Med Chem > Exam 2 > Flashcards

Exam 2 Flashcards

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1
Q

Amantadine hydrochloride

A
  • antiviral agent
  • tricyclic primary amine
  • inhibits penetration of RNA virus particles into host cell
  • inhibits early stages of viral replications by blocking uncoating
  • treats all strains of A influenza
  • good oral absorption
  • excreted unchanged
  • CNS and GI side effects
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2
Q

Rimantidine hydrochloride

A
  • antiviral agent
  • synthetic adamantane derivative
  • MOA: inhibits virus uncoating only - can’t go into nucleus
  • more effective
  • less side effects
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3
Q

Tecovirimat

A
  • antiviral agent
  • only oral approved drug for pox viruses
  • inhibits formation of viral envelope
  • metabolized by hydrolysis of amide bond
  • half life: 20 hours
  • major metabolite is glucuronide
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4
Q

Zanamivir

A
  • Neuraminidase Inhibitor
  • Substitution of the 4-hydroxy in DANA with a larger guanidino group increases the binding of the drug
  • forms a salt bridge with glutamic acid of NA
  • not available orally
  • active against influenza A and B
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5
Q

Oseltamivir Phosphate

A
  • NA inhibitor
  • prodrug: undergoes ester hydrolysis in liver to active carboxylic acid
  • 2 additional binding sites for NA
  • orally active against flue A and B
  • minor SE: nausea and vomiting
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6
Q

Peramivir

A
  • NA inhibitor
  • emergency use for N1N1 influenza
  • administered via IV
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7
Q

Baloxavir Marboxil

A
  • NA inhibitor
  • prodrug: ester cleavage provides oral activity
  • once daily dosing
  • 93% plasma bound
  • metal chelator
  • contraindicated with multivitamins
  • Metabolism: phase 2 conjugation by UDP-UGT
  • used for uncomplicated flu A and B
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8
Q

Enfuvirtide

A
  • Entry inhibitor
  • 1st approved fro HIV-1
  • oligopeptide with 36 AA - subcutaneous injection
    MOA
  • mimics HR-2 peptide fragment of viral gp41
  • blocks formation of 6-bundle structure critical in the fusion of HIV-1 viron to a CD4-positive T-lymphocyte
  • used in combo with antiretroviral agents
  • highly bound to plasma proteins = DDI
  • prone to proteolytic metabolism
  • adverse effects: pain, erythema and pruritus at site of infection
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9
Q

Maraviroc

A

MOA
- selectively bind to the host chemokine CCR-5 coreceptor, inhibiting binding of HIV-1 to CCR-5 and gp120 / gp41 complex
- prevents fusion and penetration into host cell
- binds to host

  • orally active and highly bound to plasma proteins
  • poor oral availablity due to gp efflux
  • adverse effects: allergic reactions, liver toxicity
  • metabolism: N-dealkylated to inactive metabolite by CYP-3A4
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10
Q

MOA of agents interfering with viral nucleic acid replication

A
  1. conversion of active monophosphate by thymidine kinase followed by conversion of monophosphate to di and tri phosphate by guanosine
    monophosphate kinase
    - triphosphate is active metabolite that inhibits DNA polymerase
  2. incorporation of triphosphate into viral DNA chain during DNA synthesis
    - terminates elongation of DNA chain
  3. preferential uptake of the drug into herpes cells
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11
Q

PK of Acyclovir

A
  • bioavailability: 20%
  • half life: 3 hours
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12
Q

PK of Valacyclovir

A
  • bioavailability: 54%
  • valine AA ester prodrug that is metabolized in liver or intestine to acyclovir
  • lipophilic valine group results in increased absorption and increased blood levels of acyclovir
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13
Q

PK of Famciclovir

A
  • diacetyl ester prodrug
  • undergoes ester hydrolysis
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14
Q

PK of Valganciclovir

A
  • valine ester prodrug
  • undergoes ester hydrolysis
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15
Q

PK of Cidofovir

A
  • phosphorylated nucleotide
  • additionally phosphorylated to cidofivir diphosphate
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16
Q

PK of Adefovir dipivoxil

A
  • hydrolyzed to active drug adefovir diphosphate
  • inhibits HBV DNA polymerase
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17
Q

Acyclovir and Valacyclovir clinical applications

A
  • HSV-1 and HSV-2
  • topical and IV used for immunocompromised patients
  • oral valacyclovir for acute, localized herpes zoster in immunocompetent patients and initial and recurrent HSV-2
  • side effects: headache and GI disturbances
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18
Q

Famciclovir clinical applications

A
  • used for recurrent cold sores, genital herpes and varicella zoster virus
  • side effects: headache and GI
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19
Q

Ganciclovir clinical applications

A
  • HCMV, EBV, HSV infections
  • in some HSV mutants that are resistant to acyclovir
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20
Q

Cidofovir clinical applications

A
  • HSV-1, HSV-2, HCMV, EBC
  • resistant strains of HSV and HCMV
  • side effects: nephrotoxicity
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21
Q

Adefovir Dipivoxil clinical applications

A

chronic hepatitis B

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22
Q

Ribavirin

A
  • conventional nucleoside
  • guanosine analogue
  • broad spectrum activity against flu A and B, genital herpes, herpes zoster, measles and acute hepatitis A, B, C

Prodrug
- phosphorylation by adenosine kinase to the triphosphate that inhibits viral RNA polymerase
- very similar MOA to the acyclic nucleosides

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23
Q

NRTI characteristics

A
  • RT requires purine and pyrimidene nucleosides and nucleotides to convert HIV RNA into HIV DNA
  • modifications have resulted in active drugs
  • remove 3’ hydroxy group
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24
Q

NRTI MOA

A
  • incorporate into proviral DNA as triphosphate
  • interrupt DNA elongation due to lack of 3’ hydroxyl
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25
Zidovudine PK
- sensitive to heat and light due to azine group - stored in colored bottles at room temp - excreted urine as inactive glucuronide metabolite - probenecid prolong half life - good DDI
26
Didanosine PK
- prodrug - metabolized to active deoxyadenosine triphosphate
27
Stavudine PK
- rapidly absorbed - oral bioavailability: 85%
28
Lamivudine PK
- rapidly absorbed - bioavailability: 86% - metabolized to trans-sulfoxide - most is eliminated unchanged
29
Avacavir Sulfate PK
- well absorbed - bioavailability: >75% - active drug: tenofovir - phosphorylated to active tenofovir diphosphate - once daily dosing
30
Emtricitabine PK
- orally active - metabolized int vivo to 5'-triphosphate - once daily dosing - -ve enantiomer is most active - metabolized to 3'-sulfoxide and 2'-hydroxymethyl-O-glucuronide
31
Zidovudine clinical applications
- AIDS - raising absolute CD4+ lymphocyte counts - increase effectiveness of didanosine and lamivudine
32
Trizivir clinical applications
- Abacivir 300 mg - Lamivudine 150 mg - Zidovudine 300 mg - superior to other combos in reducing viral load and increasing CD4+ count
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zidovudine side effects
bone marrow toxicity
34
didanosine side effects
peripheral neuropathy and pancreatitis
35
stavudine side effects
peripheral neuropathy, pain and numbness in hands and feet
36
lamivudine side effects
peripheral neuropathy, GI disturbances
37
abacavir side effects
headache and GI disturbance
38
NNRTI MOA
- used with NRTIs to obtain synergistic activity in decreasing viral load and increasing CD4+ cell count MOA - inhibit HIV-1 reverse transcriptase by inactivating catalytic site of the enzyme and prevents RNA formation - binds to HIV-1 RT at the allosteric site - inhibits both RNA and DNA dependent polymerases
39
Nevirapine PK
- good bioavailability with oral administration - metabolized by CYP-450 to several hydroxylated metabolites that are excreted in urine - hepatotoxic and rash: quinone intermediate
40
Delavirdine PK
- rapidly absorbed after oral administration - highly protein bound: 98% - metabolized to N-desisopropyl metabolite in liver
41
Efavirenz PK
once daily dosing
42
Etavirine PK
- highly bound to plasma proteins - metabolized by CYP-450 and UGT enzymes to inactive metabolites
43
Rilpivirine PK
metabolized by CYP-3A4 and CYP-3A5
44
Doravirine PK
- metabolized by CYP 3A4 and phase 2 conjugation - once daily dosing - newest with least resistance
45
Nevirapine clinical applicaitons
- AZT resistant HIV strains - synergy with zidovudine and didanosine NRTIs
46
Delaviridine clinical applications
- additive or synergistic with zidovudine and didanosine - adverse effect: skin rash
47
Efavirenz clinical applications
- approved as single agent or in several combos with indanavir or zidovudine - adverse effect: skin rash
48
Rilpivirine clinical applications
- first line therapy in antiretroviral naïve patients and those on HAART therapy - orally available as single product - Juluca: with dolutegravir - Odefsey: with emtricitabine and tenofovir disoproxil
49
Doravirine clinical applications
- single agent - Delstrigo: with tenofovir disoproxil and lamivudine - highest genetic barrier to developing resistance - better safety profile - once daily dosing
50
INSTI MOA
- integrase: 1 of 3 core enzymes that is required for successful integration of viral genetic material into host genome - bind to integrase enzyme and prevent replications and block spread of virus - proposed mechanism: bind to key metals that are involved in the action of integrase and thus blocks the viral enzyme
51
Raltegravir
- first line agent and one of the best tolerated antiretroviral meds - metabolically stable - lacks significant DDI - taken twice daily
52
Elvitegravir
- available as single drug - Genvoya: Eltegravir + cobicistat + emtricitabine + tenofovir disoproxil - metabolized by CYP-3A4 to inactive metabolites followed by phase 2 glucuronidation - 99% plasma protein bound
53
Dulotegravir
- long plasma half life - once daily dosing - safe profile with lowest incidence of resistance - little potential for DDI
54
Bictegravir
- Bikrarvy: bictegravir + emtricitabine + tenofovir - once daily dosing - does not require boosting with a CYP inhibitor - metabolized by CYP-3A4 oxidation and glucuronidaiton
55
HIV protease enzymes
- responsible for cleaving viral precursor polypeptides into effective virions - when inhibited: prevent formation of structural proteins for mature viral particles - contain pair of aspartate that work together to complete reaction
56
HIV protease inhibitors MOA
- transition state mimics that bind at the active site of HIV-1 protease - contain hydroxyethylamine as the transition state cores that bind to 2 aspartic acid residues and inhibit protease
57
Nelfinavir PK
metabolized to active hydroxylated metabolite
58
Fosamprenavir PK
- prodrug - hydrolysis by serum phosphatases to active amprenavir
59
Ritonavir PK
- preferential substrate for CYP-3A4 - combo with other protease inhibitors purely to block metabolism and increase efficacy
60
Atazanavir Calcium
- orally dosed once daily - good oral absorption with food - metabolized by and inhibitor of CYP-3A4
61
Nelfinavir Mesylate
- peptidomimetic - metabolized to active form - HIV-1, HIV-2, Zidovudine resistant strains - well tolerated with azole antifungals or macrolide antibiotics - GI side effects
62
Saquinavir Mesylate
- 1st protease inhibitor - advaced HIV infections - well tolerated with zidovudine - GI side effects
63
Ritonavir
- HIV-1 and HIV-2 inhibitor - used in combo with other protease inhibitors due to preferential substrate - GI and CNS side effects
64
Indinavir
- drug interactions with rifoabutin (inducer) or ketoconazole (inhibitor)
65
Lopinavir
Hydroxyethylene based
66
Darunavir
- 2nd generation - treatment naive and treatment-experienced adult and pediatric patients
67
Fosamprenavir
- prodrug - hydrolysis by serum phosphatases to active amprenavir
68
Tipranavir
- non-peptidomimetic inhibitor - very potent - severe side effects: intracranial hemorrhage, hepatitis, diabetes mellitus
69
Nystatin
- conjugated tetraene - topical anti-fungal agent - low oral absorption, may be administered orally to treat fungal infections of mouth and GI
70
Amphoterian B
- heptaene used to treat systemic infections following IV administration - does not cross BBB: administer directly to CSF to treat CNS infection - causes severe nephrotoxicity
71
Natamycin
- tetraene available as a 5% suspension - used topically for the treatment of fungal infections of the eye
72
ketoconazole
- imidazole - treats systemic infections of candidiasis - oral absorption depends on stomach pH - contraindicated with antacids - metabolized by CYP-3A4 - potent inhibitor of P-glycoprotein
73
Itraconazole
- orally active triazole - strong acidic pH is required for good oral absorption - metabolism: strong inhibitor of CYP-3A4 - coaministration with lovastatin or simvastatin causes muscle break down - substrate and strong inhibitor of P-glycoprotein
74
Fluconazole
- equal bioavailability following oral or IV administration - penetrates BBB and effective against Cryptococcus neoformans - not extensively metabolized: excreted mostly unchanged - strong inhibitor of CYP-2C9 - co admin with warfarin doubles AUC and prolongs prothrombin time - decreases metabolism of phenytoin: severe side effects
75
voriconazole
- analogue of fluconazole: overcomes its limitations - broad spectrum activity - orally bioavailable - can cross BBB - metabolism: extensive by CYP450 - inhibits CYP2C19, CYP2C9 and CYP3A4 - CYP2C19 exhibits genetic polymorphisms, can increase voriconazole plasma levels in poor metabolizers
76
Posaconazole
- structurally similar to itraconaozle - broad spectrum activity - active against hospital acquired infection - active against CYP51B sensitive and CYP51A resistant isoforms, enhanced activity against Asperigillus - metabolizes primary by Phase-II conjugation - inhibits CYP3A4 - no CYP DDI
77
Isavuconazonium Sulfate
- a prodrug - undergoes rapid enzymatic hydrolysis in plasma to isavuconazole - promising systemic antifungal with broad spectrum activity - metabolized by CYP3A4 and CYP3A5 - weak inhibitor of all major drug enzymes - small potential for DDI
78
Allyl Amines
- narrow spectrum antifungal activity - treatment of nail and skin fungal infections - butenafine, naftifine, terbinafine - MOA: inhibit squalene epoxidase, decrease in total sterol content and buildup of squalene
Med Chem
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