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Flashcards in Antiviral Agents Deck (21):

Process of HIV infection of CD4 T Cell

HIV binds to receptors and enter the cell to get conversation of viral RNA to DNA via reverse transcriptase and this involves integrase, but after transcription and translation you get viral polyproteins and then broken down with protease in HIV and then the completed virus is released

Drugs for entry blockage (entry inhibitors) and then reverse transcriptase inhibitors, and have protease inhibitors, and integrase inhibitors


Reverse Transcriptase Inhibitors (RTIs)

Zidovudine: also known as AZT; look like endogenous nucleotides (A, G, T, and C), but do not have phosphate groups (require 3 phosphates to be involved in DNA synthesis)

In order to have chain elongation, need 3’ hydroxyl group; so reverse transcriptase inhibitors can compete because looks alike, but must have hydroxyl group for DNA synthesis to continue so it stops the DNA synthesis of the virus


Zidovudine Mechanism of Action

Undergoes three phosphorylations by cellular (host cell) kinases

The triphosphate acts as a competitive inhibitor of reverse transcriptase (RNA-dependent DNA polymerase)

Functions as a DNA chain terminator after incorporation into DNA

AZT must be converted to triphosphate to have good inhibition


Zidovudine Pharmacokinetics

Rapidly absorbed after oral administration (oral bioavailability approx. 65%)

Well distributed throughout body (CSF levels approx. 60% of those in serum)

Undergoes liver metabolism (glucuronidation); some unchanged drug & the glucuronide eliminated renally (glomerular filtration & tubular secretion)


Zidovudine Clinical Uses

Used in combination regimens for initial treatment of HIV (human immunodeficiency virus) infections for many years (has given way to less toxic agents); monotherapy leads to rapid resistance

Included in some regimens for prevention of maternal-fetal HIV transmission

Included in some alternative combination regimens for post-exposure prophylaxis (PEP) in health care workers


Zidovudine Adverse Effects

Bone marrow suppression (anemia; neutropenia)
Gastrointestinal intolerance (nausea & vomiting)
Headaches, insomnia, and muscle pain


Nucleoside RTIs

Nucleoside RTIs (same mechanism of action as zidovudine); called NRTIs

Lamivudine (& its fluorinated analog emtricitabine) & abacavir


Nucleotide RTIs

Nucleotide RTIs (same mechanism of action as zidovudine, but fewer phosphorylations required for activation); a NTRTI



Non-Nucleoside RTIs

Nonnucleoside RTIs (inhibit reverse transcriptase by binding directly to the enzyme & inducing a conformational change; called NNRTIs)

Efavirenz, nevirapine & delavirdine

Does not resemble DNA, and binds outside of catalytic site
Not meant for monotherapy because virus will develop resistance eventually


Adverse Effects – Other RTIs (NRTIs & NTRTIs)

Abacavir - possible severe hypersensitivity reactions

Lamivudine (& Emtricitabine) – nausea, diarrhea, headache & rash

Tenofovir (an NTRTI) – nausea, diarrhea, vomiting & flatulence; possible renal insufficiency (damage to proximal renal tubules)


Adverse Effects-NNRTIs

Delavirdine & nevirapine - skin rash

Nevirapine – hepatotoxicity

Efavirenz - CNS toxicity (dizziness/headache/insomnia & nightmares) & skin rash

All 3 are substrates for cytochrome P450 enzymes & modify the metabolism of other drugs by these enzymes

Nevirapine & efavirenz induce the system (including CYP3A4) and delavirdine inhibits it.
If you induce it, then it can degrade the drugs to make them less useful
If you inhibit it, then it can increase drug toxicity


Other Adverse Effects Associated with NRTIs

Severe hepatomegaly, lactic acidosis, fatty liver

Lipodystrophy (especially lipoatrophy in limbs; fat redistribution to abdomen & other areas); also metabolic changes including:
Elevations of plasma triglycerides & total cholesterol
Hyperglycemia & hyperinsulinemia

*may be related to inhibition of DNA polymerase gamma in mitochondria; some newer RTIs have low affinity for this enzyme & thus are less toxic by this mechanism: lamivudine, emtricitabine, abacavir (also, the NTRTI tenofovir)


Protease Inhibitors


Structure: active site of HIV protease = based off of that site

Mechanism of Action: prevents maturation of virus protein by competitively inhibiting HIV protease, an enzyme essential for viral protein cleavage (to dissect the proteins into their active components)


Ritonavir Pharmacokinetics

Well absorbed orally (bioavailability of 60 to 80%)
Undergoes metabolism by the hepatic cytochrome P450 enzymes
Concern: drug to drug interactions with metabolism by the liver
May have TB infection at the same time as HIV for example


Ritonavir Clinical Use

Treatment of HIV infection (in combination with other antiretroviral drugs)

Current primary use is as a ‘booster’ agent to increase the bioavailability of other protease inhibitors
ritonavir is a potent inhibitor of CYP3A4 and thus reduces the metabolism of other co-administered protease inhibitors

By inhibiting P450 enzyme it protects the more potent protease inhibitor it is combined with so not metabolized as much


Ritonavir Adverse Effects

G.I. Intolerance - nausea, vomiting, diarrhea
Paresthesias - circumoral and peripheral
Elevated serum triglycerides & cholesterol
Drug interactions - ritonavir is an inhibitor as well as a substrate for cytochrome P450 enzymes

Round mouth circumoral (like seen in CMV and scarlet fever)


Ritonavir Drug-Interactions

Inducers of one cytochrome P450 enzyme isoform (CYP3A4) will accelerate the metabolism of ritonavir & may result in treatment failure
Examples: rifampin & rifabutin

By inhibiting certain other cytochrome P450 enzyme isoforms (CYP3A4 & 2D6), ritonavir will inhibit the metabolism of other drugs, thus increasing their toxicity
Examples: lovastatin, simvastatin, clarithromycin, diazepam, & desipramine


Other HIV Protease Inhibitors


As you go down the list you have decreased toxicities and longer half lives
Bottom two are newest – more popular because less toxicity


Adverse Effects of Selected Protease Inhibitors

Fosamprenavir – rash (skin eruptions)

Atazanavir – headache, peripheral neuropathy, EKG changes (PR interval prolongation), hyperbilirubinemia, jaundice and skin rash

Darunavir – headache & skin rash; possible liver toxicity

Tripranavir – rash; severe liver toxicity; possible intracranial hemorrhage


Adverse Effects Common to Most HIV Protease Inhibitors

Lipodystrophy - altered body fat distribution consisting of central fat accumulation called hyperadiposity (buffalo hump & truncal obesity) & peripheral fat wasting called lipoatrophy (face, buttocks & limbs)

Insulin resistance & hyperglycemia (along with increased triglyceride and cholesterol levels)

Note: The above effects do not appear to be associated with atazanavir & the magnitude of these effects may be less with darunavir than other ‘boosted’ PIs.


Examples of Antiretroviral Drug Regimens Recommended (or Alternative) for Initial Treatment

NNRTI-based regimen (1 NNRTI + 2 RTIs)

PI-based regimen (1 PI + 2 RTIs)

INSTI-based (integrase inhibitor) regimen (1 INSTI + 2 RTIs)

Example of 1st regimen above = efavirenz + tenofovir + emtricitabine (EFV/TDF/FTC) **

Example of 2nd regimen above = darunavir/ritonavir (i.e. ritonavir-boosted darunavir) + tenofovir + emtricitabine (DRV/r + TDF/FTC) *

Example of 3rd regimen given on previous slide = raltegravir (an INSTI) + tenofovir + emtricitabine (RAL + TDF/FTC) *
Note: INSTI = integrase strand transfer inhibitor

* Recommended regimen
** Alternative regimen