Novel Proton Pump Inhibitors

Proton pump inhibitors (PPIs) are the most effective drugs for treatment of acid-related disorders, such as peptic ulcer disease, ulceration caused by NSAIDs, gastroesophageal reflux disease (GERD), dyspepsia, and stress-mediated ulceration (ie, that occurring in the intensive care setting). These drugs act by specifically inhibiting the activity of proton pumps in the canalicular membrane of gastric parietal cells, which are responsible for secretion of acid in the stomach. For inhibition to occur, the proton pumps must be expressed by the parietal cells, and this expression only occurs when they are actively secreting acid, such as with a meal. Thus, one limitation of PPIs is that they need to be given just before a meal to be maximally effective. This limitation has a significant effect on patient compliance, and limits the on-demand use of the drug for symptomatic relief.

Despite the enormous commercial success of PPIs, there remains a significant unmet need in providing adequate suppression of gastric acid secretion, particularly for patients with GERD. Indeed, as many as 25% of GERD patients are not satisfied with their therapy. These needs can be divided into 2 categories: rapid onset of symptom relief and sustained activity (particularly through the night). The lack of a rapid onset of activity of PPIs is largely attributable to the fact that they are acid-labile, so PPIs have to be administered in formulations that protect the drug until it enters the duodenum. The lack of sustained activity is mainly manifest as nocturnal acid breakthrough (NAB). NAB occurs in a significant percentage of regular PPI users (GERD and non-GERD). It is largely related to the earlier-mentioned need to take PPIs in conjunction with a meal, along with the relatively short plasma half-lives of most PPIs. In short, taking a PPI with the last meal consumed before a patient goes to bed does not provide acid suppression for long enough to control nocturnal acidification and maintain a sufficiently elevated intragastric pH until the patient wakes in the morning. A further complication is that GERD patients are often instructed not to ingest food for at least 3 hours before going to sleep.

Several new PPIs have been designed to address the 2 key issues presently limiting the effectiveness/use of these drugs: the need for a faster relief of symptoms and the need for prevention of NAB. Table 1 lists some of the new PPIs (recently launched or in late stage of development). Those developed to have a faster onset of symptom relief include Zegerid and VECAM. Zegerid is a formulation containing omeprazole and sodium bicarbonate. The sodium bicarbonate raises intragastric pH to provide rapid relief of symptoms during the lag-time between ingestion of the omeprazole and its onset of activity. VECAM is a formulation containing omeprazole with a “meal-mimicking agent.” The rationale of this approach is to overcome the meal-dependence of omeprazole by way of the meal-mimicking agent, which stimulates gastric acid secretion and thereby facilitates omeprazole’s interaction with the proton pumps in parietal cells.

As shown in Table 1 , solving the NAB problem is the focus of more drug development than the need for faster onset of activity. Dexlansoprazole is a delayed-release formulation of the R -enantiomer of lansoprazole. The patients should be able to take dexlansoprazole with their final meal of the day, several hours before bedtime. The delayed release of the active ingredient several hours later would then provide significant suppression of acid secretion through the night. A somewhat similar approach was taken in the design of DM-3458. DM-3458 remains in the stomach for 4 to 6 hours before releasing omeprazole. AGN-201904-Z is an acid-stable prodrug of omeprazole that exhibits a prolonged half-life compared with conventional omeprazole; therefore AGN-201904-Z should provide better nighttime suppression of acid secretion. There are also some new PPIs that may also offer a solution to NAB. Tenatoprazole and Ilaprazole are both reported to exhibit prolonged acid secretion as compared with older PPIs.

Potassium-Competitive Acid Inhibitors

The next generation of acid suppressors will likely be the potassium-competitive acid inhibitors (P-CAI). The drugs act by competitively inhibiting the potassium-binding region of the H ⁺ ,K ⁺ -ATPase on activated parietal cells. These drugs also accumulate within the parietal acid compartment to a much greater extent than do PPIs, and this accumulation contributes to their enhanced antisecretory activity. An additional enhancement of activity is achieved as a result of more favorable pharmacokinetic properties of P-CAIs versus PPIs. Unlike PPIs, the duration of activity of P-CAIs is directly related to their plasma half-life. Also, a full effect is observed after a single dose of a P-CAI, as compared with the need for several doses of a PPI before achieving a full effect.

Combination Histamine H ₂ -Receptor Antagonists–PPIs

Although the introduction of PPIs has largely supplanted the use of histamine H ₂ -receptor antagonists (H ₂ -RAs), there remains a significant niche for these drugs, such as in the treatment of nocturnal symptoms of GERD. A proof-of-concept of the utility of combination H ₂ -RAs and PPIs was provided by the study of Fandriks and colleagues. Coadministration of omeprazole (20 mg) and famotidine (10 mg daily) led to a significantly faster onset of antisecretory activity (ie, raising intragastric pH >4) as compared with omeprazole alone, as well as improving the duration of acid suppression.

Prokinetics

Serotonin (5-HT) is an important mediator of normal secretory and motor function in the GI tract. The enterochromaffin cell is the major source of serotonin in the gut, and the gut accounts for more than 90% of serotonin in the human body. Serotonin plays a role in triggering peristaltic reflexes and can modulate the release of other mediators that influence smooth muscle contraction. The effects of serotonin are complex, with different receptors sometimes producing opposing effects on contractility (eg, 5-HT ₃ vs 5-HT ₄ ).

Serotonergic prokinetic agents have been in use for many years, but serious adverse cardiac events (fatal cardiac arrhythmias) led to the withdrawal of cisapride and tegaserod. Cisapride remains available in some countries under very strict conditions (restricted investigational drug protocol) for treatment of certain conditions, including pseudo-obstruction, gastroparesis, and GERD. Thus, its use is limited and there is a considerable gap left for the treatment of conditions characterized by disturbed GI motility. Recently, a new 5-HT ₄ agonist, prucalopride, was approved in Europe for symptomatic treatment of chronic constipation in women who have not obtained adequate relief from treatment with laxatives.

Prucalopride acts throughout the intestine. Although not affecting gastric emptying, prucalopride increases oral-cecal and colonic transit in healthy volunteers. These effects are attributed to enhancement, via activation of 5-HT ₄ receptors, of cholinergic neurotransmission. Prucalopride has been shown to promote normalization of bowel habits (improved stool consistency and frequency) in patients with chronic idiopathic constipation. Prucalopride has also been shown to be effective in patients who are dissatisfied with conventional laxatives. Like some other prokinetics, prucalopride blocks a potassium channel called the HERG channel, and thereby has the potential to trigger cardiac arrhythmias, but only at concentrations well above those likely to be achieved with clinically relevant doses.

Opioid-Induced Constipation

Opioids relax intestinal smooth muscle, interfering with propulsive contractions. The actions are mediated via μ-opioid receptors. Many patients taking opioids for pain relief, such as after surgery, experience significant impairment of intestinal motility (itself a significant source of discomfort). Alvimopan is a peripherally acting μ-opioid receptor antagonist. Alvimopan has very limited ability to cross the blood-brain barrier, and therefore can block the peripheral actions of opiates that are mediated through the μ-receptor without affecting other, desirable actions of opiates. Thus, the constipation normally associated with opiate use can be minimized, without affecting the analgesic effects of the opiate. As a result, greater compliance can also be achieved.

The USFDA has approved alvimopan for acceleration of the restoration of normal bowel function in adults after intestinal resection surgery. The goal of intestinal resection surgery is to accelerate the postoperative recovery and improve bowel function, allowing the patient to reestablish a normal diet more quickly. It is hoped that postoperative ileus (a temporary impairment of GI motility that is often seen when opioid analgesics are used postoperatively) can be alleviated through the use of alvimopan. In 5 randomized, double-blind, placebo-controlled clinical trials (phase 3), alvimopan significantly accelerated the time to recovery of GI function and to hospital discharge after bowel resection.

Methylnaltrexone bromide was approved by the USFDA in April 2008 for restoration of bowel function in patients with late-stage, advanced illnesses who require continuous opioids to relieve pain. Clinical trials demonstrated efficacy of methylnaltrexone bromide in initiating bowel movements in end-stage patients with cancer. In one trial, methylnaltrexone bromide given every other day for 2 weeks was found to produce bowel movements in half of the patients, compared with only 8% to 15% of patients treated with placebo.