Please enable JavaScript.
Coggle requires JavaScript to display documents.
Antiretroviral drugs, NNRTIs:, Entry inhibitors:, Post-exposure…
-
NNRTIs:
these drugs inhibit reverse transcriptase by acting at a site(allosteric site) different from that of NRTIs.
These are selective for HIV-1 and have no activity against HIV-2. resistance to these drugs develop very rapidly.
Drugs in this group are nevirapine, efavirenz, etravirine, delavirdine.
Skin rash is an adverse effect of all these drugs
and nevirapine can cause steven johnson syndrome and toxic epidermal necrolysis.
Delavirdine and efavirenz should be avoided in first trimester of pregnancy.
Nevirapine is used in pregnancy to prevent vertical transmission(single oral dose of 200mg to mother during labour and single 2mg/kg oral dose to neonate within 3 days after birth.
Entry inhibitors:
-
-
monoclonal antibody that prevents HIV from infecting CD4 cells by binding to domain 2 of the CD4 receptor.
This binding causes conformational changes in the CD4 receptor–gp120 complex, which prevents HIV from fusing with and entering the host cell.
-
-
antiretroviral drug that prevents HIV from attaching to CD4+ lymphocytes by binding to the gp120 subunit of the HIV envelope protein:
enfuvirtide is a drug that binds to Gp41 subunit of HIV envelope protein and inhibits the fusion of viral and host cell membranes.
This prevents the entry of the virus in host cells.
Used subcutaneously and causes injection site reactions, hypersensitivity and pneumonia.
Not effective against HIV-2.
Maraviroc: is the first CCR5 coreceptor antagonist to be approved for use.
It is only active against CCR-5-tropic virus and coreceptor tropism assay should be performed before starting maraviroc.
This type of HIV-1 virus tends to predominate early in infection. Can be given orally.
-
Drug classification
NRTI – nucleoside -zidovudine, stavudine, lamivudine, zalcitabine, didanosine, abacavir and emtricitabine.
-
NNRTI: efavirenz, etravirine, nevirapine, delavirdine, doravirine and rilpivirine
Protease inhibitors: ritonavir, indinavir nelfinavir, saquinavir, amprenavir, fosamprenavir, lopinavir, darunavir and tipranavir.
-
Integrase inhibitor: raltegravir and elvitegravir, bictegravir.
-
Zidovudine
Zidovudine is frequently used NRTI in the treatment of HIV infections.
It can also be used for prophylaxis of needle stick injury patients and for the prevention of vertical transmission of HIV from mother to foetus.
Major adverse effect of zidovudine is bone marrow suppression leading to megaloblastic anemia,
neutropenia and thrombocytopenia(ganciclovir should not be combined).
It is contraindicated in patients with Hb<8g.
It can also cause myopathy.
Rifampicin increases the clearance of the drug.
Chronic administration associated with lipodystrophy syndrome, nail hyperpigmentation and lipoatrophy.
Notes on NRTI
All NRTIs are excreted by the kidney which requires dose adjustment in renal failure except abacavir which gets metabolized by alcohol dehydrogenase.
Hypersensitivity is the major adverse reaction of abacavir. Should not be restarted.
All NRTIs may cause lactic acidosis, hepatomegaly and steatosis by inhibiting mammalian mitochondrial DNA polymerase.
Risk factors are obesity and pre-existing liver dysfunction.
Notes on NNRTI
Etravirine is a recently approved NNRTI.
This second generation NNRTI is effective against HIV resistant to first generation NNRTI like efavirenz, nevirapine and delavirdine.
Another recently approved second generation NNRTI is rilpivirine
NNRTI donot cause lipodystrophy.
Nelvirapine and efavirenz are CYP 450 enzyme inducers
whereas delavirdine is enzyme inhibitor.
-
Atazanavir
Atazanavir frequently causes asymptomatic unconjugated hyperbilirubinemia like indinavir
and increase in PR interval in ECG.
It requires acidic pH to remain in solution, therefore should not be given with proton pump inhibitors.
Both tenofovir and efavirenz lower the serum concentration of atazanavir,
therefore when used with these drugs, it must be boosted by ritonavir.
Pre-exposure prophylaxis
-
for MSM, sex workers, injection drug users
-
NRTI vs NtRTI
-
Structure: NRTIs are analogs of nucleosides, which are the building blocks of DNA and RNA but lack a phosphate group.
Activation: Once inside the host cell, NRTIs need to undergo three phosphorylation steps to become active. The host cell's kinases phosphorylate them, converting them into the active triphosphate form.
Mechanism of Action: Once activated, NRTIs incorporate into the viral DNA chain during reverse transcription, causing premature chain termination because they lack a 3' hydroxyl group required for the addition of further nucleotides.
-
-
-
-
-
-
-
-
Structure: NtRTIs are already partially phosphorylated; they are analogs of nucleotides, meaning they already have one phosphate group attached.
Activation: Since NtRTIs already have a phosphate group, they only need to undergo two phosphorylation steps within the host cell to become the active triphosphate form, making them faster acting compared to NRTIs.
Mechanism of Action: Similar to NRTIs, they incorporate into the viral DNA chain and cause chain termination during reverse transcription.
-
Tenofovir: The most commonly used NtRTI, which is available in two prodrug forms:
-
-
NRTIs:
these are prodrugs and are activated by host cell kinases to form triphosphates.
These drugs competitively inhibit reverse transcriptase
and also act as chain terminators by incorporation into the DNA chain.
Resistance to these drugs emerges rapidly if used alone.
Didanosine
Didanosine is another NRTI. Its oral bioavailability is reduced by food.
It can led to dose limiting pancreatitis maximum chances, hyperuricemia, optic neuritis and also painful sensory peripheral neuropathy.
Diarrhea is more common than with other NRTIs.
It may cause neutropenia(not anemia) and fulminant hepatic failure and electrolyte abnormalities.
Stavudine
Stavudine causes dose limiting peripheral neuropathy.
It has maximum chance of causing lactic acidosis(mitochondrial toxicity).
It can also result in pancreatitis.
It is most strongly associated with lipodystrophy syndrome among all NRTIs and protease inhibitors.
-
Zalcitabine
Zalcitabine has unique toxicity to cause oral ulceration and stomatitis.
it is least effective NRTI.
It also results in peripheral neuropathy and pancreatitis.
Abacavir
Abacavir increases the risk of MI.
it may cause severe hypersensitivity reaction particularly in patients having HLA B*5701 allele.
Testing of this allele should be done before starting abacavir.
-
Nevirapine
It decreases transmission to 13 % as compared to 21.5% by zidovudine.
However because of hepatotoxicity and less effectiveness of nevirapine, it is not preferred for this condition.
Efavirenz
Efavirenz is neurotoxic and side effects may range from lack of concentration to vivid dreams to delusions and mania.
Protease inhibitor:
protease helps in the maturation of infectious virions
and inhibitors of this enzyme can be used in the treatment of HIV infections by inhibiting the post translational modifications of viral proteins.
Indinavir
Oral bioavailability of indinavir is decreased by food.
It can cause crystalluria and kidney stones.
To prevent renal damage, good hydration must be maintained.
It can also cause asymptomatic hyperbilirubinemia
Booster drug - Ritonavir
This group of drug inhibits the metabolism of several drugs by inhibiting the CYP3A4.
ritonavir in low doses can be used with other protease inhibitors to increase their plasma concentration.
-
Tipranavir
Tipranavir is the only nonpeptidic protease inhibitor.
It is effective against HIV resistant to other protease inhibitors.
It can cause hepatotoxicity and intra-cranial haemorrhage.
-
Tesamorelin
Tesamorelin is a synthetic analogue of growth
hormone releasing factor indicated to reduce
excess abdominal fat in HIV infected patients with lipodystrophy.
Integrase inhibitors:
raltegravir, elvitegravir and dolutegravir are the oral drugs approved by FDA that act by inhibiting the integrase enzyme.
Cobicistat is used to boost the effect of elvitegravir.
cobicistat has been approved to boost the effect of darunavir and atazanavir.
-