Risky Cocktails, Risky Business

Drug Interactions between Recreational Drugs and HAART

Prepared by Patricia Martin, Pharm.D.

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

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.

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

PK Interactions
Absorption Distribution Metabolism Excretion

Piscitelli SC, Gallicano KD. N Engl J Med 2001;344:984-96

PD Interactions
Antagonistic
AZT + d4T

1+1=0

Synergistic

1+1=3

Hydroxyurea + NRTIs

Additive
Overlapping toxicities

1+1=2

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.

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

Cytochrome P450 Nomenclature

CYP 3A4
Specific enzyme Subfamily Family CYP Substrates GENE for mammalian cytochrome CYP Inducers CYP Inhibitors

Effect of Antiretrovirals on Drug Metabolism

Induced by:

3A4
Inhibited by: RTV Induced by: RTV, NFV

RTV, NFV, LPV, EFV, NVP, TPV

Inhibited by: RTV, NFV, IDV, APV, SQV, ATV, DLV Induced by: RTV, NFV

Inhibited by: EFV, DLV

2C19 2D6 2C9

Inhibited by: DLV, ATV

Induced by:

RTV, NFV ?

Induced by:

1A2 2E1 2A6 2B6 2C8

EFV, NVP

Inhibited by: ATV

Fichtenbaum.Clin Pharmacokinet.2002; Lafay et al. ICAAC 2003; Product inserts

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

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

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.

Drug Interactions (Liver)

CYP Substrate CYP Inhibitor

Substrate concentration

Toxicity

CYP Substrate CYP Inducer

Substrate concentration

Efficacy

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.

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, nearfatal 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 1998;352:17512.

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 nonnucleoside 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.

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.

Ecstasy HIV Program/Inner City Health, (X, MDMA) Recommendations from

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 Oct;36(10):1598-613.

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.

GHB,Liquid X
(GABA, -aminobutyric acid, date rape drug) 2D6 substrate GHB is potentially dangerous with ritonavir and other PIs. One man had serious lifethreatening 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 1999;159:22214.

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

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.

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.

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.

LSD (acid, blotters)

No known interactions.

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.

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.

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.

Mushrooms
(shrooms, boomers, psilocybin)

No known interactions.

Methylphenidate (Ritalin) (Ritalin

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

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.

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.

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.

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.

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 antiHIV 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.

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.

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

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

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

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.