Protease inhibitors

Definitions & Key takeaways

Protease inhibitors (PIs) are a class of antiviral drugs that are widely used to manage HIV/AIDS. Protease inhibitors prevent viral replication by selectively binding the enzyme HIV-1 protease, and prevent the formation of new viruses and further infection of the host's cells. Common medications in this class include atazanavir, darunavir, indinavir, lopinavir, tipranavir, and ritonavir. Common side effects of protease inhibitors include gastrointestinal problems such as diarrhea, nausea, and vomiting; and metabolic disorders such as hyperglycemia, insulin resistance, and hyperlipidemia.

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Introduction0:00–0:35

Protease inhibitors are an important part of HAART, or highly active antiretroviral therapy, which is the combination of medications used in the treatment of AIDS.
AIDS is caused by an RNA containing retrovirus called human immunodeficiency virus, or HIV. Protease inhibitors, or PIs, work by inhibiting the enzyme HIV-1 protease, which prevents the formation of new viruses and further infection of the host’s cells.HIV is a single-stranded, positive-sense, enveloped RNA retrovirus that targets cells in the immune system that have molecules called CD4 on their membranes.

Pathology0:35–3:02

These include macrophages, dendritic cells, and especially CD4+ T-helper cells. HIV attaches to the CD4 molecule via a protein called gp120 found on its envelope.
Now, inside its envelope, HIV contains a nucleocapsid which is a capsule containing a single-stranded RNA and some viral enzymes, like reverse transcriptase, integrase, and aspartate protease, also known as a mature HIV-1 protease.
As HIV binds to the receptors, the viral envelope fuses with the cell membrane of the immune cell, releasing the contents of the nucleocapsid into the helpless host cell’s cytoplasm.
Once it’s inside the CD4+ cell, reverse transcriptase gets to work immediately. It uses the single-stranded viral RNA as a template and uses the nucleotides present in the cytoplasm of the CD4+ cell to transcribe a complementary double-stranded “proviral” DNA.
This proviral DNA enters the T-helper cell’s nucleus and pops itself into the cell’s DNA, ready to be transcribed into messenger RNA (mRNA).
These mRNA travel to the ribosomes which translate this into long Gag-Pol polyproteins, which are a bunch of viral proteins joined together.
Now, human cells don’t come with the equipment to process these long polyprotein chains, but one of the enzymes that HIV releases into the cell is a protease called aspartate protease, or HIV-1 protease.
This enzyme cuts the polyprotein into individual, functional viral proteins. These proteins are then packed together to form new HIV viruses, which bud off from the cell membrane to infect more cells.
Very sneaky indeed! Over time, more and more immune cells are infected, and the immune system begins to fail, which is called immunodeficiency, and this increases the risk of infections and tumors that a healthy immune system would usually be able to fend off.These complications are referred to as AIDS, or acquired immunodeficiency syndrome.Now, in order to prevent the formation of new HIV viruses and further infection of the host’s cells, we can use protease inhibitors, or PIs.

Mechanism of action3:02–4:16

As their name implies, protease inhibitors bind and inhibit HIV-1 protease, thereby making it incapable of processing the Gag-Pol polyproteins so new viruses can’t be made.
Common medications in this class include atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir, and ritonavir.
These medications are rarely used alone since HIV quickly develops resistance to them by point mutations of the pol gene, which is the gene that encodes HIV-1 protease.
Typically, protease inhibitors are used as a part of the highly active antiretroviral therapy, or HAART, along with nucleoside reverse transcriptase inhibitors, or NRTIs, like tenofovir.
This is so that, if HIV were to develop a mutation making it resistant to protease inhibitors, then it can still be killed by the NRTIs.
Now, all of the protease inhibitors are metabolized by a class of enzymes called cytochrome P450, so they have a lot of drug interactions.

Drug interactions4:16–4:52

Medications that inhibit this enzyme, like cimetidine and macrolides, increase the concentration of protease inhibitors in the blood, while medications that induce the enzyme’s activity, like rifampin, decrease their concentration.
But, besides being substrates, protease inhibitors are also inhibitors of cytochrome P450, especially ritonavir, which inhibits the metabolism of medications like warfarin.
Alright, now switching gears and moving on to side effects. The most common side effects of protease inhibitors include gastrointestinal problems like diarrhea, nausea, and vomiting; and metabolic disorders, like hyperglycemia, insulin resistance, and hyperlipidemia.

Side effects4:52–5:47

These metabolic disorders are usually followed by lipodystrophy, which is an abnormal accumulation of fat tissue. It’s important to note that unlike most protease inhibitors, atazanavir is not associated with metabolic disorders.
For medicine-specific side effects, indinavir can cause thrombocytopenia, hematuria, and nephrolithiasis, so individuals treated with this medication should maintain good hydration; while atazanavir and ritonavir can cause neurological problems, like paresthesia.
In addition, ritonavir may also cause damage to the liver, resulting in increased liver transaminases.Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharmacology facts!

Memory palace5:47–7:46

Alright, since the protease inhibitors have the suffix “navir” we’ll use a naval battleship. This ship is named the S.S.
HAART with a heart symbol on it to help you remember it should be used as a part of HAART therapy. Now, a large chrome colored cell is trying to eat the ship, since protease inhibitors are metabolized by cytochrome P450; but the ship is shooting back, which represents the inhibition of cytochrome P450.
For the general side effects, a sailor had diarrhea on the aptly named “poop deck,” which represents GI disturbances. Next, a rather chubby sailor that’s eating a candy bar is trying to clean up the mess, which represents metabolic syndromes like hyperglycemia, insulin resistance, and hyperlipidemia.
To remember that atazanavir is the only medication in this class that doesn’t cause metabolic syndrome, let’s have a sailor dressed as Tarzan who’s super fit with bulging muscles, and instead of a candy bar, he’s eating a healthy carrot.
For some of the important drug-specific side effects, let’s give one of the sailors a cape and wizard hat and have him performing a summoning ritual, for ritonavir.
The thing he summoned is a big, sick-looking liver, since this medication can cause liver damage. Both the wizard and the Tarzan sailors have bandages covering their arms since these two medications cause paresthesia.
Next, a sailor is covering his ears against a loud din, for indinavir, made by smashing a bunch of plates, for decreased platelets.
He was in a hurry to pee so he’s peeing into the ocean, but his pee is red, which represent hematuria. Unfortunately, he’s peeing onto a sea mine, which looks like a kidney stone.
##SummaryAll right, as a quick recap. Protease inhibitors bind and inhibit HIV-1 protease, making it incapable of processing Gag-Pol polyproteins, so no more viral proteins can be made.

Review7:46–8:33

Common medications in this class include atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir, and ritonavir.
These medications are both substrates and inhibitors of cytochrome P450, especially ritonavir. The most common side effects of protease inhibitors include gastrointestinal problems such as diarrhea, nausea, and vomiting; and metabolic disorders such as hyperglycemia, insulin resistance, and hyperlipidemia.
of Cytochrome P 450 especially ritonavir The most the most common common side effects of protease inhibitors include gastrointestinal problems such as diarrhea nausea and vomiting and metabolic disorders such as hyperglycemia insulin resistance and hyperlipidemia But wait there's more here's a mind map with all of the mnemonics from the video go ahead and pause so you can test yourself and see what you remember

Mind map8:33–8:42