C6+7 Flashcards
Antiretroviral drugs?
- **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
Anti-HIV drugs modes?
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
NRTIs examples?
Abacavir
Emtricitabine
Lamivudine
Tenofovir
Zidovudine
NRTIs MOA?
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
what about Abacavir?
Bioavalibility
half life
SE
- A guanosine analog
- good oral bioavailability
- 1/2 life: 12–24h
- in 5%: Hypersensitivity reactions (fatal)
What about Emtricitabine?
bioaval
elimination
t1/2
CI
- 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)
Emtricitabine Toxicity?
- asthenia = abnormal physical weakness
- GI distress
- headache
- hyperpigmentation of the palms and/or the soles.
What about Lamivudine ?
- bioavailability: 80% by the oral route
- elimination: kidney
- also effective in hepatitis B infections
- Dosage adjustment is needed in patients with renal insufficiency
What about Tenofovir?
NRTI
- renal elimination
- also has activity against HBV
- it is a nucleotide
- competitively inhibit reverse transcriptase and cause chain termination after incorporation into DNA.
Tenofovir Pharmacokinetix?
- bioavailability: 25–40% Oral
- 1/2 life: > 60h
- Elimination: kidney
- may impede the renal elimination of acyclovir and ganciclovir
Tenofovir Toxicity?
- include GI distress
- asthenia
- headache
same as emtricitabine toxicity
Zidovudine Pharmacokinetix?
- 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
Zidovudine Toxicity?
- 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
NNRTIs Example?
Etravirine
NNRTIs MOA?
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
Etravirine Clinical uses?
- treatment-experienced HIV patients
- effective against HIV strains resistant to other drugs in the group
- rash, nausea, and diarrhea
Protease inhibitors examples?
Darunavir
Lopinavir
Ritonavir
Protease inhibitors MOA?
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
what about Darunavir?
- 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
What about Ritonavir PharmacoKinetix?
- biovavailability: Orally good (should be taken with meals)
- Clearance: liver
- dosage reduction is necessary in hepatic impairment
Ritonavir Toxcitiy?
- 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
Entry and Fusion Inhibitors?
Maraviroc= entry inhibitor CCR5 receptor antagonist
Elvitegravir = integrase inhibitor
Dolutegravir
Maraviroc MOA?
- binds to CCR5 and block the binding of the envelop protein gp120 to CD4, macrophages and dendritic cells
Maraviroc PharmacoKinetix?
- bioavailability: used orally
- Distribution: good tissue penetration
- It is a substrate for CYP3A4
Maraviroc Toxicity?
- cough
- diarrhea
- muscle and joint pain
- increase in hepatic transaminases
example of Integrase inhibitor?
Elvitegravir
Dolutegravir
about Elvitegravir , dolutegravir
MOA
Indication
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.
elvitegravir Dolutegravir PharmacoKinetix?
* 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
Elvitegravir, Dolutegravir Toxicity?
GI upset
headache
Rhabdomyolysis (rare)
nausea, dizziness, and fatigue
Drugs against Hepatitis?
-
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
-
NS5A inhibitors :
Interferon-Alpha MOA?
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
IFN-Alpha PharmacoKinetix?
- Absorption: Parenteral ( intramuscular or subcutaneous injection (slow))
- elimination: kidney (proteolytic hydrolysis)
- administration: daily or 3 times a week
IFN-Alpha clinical uses?
- Suppressive treatment of HBV
- 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
IFN-Alpha Toxicity?
-Myalgia, fatigue
-alopecia
- a flu-like syndrome
-depression
- GI irritation
- neutropenia
- Thyroid dysfunction
*Contraindication in pregnancy*
Entecavir?
MOA
Administration
elimination
SE
- inhibits HBV DNA polymerase
- Effective orally
- renal elimination in part via active tubular secretion
- can cause headache, dizziness, fatigue, and nausea
What about Lamivudin?
MOA
Indication
T1/2
- 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
aboout Tenofovir?
MOA
Indication
- antiretroviral drug
- used for chronic HBV infection
- active against lamivudine- and entecavir-resistant strains
what about Sofosbuvir?
MOA
indication
- inhibits RNA polymerase in HCV
- given alone or in combination with interferon or ribavirin and achieves very high cure rates (90–95%)
Grazoprevir and Paritaprevir?
MOA
Elimination
should NOT be administered in?
SE
- 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
