C6+7 Flashcards
(39 cards)
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
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
3
Q
NRTIs examples?
A
Abacavir
Emtricitabine
Lamivudine
Tenofovir
Zidovudine
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
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)
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)
7
Q
Emtricitabine Toxicity?
A
- asthenia = abnormal physical weakness
- GI distress
- headache
- hyperpigmentation of the palms and/or the soles.
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
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.
10
Q
Tenofovir Pharmacokinetix?
A
- bioavailability: 25–40% Oral
- 1/2 life: > 60h
- Elimination: kidney
- may impede the renal elimination of acyclovir and ganciclovir
11
Q
Tenofovir Toxicity?
A
- include GI distress
- asthenia
- headache
same as emtricitabine toxicity
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
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
14
Q
NNRTIs Example?
A
Etravirine
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
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
Maraviroc Toxicity?
- cough
- diarrhea
- muscle and joint pain
- increase in hepatic transaminases
26
example of Integrase inhibitor?
**Elvitegravir**
Dolutegravir
27
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.
28
**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
29
**Elvitegravir**, Dolutegravir Toxicity?
GI upset
headache
Rhabdomyolysis (rare)
nausea, dizziness, and fatigue
30
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
31
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
32
IFN-Alpha PharmacoKinetix?
- Absorption: Parenteral ( intramuscular or subcutaneous injection (slow))
- elimination: kidney (proteolytic hydrolysis)
- administration: daily or 3 times a week
33
IFN-Alpha clinical uses?
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
IFN-Alpha Toxicity?
**-Myalgia, fatigue**
**-alopecia**
**- a flu-like syndrome**
**-depression**
- GI irritation
- neutropenia
- Thyroid dysfunction
**\*Contraindication in pregnancy\***
35
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
36
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
37
aboout Tenofovir?
MOA
Indication
- antiretroviral drug
- used for chronic HBV infection
- active against lamivudine- and entecavir-resistant strains
38
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%)
39
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
