Behind the withdrawal of pergolide (Permax)

I noted a couple of days ago the voluntary withdrawal of a drug used to treat Parkinson's disease called pergolide (Permax). The reason for the withdrawal is that the drug has been linked to reports of valvular heart disease (VHD) and I promised further explanation. The story is a continuing episode in pharmacology and drug safety that has been developing since 2000 or so when the diet drug combination, Fen-Phen, was withdrawn for a similar reason.

But what do diet drugs have to do with a drug for Parkinson's disease?

These stories illustrate just how much we have to learn about the human body and the need to understand completely all of the targets that drugs hit besides those that are intended.

Fen-Phen was a combination of fenfluramine, a serotonin reuptake inhibitor, and phentermine, a derivative of amphetamine. Surprisingly, fenfluramine was the more dangerous of the two drugs but not because fenfluramine blocked neurons from taking up the neurotransmitter, serotonin (also called 5-HT for 5-hydroxytryptamine.). It turns out that fenfluramine (and its active metabolite, norfenfluramine) also directly stimulated a specific subtype of receptors for serotonin called 5-HT_2B receptors.

A great review by Dr Bryan Roth in the New England Journal of Medicine (sub req'd, unfortunately) describes how this association was made:

In 1997, Connolly et al. reported that both racemic fenfluramine (Pondimin) and dexfenfluramine (Redux) were associated with valvular heart disease.1 The valvular abnormalities seen in patients treated with these agents were distinctive. On echocardiography, leaflet thickening as well as chordal thickening and retraction were observed. Surgically removed valves were noted to have a glistening white surface, with histologic evidence of a plaque-like process extending along the leaflet surfaces and encasing the chordae tendineae. These findings were similar to those in patients with heart-valve damage induced by serotonin-secreting carcinoid tumors.1

[...]

Valvulopathic drugs have been shown to induce mitogenesis in cultured interstitial cells from human cardiac valves by activating the 5-HT_2B receptor.4 My research group has suggested that valvulopathy induced by 5-HT_2B receptors is caused by the inappropriate mitogenic stimulation of normally quiescent valve cells, resulting in an overgrowth valvulopathy.

The overgrowth and "floppiness" of such valves decrease the efficiency of the heart and can lead to pulmonary hypertension. More problematic is that the regurgitation of blood within the heart can cause damage leading to cardiac fibrosis, a situation not compatible with life for an organ meant to pump continuously for 70 or more years.

So what about the Parkinson's drug, pergolide?

It was subsequently discovered that two antiparkinsonian dopamine agonists, pergolide and cabergoline, are potent 5-HT_2B agonists; they were therefore predicted to be valvulopathic agents.5 Other commonly prescribed antiparkinsonian drugs such as apomorphine, pramipexole, bromocriptine, lisuride, and roxindole are devoid of 5-HT_2B-agonist activity and, accordingly, were not expected to induce valvular regurgitation. As predicted, case reports of cabergoline- and pergolide-induced valvular heart disease soon appeared.

What this means is that other drugs for Parkinson's are devoid of this potentially fatal side effect. Parkinson's treatments are usually designed to enhance the neurotransmitter, dopamine, in its action at dopamine D₂ receptors (or to block acetylcholine, which normally inhibits dopamine release). So, patients taking other drugs for Parkinson's needn't be alarmed since only pergolide and cabergoline act on 5-HT_2B receptors. This action is a side-effect of these two drugs and is not required for the beneficial action on dopamine D₂ receptors. That's why other treatments for Parkinson's disease are far safer.

So, what does this new information mean for other drugs that were designed to act by one mechanism but that may have this untoward effect at 5-HT_2B receptors? Dr Roth explains:

On the basis of these findings, my colleagues and I have urged pharmaceutical companies and regulatory agencies to screen candidate drugs and their major metabolites at 5-HT_2B receptors comprehensively before launching clinical trials, in order to prevent "fen-phen"-type disasters.3,5 Clearly, practitioners should avoid prescribing drugs that are potent 5-HT_2B-receptor agonists -- a growing list of medications that now includes ergot derivatives (ergotamine, methysergide, and dihydroergotamine), dopamine agonists (pergolide and cabergoline), and amphetamine derivatives (fenfluramine and methylenedioxymethamphetamine [MDMA, or "ecstasy"]).