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Pharmacology FINAL (2nd sem) > C6+7 > Flashcards

C6+7 Flashcards

1
Q

Antiretroviral drugs?

A
  • **Nucleoside revese transcriptase inhibitors (NRTI’s**): inhibit HIV RT after Phosphorylation by cellular enzymes
  • abacavir
  • emtricitabine
  • lamivudine
  • tenofovir
  • zidovudin
  • **Non-nucleoside reverse transcriptase inhibitors (**NNRTI’s): Inhibit HIV RT (no phosphorylation)
  • etravirine
  • **Protease inhibitors**: inhibit viral protein processing
  • Darunavir
  • Ritonavir
  • Lopinavir

*Entry inhibitor :
maraviroc = CCR5 receptor antagonist

*Integrase inhibitors: Block viral integrase of HIV-1, HIV2
dolute-gravir
Elvite-gravir

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2
Q

Anti-HIV drugs modes?

A

NRTIs: nucleoside reverse transcriptase inhibitors

PI: inhibitors of HIV protease

HAART: Highly active antiretroviral therapy

involving drug combinations can slow or reverse the increases in viral RNA load that accompany progression of disease

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3
Q

NRTIs examples?

A

Abacavir
Emtricitabine
Lamivudine
Tenofovir
Zidovudine

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4
Q

NRTIs MOA?

A

Inhibit HIV RT after phosphorylation by cellular enzymes

Incomplete cross resistance

  • prodrugs converted by host cell kinases to triphosphates
  • competitively inhibit binding of natural nucleotides to the dNTP-binding site of reverse transcriptase
  • chain terminators via their insertion into the growing DNA
  • they lack a 3′-hydroxyl group on the ribose ring –> attachment of the next nucleotide is impossible
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5
Q

what about Abacavir?

Bioavalibility

half life

SE

A
  • A guanosine analog
  • good oral bioavailability
  • 1/2 life: 12–24h
  • in 5%: Hypersensitivity reactions (fatal)
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6
Q

What about Emtricitabine?

bioaval

elimination

t1/2

CI

A
  • bioavailability: Good oral
  • Elimination: Renal
  • 1/2 life: long (dosing once-daily)
  • contraindicated in
    1. pregnancy and
    2. young children and
    3. in patients with hepatic or renal dysfunction (propylene glycol in the oral solution)
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7
Q

Emtricitabine Toxicity?

A
  1. asthenia = abnormal physical weakness
  2. GI distress
  3. headache
  4. hyperpigmentation of the palms and/or the soles.
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8
Q

What about Lamivudine ?

A
  • bioavailability: 80% by the oral route
  • elimination: kidney
  • also effective in hepatitis B infections
  • Dosage adjustment is needed in patients with renal insufficiency
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9
Q

What about Tenofovir?

A

NRTI

  • renal elimination
  • also has activity against HBV
  • it is a nucleotide
  • competitively inhibit reverse transcriptase and cause chain termination after incorporation into DNA.
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10
Q

Tenofovir Pharmacokinetix?

A
  • bioavailability: 25–40% Oral
  • 1/2 life: > 60h
  • Elimination: kidney
  • may impede the renal elimination of acyclovir and ganciclovir
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11
Q

Tenofovir Toxicity?

A
  • include GI distress
  • asthenia
  • headache

same as emtricitabine toxicity

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12
Q

Zidovudine Pharmacokinetix?

A
  • bioavailability: active orally
  • distribution: most tissues (alsoCNS)
  • Elimination: both hepatic metabolism to glucuronides and renal excretion
  • Dosage reduction is necessary in uremic patients and cirrhosis
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13
Q

Zidovudine Toxicity?

A
  • bone marrow suppression
    (anemia & neutropenia –> may require transfusions)
  • GI distress
  • thrombocytopenia
  • headaches
  • myalgia
  • acute cholestatic hepatitis
  • Drugs that increase plasma levels of zidovudine:
    *azoles antifungals and protease inhibitors

-Drugs that increase clearance of zidovudine:
*Rifampin

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14
Q

NNRTIs Example?

A

Etravirine

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15
Q

NNRTIs MOA?

A

Inhibit HIV RT

  • cross resistance between NNRTI but not with NRTI
  • bind to a site on reverse transcriptase
  • do not require phosphorylation to be active and do not compete with nucleoside triphosphates
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16
Q

Etravirine Clinical uses?

A
  • treatment-experienced HIV patients
  • effective against HIV strains resistant to other drugs in the group
  • rash, nausea, and diarrhea
17
Q

Protease inhibitors examples?

A

Darunavir
Lopinavir
Ritonavir

18
Q

Protease inhibitors MOA?

A

Inhibits viral protein processing

  • cross resistance between PI’s common
  • it targets aspartate protease –> assembly HIV virions is impaired
  • most commonly in combinations with reverse transcriptase inhibitors as components of HAART
19
Q

what about Darunavir?

A
  • used in combination with ritonavir in treatment-experienced patients with resistance to other PIs.
  • The drug is a substrate of CYP3A4
  • Toxicity: GI, rash and liver toxicity
20
Q

What about Ritonavir PharmacoKinetix?

A
  • biovavailability: Orally good (should be taken with meals)
  • Clearance: liver
  • dosage reduction is necessary in hepatic impairment
21
Q

Ritonavir Toxcitiy?

A
  • GI irritation and a bitter taste (most common)
  • Paresthesias and elevations of hepatic aminotransferases and triglycerides
  • anticonvulsants and Rifamycins: reduce serum levels of ritonavir
    (increase the activity of the cytochrome P450-CYP3A4)
  • azole antifungals, cimetidine, erythromycin: elevate serum levels of the antiviral drug (by inhibiting P450-CYP3A4)
  • Ritonavir inhibits the metabolism of:

Antihistamine. antiarrhythmic, HMG-co reductase inhibitors, oral contraceptive, sedativehypnotics

erythromycin, ketoconazole, prednisone, rifampin, and saquinavir

22
Q

Entry and Fusion Inhibitors?

A

Maraviroc= entry inhibitor CCR5 receptor antagonist

Elvitegravir = integrase inhibitor
Dolutegravir

23
Q

Maraviroc MOA?

A
  • binds to CCR5 and block the binding of the envelop protein gp120 to CD4, macrophages and dendritic cells
24
Q

Maraviroc PharmacoKinetix?

A
  • bioavailability: used orally
  • Distribution: good tissue penetration
  • It is a substrate for CYP3A4
25
Q

Maraviroc Toxicity?

A
  • cough
  • diarrhea
  • muscle and joint pain
  • increase in hepatic transaminases
26
Q

example of Integrase inhibitor?

A

Elvitegravir

Dolutegravir

27
Q

about Elvitegravir , dolutegravir

MOA

Indication

A

Block viral integrase of HIV-1, HIV-2

  • pyrimidine derivative
  • binds integrase (essential for replication) –> inhibit strand transfer –> integration of reverse-transcribed HIV DNA into host cell chromosomes is inhibited
  • used mainly in treatment-naive HIV patients, usually in combination regimens.
28
Q

elvitegravir Dolutegravir PharmacoKinetix?

A

* metabolized by UGT1A1 and/or CYP3A

* inducers and inhibitors of P450 alter the elimination of both.

*Elvitegravir induces CYP2D9

  • if used with rifampin (induces UDP-glucuronosyltransferase) the dose should be doubled
29
Q

Elvitegravir, Dolutegravir Toxicity?

A

GI upset

headache

Rhabdomyolysis (rare)

nausea, dizziness, and fatigue

30
Q

Drugs against Hepatitis?

A
  • Anti-hepatitis drugs:
    • interferon-alpha
    • entecavir
    • Ribavirin ( treats HCV only)
    • sofosbuvir
  • NRTI: tenofovir
  • Anti-HCV drugs:
    • NS5A inhibitors :
      • Elbasavir
      • velpatasvir
    • NS5B RNA pol inhibitors:
      • Dasabuvir
      • Sofobuvir
    • NS3/4A protease inhibitors :
      • paritaprevir
      • grazoprevir
31
Q

Interferon-Alpha MOA?

A

activates host cell RNase > degrades viral RNA

  • it is a cytokine that acts through host cell surface receptors –> increase JAKS activity
  • These enzymes phosphorylate STATS to increase the formation of antiviral proteins
  • promotes formation of natural killer cells that destroy infected liver cells
32
Q

IFN-Alpha PharmacoKinetix?

A
  • Absorption: Parenteral ( intramuscular or subcutaneous injection (slow))
  • elimination: kidney (proteolytic hydrolysis)
  • administration: daily or 3 times a week
33
Q

IFN-Alpha clinical uses?

A
  1. Suppressive treatment of HBV
  2. Treatment of HCV (sofosbuvir, ribavirin +/- INF-a)
    - in chronic HBV as an individual agent or in combination with other drugs
    - When used in combination with Ribavirin, the progression of acute HCV infection to chronic HCV is reduced
  • treatment of Kaposi’s sarcoma
  • papillomatosis
  • topically for genital warts
34
Q

IFN-Alpha Toxicity?

A

-Myalgia, fatigue

-alopecia

- a flu-like syndrome

-depression

  • GI irritation
  • neutropenia
  • Thyroid dysfunction

*Contraindication in pregnancy*

35
Q

Entecavir?

MOA

Administration

elimination

SE

A
  • inhibits HBV DNA polymerase
  • Effective orally
  • renal elimination in part via active tubular secretion
  • can cause headache, dizziness, fatigue, and nausea
36
Q

What about Lamivudin?

MOA

Indication

T1/2

A
  • nucleoside inhibitor of HIV reverse transcriptase is active in chronic HBV infection
  • lamivudine rapidly suppresses HBV replication and is remarkably nontoxic
  • has a longer intracellular 1/2 life in HBV-infected cells than in HIV-infected cells –> can be used in lower doses for hepatitis than for HIV infection
  • Used as monotherapy
37
Q

aboout Tenofovir?

MOA

Indication

A
  • antiretroviral drug
  • used for chronic HBV infection
  • active against lamivudine- and entecavir-resistant strains
38
Q

what about Sofosbuvir?

MOA

indication

A
  • inhibits RNA polymerase in HCV
  • given alone or in combination with interferon or ribavirin and achieves very high cure rates (90–95%)
39
Q

Grazoprevir and Paritaprevir?

MOA

Elimination

should NOT be administered in?

SE

A
  • protease inhibitor
  • it has pan-genotypic activity
  • It is only available in combination with elbasvir for treatment of HCV
  • It is partially eliminated by oxidative metabolism (by CYP3A)
  • eliminated in the feces
  • Elbasvir/grazoprevir should not be administered to patients with moderate or severe hepatic impairment
  • Toxicity: fatigue, headache, and nausea

Pharmacology FINAL (2nd sem) (37 decks)

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