no involvement of cyt P450)
14
Q
What are the adverse effects of Enfuvirtide?
A
- injection-site rxns (lrg # of pts. )
- Hypersensitivity rxnn (occurs rarely <1%)
- increased risk of bacterial pneumonia (8x more frequently than placebo)
15
Q
What is Maraviroc, and what is its mechanism of action?
A
Fusion Inhibitor
- chemokine receptor 5 antagonist
- binds ot CCR5 co-receptor
- prevents virus form entering the host cell
16
Q
What are the ADMEs of Maraviroc?
A
-Oral
-Substrate for both CYP3A4 and P-glycoprotein
T 1/2— 14-18 h
-both feces adn urine
17
Q
Why would you use Maraviroc?
A
- txment of CCR5-tropic HI-1 (not CXCR4)
- in combo for patients failing other antiretroviral drugs
- Only ~50% of txment experienced pts will be eligible to take
18
Q
What are the adverse effects of Maraviroc?
A
- cough, pyrexia, rash, musculoskeletal symptoms, abdominal pain and psotural dizzziness, bladder irritation
- Phase II studies reported possible liver and cardiac problems (1.3%)
19
Q
What are the drug interactions of Maraviroc??
A
CYP3A4 inducers or inhibitors
-dosage adjustment needed with efavirenx and lopinavir/ritonavir
20
Q
What are the combination therapies used for NRTIs?
A
Combirvir (AZT+3TC) (Zidovudine+ Lamivudine)
Trizivir (AZT+3TC+ABC)(Zidovudine+ Lamivudine+ Abacavir)
21
Q
What is the mechanism of action of the nucleoside reverse transcriptase inhibitors (NRTIs)?
A
- analogs of naturally occuring nucleosides (3’ hydroxyl replaced by an azido, hydrogen or other )
- competitive inhibitor of viral reverse transcriptase
- DNA chain terminator
22
Q
How does do the NRTIs work (2 steps)
A
Triphosphate competes with native nucleotides
incorporation and chain termination
23
Q
What are the properties of Zidovudine and Stavudine?
A
- analogs of pyrimidine nucleoside (T)
- phosphorylated to active triphosphate forms
- competes with deoxythymidine thriphosphate for incorporation into DNA
24
Q
What are the properties of Lamivudin adn Emtricitabine?
A
- Analogous of pyrimiden nucleoside (C)
- compete with deoxycytidine triphosphate for incorportation into viral DNA
25
What are the properties of Didanosine?
Alalog of purine nucleosides (A,G)
-Active 2' 3'- dideoxyadenosine 5'- triphosphate (ddATP) competes iwth cellular deoxyaadenosine triphosphate for incorporation into viral DNA
26
What are the properties of Abacavir?
analog of purine nucleosides (G)
27
What are theindications of NRTIs?
- management of HIV infection as components of combination HAART
- prevent acute infection of susceptible cells
- little effect on cells already infected by HIB
- Zidovudine (only NRTI shown to reduce perinatal HIV transmission )
28
What are the resistance mechanisms for NRTIs?
drugs select for differnet mutations of the reverse transcriptase gene at the level of specific codons
29
What two drugs have AUC changes due to meals and what are they?
Zidovudine: v 24 (high fat)
Didanosine: v 50% (acidity)
30
What is important about the metabolism adn renal excretion of Abacavir?
metabolism >80%
| renal excretion <5% of parent drug
31
How is Zidovudine metabolized?
glucuronidation
32
What are the pharmacological propertis of NRTIs?
- good oral absorption
- poor bindding to plama proteins
- metabolism does not rely on CYP450 system
- excteted unchanged in urine except (zidovudine and abacavir)
- Didanosine is acid labile (~take 1/2 h beofre or 2 h after meals)
33
How is Abacavir metabolized?
by alcohol dehydrogenase
34
What are the common adverse effects of NRTIs?
-GI distress
Lactic acidosis with hepatic steatosis due to mitochondrial toxicity
-higher with stavudine
Lipodystropy (most common with stavudine and zidocudine)
35
What are the unusual toxicities of Zidovudine?
can cause bone marrow suppression
36
What are the unusual toxicites of Dianosine?
diarrhea,
peripheral neuopathy
pancreatitis
37
What are the unusual toxicities of stavudine?
peripheral neuopathy
| pancreatitis
38
What are the unusual toxicities of Abacavir?
Hypersensitvity rxn due to genetic predisposition
| -HLAB5701 screening , to reduce risk of hypersensitive rxn, if positive do not receive treatment
39
What are the D-D interactions of Zidovudine?
avoid concurrent admistration with drugs that are bone marrow suppressive
- ganciclovir, interferon alpha, dapsone, flucytosine, vincristine, vinblastine
- avoid use ith stavudine as antagonism results
40
What are the D-D interactions of Didanosine?
- early virologic failure result in combination with lamivudine )or emtricitabine) + tenofovir
- some drugs can augment the neuropathy and pancreatitis
- - Ethambuto, isoniazid, vincristine, cis-platin
- stavudine
- Ganciclovir increases plasma conc 2X
- methadone decreases plasma levels
- -dosage adjustment needed
41
What are the D-D interatcions of stavudine?
Same as dianosine!!
- - augments the neuopathy and pancreatitis with didanosine, ethambuto, isoniazid, vincristin, cis-platin
- competition with Zidovudine for activation enzymes
- --theymidine kinase>thymidylate kinase>nucleoside diphosphate kinase
42
What are the D-D interactions of Laivudine?
-trimethoprim-sulfamethoxazole increases plasma concentration
43
What are the D-D interactions of Abacavir?
Ethanol significantly increases plasma levels
44
What are the indications of NRTIs?
treatmetn of HIV as a part of combo therapy
45
What are the MoA of MRTIs?
inhibit viral reverse transcriptasze
46
What are the resistance mechanisms against NRTIs?
mutations in reverse transcriptiase gene
47
What are ADMEs for NRTIs?
- Well absorbed by the GI tract; good oral biovalibilty
| - excreted unchanged by kidney ep AZT and ABC
48
What are the adverse effects of NRTIs?
all cause GI distress
| -lactic acidosis with hepatic steatosis due to mitochondrial toxicity
49
What are the D-D interactions of NRTIs?
cam be sever due to synergistic effects on myelosuppression and peripheral neuropathy
50
What is a Nucleotide reverse Transcriptase inhibitor ?
Renofovir disoproxil fumarate (DF)
51
What are the properties of Tenofovir?
- first nucleotide reverse transcriptasze inhibitor
- apporved for use in combo with other anti-HIV agents
- requires only tow intracellular phosphorylation steps for activation
- more rapid and complete conversion to active triphosphate
52
What is the MoA for Tenofovir?
inhibits viral revese transcriptase?
53
What are the mechanisms of resistance for Tenofovir?
-thymidine analogue mutations
(corss resistance with preexisitng AZT associated mutations)
-not effected by lamivudine-abacavir associated mutations
54
How is tenofovir administered?
1x a day
increased bioavilibility taken with a meal
spearte dosing form didanosine by 1-2 hrs
55
What is the metabolism of tenofovir?
not substrate for P405
| no adverse D-D interactions with other p450 substrate drugs
56
What are the adverse effects of Tenofovir?
- most commonly (>3%) inclinical trials- nausea, diarrhea, asthenia, headache, vomiting, flatulence, abdoinal pain, and anorexia
- increased liver enzymes
57
What is improtant about tenofovir and emtricitabine?
- Truvada
- better than Abacavir-Lamivudine for initial HIV therapy
- truvada better at extending time to virologic failure an fist adverse event
- truvada effective as antiretrovial chemophrphylasxis before exposure
58
What are the indications of Non nucleoside reverse transcriptase inhibitors (NNRTIs)?
- Hiv-I inffections
| - do not have signigicant activity against HIV-2
59
What are the mechanism of action for NNRTIs?
- bind directly to a hydrophobic pocket of the RT protein
- induce confrontational change in active site and block enzyme activity
- do not require intraccellular phophorylation for activity
60
What are the mechanism of resitance for NNRTIs?
-each drug selects of differnt muations of the RT gene at the level of specific codons
61
What are the properties of NNRTIs?
- excellent oral absoprtion
- highly bound to plasma proteins
- metabolized by the CYP450 systems (siginication d-d interations)
- excreted therouh the urine as glucuronide conjugates
62
What is unique about Dlavirdin with CYP3A4?
it is an inhibiotr
| -increase PIs, rifabutin, clathromycin, methadone, and ethinyl estradiol plasma levels
63
What is unique about Efavirenz adn Neviraphine with CYP3A4?
inducer
| -reduces PIs, rifabutin, clathromycin, methadone, and ethinyl estradiol plasma levels
64
What are the common toxicites of NNRTIs?
-maculopapular rashes in the trunk and extremities
65
What are the unique toxicites of Nevirapine?
- fever, fatigue, headache, comnolence, nausea,
| - hepatotoxicity (elevated liver enxymes); may be sever and life-threatening
66
What are the unique toxicites of Efavirenz?
NEUROPSYCHIATRIC (headache, dizziness, abnormal dreams, psychosis, sucidal ideation)
- teratogenic in nonhuman primates
- FDA pregnacy Category D
67
What are the mechanism of actions for Integrase inhibitors?
inhibits HIV-1 integrase enxyme
| -needed for insterion of viral DNA into host genome
68
What are the ADMEs for the integrase inhibitors?
- oral
- glucuronidation in liver
- T1/2 --- 9h
- feves and urine
69
What are the indication of Raltegravir?
-use in combination therapy for treatment-experienced adults with HIV-1 strains restraint to mltiple antiretroviral agents
70
What are the adverse effects of Raltegravir?
Diarrhea
nausea
headache
fever
71
What are the in drug-drug interaction of raltegravir?
- not inducer, inhibitor or substrate of CYP3A4
- metabolized by UDP glucoruronsylatransferase (UFT)
- rifampin induces UGT
- PI atazanavir inhibits UGT
72
What are the indications of Protease inhibitors?
treatmetn of HIV as part of combination therapy
most effective ART availble
-Effective in both acutely adn chroic HIV-1 infected cells
-Effective in monocytes and macrophages (not affected by RT inhibitors)
-early stages of HIV-1 replication cycle no affected
73
What is the MoA of protease inhibitors?
- selective, competivie inhibitors of HIV proteases
- Bind reversibly to protease active site
- prevent cleavage of polyprotein and block viral maturation
74
What is the resistance to Protease Inhibitors?
-EAch drug selects for differnt mutations in protease gene at level of specific codons
75
What is the ADMEs of protease inhibitors?
- oral absorption varies
- bind extensively to plasma proteins
- metabolized by cyp450 (concurrent use of potent P450 inducer -rifampin- leads to decresaed PI concetration
- renal excreation is minimal (no adjustments needed for renal dysfunctions
76
what are protease inhibitors effects on CYP3A4?
INHIBITORS!!!
- ritonavir used ot increase plasma of other PIs (inhibits GI p450, during absorption and hepatic p450 for metabolism)
- toxic adverse effects related to drug accumulation due to PI-=mediated inhibition of hepatic P450 system
77
What are the drug interactions with PIs?
carbamazepines lower indiavir AUC potentially other PIs (adjust dose)
- Ketoconazole upregulates PIs AUC (adjust does)
- sildenafil AUC augmented by PIs
- methadone AUC reduced by rionavir and lopinavir
- oral contraceptive AUC reduced by PIs
78
What are common Adverse effects of PIs?
- Hyperlipiemia
- insulin resistance and diabetes
- lipodystrophy -- fat wastingm buffalo hump, crix-belly,- extremity wasting with venous prominence- facial thinning- breat enlargement
- elevated liver function tests
- possible increased bleeding risk in hemophailiacs
- D-Dinteractions
79
Ritonavir AEs?
- hepatotoxicity at high doses
| - used at low doses to boost level of other PIs
80
Undinavir AEs?
- Alopecia, kidney stones, and renal insufficiency
| - pts should drink water
81
Atazanavir AEs?
-hyperbilirubinemia due to inhibiton of UDP glycuronsyltranferase (reversible)
82
Tipranavir AEs?
induces PP-glycoprotein transporter
83
What is the selectivity of NRTIs?
once phosphorylated by cellular kinases have grater affinity for viral reverse transcriptase than for cellular DNA polymerases
84
What is the selectivity of NNRTIs?
- dont undergo phosphorylation
| - have grater affinity for viral reverse transcripatse
85
What is the selectivity for PIs?
-greater affinity for HIV aspartyl protease than for human protease
