1
Q
Antiretroviral drugs?
A
zidovudin lamivudine tenofovir emtricitabine abacavir etravirine darunavir ritonavir lopinavir dolutegravir maraviroc
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
- 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?
A
- A guanosine analog
- good oral bioavailability
- 1/2 life: 12–24h
- in 5%: Hypersensitivity reactions (fatal)
6
Q
What about Emtricitabine?
A
- bioavailability: Good oral
- Elimination: kidney
- 1/2 life: long (dosing once-daily)
- contraindicated in pregnancy and young children and in patients with hepatic or renal dysfunction (propylene glycol in the oral solution)
7
Q
Emtricitabine Toxicity?
A
- asthenia
- 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
- it is a nucleotide
- competitively inhibit reverse transcriptase and cause chain termination after incorporation into DNA.
- also has activity against HBV
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
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
- 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
- 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
- ianticonvulsants 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:
erythromycin, ketoconazole, prednisone, rifampin, and saquinavir
22
Q
Entry and Fusion Inhibitors?
A
Maraviroc
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 INSTs?
Dolutegravir
27
about dolutegravir
- 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
Dolutegravir PharmacoKinetix?
- metabolized by glucuronidation and is not affected by agents that induce or inhibit hepatic cytochromes P450.
- if used with rifampin (induces UDP-glucuronosyltransferase) the dose should be doubled
29
Dolutegravir Toxicity?
nausea, dizziness, and fatigue
30
Drugs against Hepatitis?
```
interferon-alph
entecavir
tenofovir
sofosbuvir
dasabuvir
paritaprevir
grazoprevir
velpatasvir
elbasavir
```
31
Interferon-Alpha MOA?
- 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: from intramuscular or subcutaneous injection (slow)
- elimination: kidney (proteolytic hydrolysis)
- administration: daily or 3 times a week
33
IFN-Alpha clinical uses?
- 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?
- GI irritation
- a flu-like syndrome
- neutropenia
- profound fatigue and myalgia
- alopecia
- Thyroid dysfunction
- severe depression
*Contraindication in pregnancy*
35
What about Entecavir?
- 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?
- 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?
- antiretroviral drug
- used for chronic HBV infection
- active against lamivudine- and entecavir-resistant strains
38
what about Sofosbuvir?
- 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?
- 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
mrts
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