28/08/2023
The Well-known Drug that Could Damage Your Brain Leading to Dementia, According to New Study https://newswav.com/A2308_pGTbqT?s=A_mIkEcyC&language=en
PROTON PUMP INHIBITORS - mechanisms for dementia via long term medication
Since the parietal cell was known to secrete gastric acid, many drugs were developed to target the parietal cell in order to inhibit acid secretion. Proton pump inhibitor (PPI) is a prodrug which is activated by acid. Activated PPI binds covalently to the gastric H+, K+-ATPase via disulfide bond. Cys813 is the primary site responsible for the inhibition of acid pump enzyme, where PPIs bind (1).
PPIs achieve a greater degree and longer duration of gastric acid suppression, and better healing rates in various gastric acid-related disorders, than histamine H2 receptor antagonists (2).
Since the introduction of the first PPI in 1989, PPIs, as a class became a staple in the management of gastroesophageal reflux disease (GERD) and other acid-related disorders as they significantly reduce acid reflux (3) but problems may arise in long term use via inhibition of cytochrome P450 system and antioxidant and mineral deficiencies.
PPIs are used extensively for the treatment of gastric acid-related disorders, often over the long term, which raises the potential for clinically significant drug interactions in patients receiving concomitant medications. This is particularly relevant for elderly patients taking multiple medications, or for those receiving a concomitant medication with a narrow therapeutic index (4).
The PPIs, such as rabeprazole, omeprazole, lansoprazole, and pantoprazole undergo an extensive biotransformation in liver. In the liver, they are metabolized to varying degree by several cytochrome P450 (CYP) isoenzymes which are further categorized into subfamilies of related polymorphic gene products (5).
The human clearance of drugs and PPIs, of the substituted benzimidazole class is carried out primarily by the hepatic cytochrome P450 system (6). Chronic use of Ppis in patients with impaired liver function may worsen cytochrome P450 (CYP450) activity, predisposing them to clinically relevant drug-drug interactions (7). The PPIs can interact with other drugs by increasing gastric pH, inhibiting hepatic cytochrome P450 system, or by inducing specific isoforms of this enzyme system (8). Reversible PPIs are mostly K+-competitive inhibitors, which inhibit gastric H+-, K+-ATPase activity by competing with potassium ions (9).
Human cytochrome P450 system plays very important roles in the detoxification of drugs. The
excess or long term use of drugs that are metabolised by the C P450 system leads to depletion of enzymes in this system and inhibits the system and inhibits drug clearance. Lansoprazole sodium is a proton-pump inhibitor (PPI) and also can inhibit cytochrome P450. Lansoprazole, omeprazole and pantoprazole are extensively metabolized by several human cytochromes P450, most prominently by mephenytoin hydroxylase (CYP2C19) and nifedipine hydroxylase (CYP3A4) (10).
Over the years, there has been a growing concern over potential adverse effects associated with long-term therapy. Some of these concerns include hypergastrinemia, development of pneumonia, dementia, and drug interactions (11). The suppression of gastric acid by PPI or H2RA use (or pathophysiologic conditions that affect gastric acid production, such as atrophic gastritis), will reduce the digestive capacity to release vitamin B-12 from foods, and thus reduce the amount of vitamin B-12 that is absorbed in the body. Inhibited vitamin B-12 absorption has been directly shown in empirical studies. Now, there is general consensus that gastric acid lowering drugs, including PPIs and H2-receptor antagonists (H2RAs), and the antidiabetes drug metformin can reduce circulating vitamin B-12 concentrations with prolonged use. Its deficiency disturbs many biochemical pathways while homocysteine and methylmalonic acid accumulate. (12). Natural B12 is a highly complex essential vitamin, and is a co-factor for enzymatic reactions in humans catalysed by methionine synthase by and methylmalonyl-CoA mutase. It is well associated with pernicious anaemia, human B12 deficiency may also be a risk factor for neurological illnesses, heart disease and cancer (13). About 6% of adults younger than 60 years have Vit B12 deficiency, but the rate is closer to 20% in those older than 60 (14).
The cytochrome P450 (CYP) system is the most important drug metabolizing enzyme family, which plays a significant role in the breakdown (detox) of endogenous or exogenous substances. In liver cells, drugs and inflammation can drop cytochrome P450 enzymes levels (15).
Several cytochrome P450 enzymes (CYPs, such as CYP2R1, CYP27A1, CYP3A4, CYP2D25, CYP24A1, CYP27B1, and CYP11A1) are involved in Vit D metabolism which has antiviral activity. CYPs participate in the biosynthesis or catabolism of steroids, vitamins, antibodies, eicosanoids, and fatty acids and may be involved in pathogenesis in COVID-19. Vitamin B12 is needed to form red blood cells and DNA. It is also a key player in the function and development of brain and nerve cells and DNA synthesis (16).
Vitamin B12 plays an important regulatory role in the immune system. Vitamin B12 is integral to red blood cell production, ensuring the immune system gets the oxygen it needs. The leucocyte and lymphocyte (CD4+, CD8+, CD56+) counts of patients increased significantly after methyl-B12 treatment.
(17). Vit B12 plays an important role in immunity by facilitating production of T lymphocytes. A detailed examination of vitamins suggests that vitamin B12 may be the component that reduces virulence by blocking furin which is responsible for entry of virus in the host cell (18) via blocking Spike protein cleavage to yield S1 & S2, and S1infects host cells and hijacks TLR inflammasomes to produce chemokines for inflammatory injury in cells.
Vitamin B12 deficiency only occurs in elderly people. Also glutathione declines with age. Vitamin B12 deficiency diagnosis based on low serum B12 levels, may have elevated biomarkers like methylmalonic acid and/or homocysteine. Since B6 and B12 can regulate inflammation, it explains why the elderly have a slightly higher state of inflammation (19). Glutathione also declines with age. Nutrient factors are vital to downregulate inflammation.
The vitamins A, B6, B12, C, D, E and folic acid and the trace elements iron, zinc, copper and selenium work in synergy to support the protective activities of the immune cells. Finally, all these micronutrients, with the exception of vitamin C and iron, are essential for antibody production (20) after infections.
PPIs may also increase platelet reactivity and thrombosis by impairing the activity of the enzyme dimethylarginine dimethylaminohydrolase (21) that degrades asymmetric dimethylarginine (ADMA). Its accumulation inhibits generation of vascular NO and is associated with an increased risk of Major Adverse Cardiovascular Events (MACE), increasing the risk of coronary thrombosis and accelerates atherosclerosis and coronary artery disease (22).
Accumulating clinical data from long term PPI use has revealed associations between extended PPI use and the occurrence of serious adverse sequelae, including increased risk of fractures, renal failure, myocardial infarction, and dementia, and low mineral absorption, including Mg, Ca, Fe. Symptoms of low magnesium include muscle cramps, dizziness, tremors, abnormal heart rhythms, and seizures.
(23). Mg+ is necessary for activation of Vit D. Long-term use of proton pump inhibitors (PPIs) is common in patients with muscle wasting related chronic diseases. PPI use has been described to alter the microbiota’s composition in the gut, which, over time, might lead to increased inflammation (24).
There is a complex interplay of factors for aberrant physiology for dementia in atherosclerosis risk communities and may involve Covid-19 severity.
Interferons and proinflammatory cytokines can downregulate P450 expression ex vivo (in hepatocyte cultures) and in vivo (25). Antioxidants improve C P450 function. C and E improve hepatic drug metabolizing dysfunction as indicated by abnormalities in CYP isoforms during sepsis, and this protection is, in major part, caused by decreased oxidant stress and lipid peroxidation (26).
Vitamin B12 is known to play critical roles during the development and aging of the brain, and Vit B12 deficiency is linked to neurodevelopmental and degenerative disorders. It was found that the uptake of diet-supplied vitamin B12 in the intestine to be critical for the expression of a long isoform of PTP-3 (PTP-3A) in neuronal and glial cells, and glial migration and synapse formation defects can stem from Vit B12 deficiency (27). Glial cells perform a wide range of vital roles in brain and nervous system. Synaptic disconnections, imbalances of neurotransmitter homeostasis, and axonal degeneration and neuronal death can ultimately lead to memory impairment (28).
Dementia is a term used to describe the symptoms that occur related to decline in brain function. It can be see that long term use of drugs that deplete enzymes in cytochrome P450 system in cells and deficiencies in glutathione, B6 and B12 and other dietary antioxidants over time in the elderly impairs glial cell functions. The ensuing oxidative stress activates glial cells that generate inflammation
(29) in the brain. Such microglial activation can be detrimental to neurons, which promotes the degenerative changes and the decline in brain function leading to dementia.
Beldeu Singh
28 Aug 2023
References
1. Shin JM, et al, Journal of Neurogastroenterology and Motility 2013; 19(1): 25-35.
2. Wedemeyer R-S, et al, An Update. Drug Safety, 37, 201–211, Feb 2014.
3. Ambizas EM, et al, Proton Pump Inhibitors: Considerations With Long-Term Use, US Pharm. Jul 2017;42(7), 4-7.
4. Wedemeyer R-S, et al, An Update. Drug Safety, 37, 201–211, Feb 2014.
5. Ishizaki T, et al, Aliment Pharmacol There, 1999 Aug;13 Suppl 3:27-36.
6. Li X-Q, et al, Drug Metab Dispos, 2004 Aug;32(8):821-7.
7. Rocco A, et al, Aliment Pharmacol There, 2021 Mar;53(5):608-615.
8. Meyler's Side Effects of Drugs, 16th Edn, 2016 Editor, Aronson JK.
9. Jai Moo Shin, George Sachs, in Encyclopedia of Gastroenterology, 2004.
10. Meyer UA, European Journal of Gastroenterology & Hepatology 1996, 8 (suppl 1), S21–S25.
11. Ambizas EM, et al, Proton Pump Inhibitors: Considerations With Long-Term Use, US Pharm. Jul 2017;42(7), 4-7).
12. Miller JW, Adv Nutr. 2018 Jul; 9(4): 511S–518S.
13. Watson WP, et al, Chemico-Biological Interactions, Vol 382, 1 Sept 2023, 110591.
14. Hunt A, et al, BMJ, 2014 Sep 4;349:g5226.
15. Wang G, et al, Front. Pharmacol., 02 February 2022, Sec. Drug Metabolism and Transport, Vol 13, 2022.
16. Stabler SP, et al, 11th ed. Washington, DC: Elsevier; 2020, 257-71.
17. Tamura J, et al, Clin Exp Immunol. 1999 Apr; 116(1): 28–32.
18. Pandya M, et al, Inform Med Unlocked. 2022; 30: 100951.
19. Suardi C, et al, Int. J. Environ. Res. Public Health 2021, 18(5), 2455.
20. Maggini S, et al, Cambridge University Press: 01 Oct 2007.
21. Ghebremariam YT, et al, Circulation, 2013 Aug 20;128(8):845–53.
22. Cooke JP, et al, Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):768–70.
23. Ariel H, et al, Methodist Debakey Cardiovasc J. 2019 Jul-Sep; 15(3): 214–219.
24. Vinke P, et al, Int. J. Mol. Sci. 2020, 21(1), 323.
25. Aitken AE, et al, Annu Rev Pharmacol Toxicol, 2006, 46,
123–49.
26. Kim J-Y, et al, Eur J of Pharmacology, Vol 534, Issues 1–3, 18 Mar 2006, 202-209.
27. Zhang A, et al, Cell Reports, Vol 30, Issue 12, P3981-3988.E3,
Mar 24, 2020.
28. Venkata SSSS, et al, Front Integr Neurosci. 2016; 10: 7., 29 Feb 2016.
29. Uddin MS, et al, Ageing Research Reviews, Vol 78, June 2022, 101622.
Copyright/IP : beldeusingh
