Gastro Perlas AMG - Episodio #78 "P-CAB"

Introduction to the Podcast

Overview of the Podcast

• The podcast is designed for educational purposes aimed at healthcare professionals and should not be considered medical advice.

• This is episode 78, marking the end of season 2. Gratitude is expressed to all sponsoring laboratories involved in continuous medical education.

Discussion on New Therapeutic Class

Introduction of Guests and Topic

• The episode features two expert guests discussing a new therapeutic class relevant to gastroenterology, particularly focusing on acid-related diseases.

• The aim is to understand this new therapeutic class's utility for gastroenterologists.

Guest Introductions

• Dr. Miguel Ángel Aldovino Díaz, former president of the Mexican Association of Neurogastroenterology, and Dr. José María Remestroches, director at the University Veracruzana’s Medical Biological Research Institute, are introduced as experts.

Understanding Potassium Competitive Acid Blockers

Mechanism of Action

• Dr. Aldovino explains that potassium competitive blockers inhibit hydrogen-potassium ATPase differently than proton pump inhibitors (PPIs).

• These drugs block potassium channels reversibly, inhibiting hydrochloric acid secretion without needing active proton pumps.

Comparison with Proton Pump Inhibitors

• Unlike PPIs which form irreversible bonds, potassium blockers can act on both active and inactive pumps continuously.

• This mechanism makes them potentially more efficient compared to traditional PPIs.

Clinical Experience with New Drugs

Historical Context

• Dr. Remestroches discusses how H2 blockers dominated in the 1980s and PPIs emerged in the 1990s; it took nearly three decades for a new class like potassium competitive blockers to arrive.

Importance of New Therapeutics

• There remains unmet need in treating conditions like reflux and Helicobacter pylori infections; thus, these new medications represent an exciting development in gastroenterology.

Evaluating Efficacy of Antisecretory Medications

Key Parameters for Effectiveness

• Dr. Aldovino states that efficacy is measured by how long a dose maintains intragastric pH above four.

• A sustained pH above four is crucial for healing peptic ulcers and esophagitis due to reflux; however, eradicating Helicobacter pylori requires a pH above six.

How is the Effectiveness of Medications Measured?

Measuring Clinical Effectiveness

• The effectiveness of medications is assessed through symptom resolution, such as alleviating pyrosis and regurgitation, or healing esophagitis. Maintaining intragastric pH above four and healing lesions are key parameters for evaluating drug efficacy.

Reversible vs. Irreversible Binding

• Dr. Baldovinos explains that these medications bind reversibly, unlike irreversible proton pump inhibitors (PPIs). This raises a common clinical question regarding the potency of reversible drugs.

• José María clarifies that the belief that irreversible binding equates to greater potency is a misconception; understanding pharmacological properties is crucial for clinicians.

Mechanism of Action

• The mechanism involves rapid concentration in parietal cells where the drug binds reversibly to potassium channels in both active and inactive pumps, enhancing inhibition efficiency.

• The quick action leads to prolonged effects but may require subsequent doses after 24 hours due to physiological changes in proton pump production.

Administration Guidelines

• Unlike PPIs which are prodrugs requiring fasting for optimal absorption, these new medications do not need specific timing related to food intake for effective action.

• Traditional PPIs have an enteric coating that must dissolve before reaching circulation; however, these newer drugs are stable in acidic environments and can be taken without regard to meals.

Pharmacokinetics and Food Interaction

• Studies show that the pharmacokinetics and dynamics of these new drugs remain unaffected by food intake, allowing flexibility in administration compared to traditional PPIs which require pre-meal dosing.

• The ability to take these medications at any time offers significant therapeutic advantages over PPIs which must be timed with meals for activation of proton pumps.

Potassium Intracellular Concerns

• A common concern among physicians is whether blocking potassium exit from parietal cells could lead to intracellular potassium issues.

• José María reassures that intracellular potassium levels remain stable despite medication use; high concentrations are essential for cellular processes and will not significantly change due to drug action.

Overview of Approved Molecules for Human Use

Introduction to Approved Molecules

• Currently, several molecules are fully approved for human use, with a history dating back to the 1980s when prototypes were developed.

• The four main approved molecules in Asia include bonoprasam, tegoprasam, fexuprasán, and revaprasan. In Mexico, COFEPRIS has approved tegoprasam, bonoprasam, and fexuprasán.

Pharmacological Advantages

• These new drugs act almost immediately; physiological evidence shows action within the first 30 minutes after administration.

• Unlike prodrugs, these medications are highly selective and reversible, leading to rapid effects without dependency on food intake.

Efficacy in Healing Lesions

Comparative Efficacy Against IBPs

• Clinical trials indicate that these new drugs heal lesions more quickly than traditional proton pump inhibitors (PPIs), particularly in cases of reflux esophagitis.

• For severe esophagitis (Los Angeles classification), a single dose of these new drugs is significantly more effective than a dose of PPIs.

Symptom Resolution

• Patients using these new medications experience faster symptom resolution compared to those on PPIs; for instance, tegoprasam can elevate intragastric pH above four within 30 minutes.

Nighttime Acid Leakage Management

Comparison with Traditional Medications

• Nighttime acid leakage is a known issue with PPIs due to their short half-lives. New medications may provide better control over nighttime acidity.

• While preliminary evidence suggests that morning doses could maintain adequate pH levels overnight, further clinical data is needed.

Helicobacter Pylori Eradication

Required pH Levels for Eradication

• To effectively eradicate Helicobacter pylori (HP), an intragastric pH above six is necessary. This often requires double dosing with traditional IBPs.

Effectiveness of New Drugs

Helicobacter Pylori Eradication and Proton Pump Inhibitors

Effectiveness of Proton Pump Inhibitors (PPIs) in Treatment

• The effectiveness of Helicobacter pylori eradication increases with greater acid inhibition, suggesting that traditional treatments may be less effective than newer regimens.

• Traditional treatments using amoxicillin and clarithromycin may show improved efficacy when combined with PPIs, potentially leading to better outcomes in H. pylori eradication.

Advantages of Shorter Treatment Regimens

• Incorporating PPIs allows for shorter treatment durations, proposing 7 to 10-day regimens instead of the standard 14 days.

• Reduced treatment duration is beneficial as it minimizes exposure to antibiotics like amoxicillin and clarithromycin, which have known resistance issues in Mexico.

Pharmacological Interactions and Metabolism

• The use of PPIs can lead to higher eradication rates (above 80%) while reducing the number of doses required per day.

• Concerns regarding drug interactions with cytochrome P450 enzymes (CYP2C19 and CYP3A4) are raised, particularly how they affect the metabolism of various drugs.

Polymorphisms and Drug Efficacy

• Variability in metabolism among patients affects the efficacy of PPIs; extensive or rapid metabolizers may experience reduced effectiveness compared to slow metabolizers.

• Unlike traditional PPIs, newer medications do not exhibit significant polymorphisms affecting their metabolism, enhancing their reliability across different patient profiles.

Drug Interaction Considerations

• Newer medications have fewer drug-drug interactions compared to traditional PPIs, making them safer options for patients on multiple medications.

• Studies indicate no need for dose adjustments for clarithromycin when used alongside new therapies aimed at eradicating H. pylori.

Gastrin Levels and Cancer Risk

• Historical concerns about gastrin levels rising due to acid suppression from PPIs are discussed; however, current evidence does not link high gastrin levels with increased cancer risk.

• Similar physiological responses occur with both traditional PPIs and newer agents concerning gastrin production but without documented risks associated with neuroendocrine tumors or adenocarcinoma.

Microbiota Alteration by Medications

Impact of Proton Pump Inhibitors on Gut Microbiota and Clinical Outcomes

Role of Gastric Acid and Proton Pump Inhibitors (PPIs)

• Gastric acid serves as a physiological barrier against pathogenic germs. The use of PPIs has been linked to an increased risk of bacterial overgrowth in the gut.

• Studies indicate that PPIs alter intestinal microbiota composition, leading to bacterial overgrowth in the small intestine, similar to findings with other medications.

Clinical Consequences of Altered Microbiota

• Despite observed changes in microbiota due to PPI use, no clinical consequences have been definitively established; studies from Japan and Korea show no increased risk for enteric infections.

• Current understanding suggests that while PPIs impact gut microbiota, significant clinical concerns are not evident at this time.

Probiotics and PPI Use

• Research combining PPIs with probiotics aimed at mitigating microbiota alterations has shown no proven benefits; thus, probiotic use is not recommended alongside anti-secretory medications.

Long-term Use of PPIs

• Duration of PPI therapy should be tailored based on the underlying condition rather than a fixed timeframe. For example:

• Eradication regimens: 7 to 14 days.

• Erosive esophagitis: Up to 12 weeks.

• Maintenance therapy may extend beyond two years for reflux disease without adverse effects noted.

Specific Conditions and Recommendations

• There is no clinical trial evidence supporting PPI use in eosinophilic esophagitis despite their anti-inflammatory properties being beneficial in other conditions like dyspepsia.

• In cases of acute upper gastrointestinal bleeding, intravenous administration of PPIs can be life-saving prior to endoscopic intervention; however, further evidence is needed for routine application.

Considerations for Special Populations

• No evidence supports the safety or efficacy of PPIs in pediatric or pregnant populations; caution is advised.

• Patients with cirrhosis can safely use these drugs as they do not require extensive metabolism. However, renal function must be monitored closely when prescribing these medications.

Gastroprotection and New Therapeutic Classes in Acid-Related Diseases

The Importance of Gastroprotection

• There is a tendency to overprescribe gastroprotective medications, often inappropriately, leading to a need for reevaluation of the concept of gastroprophylaxis.

• Caution is advised against excessive prescription of new therapeutic classes; they should only be given when truly necessary.

Insights on New Therapeutic Drugs

• The introduction of new therapeutic classes is exciting as scientific evidence suggests advancements in managing acid-related diseases.

• These new drugs are characterized as stronger, faster, more effective, and longer-lasting, indicating their potential niche in treating acid-related conditions.

Clinical Considerations and Usage

• It’s crucial to use these potent drugs judiciously; overutilization can lead to adverse effects that have been observed with previous medications.

• Experience from post-marketing studies will clarify the true therapeutic niche for these new drugs.

Addressing Unmet Needs

• Acknowledgment of unmet needs in patient care: 30% of patients with difficult-to-manage reflux and hard-to-eradicate Helicobacter pylori infections highlight the necessity for these new treatments.

Rational Use and Confidence in New Treatments

• Encouragement to utilize these powerful inhibitors rationally despite initial fears regarding their potency and potential side effects.

• Trust in clinical evidence regarding safety monitoring can foster confidence among healthcare providers about using these newer therapies effectively.

Conclusion and Future Directions