Nicotine Replacement Drug's Bad Trip

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Nicotine Replacement Drug's Bad Trip

Rocky debut for a nicotine mimic tempers hope for widespread use

By Christine Soares

 

As the pharmaceutical giant Pfizer was reminded in May, arriving first has its

rewards, but they come with the risks of venturing into uncharted territory.

This past spring the Federal Aviation Administration banned pilots and air

traffic controllers from taking the company’s popular smoking-cessation aid,

varenicline, which is sold in the U.S. as Chantix. Amid 6.5 million

prescriptions written worldwide since 2006, the drug had spawned highly

publicized reports of acute psychiatric episodes that included seizures,

psychosis and suicidal depression. In May the nonprofit Institute for Safe

Medication Practices documented 988 such “adverse events,” prompting the

aviation ban.

 

The Food and Drug Administration has now added strong warning language to

varenicline’s medication guide, and Pfizer is reviewing evidence that might help

explain the rare but severe incidents. Although the bad publicity may dampen

sales of the drug, observers say that some adverse events are not unexpected

when a new drug hits the market, especially one that is the first of its kind.

Varenicline is not just a novel smoking-cessation tool; it is the first of an

entire class of medications specifically designed to target a powerful family of

receptors on the surface of brain cells. Known as neuronal nicotinic

acetylcholine receptors, they can mediate pain, mood, memory, attention and

other cognitive functions.

 

Abbott Laboratories, Targacept and AstraZeneca have nicotinic receptor drugs in

clinical trials for memory impairment, adult attention-deficit hyperactivity

disorder and pain. The National Institute on Drug Abuse is testing varenicline

itself as a treatment for cocaine and alcohol dependence. Preclinical studies

are looking at other new nicotinic receptor compounds for Parkinson’s disease,

Alzheimer’s disease, depression, ulcerative colitis and inflammation as well,

attesting to the broad influence of this receptor family.

 

The effects of nicotinic receptors are so pervasive, in fact, that some of the

mechanisms involved are not completely understood. “It’s a story that’s still

evolving, and it’s very complicated, so going in with a drug like varenicline,

I’m not surprised that there are side effects,” says Lorna Role, who studies the

receptors’ biology at Columbia University and Stony Brook University. This type

of acetylcholine receptor, which also responds to nicotine, acts as “a volume

control” for other neurotransmitters, according to Role. “A little nicotine

turns up transmitter release,” she explains. “It’s been shown to increase the

release of dopa­mine, glutamate, GABA—every major neurotransmitter.”

 

Activating a subtype of nicotinic receptor known as alpha4beta2 causes dopamine

to be released in a part of the brain involved in reinforcing reward, for

example, and that receptor is the primary target of varenicline. The drug works

as a “partial agonist,” meaning it binds to the receptor, producing moderate

stimulation intended to stave off nicotine withdrawal. In so doing, it blocks

nicotine from getting to the receptor as well, which prevents a smoker from

receiving a dopamine surge from a cigarette.

 

In cell studies, varenicline also acts as a potent full agonist for another

receptor subtype called alpha7 that is associated with some of the positive

cognitive effects of nicotine, such as enhanced focus. Variations in the alpha7

receptor gene are implicated in the difficulties schizophrenics tend to have

with shutting out sounds or other stimuli. “I was hopeful that varenicline could

be used for schizophrenia,” Role says, “then the first report came out of it

causing a psychotic episode, and it was hands off.”

 

Given the complexity of the neuro­psychological systems affected by nicotinic

receptors, most of the episodes involving varenicline may never be explained.

Pfizer representatives point out that smokers as a group have higher than

average rates of anxiety and depressive disorders, suggesting that mild or

undiagnosed preexisting mental illness might have played a part in some of the

reactions to the drug. Moreover, symptoms such as agitation and suicidal

thinking are well-documented side effects of tobacco withdrawal, notes Anjan

Chatterjee, a director of medical affairs for Pfizer: “So it’s hard to decide,

is it the smoker’s past history, or is it varenicline?”

 

Antidepressants in the class known as selective serotonin reuptake inhibitors

(SSRIs), which debuted more than 20 years ago, have also been associated with

adverse events such as suicidal thinking. The first generation of such drugs,

which included Prozac, was notorious, too, for lesser side effects, including

stomach upset and sexual dysfunction. Subsequent generations of SSRIs addressed

some of those issues by building in blockers of certain serotonin receptor

subtypes to eliminate unwanted drug actions. 

 

“As with serotonin, people discovered there are subtypes of [receptor] subtypes.

I think as time goes on there will be more sophisticated [nicotinic] drugs

coming out,” says Edward D. Levin, a behavioral pharmacologist at Duke

University, who has consulted for Targacept and for the National Institutes of

Health.

 

“It’s just like the SSRIs,” Role agrees. “I think refining the compounds in

terms of the balance of their activities is really key, but that’s not to say

that’s trivial. It’ll take time.” Targeting nicotinic receptors “has enormous

therapeutic potential,” she says, adding that the biggest joke on the tobacco

industry may be that they missed seeing it.

 

Note: This story was originally printed with the title, " First in Class " .

 

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