EVMSPharm 5

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EVMSPharm 5
2013-12-07 14:33:47
Pharm exam

Pharm exam 5
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  1. Antiretroviral therapy of HIV
    • HAART – Highly Active Anti-Retroviral Therapy:
    • Multiple drug combinations (at least 3 drugs) necessary to reduce viral load as well as to reduce development of resistance
    • HAART has made a dramatic impact on the viral load of patients with HIV
  2. Antiviral drug classification for HIV Infection
    • Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI)
    • Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)
    • Protease Inhibitors (PI)
    • Entry and Fusion Inhibitors
    • Integrase Inhibitor
  3. Antiretrovial drug therapy issues
    • Multiple drug therapy combinations
    • Significant adverse reactions
    • Multiple drug-drug interactions
    •      -Between antiretroviral drugs
    •      -With many other drugs used by HIV patients
    • High cost
    • Adherence
  4. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NNRT)
    • “Backbone” of antiretroviral regimens
    •      Use two NRTIs (start with emtricitabine [nuscleoside] + tenofovir [nucleotide])
    • Oral
    • Nucleoside and nucleotide reverse transcriptase inhibitors = structurally distinct but same MAO
    • -------------------------------------------------
    • MOA: Competitively inhibit reverse transcriptase to prevent formation of viral DNA from viral RNA
    •      -DNA chain termination similar to action
    • of acyclovir
    • ------------------------------------------------
    • Class Adverse Effects:  potential for lactic acidosis, hepatic steatosis, and lipodystrophy (all higher with stavudine)
    •       occur more or less depending on which drug in class
    • Drug Interactions: not significant
    • -----------------------------------------------
    • Don't need to memorize names
    • only on nucleoTide transcriptase inhibitor (tenofovir/viread)
  5. Non-nucleoside reverse transcriptase inhibitors (NNRTI)
    • Oral
    • MOA: Direct, non-nucleoside inhibitors of reverse transcriptase
    •      -Do not require metabolic conversion and are not incorporated into viral DNA
    •      -Additive effect to NRTI
    • ------------------------------------------------
    • Class Adverse Effects: rash, sometimes severe and progressing to Stevens Johnson Syndrome. + others depending on specific drug
    • Drug Interactions: significant, primarily involve P450 enzymes (own card)
    • ------------------------------------------------
    • can't memorize all
  6. NNRTIs and drug interactions
    • Nevirapine:
    •      -A modest inducer of CYP3A4. May precipitate withdrawal in methadone maintenance patients.
    • Efavirenz:
    •      -A modest inducer of CYP3A4.
    • Etravirine:
    •      -A modest inducer of CYP3A4
    •      -Inhibitor of CYP2C9 and 2C19
    • Delavirdine  (rarely used due to low potency-had to give too many doses/day)
    •      -A strong inhibitor of CYP3A
  7. Protease Inhibitors (PIs)
    • Oral
    • MOA: prevent viral protease from forming functional viral proteins necessary for maturation of viral particle and viral replication
    • Class Adverse Effects: GI distress, hyperglycemia & insulin resistance (aka diabetes), hyperlipidemia (yellow blood, must tx), CAD, fat accumulation, and hepatotoxicity
    •      -Treat as you would other diabetic or CAD patients
    • ---------------------------------------------
    • don't need to memorize names
    • all end in "-navir"
  8. Protease Inhibitors (PIs) and drug interactions
    • All PIs are metabolized by, and inhibit, CYP3A4. (considered some of most potent inhibitors of 3A4)
    • Rank order of CYP3A4 inhibition:
    •      -Ritonavir > indinavir  > saquinavir > nelfinavir > amprenavir
    • Ritonavir only used to “boost” drug levels of other PI agents, thus reducing # tablets/day (bc of strong 3A4 inhibition)
    •      -Kaletra = lopinavir + ritonavir
    • Metabolism of PIs is induced by rifampin and phenytoin
    • Absorption of PIs is reduced as gastric pH rises secondary to H2 antagonists and PPIs
  9. Fusion Inhibitor
    • Enfuvirtide (Fuzeon)
    • MOA: Binds to transmembrane glycoprotien and prevents fusion of viral particle to CD4 cell membrane
    • Given by SC injection BID (painful)
    • Only for treatment-experienced patients (= add on drug)
    • Adverse Effects: injection site reactions and hypersensitivity reactions
  10. CCR5 Antagonist Entry Inhibitor
    • Maraviroc (Selzentry)
    • MOA: Antagonist of CCR5 receptor on CD4 cell surface necessary for HIV entry
    • Active against HIV strains resistant to other classes
    • Adverse effects: cough, rash, infections
    • Drug interactions: substrate of CYP 3A4
    • Will interact with PIs
  11. Integrase Strand Transfer Inhibitor (INSTI)
    • Oral
    • -----------------------------------------------
    • Raltegravir (Isentress)
    • MOA:blocks integrase
    • enzyme necessary for integration of viral DNA into cellular DNA
    • Adverse effects: diarrhea, nausea, headache, and myositis (monitor CPK)
    • CYP 450 drug interactions: none
    • ------------------------------------------------
    • Elvitegravir combination (Stribild)
    • Four drug combination just approved using new INSTI and CYP450 inhibitor (see below)
    • = 3 retroviral drugs + CYP450 inhibitor
  12. Raltegravir (Isentress)
    • = Integrase Strand Transfer Inhibitor (INSTI)
    • oral
    • MOA:blocks integraseenzyme necessary for integration of viral DNA into cellular DNA
    • Adverse effects: diarrhea, nausea, headache, and myositis (monitor CPK)CYP 450 drug interactions: none
  13. Elvitegravir combination (Stribild)
    • = Integrase Strand Transfer Inhibitor (INSTI)
    • oral
    • Four drug combination just approved using new INSTI and CYP450 inhibitor (see below)
    • = 3 retroviral drugs + CYP450 inhibitor
    • ---------------------------------------------------
    • >Drug combination
    • Elvitegravir = INSTI
    • Cobicistate = CYP3A inhibitor (boost INSTI levels)
    • Emtricitabine/tenofovis = preferred NRTI combination
  14. HIV medication Combination Products
    • Two NRTIs (for new patient)
    •      -Truvada – emtricitabine/tenofovir (1st choice)
    •      -Combivir – zidovudine/lamivudine
    •      -Epizicom – abacavir/lamivudine
    • Three NRTIs (currently not recommended)
    •      -Trizivir - zidovudine/lamivudine/abacavir
    • One NNRTI plus two NRTIs (standard 3 drugn combo)
    •      -Atripla – efavirenz/emtricitabin/tenofovir* choice for naive patient
    •      -Complera – rilpivirine/emtricitabin /tenofovir
    • PI “boosting” (to boost blood levels of other drugs)
    •      -Kaletra – lopinavir/ritonavir
  15. Antiretroviral (ARV) Therapy goals
    Eradication of HIV infection cannot be achieved with current ARV therapy, so

    • -Reduce HIV-associated morbidity and prolong the duration and quality of survival
    • -Restore and preserve immunologic function
    • -Maximally and durably suppress plasma HIV viral load
    • -Prevent HIV transmission
  16. Predictors of ARV success (long term)
    • High potency of ARV regimen
    • Excellent adherence to treatment regimen
    • Low baseline viremia
    • Higher baseline CD4 count (>200 cells/mm3), and
    • Rapid reduction of viremia in response to treatment
  17. Antiretroviral regimens for treatment of naive patients
    • ARV therapy is now recommended for all HIV-infected individuals
    • Regardless of CD4 count, ARV therapy is strongly recommended for the following:
    •      -Pregnancy
    •      -History of AIDS-defining illness
    •      -HIV-associated nephropathy
    •      -HIV/Hepatitis B coinfection
    • -------------------------------------------------
    • >Class-sparing approach
    • Add class agent to two NRTIs – usually tenofovir + emtricitabine to start => add one or more of the following based on pt/hx/comorbidities:
    • NNRTI-Based
    •      -NNRTI + 2 NRTIs
    • lPI-Based
    •      -PI (w/ ritonovir boost) + 2 NRTIs
    • INSTI-Based
    •      -Raltegravir + 2 NRTIs
    • CCR5 antagonist-based
    •      -Maraviroc + 2 NRTIs
  18. Factors to consider when selecting initial regimen for ARV
    • Co-morbid conditions (e.g., cardiovascular disease , chemical dependency, liver disease, psychiatric disorders, renal diseases, or tuberculosis)
    • Potential adverse drug effects
    • Potential drug interactions with other medications
    • Pregnancy or pregnancy potential
    • Result of genotypic drug-resistance testing
    • Gender and pretreatment CD4 count if considering nevirapine
    • HLA-B*5701 testing if considering abacavir (ABC)
    • Co-receptor tropism assay if considering maraviroc (MVC)
    • Patient adherence potential
    • Convenience (e.g., pill burden, dosing frequency, and food and fluid considerations).
  19. Drug-Resistance Testing
    • HIV drug-resistance testing recommended for all HIV infected persons when they enter into care
    • Genotypic testing preferred in ARV-naïve patients
    • Testing for mutations in reverse transcriptase and protease genes as well as INSTI resistance
    • Assists in selection of active drugs when changing ARV regimens with virologic failure and high HIV RNA levels
    • Phenotypic assays (testing viral growth in different ARV concentrations) reserved for patients with known complex drug-resistant patterns
  20. Pregnancy and Perinatal Transmission/meds
    • Recommendedregimen throughout pregnancy:
    •      -*Lopinavir/ritonavir + zidovudine/lamivudine *
    •      -PI may increase hyperglycemia risk
    • Transmission to infant occurs mostly during labor & delivery
    • Zidovudine recommended in the infant for the first 6 weeks of life
    • Avoid efavirenz – teratogenic
    • Avoid nevirapine if CD4 > 250 cells/mm3 – increased risk of hepatotoxicity
  21. Drugs for HIV prevention
    • Truvada ( emtricitabine/tenofovir) just approved 2012 by FDA for pre-exposure prophylaxis to reduce the risk of sexually acquired HIV in adults at high risk.
    • Daily use reduced risk by 44% overall and by 87%  in men who were adherent to regimen
    • Daily use reduced risk by 75% compared to placebo in heterosexual couples
  22. Preferred NNRTI for initial tx
    Efavirenz (AI)
  23. Preferred Protease Inhibitors for initial Tx
    • Atazanavir + ritonavir -- once daily (AI)
    • Darnuavur + ritonavir -- once daily (AI)
    • Fosamprenavir + ritonavir -- 2x daily (BI)
    • Lopinavir/ritonavir -- once or 2x daily (AI)
  24. Preferred Dual-NRTI options for initial tx
    tenofovir + emtricitabine (AI)
  25. Mycoses Classifications
    • Superficial Mycoses:
    • Dermatophytes - Tinea infections (foot, groin), ringworm (inflammatory reaction), onychomycosis (nails)
    • Candidiasis - Vulvovaginal, Oral (thrush), Esophageal
    • -----------------------------------------
    • Subcutaneous Mycoses
    • -----------------------------------------
    • Systemic Mycoses: (mostly opportunistic)
    • Candidiasis
    • Aspergillosis
    • Mucormycosis
    • Blastomycocis
    • Histoplasmosis
    • Coccidiomycosis
  26. Fungal Cell Biology
    • Fungal cells similar to mammalian cells - nucleus w DNA in chromosomes, mitochondria, ER
    • Cell Wall + Cell Membrane
    • Larger, more complex than bacteria
    • Difficult to design drugs selectively toxic to fungi but not human cells
    • Antifungal drugs are usually more toxic than antibiotics
    • Sterols 25% of cell membrane
    • Ergosterol in fungal cell membrane
    • Most antifungals bind selectively to ergosterol or inhibit P450-mediated ergosterol synthesis
    • Echinocandins inhibit cell wall synthesis
    • Organ toxicities and drug interactions directly related to cross-over effect on human cells
  27. Factors in Choosing Antifungals
    • Site of Infection - superficial vs systemic
    • Spectrum of Activity - importance to identify species
    • Immunocompetence - Compromised host: HIV, steroids, severe diabetes
    • Adverse reaction profile
    • Drug Interaction Potential - Cytochrome P450 enzyme inhibition
    • Cost
  28. Azole Antifungals
    • Block ergosterol biosynthesis
    • Inhibit cytochrome P450-dependent lanosterol C14-demethylase
    • Differ in affinity for mammalian P450 enzymes
    • Concerns: drug interactions, cholesterol synthesis, cell toxicity
    • Pregnancy category C, except category D for voraconazole
    • Dose limiting toxicity - liver failure (need to monitor liver function tests)
  29. Topical Azole Antifungals
    • Tinea infections (foot, groin)
    • Creams, lotions, powders, sprays
    • Clotrimazole
    • Miconazole
    • Econazole, oxicanazole, sertaconazole

    • Vulvovaginal candidiasis
    • Specially formulated creams, tablets, suppositories
    • OTC - clotrimazole, miconazole
    • Rx - econazole, terconazole
  30. Systemic Azole Antifungals
    • Ketoconazole
    • Fluconazole
    • Itraconazole
    • Voriconazole
    • Posaconazole
  31. Ketoconazole
    • First oral azole antifungal
    • Less specific affinity for fungal P450 enzyme
    • Only for superficial dermatophytes (low plasma levels
    • Relies on gastric acidity for absorption
    • Adverse reactions: gastrointestinal (20-50%), rash, inhibition of adrenal steroid synthesis, hepatotoxic potential
    • Decreased testosterone - hynecomastia, decreased libido, ED in men
    • Drug interactions: potent inhibitor of CYP 3A4 enzyme
    • Rarely used now
    • Non-infectious uses:
    • Cushing's syndrome
    • Prostate cancer
    • Hypercalcemia in sarcoidosis
  32. Fluconazole
    • Azole Antifungal
    • Oral and IV formulations
    • Most common prescription azole for Candida infections - used for prophylaxis and treatment
    • Large volume of distribution: can reach CSF, eye, urine
    • Renally eliminated (most azoles metab by liver) - adjust dose w renal failure
    • Best tolerated of azoles
    • Given once daily - doses range from 150mg to 800mg - for vulvovaginal candidiasis (one time dose of 150mg) - for coccidiomycosis - 800mg/day for >1yr
    • Adverse Reactions: GI (5-10%), rash, headache, alopecia (high doses)
    • Drug Interactions: Strong inhibitor of CYP 2C9 and 2C19 - Moderate inhibitor of CYP 3A4, except at high doses
  33. Itraconazole
    • Azole Antifungal
    • Oral form in capsules/solution only
    • Greater spectrum than fluconazole, including activity against Aspergillus (mold)
    • Absorption poor w capsules (requires low gastric acid pH)
    • Absorption 60% greater with solution under fasting conditions
    • Does not penetrate urine or CSF well
    • Onychomycosis - pulse therapy of 400mg/day for 7 days/month for 2 months (fingernails) or 3 months (toenails)
    • Adverse Reactions - GI (20%) - diarrhea, taste disturbances, elevated liver enzymes, rare heart failure with longer therapy (negative inotropic agent)
    • Drug interactions: strong inhibitor of CYP 3A4 enzyme and P-glycoprotein
  34. Voriconazole
    • Azole Antifungal
    • Similar in spectrum of activity to itraconazole - better activity against Aspergillus
    • Oral and IV formulations, given twice/day - oral bioavailability >90%
    • Indicated for invasive candidiasis and aspergillosis
    • Penetrates CSF, but not urine
    • Adverse reactions: transient vision disturbances (30%), rash, photosensitivity reactions, hallucinations, prolonged QT interval
    • Drug interactions: Inhibits CYP 2C9, 2C19, 3A4
    • Pregnancy category D
  35. Posaconazole
    • Newest azole antifungal
    • Similar in spectrum of activity to voraconazole - better activity against Mucormycoses
    • Available as oral suspension that must be taken with high-fat meal or liquid supplement - must be given up to 4x/day
    • Poor penetration to CSF/urine
    • Adverse reactions: similar profile to fluconazole
    • Drug Interactions: strong inhibitor of CYP3A4 enzyme
    • Reserve for moderate fungal infections resistant to oral itraconazole
  36. Echinocandin Antifungals
    • First novel class of antifungal drugs in 40 years
    • Disrupt synthesis of glucan polymers in cell wall - less crossover toxicity with mammalian cells
    • Given IV once daily
    • Now drugs of choice for invasive candidiasis - minimal CSF and urine penetration
    • Alternative to azole antifungals for Candida and Aspergillus infections
    • Adverse reactions: fever, phlebitis at infusion site, and elevated liver function tests
    • Cost - $220-400/day
    • Caspofungin, Micafungin, Anifulafungin
  37. Amphotericin B - Polyene Antifungal
    • Nicknamed "amphoterrible" - adverse effects
    • Binds directly to ergosterol in cell membrane
    • Still drug of choice for many systemic infections
    • Given slow IV infusion
    • Preferred drug for deep fungal infections in pregnancy
    • Original formulation - Amphotericin B deoxycholate (AmB-d) is least expensive
    • Lipid formulations - used to reduce acute reactions but are much more expensive (up to $1000/day) - Amphotericin B lipid complex, Liposomal amphotericin B, Amphotericin B colloidal dispersion
    • -----------------------------------
    • Adverse reactions:
    • Toxicity less severe with lipid formulations
    • Infusion-related reactions: fever, chills, N&V, headache, myalgias - prophylaxis with NSAID, hydrocortisone, diphenhydramine
    • Nephrotoxicity - secondary to afferent arteriole constriction - prophylaxis with 1000mL normal saline IV infusion can decrease risk
    • Hypokalemia secondary to renal tubule toxicity
  38. Allylamine:
    • Allyamine that blocks ergosterol synthesis by inhibiting squalene epoxide
    • Oral drug indicated for onychomycosis of toenail and fingernails - 250mg/day for 6 weeks (fingers) or 12 weeks (toes) - drug levels can persist in nails for 30 weeks - Usually more effective than itraconazole
    • Adverse reactions: Common - GI complaints, headache, rash - Less common - hepatotoxicity, Stevens-Johnson Syndrome, blood dyscrasias, taste disturbance
    • Drug Interactions: Strong CYP2D6 inhibitor
    • Pregnancy Category B
  39. Nystatin
    • Older polyene antifungal used in OTC topical creams and ointments
    • Sometimes given oral suspension for oral thrush
  40. Griseofulvin
    • Older oral antifungal for dermatophyte infections
    • Poor tolerance due to allergic reactions, photosensitivity, GI distress and neurologic effects
    • High fat meal for best absorption
  41. Flucytosine
    • For severe systemic infections w Amphotericin B
    • Converted to 5-flurouracil intracellularly: antimetabolite that is very toxic to bone marrow
  42. Types of Drug interactions
    • 1. Drug-Drug
    •     a. Pharmacodynamic --> due to differences in MOA, can be additive or antagonistic
    •     b. Pharmacokinetic --> due to changes in ADME of one or both drugs
    • 2. Drug Food
    • 3. Drug-Disease
  43. Drugs with Potential Adverse Effects --> Additive
    • 1. Anticholinergics 
    • 2. Anticoagulant and Antiplatelet agents
    • 3. Drugs that prolong QT interval (Torsades risk)
    • 4. CNS depressents
    • 5. Negative inotropic and chronotropic drugs
    • 6. Sertonergic agents
  44. Anticholinergics classified by risk
    • 3 points --> amitriptyline, chlorpheniramine, diphenhydramine, hydroxyzine, Oxybutinin
    • 2 points --> Cetirizine, Loratidine, Olanzapine, Tolterodine
    • 1 point --> Mirtazapine, Paraxetine, Quetiapine, Risperidone
  45. Drugs causing prolonged QT interval (TdP) + Risk Factor
    See slide 7. 

    Risk factors --> use of drugs known to prolong QT in combination, advanced age, use of CYP 450 inhibitors, hypokalemia, hypomagnesemia, bradyacardia, CAD, LV hypertrophy or dysfunction
  46. Central Nervous System Depressants Risks and Drugs
    Drugs --> Antiepileptics (used often for non-seizure indications), antihistamines (1st generation OTC), Antidepressants, Benzodiazepinse, Hypnotic agents, Opiates, Barbituates, EtOH

    Risks --> increase in falls, driving accidents, and respiratory failure
  47. Serotonin syndrome
    Drugs --> All antidepressants (except bupropion), buspirone, dextromethorphan, Levodopa, Lithium, Meperidine, Ondansetron, Tramadol, Triptans

    Result of combining drugs that increase serotonin levels

    Sx --> agitation, diaphoresis, diarrhea, fever, hyperreflexia, incoordination, mental status changes, myoclonus, shivering, tremor --> can be fatal if agents are no discontinued
  48. Antagonistic Pharmacodynamic drug interactions
    Ex --> Acetylcholinesterase inhibitors and anticholinergic agents, antipsychotics and parkinsonian drugs, Ibuprofen plus aspirin (decreased antiplatelet effects of ASA), NSAID +ACEI or ARBs, oral bisphosphanates + PPIs
  49. Pharmacokinetic Interactions
    • 1. Absorption --> Ex: Fluoroquinolones + cation containing drugs, Levodopa/Carbidopa + iron, phenytoin + calcium, etc. 
    • 2. Excretion --> Probenicid and PCNs, Lithium and diuretics, Methotrexate and NSAIDs
    • 3. Metabolic --> most common type of drug-drug interactions,usually involve CYP 450 or P-glycoprotein system, drugs may induce or inhibit metabolism of another drug
  50. CYP 450
    • 1. Function --> Phase I oxidative reactions, Synthesis and degredation or many endogenous substances such as steroids, lipids, and vitamins, metabolism and inactivation of many drugs nutrients and environmental toxins
    • 2. Nomenclature --> CYP 1A2--> CYP=Cytochrome P450 family, 1=family A=subfamily 2=individual enzyme
    • 3. Primarily in the liver but also in intestinal lining, 50+ identified so far

    5 main CYP 450 enzymes --> CYP 1A2, 2C9, 2C19, 2D6, 3A4

    Be able to recognize or identify P450 substrate, P450 substrate as a prodrug, inducers, and inhibitors
  51. CYP 450 Substrates
    Drug or substance metabolized by the CYP 450 enzyme, may be metabolized by one or several enzymes

    Clinically significant substrate drugs: have a narrow therapeutic index and/or are inactivated or eliminated by only one P450 enzyme

    • Significant CYP450 Substrate drugs
    • 1A2--> Caffeine, Clozapine, Lanzapine, Theophylline
    • 2C9--> Glipizide, Nateglinide, S-Wafarin
    • 2C19 -->  Clopidogrel, phenytoin
    • 2D6 --> Atomoxetine, Carvedilol, haloperidol, hydrocodone, metoprolol, tomoxifen, TCAs
    • 3A4 --> Alprazolam, Amiodarone, CCBs, Cyclosprone, Ethinyl estradiol, Fentanyl, Methadone, midazolam, Oxycodone, Quetiapine, PIs, Repaglinide, Simvastatin
  52. CYP 450 Inducers
    MOA: bind to regulatory gene of CYPE gene to upregulate DNA transcription -->Increase CYP 450 metabolism leading to increase in metabolism of substrate

    Onset of effect may be delayed by 2-3 wks
    , once discontinued reversal of effect also delayed

    Usually effect multiple CYP enzymes, drugs can be both inducers and inhibitors, drugs can be both substrates and inducers

    For a chart on CYP inducers see slide 26
  53. NNRTIs and Drug interactions
    • 1. Nevirapine --> modest inducer of CYP3A4, may precipitate withdrawal in methadone maintenance patients
    • 2. Efavirenz --> modest inducer of CYP3A4
    • 3. Etravirine--> modest inducer of CYP3A4, Inhibitor of CYP2C9 and 2C19
    • 4. Delavirdine (rarely used) --> strong inhibitor of CYP3A
  54. Rifampin as A CYP Inducer
    Rifampin induces CYP3A4 which is known to participate in phase 1 metabolism of ethinyl Estradiaol birth control, decrease AUC by 68%

    Rifampin induces metabolism of somatostatin
  55. CYP Inhibitors
    • 1. Decrease CYP450 activity to decrease in metabolism of substrate
    •     --> decrease clearance and increase concentration of substrate drug
    •     --> Reactive metabolite of inhibitor inactivates p450
    •     --> Onset is usually immediate

    Potency determined by in vitro K1 (concentration necessary to decrease the metabolism of a substrate drug 2-fold) and plasma concentration of the inhibitor. 

    A drug can be both an inhibitor and substrate resulting in non-linear drug accumulation

    Many drugs (ex. Terfenadine) removed from market due to fatal inhibition of CYP450
  56. Commonly prescribed strong CYP450 inhibitors
    • 1A2 --> Fluvoxamine
    • 2C9 --> Fluconazole
    • 2C19 --> Fluvoxamine, Isoniazid, Lansoprazole, Omeprazole
    • 2D6 --> Bupropion, Fluoxetine, Paroxetine, Quinidine, Terbinafine
    • 3A4 --> Clarithromycin, Grapefruit, Isoniazid, Itraconazole, Ketocoazole, Nefazodone, Protease inhibitors
  57. Protease inhibitors and drug interactions
    • 1. All PIs are metabolized by, and inhibit, CYP3A4
    • 2. Ritonavir is the most potent. Used to boost drug levels of other PI drug agents thus reducing #tablets/day
  58. Commonly prescribed moderate CYP inhibitors
    • 1A2 --> Cemetidine, Ciprofloxacin, Fluoxetine
    • 2C9 --> Amiodarone, Fluoxetine, Metronidazole, TMP-SMX
    • 2C19 --> Cimetidine
    • 2D6 --> Amiodarone, Depenhydramine, Duloxetine, Sertraline
    • 3A4 --> Amiodarone, Cemetidine, Diltiazem, Erythromycin, Fluconozole, Fluoxetine, Verapamil
  59. CYP450 Substrate Drugs to worry about
    • 1A2 --> Caffeine Clozapine, Olanzapine, Theophylline
    • 2C9 --> Glipizide, Nateglinide, S-Wafarin
    • 2C19 --> S-Wafarin
    • 2C19 --> Atomoxetine, Carvedilol, Haloperidol, Hydrocodone, Metoprolol, Tamoxifen, TCAs
    • 3A4 --> Alprazolam, Amiodarone, CCBs, Cyclosporine, Ethinyl estradiol, Fentanyl, Methadone, Midazolam, Oxycodone, Quetiapine, PIs, Repaglinide, Simvastatin

    Commonly prescribed, have narrow TI, and or depend on one CYP450 for metabolism
  60. Examples of CYP drug interactions
    • 1. Itraconazole and Ketoconazole significantly effect PK of midazolam and psychomotor function
    • 2. Erythromycin and Cyclosporine
    • 3. Voriconazole inhibits phenytoin metabolism and phenytoin induces voriconazole metabolism --> phenytoin toxicity or antifungal failure
  61. Intestinal CYP3A4 and Grapefruit drug interactions
    CYP3A4 in intestinal epithelial cells (pre-portal vein metabolism of toxins) --> inhibition of CYP3A4  increases plasma concentration of substrate but not half life--> Grapefruit juice irreversible inhibitor of 3A4 and intestinal level --> 100-300% increase in 3A4 substrates
  62. P-Glycoprotein Drug Tranpsorters
    P-gp --> efflux transporter that takes drug molecules from enterocyte and transports them back into intestinal lumen for excretion. Transports many drugs that are CYP3A4 substrates --> act together as barriers to systemic absorption of many compounds including drugs --> many CYP 3A4 also inhibit P-gp

    For a list of substrates, inducers and inhibitors see slide 54
  63. CYP450 Prodrug Substrates
    • Metabolite is the primary active compound. 
    •     Inhibition of substrate --> Therapeutic failure
    •      Induction of substrate --> Excessive defect

    • Examples: 
    • 1. Clopidogrel + 2C19 inhibitor --> increase risk of thrombosis
    • 2. Tamoxifen + 2D6 inhibitor --> increase risk of breast cancer
    • 3. Hydrocodone + 2D6 inhibitor --> Less pain relief
  64. Factors that increase potential for clinically significant CYP450 drug/drug interaction
    • 1. Potent inhibitor or inducer prescribed
    • 2. Substrate with narrow TI
    • 3. Substrate dependent primarily on one CYP450 enzyme for metabolism
    • 4. High dose of substrate drug before addition of interacting drug
    • 5. High dose of inhibitor or inducer
    • 6. Elderly and/or chronic disease
    • 7. Reduced hepatic function
  65. Types of Parasitic Infections
    • 1. Endoparasites ---> in lumen, tissue, or blood
    •       a. protozoa
    •       b. Helminths (worms
    • 2. Ectoparasites --> live on skin and hair shafts 
    •       a. lice and scabies
  66. Drug Therapy for Malaria
    • Sporozites not affected by drug --> target schizonts and merozoites in liver and RBCs
    • - Primaquine only drug able to eradicae tissue plasmodia
    • - Cloroquine prevents replication in RBCs

    • Three forms of therapy
    • 1. Suppressive Therapy (prophylaxis) --> for travelers, dependent on region
    • 2. Treatment of acute attack --> drug depend on type of malaria
    • 3. Prevention of relapse (radical cure) --> only after patient leaves endemic area

    Diagnosis must be confirmed before treatment. Diagnosis must be species specific. Consider clinical status of patient and geographic area of infection
  67. Chloroquine
    For chloroquine sensitive plasmodia only

    • Prophylaxis --> 500 mg 1/wk starting 1-2 wks before travel
    • Treatment --> 1 gm, then 500 mg at 6,24, and 48 hrs

    Adverse effects --> nausea, abdominal pain, headache, visual disturbances
  68. Quinine Sulfate
    • *Toxicity* 
    • MOA: blocks erythropoeitic replication
    • 1st line agent for chloroquine resistant strains
    • Short T1/2 and immediate onset
    • Dose: 650 mg TID for 3-7 days
    • Often used in combo with doxycycline, tretracycline, or clindamycin for 3-7 days depending on region

    Adverse effects --> cinchonism, GI Sx, hypoglycemia, blackwater fever (possible hypersensitivty, massive hemolysis, hemoglobinemia, and hemoglobinurias

    Gin and tonic doesn't work for malaria. Generic quinine capsules cost: $6/capsule
  69. Quinidine Gluconate
    MOA: Blocks erythrocytic reproduction of schizonts. Stereoisomer of quinine

    Drug of choice for sever, life threatening malaria

    Dose: Only parenteral antimalarial drug. Give with doxycycline etc like quinine

    Drug interactions: Inhibitor of CYP 2D6

    Adverse effects: Proarrhythmic (Class 1a antiarrhythmic), others are same as quinine
  70. Malarone
    MOA: Combination of atovaquone and proguanil. Blocks erythrocytic stage 

    Use: 1st line for prophylaxis and treatment of chloroquine resistant plasmodia. Effective for primary liver stage of P. falciparum

    Dose: Single dose with meals for 3 days

    Adverse effects: N/V, rash, and HA
  71. Coartem
    MOA: combination of artemether and lumefantrine 

    Use: 1st line agent for Tx of chloroquine resistant plasmodia

    Dose: BID with meals for 3 days

    Adverse effects: N/V, HA, dizziness, weakness, can prolong QT

    Drug interactions: Avoid CYP 3A4 inhibitor drugs
  72. Doxycycline
    Use: Alternative for prophylaxis against chloroquine resistant strains

    Dose: 100 mg QD 1-2 days before travel
  73. Mefloquine
    MOA: block erythrocytic stage. Chemically related to quinine

    Use: prophylaxis and treatment of chloroquine resistant strains. 2nd line agent

    Dose: 1/week prophylaxis (T1/2 of 20 days)

    Adverse effects: neuropsychiatric syndrome

    Drug interactions: quinine and beta blockers can lead to cardiac arrest
  74. Primaquine
    MOA: Extra-erythrocytic stage

    Use: Only drug for prevention of relapse from P. vivax and P. ovale infections

    Dose: 15 mg/day x 14 days, used with chloroquine or quinine

    Adverse effects: abdominal cramps, nausea, hemolytic anemia with G6PD deficiency (screen before use)
  75. G6PD Deficiency
    • 1. Most common inborn error of metabolism
    • 2. More sever in males
    • 3. Sensitivity to primaquine, quinine, sulfonamides, nitrofurantoin, phenazopyridine, aspirin, and quinolones
    • 4. Hemolytic anemia by day 3 of drug therapy
  76. Amebiasis and Drug treatment
    1. 10% of population w/ Entamoeba histolytica (10000 deaths anually) --> ingest cysts in contaminated food and water --> ulceration of bowel and amebic dysentry, liver abscesses

    2. Luminal Amebicides --> poory absorbed drugs used to treat asymptomatic disease (Idoquinol, Paromycin) 

    3. Tissue amebicides --> drugs of choice for invasive disease (Metronidazole, Tinidazole)
  77. Metronidazole
    MOA: converted to toxic nitro radical by anerobic bacteria and protozoans, results in cell death by DNA destruction 

    Dose: 750 mg po TIDx10 days. PO and IV

    Use: protozoa causing amebiasis, giardiasis, trichomoniasis. Also active against most bacteria

    Adverse effects: Contraindicated during 1st trimester of pregnancy. Category B  for 2nd and 3rd trimester. Nausea, HA, dry mouth, metallic taste

    Drug interactions: Wafarin (increased INR), Ethanol (acetaldehyde poisoning) must caution against drinking
  78. Tinidazole
    MOA: 2nd generation nitroimidazole. Same mechanism as metronidazole but is active against some resistant strains of trichomonas, and has a longer half life

    Use: Single dose against Giardia

    Adverse effects: same as metronidazole, Pregnancy category C
  79. Giardiasis
    • 1. Acute and Chronic Diarrhea secondary to giardia lamblia, infection from contaminated water
    • 2. Treat with metronidzole 250 mg TID x 7 days, Tinidazole single dose of 2 gm
  80. Trichomoniasis
    • 1. STD due to trichomonas vaginalis
    • 2. Treatment: metronidazole or tinidazole 2 gm x 1 dose
  81. Toxoplasmosis
    • 1. Toxoplasma gondii infection in immunocompromised patients such as with AIDS
    • 2. Treatmentpyrimethamine and sulfadiazine (potent inhibitors of dyhydrofolate reductase, must add daily folinic acid to prevent anemia)
  82. Helminthic Infections
    • 1. Nematodes (roundworms) 
    • 2. Trematodes (flukes) --> shistosomiasis and liver flukes
    • 3. Cestatodes (Tapeworms)
  83. Albendazole
    MOA: inhibits microtubule function and depletes glycogen leading to worm death. Poorly absorbed. Drug of choice for nematodes. FDA approved for tapeworms

    Dose: 100 mg once then repeat in 2 weeks. 

    Adverse effects: avoid during 1st trimester of pregnancy

    Mebendazole (similar drug) no longer available due to limited market
  84. Pyrantel pamoate
    OTC product for nematode infections 

    MOA: depolarizing neuromusc. blocking agent leading to paralysis of helminths

    Adverse effects: GI upset, HA, fever

    Dose: Single dose of 11 mg/kg, repeated in 2 weeks

    Avoid during pregnancy
  85. Praziquantel (Biltricide)
    MOA: For schistosomiasis, flukes, and tapeworms --> increases cell membrane permeability 

    Adverse effects: malaise, HA, dizziness, and drowsiness

    Dose: 20 mg/kg/dose BID-TID x 1 day. Advise patients to swallow whole and avoid driving for 2 days. Single or divided does depending on GI tolerance
  86. Pediculosis (lice) and Scabies
    • Pediculus humanus capitis (head lice) 
    • P. humanus (body lice
    • Phthrius pubis (crab lice) 

    Spread by direct contact, crowded living, infrequent washing. Nyphs hatch and grow and feed on blood --> itching

    Scabies: Sarcoptes scabei. Burrows into skin of host and lays eggs which hatch into larvae. Gravid females continue to burrow into new areas causing a dermatitis with intense itching, excoriations, and erythematous papules

    Drug treatment is pediculocidal but not ovacidal
  87. Pyrethrin and permethrin
    Pyrethrin --> extract of chrysanthemum flower used in some combination OTC products such as RID. 

    Permethrin --> drug of choice for lice and scabies. 

    synthetic derviative of pyrethrin. Acts on nerve cell membrane to paralyze ectoparasites. 

    Dose: OTC 1% liquid rinse for head lice. One time application must remove nits afterwards. 2nd application in 7-9 days. 5% cream for scabies 

    Safe for kids and pregnant women. Resistance is becoming widespread
  88. Spinosad and Invermectin
    Use: Permethin resistance lice and scabies

    Spinosad 0.9% suspension --> new Rx product approved by the FDA in 2011 for head lice in patients older than 4 yo. 

    Invermectin 0.5% lotion --> Rx product just approved as single use topical Tx in patients older than 6 mo. 

    Drug cost --> VERY EXPENSIVE compared to OTC
  89. Lindane 1%
    Can be absorbed and cause neurologic toxicity

    Available OTC as lotion or shampoo

    Should avoid in young kids, during pregnancy, and with any concurrent skin inflammation that can lead to increased absorption

  90. Crotamiton 10%
    Cream and lotion for scabies only