Lec #4 (Wk 3): HIV Drugs (Pharmacology) Flashcards
What are the cells with CD4 receptors? Function of the CD4 receptors?
1- CD4+ Helper T cells.
2- Macrophages.
3- Dendritic cells.
Function: Helps cells communicate with other immune cells.
What are the characteristics of HIV?
- pair of single-stranded RNA.
- Positive sense.
- Enveloped
retrovirus which contains reverse transcriptase enzyme for every single-stranded RNA (thus 2).
The outer envelope contains glycoproteins. Each glycoprotein (gp) consists of 2 subunits known as gp41 & gp 120.
(inside this envelope we have a capsid).
What are the types of HIV?
HIV-1: found worldwide, more common & infectious.
HIV-2: Found mainly in West Africa.
Although HIV-1 & HIV-2 differ with respect to genetic makeup & antigenicity, they both cause similar disease syndromes.
What does HIV virus target?
CD4 T-cells MAINLY.
They can also infect macrophages & microglial cells both of which carry CD4 proteins. Since macrophages & microglial cells are resistant to destruction by HIV, they don’t die immediately after infecting a CD4 cell thus they serve as a reservoir of HIV during chronic infection.
What is HIV replication cycle?
1- HIV virus attaches to the host cell (e.g CD4+ T-helper cells, dendritic cells, macrophages, & dendritic cell. All contain CD4 protein) via the gp120 on the HIV envelope with a CD4 protein & a co-receptor (either CCR5 or CXCR4) on the host cell membrane.
2- Lipid bilayer envelope of HIV fuses with the lipid bilayer of the host cell membrane. Fusion is followed by release of nucleocapsid (contains 2 single stranded RNA, reverse transcriptase, & integrase)
3- HIV RNA is transcribed into a double stranded HIV DNA by reverse transcriptase enzyme.
4- Double stranded HIV DNA becomes integrated into the host’s DNA with the help of an enzyme called integrase.
5- HIV DNA undergoes transcription into RNA. Some of the resulting RNA becomes the genome for the daughter HIV virions. The remaining RNA is messenger RNA coding for HIV proteins which are then translated into HIV glycoproteins & HIV enzymes.
6- The components of HIV migrate to the cell surface & assemble into a new virus. The newly formed virus buds off from the host cell. The outer envelope of the virion is derived from the cell membrane of the host.
7- Now, this step happens during or right after budding off: maturation.
HIV undergoes maturation under the influence of protease which is an enzyme cleaving large proteins into their smaller, functional forms. If HIV fails to cleave these proteins, HIV will remain immature & noninfectious.
Why can HIV mutate rapidly?
HIV mutates rapidly because it contains reverse transcriptase enzyme which has poor proofreading ability. That’s how HIV can rapidly mutate from a drug-sensitive form into a drug-resistant form.
The probability of developing resistance in the individual patient is directly related to?
Viral load.
Higher viral load means higher chance of mutation & thus resistance.
Can Antiretroviral Therapy cure HIV?
No, it cannot cure HIV but can greatly reduce its levels to the point that it is UNDETECTABLE.
What are the classification of antiretroviral therapy?
1- Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
2- Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
3- Protease inhibitors.
4- Integrase Strand Transfer Inhibitor (INSTI)
5- CCR5 antagonist.
6- Fusion inhibitors.
7- Attachment inhibitor.
8- Post-Attachment Inhibitor.
What was the first drug class to be discovered to fight against HIV infection?
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs). They constitute the backbone of all treatment regimens.
NRTIs must first undergo intracellular conversion to their active forms (must undergo phosphorylation).
How do Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs) work?
Lets say during the time where the reverse transcriptase enzyme is converting HIV RNA to double stranded DNA, these drugs will create millions of mutated nucleotides. Like lets say the next nucleotide to be added is adenosine so it will create something that looks like adenosine bs a mutated version. So the chances of getting this mutated version is 1 million bs getting the real correct one is 1.
We cannot extend beyond this bad A thus elongation stops.
Provide examples of Nucleotide/Nucleoside Reverse Transcriptase Inhibitors (NRTIs).
- Zidovudine.
- Abacavir.
- Lamivudine.
- Tenofovir.
used for treating HIV. Keep in mind that we never ever give 1 medication for HIV, we always give at least 3!
What is zidovudine?
This is an analogue for thymidine.
What it does are:
- Decrease viral load.
- Increase CD4+ T-cell count.
- Delay onset of disease symptoms.
- Reduce symptom severity.
Used to treat HIV-1. Always combined with other antiretroviral agents (usually 3 drugs are used).
It can penetrate the CNS better than most of the other antiretroviral drugs hence can be valuable for relieving cognitive symptoms.
It is the drug of choice for preventing mother-to-infant HIV transmission during labor & delivery.
ADVERSE EFFECTS:
- Neutropenia
- Severe anemia
- Lactic acidosis with hepatic steatosis.
- Combining NRTIs during pregnancy may increase risk of lactic acidosis which is fatal.
Which NRTI drug is a thymidine analogue?
Zidovudine.
Which NRTI drug is the drug of choice for preventing mother-to-infant HIV transmission during labor & delivery?
Zidovudine.
Which NRTI penetrates to the CNS better than most other antiretroviral drugs hence can be especially valuable for relieving cognitive symptoms that are associated with HIV?
Zidovudine.
Why do we always combine medications in HIV patients?
We usually use at least 3 drugs.
1- Combining 2 drugs esp if they don’t have the same MoA leads to synergy thus increasing efficacy.
2- Minimizes resistance which is good since these drugs will be used for life.
What are the adverse effects seen zidovudine?
1- Severe anemia
2- Neutropenia
3- Lactic acidosis with hepatic steatosis (presence of intrahepatic fat).
Can zidovudine cause drug interaction?
Yes - taking zidovudine with other medications that are myelosuppressive (suppresses the bone marrow), nephrotoxic, or directly toxic to circulating blood cells can increase the risk of zidovudine causing neutropenia.
What is abacavir?
This is a drug belonging to the NRTI to treat HIV. It is an analogue of guanosine.
Can cause hypersensitivity reactions thus sensitized patients (those who previously experienced a reaction) should NEVER be given that drug or else they may die. Genetic test (HLA-B*5701) can be used to screen for this potential reaction.
Which NRTI medication is an analogue of guanosine?
Abacavir.
Which NRTI drug causes hypersensitivity reactions in many patients?
Abacavir.
sensitized patients (those who previously experienced a reaction) should NEVER be given that drug or else they may die. Genetic test (HLA-B*5701) can be used to screen for this potential reaction.
What is lamivudine?
This is an NRTI drug to treat HIV. It is an analogue for cytidine. Given to patients with HIV & hepatitis B.
Food reduces the rate of its absorption & the drug is eliminated intact in the urine.
Of all the NRTIs, lamivudine is the best tolerated.
Which NRTI is the best tolerated?
Lamivudine.
Which NRTI drug is used for both HIV & hepatitis B?
Lamivudine.
Which NRTI is an analogue for cytidine?
Lamivudine.
What is tenofovir?
This is an NRTI drug to treat HIV, it is an analogue of adenine.
NOTICE! It is a nucleotide reverse transcriptase inhibitor NOT Nucleoside (all other NRTIs (abacavir, zidovudine, lamivudine) are nucleoside…).
what NRTI drug is an analogue of adenine?
Tenofovir.
used to treat HIV.
What are the different types of HIV drugs with examples of each class.
