General Pharmacology

HIV Drugs Pharmacology!

Nov 24th, 2020
hiv drugs pharmacology

HIV Drugs Pharmacology

HIV – or human immunodeficiency virus – is a lentivirus that causes HIV infection. Over time, this can lead to the development of AIDS, or acquired autoimmune deficiency syndrome. Whilst there is no cure, the disease is treatable.

There are two types of HIV:

  • type 1
  • type 2

Most cases of HIV are caused by the more virulent and more infectious HIV type-1. Most cases of type 2 are confined to West Africa, with the strain being less virulent and less infective. Without treatment, the average survival time from the onset of infection to death is 10 years.

HIV can also be transmitted from mother to child through breast milk. It can also pass to the child during both pregnancy and childbirth – through infected blood or vaginal fluids. Most HIV cases are, however, contracted through sexual intercourse – such as infected semen, blood, pre-ejaculate or vaginal fluids. Once the virus enters the body, HIV targets many cells that are integral to the innate immune response – damaging T-helper cells, dendritic cells, and macrophages.

In 2019, there were 38 million cases of HIV/AIDS worldwide leading to 690,000 deaths, which has fallen from a peak of 1.1 million deaths in 2010.

Antiretroviral Drug Classes

There are five major drug classes used in the treatment HIV/AIDs – medicines also known as antiretroviral agents. Multiple drugs are used as part of what is called HAART therapy – or highly active antiretroviral drug therapy.

For example, many medicines are formulated as “fixed-dose combinations”. Some of the most common include:

  • Truvada – tenofovir disoproxil + emtricitabine
  • Atripla – tenofovir disoproxil + emtricitabine + efavirenz
  • Combivir – lamivudine + zidovudine
  • Stribild – elvitegravir + cobicistat + emtricitabine + tenofovir disoproxil
  • Epzicom – abacavir + lamivudine

Antiretroviral drugs can be classified as follows:

  1. Nucleoside/nucleotide reverse transcriptase inhibitors – NRTIs / NtRTIs
  2. Non-nucleoside reverse transcriptase inhibitors – NNRTIs
  3. Protease inhibitors
  4. Integrase inhibitors
  5. Entry inhibitors (also known as fusion inhibitors)

Reverse transcriptase inhibitors (RTIs)

There are three kinds of reverse transcriptase inhibitor:

  • Nucleoside – zidovudine, didanosine, stavudine, lamivudine, abacavir, emtricitabine
  • Nucleotide – tenofovir disoproxil
  • Non-nucleoside – efavirenz, nevirapine, etravirine, rilpivirine

Nucleoside and nucleotide RTIs are analogs of naturally occurring deoxynucleotides, whereas non-nucleoside RTIs are not.

Notenucleotide analog tenofovir can be recognised as “t” for tenofovir, “t” for “-tide”. All non-nucleoside drugs have “-vir-“ within their names.

Mechanism of action

Nucleoside and nucleotide RTIs compete with deoxynucleotides needed to synthesize viral DNA. However, they lack a 3’-hydroxyl group. When incorporated into viral DNA, then, the viral deoxynucleotide cannot extend, a process known as chain termination.

Both nucleotide and nucleoside RTIs compete with host DNA as well as viral DNA, leading to the kind of side effects listed below.

In contrast, NNRTIs work by binding directly to the reverse transcriptase enzyme. Unlike NRTIs and NtRTIs, NNRTIs are not incorporated into viral DNA.

Side effects

Side effects with RTI medicines include:

  • GI effects – nausea, vomiting, upset stomach, diarrhea
  • Headache
  • Peripheral neuropathy (more common with didanosine)

Other adverse effects include:

  • Hepatic steatosis
  • Lipodystrophy – redistribution of body fat
  • CNS effects – depression, anxiety, dizziness
  • Reduced bone density
  • Lactic acidosis
  • Pancreatitis

Tenofovir is associated with both nephrotoxicity and bone loss.

Protease inhibitors

Protease inhibitors can be used to treat both HIV and hepatitis C.

Examples of protease inhibitors include:

  • Saquinavir the first FDA-approved protease inhibitor
  • Amprenavir
  • Fosamprenavir
  • Atazanavir
  • Darunavir
  • Indinavir
  • Lopinavir
  • Nelfinavir
  • Ritonavir
  • Tipranavir

Note: All protease inhibitors end in the suffix -navir.

Protease inhibitors bind to viral proteases, such as HIV-1 protease, to stop viral replication. They also block the production of essential protein precursors needed to produce virions.

Side effects of protease inhibitors include:

  • Lipodystrophy
  • Diarrhea
  • Elevated blood sugar levels / insulin resistance
  • Hyperlipidemia
  • Kidney stones
  • Taste disturbances
  • Hepatic dysfunction
  • Jaundice
  • Rash

Protease inhibitors increase the risk of toxicity of statins, anticoagulant drugs, antidepressants, anticonvulsant drugs, and some antibacterial drugs. Protease inhibitors also disturb blood sugar levels and insulin resistance and so interact with the effects of oral antidiabetic drugs.

Protease inhibitors should be avoided with OTC drugs that reduce stomach acid production – such as PPIs and H2 antagonists – because the combination can markedly reduce protease inhibitor absorption. This effect is particularly pronounced with atazanavir.

Not all protease inhibitors are used for their intrinsic anti-HIV activity. For example – though ritonavir has anti-HIV activity (albeit minimal), it is not used for this purpose. Instead, it is used as an enzyme inhibitor – inhibiting enzymes such as CYP 3A4 that metabolize other anti-HIV medicines.

Ritonavir is an example of a pharmacokinetic enhancer.

When ritonavir is taken alongside another HIV drug – such as a protease inhibitor – a lower dose of the protease inhibitor can be used. Ritonavir is “boosting” the effects of this protease inhibitor. As a result, the lower dose means fewer adverse effects.

Cobicistat is also a pharmacokinetic enhancer. It is used to inhibit CYP 3A enzymes, often to boost the effects of the integrase inhibitor, elvitegravir (see below), as well as several other reverse transcriptase inhibitors.

Integrase inhibitors

Integrase inhibitors are an important drug class in HIV drugs pharmacology. As the drug class name suggests, integrase inhibitors block the effects of the enzyme, integrase. Integrase is a viral enzyme responsible for integrating viral DNA into the host DNA of infected cells.

Examples of integrase inhibitors include:

  • Raltegravir
  • Dolutegravir
  • Elvitegravir

Note: integrase inhibitors can be identified through the “-gravir” suffix.

As we learned above, elvitegravir is not taken in isolation. It is taken along the “booster” drug cobicistat, and alongside other drugs such as tenofovir and emtricitabine. Dolutegravir is also available in combination medicines – such as Triumeq, a combination of dolutegravir, abacavir, and lamivudine.

Side effects with integrase inhibitors include:

  • Difficulty sleeping
  • Fatigue
  • High blood sugar levels
  • Headache
  • Hepatic dysfunction
  • GI effects

As integrase inhibitors are predominantly metabolized by CYP 3A enzymes, strong inducers of this enzyme should be avoided. This includes drugs such as phenytoin, rifampicin, carbamazepine, and St. John’s wort.

Entry inhibitors

Entry inhibitors are the final class in our study of HIV drugs pharmacology. As their name suggests, entry inhibitors disrupt the ability of the HIV virus to enter cells. They target the binding, fusion, and entry phases of viral integration into the target host cell.

The binding-fusion-entry sequence for the HIV virus is as follows. Below, we learn where entry inhibitors block this process.

  1. An HIV surface protein, gp120, binds to the CD4 receptor – a protein receptor found on the surface of T-helper cells.
  2. A conformational change in gp120 takes effect. This has two effects – it increases its affinity for a co-receptor – either CCR5 or CXCR4 – and exposes gp41.
  3. gp120 now binds to one of those receptors.
  4. gp41 now penetrates the cell membrane, completing the fusion phase.
  5. The HIV virion now enters the host cell.

Examples of approved entry inhibitors include:

  • Maraviroc
  • Enfuvirtide

Maraviroc binds to CCR5, preventing gp120 from binding to this co-receptor. That is why maraviroc is also referred to as a CCR5 inhibitor. Enfuvirtide binds to gp41 – preventing fusion of the two membranes. This is why enfuvirtide is often referred to as a fusion inhibitor. Maraviroc is taken orally, whereas enfuvirtide is taken via the subcutaneous route (SC).

Side effects with maraviroc include:

  • Flu-like symptoms
  • Upper respiratory tract infections
  • Cough
  • Difficulty breathing
  • Headache
  • Hepatic dysfunction
  • Weakness, fatigue, dizziness
  • Rash

Side effects with enfuvirtide include:

  • Injection site reactions
  • GI effects – diarrhea, nausea, abdominal pain, dry mouth
  • Metabolic – weight loss, decreased appetite
  • Fatigue
  • Flu-like symptoms
  • Peripheral neuropathy
  • Shortness of breath/wheezing

That concludes our review of HIV drugs pharmacology. Check back to our pharmacy blog soon for more exclusive content to help you master the science of drugs and medicines!

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