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Transcript
CLASS: 11:00 – 12:00
DATE: December 6, 2010
PROFESSOR: King
I.
II.
III.
IV.
V.
VI.
VII.
VIII.
IX.
X.
XI.
XII.
ANTIVIRAL AND ANTI-AIDS AGENTS II
Scribe: Adam Baird
Proof:
Page 1 of 3
HUMAN IMMUNODEFICIENCY VIRUS [S59]
a. Note: You don’t need to know the drug brands. You’ll learn them eventually (in practice).
b. Video shown in class explaining viral life cycle.
ENTRY INHIBITOR [S60]
a. There are two drugs in this class: Maraviroc and T-20.
MARAVIROC [S61]
a. Inhibits the interaction between CCR5 and HIV-1 gp120 (which doesn’t allow the HIV-1 to enter the cell).
b. The cell has CCR5 (chemokine receptor 5) and CXCR4 receptor.
c. Some patient’s virus use CXCR4, other patient’s virus use CCR5, and some patient’s virus use a combination
of both.
d. This drug will only work on patient’s whose virus uses CCR5 to enter the cell.
e. A test is needed to determine which receptor the virus uses. This test costs about $3,000.
f. Although this drug is used quite frequently, it is probably not used as much as it would be if it didn’t require
such an expensive test.
g. Side effects: hepatotxicity
h. Note: it is also a substrate for cytochrome P450 (meaning that it can cause many drug interactions)
FUSION INHIBITOS [S62]
ENFUVIRITIDE (T-20, FUZEON) [S63]
a. T-20 binds to gp41 of the viral envelope glycoprotein and prevents the conformational changes needed to let
HIV enter the cell.
b. It is given subcutaneously 2x a day.
c. This drug costs $20,000/year.
d. This drug isn’t used very often.
e. When it is used, it’s often used in combination with other drugs.
INHIBITION OF REVERSE TRANSCRIPTASE [S64]
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTI) [S65]
a. The highlighted drugs (in green) do not need to be memorized. They are a combination of the drugs above
them.
b. HIV infected patients are usually treated with at least 3 drugs from 2 different classes. Many times, 2 of the
drugs are NRTI.
c. Note: You only need to know the generic names of these drugs. The names in parenthesis are just for
reference.
d. These drugs are the “backbone” of HIV therapy.
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTI) [S66]
a. NRTI act like false building blocks. They are phosphorylated in the cell to the triphosphate form. They
compete with nucleosides. They abort DNA synthesis.
b. All nucleosides need to be phosphorylated in the cell to the triphosphate form – with the exception of
tenofovir, which is phosphorylated in the cell to the diphosphate form.
c. It is commonly used in combination with other antiretroviral agents.
NRTI ADVERSE EFFECTS [S67]
a. Zidovudine can cause fatigue, headaches, N/V, bone marrow, toxicity.
b. Tenofovir can cause GI effects, altered bone density, renal effects.
c. As a class, all NRTIs are associated with lactic acidosis, steatosis, myositis, myopathy, hepatmegaly, and
lipodystorphy.
NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS [S68]
a. Bind to the enzyme (reverse transcriptase), causing a disruption of the enzyme’s catalytic site.
b. Do not compete with nucleoside analogs.
NNRTI ADVERSE EVENTS [S69]
a. There are 3 drugs in this class. Focus on these 2: Efavirenz and nevirapine. The other drug, delavirdine, is
rarely used anymore.
b. Efavirenz is the most commonly used. It is used in comibination with nucleoside analogs and/or protease
inhibitors. They are inducers of CYP3A4 (which can created significant drug interactions). Effects of
efavirenz: dizziness, insomnia, amnesia, halluncinaitons, and a possible severe rash.
c. Nevirapine is associated with major toxicity (in the form of a rash), which is most common in the first 3 weeks
of therapy (so the dosage is often altered during this time period).
d. Efavirenz is more commonly used that nevirapine.
INTEGRASE INHIBITORS [S70]
a. The newest class of drugs: integrase inhibitors.
CLASS: 11:00 – 12:00
Scribe: Adam Baird
DATE: December 6, 2010
Proof:
PROFESSOR: King
ANTIVIRAL AND ANTI-AIDS AGENTS II
Page 2 of 3
XIII.
RALTEGRAVIR [S71]
a. Inhibits integration of HIV.
b. Advantage: metabolized by glucuronidation. All the other drugs (like protease inhibitors and efavirenz) are
metabolized by CYP. There are fewer side effects with this drug too, compared to other antiretroviral agents.
c. It is used in combination with other drugs.
XIV.
PROTEASE INHIBITORS [S72]
XV.
PROTEASE INHIBITORS (PI) [S73]
a. Pay attention specifically to the highlighted PIs.
XVI.
PROTEASE INHIBITORS [S74]
a. They prevent the polyproteins from breaking down into smaller proteins, which are able to infect new cells.
b. They are metabolized by CYP450; potent inhibitors of CYP450
c. If patients don’t take proper dosage, suboptimal dosing will cause decreased concentration of PIs in the body,
allowing the virus to mutate (so that it bypasses PIs), resulting in replication. The result: patients become
resistant to PIs. Low dose ritonavir can prevent this.
XVII. PI PHARACOKINETICS [S75]
a. A decreased dose (from 600 mg to 100 mg), in combination with other PIs, can result in a positive drug
interaction.
b. This can result in higher drug exposure with less medication.
c. Many of these drugs are metabolized by CYP450. PIs and NNRTI and maraviroc all go through CYP3A4 (and
they can be reduced or inhibited). So ritanovir is a potent inhibitor of CYP3A4. Any drug that inhibits CYP3A4
allows an increase for other drugs in the plasma. Any drug that induces CYP3A4 results in an decrease for
other drugs in plasma (like rifampin, for example).
XVIII. CYP450 AND DRUG METABOLISM [S76]
XIX.
DRUG INTERACTION POTENTIAL: INHIBITION OF CYP 3A4 [S77]
a. Here are some potent inhibitors of CYP3A4.
XX.
DRUG INTERACTION POTENTIAL: INDUCTION OF CYP 3A4 [S78]
a. Here are some potent inducers of CYP3A4.
XXI.
DUAL PI THERAPY [S79]
a. Allows for decreased daily dosing, pill burden, food restrictions, etc.
b. Ability to suppress resistant HIV strains by enhancement of PI plasma levels
XXII. METABOLIS SIDE EFECTS OF PIs [S80]
a. Side effects: “buffalo hump” (which can sometimes be reversed); similar in appearance to Cushing’s
syndrome without the hypercorisolism; incidence is low.
XXIII. PERIPHERAL LIPODYSTROPHY SYNDROME [S81]
a. Other side effects: fat redistribution, hollow cheeks, visceral fat deposit, breast enlargement, etc.
XXIV. OTHER PI ADVERSE EFFECTS [S82]
a. Adverse effects: hepatotoxicities (common in co-infected patients), lipid abnormalities (increase in cholesterol
and increase in triglycerides), hyperglycemia, and insulin resistance.
XXV. CLINICAL MANAGEMENT OF HIV [S83]
XXVI. GOALS OF THERAPY [S84]
a. Goals: to suppress the viral load as best as possible, to restore/preserve immunologic function, to improve
quality of life, to reduce HIV-related morbidity and mortality.
XXVII. ARV THERAPY IN THE HIV-INFECTED PATIENT [S85]
a. This suggests when to start therapy (or when not to).
b. Typically, therapy is started immediately (if the support system is present).
c. Once a patient is on medication, and they don’t stick to the medication, there is an increased risk of mutations
(and the drug looses its effectiveness).
XXVIII. INITIAL TREATMENT STRONGLY RECOMMENEDED: NNRTI BASED REGIMEN [S86]
a. Things that are highlighted in PINK are the typical first treatments for therapy (know these for the exam).
b. Lamivudien and zidovudine are recommended to be given in combination with a drug in column C. Both are
so similar though, that they are not effective when given together.
c. Example: great regimen for a new patient = efavirenz and emtricitabine and tenofovir. One tablet now
contains all three of these drugs (and only needs to be taken once daily).
XXIX. INITIAL TREATMETN STRONGLY RECOMMENDED: PI BASED REGIMEN [S87]
a. Emtricitabine and tenofovir would be recommended first.
XXX. ANTI-RETROVIRAL REGIMENS NOT RECOMMENDED [S88]
a. Note: Audio cuts out for about one minute.
b. Stavudine and zidovudine would not be given together because they compete for phosphorylation (and it’s
the triphosphate form of the nucleoside analogs that are effective).
CLASS: 11:00 – 12:00
Scribe: Adam Baird
DATE: December 6, 2010
Proof:
PROFESSOR: King
ANTIVIRAL AND ANTI-AIDS AGENTS II
Page 3 of 3
XXXI. ANTI-RETROVIAL DRUG METABOLSIM [S89]
a. NRTI: most are excreted/secreted by kidney and do not participate in drug interactions involving the liver
(compared to the NNRTI and PI)
b. Early inhibitors: maraviroc is metabolized by CYP34, so there is a potential for drug interactions
c. NNRTI: hepatically metabolized; potent inducers (whereas the PIs are potent inhibitors).
d. Integrase inhibitor (raltegravir): metabolized by glucuronidation, UGT1A1 (so there are less interactions).
XXXII. WHICH OF THE FOLLOWING…? [S90]
a. What’s wrong with “A”? You wouldn’t want to give the first two together because they are structurally similar.
b. Answer: “B”
c. What’s wrong with “C”? The first two would compete for phosphorylation.
d. What’s wrong with “D”? The last two cause hyperbilirubinaemia
XXXIII. WHICH OF THE FOLLOWING…? [S91]
a. Answer: “B” Ritonavir
b. Raltegravir doesn’t have as many drug interactions (because it metabolized by glucuronidation instead of
CYP3A4).
XXXIV. WHICH OF THE FOLLOWING…? [S92]
a. Answer: “C”
b. Be able to recognize what class the drug falls into.
c. Exam help:
1. It may be hard to memorize retrovirals and antiretrovirals. For the antiretrovirals (columns B and C):
the nucleoside reverse transcriptase inhibitors end in “-ine”. All the protease inhibitors end in “-vir”
(with the exception of tenofovir, which is not a PI, but a NRTI).
2. Highlighted in yellow (throughout the presentation) are the most important drugs.
3. Understand how the drugs work and how they may interact with others.
4. Study how drugs differ from each other.
5. Know which drugs are eye drops.
6. There are only 6 questions over this material.
XXXV. QUESTIONS? [S93]
[End 37:00 mins]