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Street Drugs and the Immune System

Street Drugs and the Immune System. Ronald D. Wilcox MD FAAP Principal Investigator / Program Director, Delta AETC Asst Professor Internal Medicine and Pediatrics, LSUHSC. www.deltaaetc.org. 504-903-0788. Definitions.

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Street Drugs and the Immune System

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  1. Street Drugs and the Immune System Ronald D. Wilcox MD FAAP Principal Investigator / Program Director, Delta AETC Asst Professor Internal Medicine and Pediatrics, LSUHSC

  2. www.deltaaetc.org 504-903-0788

  3. Definitions • Chemokine – a glycoprotein which activates leukocytes or chemotactic activity • Examples: CXCR4, CCR5 • Cytokine – a small protein released by cells that has a specific effect on the interactions between cells, on communications between cells, or on the behavior of cells • Examples: interleukins, lymphokines

  4. Drugs reviewed: Alcohol Marijuana Methamphetamines MDMA Cocaine Opiates Topics for each drug Effects on sexual behavior Effects on the body Effects on the immune system Effects in the setting of HIV Effects on adherence to HAART Topics

  5. Alcohol and Sexual Behavior • FL HBCU (n=1330) • Alcohol use most strongly found association for unprotected sex within the preceding month and consistent risky sexual behavior • African-American male survey • Did not identify as gay or bisexual • Alcohol use and tranquilizer use more common when having sex with other men, especially unprotected Trepka MJ et al. High-risk sexual behavior among students of a minority-serving university in a community with a high HIV/AIDS prevalence.J Am Coll Health 2008 Jul-Aug;57(1):77-84. Harawa NT et al. Sexual behavior, sexual identity, and substance abuse among low-income bisexual and non-gay-identifying African American men who have sex with men. Arch Sex Behav 2008 Oct;37(5):748-62.

  6. Alcohol and Sexual Behavior • Kenya • Male commercial sex workers – more likely to have unprotected sex with clients when taking alcohol • South Africa • 6 week survey of known HIV+ people who drank moderately or heavy • 80.17% of sexual acts unprotected • 58% of these with HIV-negative or HIV-unknown partners Geibel S et al. Factors associated with self-reported unprotected anal sex among male sex workers in Mombasa, Kenya. Sex Transm Dis 2008 Aug;35(8):746-52. Kiene SM et al. High Rates of Unprotected Sex Occurring Among HIV-Positive Individuals in a Daily Diary Study in South Africa: the Role of Alcohol Use. J Acquir Immune Defic Syndr. 2008 Oct 1;49(2):219-26.

  7. Alcohol • Increases cytokine activity and levels, esp with chronic use • Lung – increased expression of transforming growth factor beta (TGF-beta) leading to respiratory distress syndrome • Liver – increases T-helper 1 (pro-inflammatory) activity leading to increases in tumor necrosis factor alpha (TNF-alpha), increasing fibrosis • Brain – cytokines felt to likely contribute to long-term changes in behavior and neurodegeneration • Augments intracellular survival of MAC

  8. Alcohol effects on immune system • Poonia: • SIV viral loads significantly elevated in rhesus monkeys consuming alcohol • Central memory CD4 counts found to be significantly depleted in the intestines and mesenteric lymph nodes in the alcoholic monkeys 8 weeks after infection with SIV • Marcondes: • Decrease in circulating CD4+ cells and increase in CCR5-expression Poonia B et al. JAIDS 2006 Apr 15;41(5):537-47 Marcondes MC et al. Chronic alcohol consumption generates a vulnerable immune environment during early SIV infection in rhesus macaques. Alcohol Clin Exp Res. 2008 Sep;32(9):1583-92. Epub 2008 Jul 9.

  9. Alcohol and Adherence • 272 HIV+ patients interviewed daily x 14 days • Days alcohol consumed: 9 times more likely to miss a dose of their HIV meds • Each drink increased odds by 20% • 3000 VS patients in New England • 2 drinks daily in HIV-infected versus 4 drinks daily in HIV-negative affected medication adherence Parsons JT et al. The Temporal Relationship Between Alcohol Consumption and HIV-Medication Adherence: a Multilevel Model of Direct and Moderating Effects. Health Psychol 2008 Sept;27(5):628-37. Braithwaite RS et al. Adjusting alcohol quantity for mean consumption and intoxication threshold improves prediction of nonadherence in HIV patients and HIV-negative controls. Alcohol Clin Exp Res 2008 Sep;32(9):1645-51.

  10. Marijuana and Sexual Activity • Stephens TT, Sprauve NE. Int J STD AIDS 2006 Jul;17(7):463-6 • Collected data from male prisoners from 2000-2003 • No variance in feeling like they would be less likely to use precautions after using marijuana • Those that had anal sex felt they were “better lovers” while using marijuana • More likely to have anal sex if under the influence of marijuana than those who were sober (p<0.03)

  11. MJ and Immunity • Heavy use suppresses lymphocyte proliferation in culture • Serum IgG levels decreased, IgE levels increased • Alveolar macrophages from MJ smokers shown to be deficient in phagocytosis and bactericidal activity

  12. Marijuana and HIV • Cristiani SA et al. J Neuropsychiatry Clin Neurosci 2004 Summer;16(3):330-5 • Examined interaction of HIV disease-stage and marijuana use in 282 subjects • After controlling for effects of depression, anxiety, and alcohol use: • Significant decrease in ability to perform memory tasks, esp in those with symptomatic HIV – NOT seen previously in those without HIV

  13. Marijuana and HIV • Abrams DI et al. Ann Intern Med 2003 Aug 19;139(4):258-66 • Randomized placebo-controlled 21 day trial in San Francisco; n = 67 • Assigned to smoke a marijuana cigarette or take a dronabinol 2.5 mg or a placebo three times daily before meals • Measured HIV RNA, CD4 cells, CD8 cells, and pharmacokinetics of PIs • No effects seen by the groups who smoked MJ or those that took dronabinol

  14. THC and HIV • Roth MD et al. Life Sci 2005 Aug 19;77(14):1711-22 • Human peripheral blood leukocytes were implanted in mice with SCID and infected with an HIV reporter construct in presence and absence of THC • Administration of THC alone decreased CD4 counts and the CD4:CD8 ratio • Administration of THC with HIV did not reduce CD4 counts further but increased % of cells infected by HIV as compared to saline-treated animals • Viral load increased 50 fold in those with THC • THC increased CCR5 and CXCR4 presentation early but lost this effect by 10 days • Both THC and HIV decreased the number of IFN-gamma producing cells with additive effects seen

  15. THC and adherence • Wilson KJ, Doxanakis A, Fairley CK. Predictors for non-adherence to antiretroviral therapy. Sex Health. 2004;1(4):251-7 • Melbourne, Australia. N=200 • Marijuana use 4 or more days per week associated with inadherence to ART • de Jong BC, Prentiss D, McFarland W et al. Marijuana use and its association with adherence to antiretroviral therapy among HIV-infected persons with moderate to severe nausea. • Those who used MJ for nausea  no change in adherence • Those who used MJ for other purposes  inadherence

  16. Meth Use and Unprotected Anal Sex • Mansergh G et al. Sex Transm Inf 2006 Apr;82(2):131-4 • Cross sectional community based survey of MSM in SF regarding sexual behavior during most recent anal sex encounter • N = 388 - Diverse in race, ethnicity, age, income, education, HIV status, and homosexual/bisexual identification • 29% reported unprotected insertive AS and 37% reported unprotected receptive AS* • Methamphetamine use reported by 15% and sildenafil use reported by 6%; 2% both • Multivariate analysis • Meth use with unprotected receptive (OR 2.03, CI 1.09 – 3.76) • Sildenafil use with unprotected insertive (OR 6.51, CI 2.46 – 17.24) *12% insertive and 17% receptive with discordant or unknown status partner

  17. Meth Use Among Heterosexual Men and HIV Risk Behaviors • MMWR 2006 Mar 17;55(10):273-7 • CA Dept of Health Services, Office of AIDS, analyzed population-based data from 5 northern CA counties in the HEY-Men (Health Evaluation in Young Men) Study • Recent meth use among heterosexual men was associated with increased incidence of: • Sex with casual or anonymous female partners • Anal intercourse • Sex with an IVDU

  18. Methamphetamine and HIV in MSM: A time-to-response association?

  19. Methamphetamine • Types: white, yellow, orange, pink or light brown crystalline powder or clear chunks resembling ice • Common names: Chalk, Crystal, Ice, Meth, Rock Candy, Speed, Tina, Tweek, Quartz • Class of drug: CNS stimulant, sympathomimetic, appetite stimulant • Routes of administration: • Snorted – effects in 3-5 minutes • Ingested – effects in 20-30 minutes • Smoked – effects in 7-10 seconds • Injected – effects in 15-30 seconds • “Booty bumped” – effects in 15-30 seconds

  20. Methamphetamine • Pharmacology • Increases synaptic levels of dopamine, serotonin, and norepinephrine • Alpha and beta agonist effects • Stimulant effects similar to cocaine but slower and longer acting • Peak concentrations after oral ingestion 2.6 – 3.6 hours with mean half-life 10 hours

  21. Methamphetamine • Physical effects: • Increases heart rate, BP, perspiration • Urinary retention, dry mouth, dilated pupils, decreased appetite • Addiction occurs quickly • Morbidity: irritability, hypothermia, insomnia, aggressiveness, paranoia, anxiety, strokes, heart attacks, Parkinson-like syndrome with chronic use, “crystal dick” • Psychological effects: • “rush” or “flash” very pleasurable but short lived • Oral or nasal use produces high but not rush • Hypersexuality, euphoria, lowering of sexual inhibitions, boredom, loneliness, increased self-esteem and confidence

  22. Methylenedioxymethamphetamine (MDMA) • Types: white, tan, or brown powder. Mainly available as tablets • Common names: Ecstasy, Adam, Candy Canes, Disco Biscuit, Doves, E, Eckie, Essence, Hug Drug, Love Drug, M&M, Rolls, White Doves, X, XTC • Class of Drugs: Mild CNS Stimulant, hallucinogenic, psychedelic • Routes administered: • Usually orally but may be dissolved and injected or crushed and snorted • Pharmacology: • Causes marked depletion of serotonin • “Suicide Tuesday” • Rapidly absorbed with half-life 7 hours

  23. Methylenedioxymethamphetamine (MDMA) • Physical Effects: • High doses: hyperthermia, possibly liver or kidney or cardiovascular failure • Low to moderate doses: muscle tension, involuntary jaw clenching, nausea, blurred vision, dilated pupils, faintness, chills, sweating, tachycardia, hypertension • Psychological effects: • High doses: agitation, panic, depression, confusion, sleep problems, hallucinations • Low to moderate doses: increased relaxation, euphoria, feelings of well-being, heightened sensitivity, changes in perception, empathy, dis-inhibition

  24. Cerebral Morphology • HIV • damages cerebral white matter and striatal gray matter • Also seen to decrease volume of thalamus, hippocampus, and cerebral cortex (frontal, temporal) • MDMA • temporal lobe shrinkage as well as decreases in gray matter of the cingulate and other limbic cortices lateralized to the right hemisphere; also have seen volume reduction in the hippocampal volume bilaterally. • Hypertrophy of cerebral white matter

  25. Yellow – MA Red – HIV Orange – MA + HIV Jernigan et al. Am J Psychiatry 162:8, August 2005, pp. 1461-72

  26. Cocaine and Crack • Types: • Cocaine – white to light brown powder • Crack – white to beige flaky solid chunks • Common names for cocaine: Coke, Snow, Flake, Blow, Cane, Dust, Shake, Toot, Nose Candy, White Lady • Common Names for crack: Rock, Freebase • Class of Drugs: CNS stimulant, local anesthetic • Routes of administration: Injected, snorted, smoked

  27. Cocaine and Crack • Pharmacology • Rapidly absorbed • Blocks uptake of dopamine, norepinephrine, and serotonin, resulting in euphoric “rush” • “Rush” lasts 5-10 minutes from smoking, 15-30 minutes from snorting

  28. Cocaine and Crack • Physical and Psychological Effects: • Increased BP, temperature, heart rate • Dilated pupils • Euphoric effects: hyperstimulation, reduced fatigue, mental clarity • May cause restlessness, irritability, anxiety • Major complications: arrhythmias, acute coronary spasm, chest pain, stroke, seizure

  29. Cocaine • Decreases mitogen-induced T-lymphocyte proliferation in rats following IV administration • Increases HIV infection of human PBMCs in vitro • Human PBMCs implanted in SCID mice showed cocaine treatment increased number of HIV-infected PBMC and viral load as well as decreased the CD4/CD8 ratio

  30. Stimulant Use and Adherence • HIV-traumatic stress associated with increased cocaine use and decreased adherence • Numerous studies have shown that ongoing cocaine use is one of the strongest predictors for inadherence to HAART. • Methamphetamine and MDMA use associated with inadherence during use  4-fold increase incidence

  31. Heroin • Three types • China White • Black Tar • Synthetic • Common Names: Smack, H, Skag, Silk, Horse, Junk, Bags, Blue-Steel, China White, P-Dope • Class of Drugs: opiate • Routes administered: • Injected (IV / mainlining or SQ / skin popping) • Smoked • Snorted

  32. Heroin • Sometimes is cut with inert or toxic adulterants: • Sugars • Starch • Powdered milk • Quinine • Meat tenderizer • Ketamine • Talc • Speedball: mixture of heroin with either cocaine or methamphetamine

  33. Heroin • Pharmacology: • Very short half life ( <30 minutes) due to rapid metabolism to active opiate • Narrow therapeutic index • High physical and psychological dependence • Tolerance requires increasing doses

  34. Heroin • Physical effects: • Respiratory depression, CNS depression, analgesia, reduced GI motility, overdose • Withdrawal within 6-12 hours, lasting 5-10 days • Psychological effects: • Rapid, intense feeling of euphoria, alternating between wakeful and drowsy states • Feeling of well-being, relaxation, sedation, lethargy, disconnectedness, self-absorption, mental clouding, delirium

  35. Opiate effects on immunity • Opioid receptors have been demonstrated on immune cells • Infectious complications and progression of HIV disease decreased in IVDUs who quit use • In vitro studies have noted decreased phagocytosis, chemotaxis, and cytokine and chemokine production when opiates present • Alters hypothalamus-pituitary-adrenal (HPA) axis, leading to alteration in glucocorticoid levels. Glucocorticoids play an important role in decreasing and regulating cellular immune responses

  36. HAART and EtOH • Abacavir and EtOH • Both use alcohol dehydrogenase for metabolism • Increase levels of ABC by 41% • Acute EtOH induces CYP2D6 and 2C19, chronic use induces CYP2E1 and 3A4 • OCP, PI, NNRTI, statin levels can all be low

  37. HAART and Benzodiazepines • Ritonavir acts as both an inducer and inhibitor of CYP3A4 • Triazolobenzodiazepines (Versed, Halcion, Xanax) – dependent on CYP3A4 for metabolism • Levels initially increased with RTV and then decreased with continued use • Flunitrazepam (Rohypnol) – when use with ritonavir, paroxetine, or nefazodone may have toxicity

  38. HAART and Cocaine • N-demethylation results in active, hepatotoxic metabolite norcocaine – primarily performed at CYP 3A4 • Levels may be increased by some ART use, esp ritonavir, indinavir, efavirenz • Potential for overdose when co-administered, leading possibly to rhabdomyolysis, arrhythmia, cardiovascular collapse

  39. HAART and GHB (Liquid X) • Up to 50% of MSM with HIV have history of use • First pass metabolism is mediated by cytochrome P450 system • Case: HIV+ man recently began HAART including RTV + SQV – took MDMA (Ecstasy) then took a small dose of GHB to counteract the extended effects of the MDMA – within 20 minutes became unresponsive with HR 40 and required intubation.

  40. HAART and Special K • Ketamine – a derivative of PCP • Metabolized by CYP2B6 primarily but also somewhat by CYP3A4 and 2C9 • Animal data suggest ketamine may inhibit CYP3A4, leading to increased PI levels and possible toxicity

  41. HAART and LSD (Acid) • Metabolism not completely understood • No known interactions with HAART

  42. HAART and MDMA (Ecstasy), methamphetamine, and amphetamine • Metabolized primarily via CYP2D6 but also by 1A2, 2B6, and 3A4 • Case: HIV + male recently started on HAART regimen including ritonavir took 180 mg MDMA. Within hours became tachypneic, tachycardic, hyperthermic, had a generalized seizure, and died. • Potent inhibitors of CYP2D6 include ritonavir, bupropion, fluoxetine, paroxetine, and quinidine

  43. HAART and Opiates • Fentanyl • may have increased levels when given with RTV, EFV, DLV • Meperidine • may have increased levels with inhibitors or decreased levels with inducers • Methadone • Withdrawal may occur with LPV/r, RTV, NVP, EFV • Increased levels seen with nRTIs • Heroin / morphine / codeine • Levels decreased with UGT inhibition (ATV, IND)

  44. HAART and PCP • Metabolized primarily by CYP 3A4 • Potential for drug interactions with IND, RTV, EFV, ketoconazole, nefazodone • No documented case reports of significant interaction though

  45. HAART and MJ • Metabolized by CYP 3A4 • No change in PI levels seen in studies but metabolism of THC slowed down.

  46. Take-Home Points • EtOH – • 2 drinks/day in HIV+ patients shown to interfere with medication adherence • May have subtherapeutic levels of PIs and NNRTIs • MJ – • May increase number of cells infected and lower CD4 counts • Increased short-term memory loss in HIV+ • MA / MDMA • Increases “risky” sexual behavior • Increases neurologic damage • May overdose with “standard” dosage after starting HAART

  47. Take Home Points • Cocaine – • May increase number of infected CD4 cells and HIV viral loads • May overdose if taking RTV, IND, EFV • Heroin / opiates – • May influence activity of immune cells • Drug interactions variable • May have withdrawal due to increased metabolism

  48. Contact Info • Rwilco@lsuhsc.edu • Office: 504-903-7301 • Pager: 504-363-1692 • Delta AETC: www.deltaaetc.org • 504-903-0788

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