Risky Cocktails, Risky Business

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Risky Cocktails, Risky Business Drug Interactions
between Recreational Drugs and HAART
Prepared by Patricia Martin, Pharm.D.
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HIV Therapy Today

• Combination therapy of at least three ARV drugs
• Medications to prevent or treat opportunistic
  infections
• Medications to treat comorbid conditions
• Medications to treat substance use
• Alternative/Herbal meds
• Investigational drugs

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Anti-HIV Medications Street Drugs

• For most drugs to be effective and not kill you,
  they need to be metabolized broken down by the
  liver or kidneys. These organs have limited
  resources and a set number of chemicals which
  accomplish this task. Because of this, certain
  drugs, whether they're HIV medications or
  recreational drugs, can affect how other drugs
  act.
• This is called a drug interaction and some of
  them can be deadly.

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Drug Interactions

• Occurs when either the pharmacokinetics or the
  pharmacodynamics of one drug is altered by the
  administration of food or a concomitant drug
• Factors that can exaggerate pharmacokinetic
  variability include
• drug-drug interactions
• drug-food interactions
• drug-disease interactions (altered GI, renal and
  hepatic function)
• Sex differences in patients
• Pregnancy
• Genetic differences in patients

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PK Interactions

• Absorption
• Distribution
• Metabolism
• Excretion

Piscitelli SC, Gallicano KD. N Engl J Med
2001344984-96
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PD Interactions

• Antagonistic 1 1 0
• AZT d4T
• Synergistic 1 1 3
• Hydroxyurea NRTIs
• Additive 1 1 2
• Overlapping toxicities

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Drug Interactions Related to the Metabolism of
HAART

• Medications used in HAART, especially the NNRTIs
  and PIs, are metabolized via the cytochrome P450
  enzyme system (CYP450)
• The isoenzyme responsible for the majority of
  this metabolism is CYP3A4, although 2C19 and 2D6
  are also common.

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Cytochrome P450 Enzymes

• Group of heme containing enzymes responsible for
  phase 1 oxidative metabolic reaction
• Family that detoxify compounds
• Absorbance of light at 450 nanometers (hence
  CYP450)
• On membranes of endoplasmic reticulum in liver,
  gut, brain, lung, kidney

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Cytochrome P450 Nomenclature
CYP 3A4
Specific enzyme
Subfamily
Family

• CYP Substrates
• CYP Inducers
• CYP Inhibitors

GENE for mammalian cytochrome
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Effect of Antiretroviralson Drug Metabolism
3A4
2C19
2D6
2C9
1A2
2E1
2A6
2B6
2C8
Inhibited by ATV
Fichtenbaum.Clin Pharmacokinet.2002 Lafay et al.
ICAAC 2003 Product inserts
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Medications that interact with the CYP450 system
do so in 1 of 3 ways

• Inhibition Generally leads to decreased rates
  of metabolism of other drugs metabolized by the
  same enzyme, resulting in higher drug levels and
  increased potential for toxicity.
• Inhibition is usually reversible, irreversible
  inhibition can occur, requiring new CYP450 enzyme
  to be synthesized.
• Inhibition tends to occur quickly with maximal
  effect occurring when highest concentrations of
  the inhibitor are reached.
• Example Ritonavir and Midazolam ? sedation

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Medications that interact with the CYP450 system
do so in 1 of 3 ways

• Induction results in the increased clearance of
  concomitant medications metabolized by the same
  enzyme.
• The body responds by increasing the production of
  specific enzymes of the CYP450 system.
• ? enzyme production can lead to ? metabolism and
  ? drug concentrations
• Example Efavirenz and methadone withdrawal
  symptoms

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Medications that interact with the CYP450 system
do so in 1 of 3 ways

• Substrates occupy the active site of a specific
  CYP450 enzyme.
• The medications metabolism is then affected by
  other medications that either induce or inhibit
  the CYP450 enzyme system.
• Example NNRTIs and PIs are substrates at CYP3A4
  and are therefore prone to drug interactions.

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Drug Interactions (Liver)
CYP Substrate
? Substrate concentration
? Toxicity
CYP Inhibitor
CYP Substrate
? Substrate concentration
? Efficacy
CYP Inducer
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Recreational Drugs and HAART

• There is very little data
• No controlled trials
• Information is largely extrapolated from in vitro
  PK experiments, case reports, or animal model
  studies.
• Best advice is to not use the two, however, if
  you have to party make sure you know which
  combinations to avoid.

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Ecstasy (X, MDMA)

• 2D6 substrate (1A2,2B6,3A4)
• Can be lethal. One case report in England
  described a fatal interaction between ritonavir
  at full dose and ecstasy (MDMA, X). Second,
  near-fatal reaction in a patients taking
  saquinavir/ritonavir (boosted dose) and a small
  dose of ecstasty. RTV ? Ecstasy levels by 5-10
  times.
• In addition, between 3-10 of the white
  population have a 2D6 deficiency, which may be
  why some people overdose on what may be a safe
  dose for others.
• Since the amount of X varies in each pill, it is
  difficult to know how much will put you in danger.

Source Henry JA, Hill IR. Fatal interaction
between ritonavir and MDMA. Lancet
199835217512.
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Ecstasy (X, MDMA)

• Clinicians should not prescribe PIs, even in low
  doses for boosting, if patients say they use
  ecstasy.
• Patients -If you are taking any protease
  inhibitor or non-nucleoside reverse transcriptase
  inhibitor X can be extremely dangerous.
• Of these, ritonavir and delavirdine seem to be
  the most dangerous, while nevirapine and
  efavirenz may be less soalthough effects are
  hard to predict.

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Ecstasy (X, MDMA)

• Recent research has found that X damages
  serotonin neurons, so avoid it if you have a
  family or personal history of depression or
  anxiety disorders.
• If you do take X with a protease inhibitor, wait
  as long as possible after taking the protease
  inhibitor to take the X, and be sure to have
  someone with you who knows what you've done in
  case you have difficulties. These overdoses are
  often not reversible, so it's really better not
  to mix these drugs!
• Taking X while on HAART may lead you to roll for
  much longer. Some people have reported rolling
  for 30 hours from two pills while taking
  ritonavir and saquinavir.

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Ecstasy (X, MDMA)
Recommendations from HIV Program/Inner City
Health, St. Michael's Hospital, Toronto, Canada.

• Use 25 of the usual amount of MDMA
• Take breaks from dancing

• Make sure rave or party has medical team on site
• Maintain adequate hydration by avoiding alcohol
  and replenishing fluids regularly

Source Antoniou T, Tseng AL. Interactions
between recreational drugs and antiretroviral
agents. Ann Pharmacother 2002 Oct36(10)1598-613.
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Amphetamines (dexedrine, amphetamine,
methamphetamine, crystal meth)

• Amphetamines work the same way that X does in
  your body. As with X, Norvir (ritonavir) should
  be avoided.
• Norvir is predicted to increase amphetamine
  levels in the blood by a factor of 2-3.
• The other protease inhibitors should have less of
  an impact, but strange opposite results are
  always possible.

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GHB,Liquid X(GABA, -aminobutyric acid, date
rape drug)

• 2D6 substrate
• GHB is potentially dangerous with ritonavir and
  other PIs.
• One man had serious life-threatening conditions
  after taking a small amount of GHB to come down
  from an X trip. He was on ritonavir and
  saquinavir at the time and had taken similar does
  of the rave drugs without problems in the past.

Source Harrington RD, Woodward JA, Hooton TM,
Horn JR. Life-threatening interactions between
HIV-1 protease inhibitors and the illicit drugs
MDMA and gamma-hydroxybutyrate. Arch Intern Med
199915922214.
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Alcohol

• Can reduce effectiveness of HARRT by reducing
  adherence.
• Can lead to hepatotoxicity either directly or
  indirectly by increasing the risk of drug-induced
  hepatotoxicity.
• Videx (ddI) can increase the risk of
  pancreatitis.
• Can ?AUC of abacavir by 41 and ?t1/2 by 26.
  Clinical significance?

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Alcohol

• Occasional and light use of alcohol is not known
  to interact with other HIV medications however,
  chronic, heavy use can be destructive to the
  liver.

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Marijuana

• 3A4,2C9,2C6 substrate
• Protease inhibitors may increase THC levels (the
  active ingredient in marijuana)let your patients
  know that smaller doses may make them more
  stoned. This is also true of the synthetic
  version (Marinol) used in the treatment of weight
  loss.

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Cocaine (coke, blow)

• There are no known interactions between cocaine
  and HIV medications, but in the test tube,
  cocaine doubles the speed at which the virus
  reproduces, meaning it may speed up how sick you
  get.
• EFV,NVP,RTV may ? hepatotoxic metabolite.

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LSD (acid, blotters)

• No known interactions.

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Ketamine (Special K, Kit Kat)

• When combined with Norvir, special K can lead to
  "chemical hepatitis," an unpleasant inflammation
  of the liver resulting in jaundice. A New York
  HIV doctor has seen two cases of it in patients
  on RTV. Both went away in several weeks.
• Weak inhibitor 2D1 and 3A4
• PIs likely to ? effect of Ketamine
• Norvir, Viracept and Sustiva are suspected to
  cause special K to build up in the body and lead
  to toxic shock.

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Amyl nitrite (Poppers)

• Glutathione is used by the liver to process amyl
  nitrite, and high glutathione is linked with
  survival. If using amyl nitrite cuts glutathione,
  it could lead to disease progression.

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PCP (angel dust, morning glory)

• Metabolized in the liver through oxidative
  hydroxylation, CYP3A4
• PIs, Rescriptor, and possibly Sustiva work in the
  same liver pathway that PCP is broken down in.
  Taking PCP while using these drugs may result in
  high PCP concentrations.

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Mushrooms(shrooms, boomers, psilocybin)

• No known interactions.

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Methylphenidate (Ritalin)

• Norvir and other similar drugs can either
  strengthen Ritalin's effects or make it weaker.
  Beware!

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Heroin (smack, brown, junk, China White)

• Norvir seems to reduce heroin levels by 50
  making overdose less likely. However, this drug
  and the other protease inhibitors have sometimes
  been known to have opposite effects (they cut
  methadone levels in real life, while test tube
  experiments predicted they would increase them),
  so caution is in order.
• Some synthetics sold as heroin (fentanyl,
  alpha-methyl-fentanyl) are potent in tiny doses
  and could be deadly if mixed with another drug.

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Sedatives

• The sedatives Halcion (triazolam), Valium
  (diazepam), Ambiem (zolpidem) and Versed
  (midazolam) can be deadly if mixed with PIs.
  Norvir has the largest negative effect. At high
  doses these drugs can stop your breathing.
• Ativan (lorazepam), Serax (oxazepam) and Restoril
  (temazepam) are safer with Norvir, and may
  actually be weakened by it since they are
  glucuronidated and norvir ? glucuronidation.

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Barbiturates

• Clinicians should avoid co-administration of
  NNRTIs and phenobarbital.
• Phenobarbital is a potent inducer of CYP3A4 and
  so are NNRTIs.
• Crixivan may increase blood levels of
  phenobarbital (Luminal), making overdose more
  likely. Other protease inhibitor interactions are
  also possible.

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Methadone (done)

• Interactions between methadone and NNRTIs and PIs
  are highly likely.
• Sustiva and Viramune strongly induce the
  metabolism of methadone (?AUC 52 and 46
  respectively)and may cause withdrawal in
  methadone pts.
• People on methadone maintenance may need higher
  doses of the opiate. Ritonavir, nelfinavir, and
  possibly Kaletra may cause similar problems.

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Methadone (done)

• Methadone increased the AUC of ZDV by 43 and
  can lead to toxicity. Patients should be
  monitored for toxicity (i.e. nausea, vomiting,
  headaches and low blood platelet levels).
• Methadone may decrease the anti-HIV action of
  Didanosine (AUC ? 63) while taking methadone.
  This could lead to resistance in the virus and
  the creation of more powerful strains of HIV.
  Using Videx EC is thought to allow the drugs to
  pass through the stomach without methadone
  weakening them.

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Buprenorphine

• Drug interaction data limited
• Metabolism was inhibited by PIs (RTV IDV
  SQV)
• Efavirenz has been shown to reduce buprenorphine
  plasma concentrations without precipitating
  withdrawal.

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Disulfiram/Naltrexone

• Published data limited
• Naltrexone not likely because it is not
  metabolized by CYP450
• Disulfiram while possible has not been documented.

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Management of drug interactions

• Familarity with ARV pathways
• Location of information
• Thorough medication history
• Maintain high index of suspicion when
• Decrease VL
• Side effects
• Consider TDM

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Websites Information about drug interactions

• www.foodmedinteractions.com
• www.hivatis.org
• hivinsite.ucsf.edu
• www.hopkins-aids.edu
• www.hiv-druginteractions.org
• medicine.iupui.edu/flockhart
• www.hivpharmacology.com
• www.aidsmeds.com

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Anti-HIV Medications Street Drugs

• Street drugs are often not what they are sold as,
  they are frequently cut with substances that may
  interact with drugs themselves and their potency
  can vary wildly, even in the same batch. With the
  lack of research in this area, it's better to
  avoid potential interactions if at all possible.