Drug News in Brief

Short takes on matters various.

Taking Aim at Pot—Researchers have recently made clinical efforts to test three drugs that might help during marijuana withdrawal to keep pot abstainers on the straight and narrow. Researchers at Columbia University, led by Margaret Haney, have been testing a synthetic THC compound called nabilone. The drug is designed to address sleep and appetite problems during withdrawal.  Whether it is any better tolerated by users than Marinol, Uncle Sam’s widely unpopular version of synthetic THC, remains to be seen. This approach can be viewed rather like methadone or buprenorphine substitution therapy. Meanwhile, work goes on with lofexidine, a drug sometimes used in combination with naltrexone for opiate detoxification. A 2008 study in Psychopharmacology showed a modest improvement over placebo when lofexidine was used for marijuana abstinence, but it worked much better when combined with, yes, synthetic THC. Finally, velafaxine, better known as the antidepressant Effexor, was used in a randomized, double-blind, placebo controlled trial of marijuana-dependent outpatients recently published in Addiction. Not only did velafaxine fail to help the patients with their cannabis dependence, but in fact “may lead to an increase in cannabis use.”

Smoking is Bad to the Bone—The Journal of Adolescent Health reports that cigarette smoking dramatically impacts the rate of bone density growth in teenage girls. Young women may be smoking their way toward a future of osteoporosis, the loss of bone density that often plagues older women. “This age group is when you should gain about 50 percent of your bone accrual,” reports study author Lorah Dorn at Cincinnati Children’s Hospital Medical Center, in Science News. A 2001 study of adult smokers found that smoking increased the risk of hip fracture by 31% in women. In addition, at the recent annual meeting of the American Academy of Orthopedic Surgeons, researchers reported on a study of 6,779 patients undergoing treatment for spinal disorders with severe pain. Those who quit smoking during treatment reported greater pain improvement than patients who didn't stop smoking. 

Dr. Google Will See You Now—Researchers are starting to data-mine the Internet to identify unanticipated side effects and interactions between prescription drugs. According to an article in Science by Sean Treacy, one study in 2011 data-mined reports to the FDA from doctors, nurses, and patients, and “uncovered a hidden drug interaction: When taken together the antidepressant paroxetine and the cholesterol suppressant pravastatin can cause hyperglycemia, or high blood sugar.”  Bioinformatics researcher Nigam Shah of Stanford told the magazine that “if a lot of people are concerned about a symptom, that in itself is valuable information.”

Fetal Health—Scientists have traced out a molecular signaling pathway that appears to play a crucial role in the development of fetal alcohol spectrum disorders (FASD). According to the researchers, whose study was published in the Proceedings of the National Academy of Sciences, “ethanol may cause FASD in part by decreasing the adhesion of the developmentally critical L1 cell adhesion molecule through interactions with an alcohol binding pocket on the extracellular domain.” In English, it means that the research points to strong candidate genes, therefore identifying a specific locus of action for future drugs designed to block alcohol neurotoxicity in the womb. A group led by Michael Charness at Harvard Medical School did the work, building on previous studies that identified the alcohol sensitivity of L1 adhesion molecules. “Prenatal alcohol exposure is the leading preventable cause of birth defects and developmental disorders in the United States,” according to perennial Acting NIAAA Director Kenneth Warren, in an NIH news release.

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Drug-Drug Interactions to Watch Out For

P450 enzymes and “poor metabolizers.”

The finding, published in Science, is a bit arcane to the layperson. The big secret of how the P450 enzyme family metabolizes drugs turns out to be a critical phase change, where an oxygen molecule temporarily joins the mix, forming “Compound I,” a process the scientists documented by cooling the enzymes at just the right rate. 

So what? Well, for starters, “cytochrome P450 enzymes are responsible for the phase I metabolism of approximately 75% of known pharmaceuticals,” write Jonathan Rittle and Michael T. Green at Pennsylvania State University’s Department of Chemistry.  And in fact, only six of the more than 50 enzymes in the P450 family account for 90% of drug metabolization in humans--the compound known as CYP2D6 being the most crucial.

In a Penn State press release, lead author Michael Green, an associate professor of chemistry, noted that human populations vary widely in the version of genes they carry for P450 enzymes. According to Green, “adverse drug-drug interactions are a well-known problem…. Now that we can see those state changes on a molecular level, a deeper investigation is possible.”

The wide variation in enzymatic reactions, says Green, causes very real consequences. People with two copies of variant alleles are poor metabolizers, people with two copies of the standard genetic variety are normal metabolizers, whereas people with one of each are “reduced” metabolizers. (People who inherit multiple copies of the alleles become “ultrarapid” metabolizers.)

 “With a drug such as caffeine, for example, one population of people might be fast metabolizers, while another might metabolize the drug more slowly,” Green said. "Because the risk of caffeine-induced heart attack may be higher in slow metabolizers, the ability to actually take a snapshot of the phase changes of the P450 enzymes could help us to understand better how certain chemicals can affect people in vastly different ways."

There are dozens of specific cases like the caffeine example. Moreover, the genetic situation is complicated by other factors.  Writing in American Family Physician, Tom Lynch and Amy Price explain that cytochrome P450 enzymes “can be inhibited or induced by drugs, resulting in clinically significant drug-drug interactions that can cause unanticipated adverse reactions or therapeutic failures. Interactions with warfarin, antidepressants, antiepileptic drugs, and statins often involve the cytochrome P450 enzymes.” Testing for these interactions is expensive, and “it has not been determined if routine use of these tests will improve outcomes.”

Not a pretty picture. And just to further complicate matters, some drugs can induce or inhibit CYP450 enzymes differentially, depending upon the dosage. “For instance,” write Lynch and Price, “sertraline (Zoloft) is considered a mild inhibitor of CYP2D6 at a dose of 50 mg, but if the dose is increased to 200 mg, it becomes a potent inhibitor. Inhibitory effects usually occur immediately.” Also, drugs can be metabolized by, and at the same time serve to inhibit, the enzyme in question, as in the case of erythromycin.

So it is buyer beware, and listen to your body’s feedback when embarking on a course of new drugs. Recommended dosages are just that: recommendations. If you feel that the drug in question is doing too much or too little, ask your prescribing doctor about drug-drug interactions and about fast and slow drug metabolizers. Of course, they should be telling YOU about that, but.

Some known enzymatic drug interactions to bear in mind:

Drugs that potentially inhibit P450 enzymes—Tagamet, Cipro, Luvox, Prozac, Flagyl, Benadryl, Paxil, Lamisil, and grapefruit juice.

Drugs that potentially increase the activity of P450 enzymes—Tegretol, phenobarbital, tobacco, Dilantin, rifampin, St. John’s wort.

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Adverse drug-drug interactions involving P450 enzymes:

Amiodarone (Cordarone) combined with Warfarin (Coumadin): possible bleeding due to increased warfarin activity.

Tegretol, phenobarbital, and Dilantin combined with contraceptives containing ethinyl estradiol: possible unplanned pregnancies due to reduced contraceptive activity.

Clarithromycin, erythromycin, and telithromycin combined with Zocor: possible muscle disorders due to increased Zocor levels.

Prozac combined with Risperidone (Risperdal): increased risk of adverse effects from the antipsychotic drug risperidone.

Grapefruit juice combined with Buspirone (Buspar): Dizziness and other effects of “serotonin syndrome” due to increased buspirone activity.


Rittle, J., & Green, M. (2010). Cytochrome P450 Compound I: Capture, Characterization, and C-H Bond Activation Kinetics Science, 330 (6006), 933-937 DOI: 10.1126/science.1193478

Graphics Credit: http://elcamino.dnadirect.com/

Alcohol and Medicine: When Drugs Interact

Is it okay if I drink with these pills?

We've all seen the warnings; the labels on prescription bottles telling us not to mix the pills with alcohol. The warnings tell us that alcohol may blunt or enhance or nullify the effect of the prescribed drugs.

But what's so bad about mixing alcohol with common medications? What, really, can go wrong? "Nausea and vomiting, headaches, drowsiness, fainting, or loss of coordination," according to the National Institute on Alcohol Abuse and Alcoholism (NIAAA). "It can also put you at risk for internal bleeding, heart problems, and difficulties breathing. In addition to these dangers, alcohol can make a medication less effective or even useless, or it may make the medication harmful or toxic to your body."

The NIAAA reminds consumers that certain medicines, such as cough syrup and laxatives, may contain up to 10 per cent alcohol to begin with. Moreover, older people are at particular risk, since the body breaks down alcohol more slowly with age. Woman are also at high risk for drug/alcohol interactions, since blood--alcohol levels are typically higher in women than in men after consuming the same amount of alcohol.

Finally, the NIAAA advises, "Timing is important. Alcohol and medicines can interact harmfully even if they are not taken at the same time."

Herewith, a partial listing of drug/alcohol reactions to watch out for, taken from the NIAAA's publication, "Harmful Interactions: Mixing Alcohol with Medicines."

Possible reactions with alcohol:

--Angina: Isordil, Nitroglycerin. Rapid heartbeat, dizziness, fainting.

--Anxiety and Epilepsy: Librium, Valium, Xanax, etc. Increased risk of overdose, difficulty breathing, impaired motor control, memory problems.

--Blood clots: Coumadin (Warfarin). Internal bleeding, strokes, heart attacks.

--Depression: Prozac, Zoloft, Lexapro, Wellbutrin, etc. Drowsiness, dizziness, increased risk of overdose.

--Diabetes: Glucophage, Orinase, etc. Abnormally low blood sugar, flushing reaction, nausea, vomiting.

--Arthritis: Celebrex, Naprosyn, Voltaren. Ulcers, stomach bleeding, liver problems.

--High blood pressure: Catapres, Cardura, Lopressor, etc. Dizziness, fainting, arrhythmia.

--High cholesterol: Crestor, Lipitor, Pravachol, etc. Liver damage.

--Infections: Acrodantin, Flagyl, Grisactin, Nizoral, Nydrazid, Seromycin, Tindamax: Rapid heartbeat, stomach pain, vomiting, flushing.

--Severe pain: Demerol, Percocet, Vicodin, etc. Drowsiness, dizziness, increased risk of overdose, difficulty breathing, impaired motor control.

--Sleep problems: Ambien, Lunesta, Sominex, etc. Dizziness, difficulty breathing, impaired motor control, memory problems.

--Enlarged prostate: Cardura, Flomax, etc. Dizziness, fainting.

And don't forget the herbals: Alcohol with Kava Kava may cause liver damage; alcohol with St. John's Wort risks dizziness and overdose. Chamomile, valerian and lavender will increase drowsiness when mixed with alcohol.

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