ANTIRETROVIRAL DRUGS Flashcards

Question

EFAVIRENZ (not ETRAVINE) CLINICAL APPLICATIONS PHARMACOKINETICS

Answer 1

* \*\*\*\*\*\*\*\*_**Preferred NNRTI on DHHS guidelines\*\*\*\*\*\*\*\*\*\*\* EFAVIRENZ DOES ERRRYTHINGGGGG B/C DRUG GOES ALL THE WAY TO THE END OF THE ALPHABET (Z)**_ * Results in increased CD4+ counts & decreased viral load Pharmacokinetics * Oral * t1/2 \>40h _**(once-a-day dosing)\*\*\*\*\***_ * Extensively metabolized to inactive products

Answer 2

EFAVIRENZ --\> it ZZZZZZZ'S --\> dizziness, **_vivid DREAMZZZZZZ_** **_DON'T GIVE TO PZYCHHOOOOOSSSS_** **_Adverse Effects_** * 1) **Mostly CNS (50%)** (dizziness, headache, vivid dreams, loss of concentration) – resolve after few weeks. * 2) **Rash (25%)** * 3) **Increased triglycerides, HDL and total cholesterol** (lipid levels must be monitored at beginning of and during therapy) **_Contraindications_** * **_Potent inducer of CYP P450 enzymes._** * **_Pregnancy (D)_** (*can be used after 1st trimester if considered best choice*)

Answer 3

MOA: * **_Reversible inhibitors of HIV aspartyl protease_** (*enzyme responsible for _cleavage of viral polyprotein into RT, protease & integrase_*_)_ * Protease inhibition prevents virus maturation & results in production of non-infectious virions * **_DO NOT REQUIRE INTRACELLULAR ACTIVATION_** * Active against both HIV-1 and HIV-2

Answer 4

**_Pharmacokinetics_** * Poor oral bioavailability * High-fat meals can increase (nelfinavir) or decrease (indinavir) bioavailability * **_Substrates for CYP 3A4_** * **_Substrates for P-glycoprotein pump_** * Bound to plasma proteins (a1-acid glycoprotein which can increase in response to trauma & surgery)

Answer 5

PROTEASE INHIBS ---\> MAKE YOU A PORKER!!!! ---\> FUCKS WITH LIPID METABOLISM --\> FAT REDISTRIBUTION + ACCUMULATION Adverse Effects * **_Parathesias, nausea, vomiting, diarrhea_** * **_Disturbances in lipid metabolism_** (diabetes, hypertriglyceridemia, hypercholesterolemia) * Chronic admin --\> _**\*\*\*\*\*fat redistribution & accumulation\*\*\*\*\***_ resulting in central obesity, dorsocervical fat enlargement, peripheral & facial wasting, breast enlargement and a cushingoid appearance * **_Atazanavir has less side effects than other PI’s_**

Answer 6

**_• Potent inhibitors and substrates of CYP isoforms_** eg, rhabdomyolysis (simvastatin or lovastatin), excessive sedation (midazolam or triazolam), respiratory depression (fentanyl) * Warfarin, sildenafil & phenytoin require dosage adjustments * **_Rifampin & St.Johns Wort are contraindicated_** RESISTANCE • Accumulation of stepwise mutations of protease gene. Can lead to high levels of resistance.

Answer 7

PROTEASE INHIBITOR ## Footnote RITONAVIR --\> RIT --\> **_RAMPS UP_** IE **_ENHANCER/BOOSTER OF OTHER PI'S d/t INHIBITION OF CYP3A4_** CLINICAL APPLICATION: -- enhancer/booster of other PIs -potent **_INHIBITOR of CYP3A4_** CONTRINDICATIONS: -numerous d/t inhibition of CYP

Answer 8

ATAZANAVIR --\> ATAZMANIAN DEVIL --\> can't give with PPI's b/c it inhibits them (give 12 hours apart from PPIs) --\> thrives in the acidic environment (that tazmanian devil) --\> go home and watch 1 CARTOON A DAY --\> IS THE PREFERRED CARTOON TO WATCH, is the **_ONCE-DAILY PREFERED PI_** **_--\> is structurally unrealted to the others because is just a cartoon (not a human)_** Clinical Application: - **_is a once-daily preferred PIs (as is Ritonavir)_** PK: -**_structurally UNRELATED to other PIs_** --\> is well absorbed with food, highly protein bound CONTRAINDICATIONS: - metabolized by and inhibits CYP3A4 - contraindicated with a proton pump inhibitor - **_administration must be \>12 HOURS APART FROM H2 BLOCKERS + ANTACIDS_** **_-less incidence of side-effects than other PIs_**

Answer 9

PROTEASE INHIBITOR ## Footnote DA-RUN-AVIR --\> think about running, in order to run well, need to absorb what you're taking quickly, so is **_BEST ABSORBED WITH FOOD_** - inhibits HIV protease resistant to other PIs - well absorbed with FOOD - is metabolized by CYP3A4, but also INHIBITS it as well

Answer 10

PROTEASE INHIBITOR ## Footnote INDIAN-AVIR --\> must be given with RITONAVIR b/c INDIANS AREN'T THAT STRONG --\> eat way too much INDIAN FOOD --\> **_GET RENAL STONES!!!_** - is given with RITONAVIR - least protein bound (60%) --\> absorption DECREASED when taken with meals -dosage should be REDUCED with hepatic insufficiency AEs: - is well tolerated but can also get - NEPHROLITHIASIS + HYPERBILIRUBINEMIA (adequate hydration important)

Answer 11

PROTEASE INHIBITOR ## Footnote LOPINAVIR --\> LOW-P**_IN_**-AVIR --\> can cause **_IN_**SULIN RESISTANCE --\> is an **_IN_**ducer --\> contains alcohol which makes you do things, therefore don't give with disulfiram or metro) --\> warts are the size of PINS --\> CYP **_INDUCER FOR ST. JOHNS WARTS_** - one of the PREFERRED Protease Inhibitors - is given with RITONAVIR - has poor intrinsic stability CONTRAINDICATIONS: --\> i**_s an ENZYME INDUCER, therefore St. Johns Wort should be avoided_** -**_oral solution contains EtOH (avoid disulfiram or metronidazole)_**

Answer 12

PROTEASE INHIBITOR ## Footnote NELFINAVIR --\> **_NEW ELF_** --\> is the best elf that santa has --\> it is already working at maximum **_efficiency so cannot be boostd by RTV_** - CANNOT be boosted by Ritonavir - metabolized by SEVERAL CYPs --\> major metabolite (CYP2C19) has antiviral actiivity equal to parent compound CONTRAINDICATIONS: NUMEROUS (d/t inhibition of CYP) AE: -diarrhea (controlled by loperamide), nausea, flatulence

Answer 13

PROTEASE INHIBITOR (don't confuse with DARUNAVIR which is well-absorbed w food) ## Footnote TIPRANOVIR --\> if run on TIPTOES --\> will make your head go crazy --\> INTRACRANIAL HEMORRHAGE --\> can also cause FATAL HEPATITIS --\> can feel the TIP of your liver while you're RUNNING (can feel the stich with your right hand) - inhibits HIV protease resistant to other PIs - twice-daily should be given with RITONAVIR - is well absorbed with food - is an INDUCER of CYP P450 AES: 1) **_SEVERE + FATAL HEPATITIS_** 2) **_FATAL + NONFATAL INTRACRANIAL HEMORRHAGES_**

Answer 14

FUSION INHIBITOR 1) ENFUVIRTIDE ENTRY INHIBITOR 1) MARAVIROC

Answer 15

FUSION INHIBITOR ## Footnote EN**_FU_**VIR**_TIDE_** --\> like the thing tries to enter but it hits the cell and hits the **_tide_** and bounces back, ie it is a FUSION INHIBITOR --\> is structurally --\> when do u see the tide? when you're 41 years old, able to afford a YACHT ---\> acts like a gp41 * First approved drug that **_inhibits viral fusion_** * **_Approved for use in treatment-experienced adults_** **_with evidence of HIV replication_** • *No activity against HIV-2* *-most common adverse effect = **_PAIN AT INJECTION SITE!!! --\> ENFU as in EFF YOU!!!!_*** **_MOA_** * **_Structurally similar to gp41_** (HIV protein mediates membrane fusion) * Binds to gp41 subunit of the viral envelope glycoprotein, preventing ability of virion to fuse cell membrane PK: parenteral administration only AE: * **_Injection-related_** (3% discontinue) * Hypersensitivity reactions & eosinophilia rarely * **_No drug interactions with other antiretrovirals have been noted_**

Answer 16

ENTRY INHIBITOR ## Footnote MARAVIROC ---\> think MARRY --\> ENTRY INTO MAIRRAGE/NEW PART IN YOUR LIFE --\> CCR5 is the song that you play at your mairrage --\> binds on surface of T cells/monocytes, inhibiting interaction with gp120. **_MOA_** * **_Binds specifically and selectively to CCR5_** (one of two coreceptors necessary for entrance of HIV into CD4+ cells) * Result in **_blocking HIV entry_** (only CCR5-tropic virus can be treated with maraviroc) Pharmacokinetics • Metabolized by **_CYP 3A4_** (reduce dose when given with PIs) AE's: --\> well tolerated, risk of hepatotoxicity

Answer 17

INTEGRASE STRAND TRANSFER INHIBITOR (INSTI) ## Footnote RALTEGRAVIR ---\> R GRAVE --\> when you're dying you start decomposing, start INTEGRATING into the soil --\> this INHIBITS the INTEGRASE enzyme --\> Leads to specific **_inhibition of the final step in integration_** of viral DNA into host cell DNA --\> ie you're put in grave and eveyrthign is allowed to occur but the final step of decomposition is inhibited --\> metabolized by **_UGT1A1-mediated glucuronidation_** ie think GUT (ugt mixed around) --\> note also that PPI's INCREASE the concentration for when you're decomposing Clinical Applications • In combination with other antiretrovirals, raltegravir is approved for **_treatment-experienced_** and **_treatment- naive patients_** with evidence of viral replication MOA * **_Binds integrase_** (enzyme essential to the replication of both HIV-1 and HIV-2) * Leads to specific **_inhibition of the final step in integration_** of viral DNA into host cell DNA Pharmacokinetics • Metabolism via **_UGT1A1-mediated glucuronidation_** **_AE:_** * **_Well tolerated_** (nausea, headache, diarrhea) * Can cause increases in creatine phosphokinase Drug Interactions * Rifampin, tipranavir & efavirenz may decrease [raltegravir] * PPI’s may increase [raltegraivr]

Answer 18

Goals: • Maximally & durably suppress viral load replication • Restore & preserve immunologic function • Reduce HIV-related morbidity & mortality **_• INCREASE QUALITY OF LIFE_**

Answer 19

Start with one of the following regimens: (1) NNRTI & **_2 x NRTI_** (2) PI (preferably boosted with ritonavir) & **_2 x NRTI_** (3) INSTI & **_2 x NRTI_**

Answer 20

Factors to consider when selecting an initial regimen: * Comorbid conditions * Potential adverse drug effects * Potential drug interactions * Pregnancy or pregnancy potential * Results of genotypic drug resistance testing * Patient adherence potential * Convenience

Answer 21

**_Selection is based on:_** * Avoiding the use of 2 agents **_of the same nucleotide analog_** * Avoiding overlapping toxicities and genotypic and phenotypic characteristics of the virus * Patient factors such as disease symptoms and concurrent illnesses * Impact of drug interactions; and * Ease of adherence to a frequently complex administration regimen

Answer 22

1) RITONAVIR-BOOSTED **_LOPINAVIR_** (twice daily) AND 2) **_ZIDOVUDINE/LAMIVUDINE_**

Answer 23

1) **_ZIDOVUDINE_** (start immediately after birth and administer for 6 weeks)

Answer 24

Upon exposure to HIV, healthcare personnel should immediately receive a postexposure prophylaxis regimen **_containing at least 3 antiretroviral drugs_** Preferred regimen: **_1) Raltegravir + (Integrase inhibitor)_** **_2) tenofovir + (NRTI)_** **_3) emtricitabine (NRTI)_** Regimen is **_given for 28 days and can be stopped if source is shown to be HIV-negative._**

Answer 25

• 1) Streptococcus pneumoniae * 2) Hepatitis A * 3) Hepatitis B and * 4) Influenza **_are generally recommended for all HIV-infected patients_** **_CONTRAINDICATED:_** **_Live vaccines eg,_** _**• MMR • Varicella and**_ **_• Zoster_** Other vaccines may be administered without regard to the patient’s CD4+