CP NHT S DNG PPI TRONG THC HNH Y HC GIA NH TS.BS CK2. Trn Th Khnh TngHYK Phm Ngc Thch
Nhc li C ch tit acid C ch hot ng ca PPIDc lc hc ca PPIChuyn ha PPIVai tr ca PPI trong iu trTng tc thucTnh an ton v vn ngng s dng PPI
T BO THNHTb thnh v bm proton khng hot ng trc n v trong ba nC CH TIT ACID (tt)
A resting parietal cell showing the tubulovesicular apparatus ( nang tiu qun) in the cytoplasm and the intracellular canaliculus (knh ni bo).B,An activated parietal cell that is secreting acid. The tubulovesicles have fused with the membranes of the intracellular canaliculus,which is now open to the lumen of the gland and lined with abundant long microvilli. Tb vin v bm proton khng hot ng trc n v trong ba n
C CH TIT ACID (tt)
Three principal physiological stimuli: acetylcholine, histamine, and gastrinmuscarinic M3 receptorenterochromaffin-like (ECL) cellsAlthough interactions among these three pathways are coordinated to promote or inhibit hydrogen ion generation, histamine appears to represent the dominant route as gastrin stimulates acid secretion principally by promoting the release of histamine from ECL cellsBecause of the dominance of this pathway, H2-receptor blockade became the principal means by which acid secretion was inhibited in the mid-1970s*
Proton ha trong mi trng acidChuyn thnh sulphenamidePhn ng vi SH ca gc cysteines ca H+,K+ - ATPasec ch H+,K+ - ATPasec chPPI
( Protonation )SulphenamideK+H+,K+ - ATPase (Proton Pump)Tiu qun bi titH+c ch tit acid mnh nht*PPIs l tin cht (pro-drug)
hot ha trong mi trng acid c ch bm protonHot ha ty thuc:pH tiu qun bi titpKa ca PPI
C CH HOT NG CA PPI* Wolfe MM, Sachs G. Gastroenterology. 2002;118(2 Suppl 1):S9.
The important thing with the PPIs is that they only inhibit active pumpsFirst of all, it's important to remember that all of these drugs are pro-drugs that require activation before they can affect the proton pump. This activation occurs in the secretory canalicular space of the parietal cell. The activation of the PPI is really dependent upon two things: First, the pH in which you place the PPI; and second, the pKa of the PPI. Another feature that's very unique and important for PPIs is that the active moiety, the sulfonamide that is created as a result of the activation, concentrates up to 1000-fold higher in the secretory canaliculus, compared with the rest of the body. This concentration accounts for the very high potency of the PPIs and yet their limited side effects. Rabeprazole is a weak base, which means that it has an affinity for the highly acidic environment of the acid spaces of the parietal cell secretory canaliculi (the most acidic site in the body).Rabeprazole is inactive at neutral pH and becomes an active acid pump inhibitor only after rabeprazole gains a proton under these acidic conditions.The active form of the drug is a sulphenamide, which, being positively charged, does not pass readily through membranes and therefore remains within the secretory canaliculi, close to the luminal membrane of the parietal cell. Sulphenamide molecules reacts with a cysteine-SH group on the luminal face of H+,K+-ATPase (proton pump).The formation of this complex permits long-lasting acid inhibition, irrespective of secretory stimuli.
PPI c hot ha trong mi trng acid
hot ho km khi dng cng lc vi cc thuc khng tit khc (antacide, H2RAs, anticholinergic agents, misoprostol, hay somatostatin)Khng nn ung PPI cng lc vi cc thuc khng tit khc
PPIs: hiu qu nht khi ung trc n 30 n 60 pht vo mu vi gi sau n lc t bo thnh c kch thch v bm proton hot ngBm proton c huy ng nhiu nht trong t bo thnh sau thi gian nhn i ko di nn ung PPI trc ba n u tin trong ngy.
Nu phi ung 2 ln/ ngy ung 30-60 pht trc n sng v 30-60 pht trc n ti
PPI nn ung 30-60 pht trc n sng c ch acid ti a
The important thing with the PPIs is that they only inhibit active pumps*
C CH HOT NG CA PPI (tt)pKa: l pH m PPI c 50% dng hot haTc hot ha ty thuc vo pKa :
Rabe >Ome/ Esome = Lanso/dexlanzo > Panto ** Shin JM, Cho YM, Sachs G. Chemistry of covalent inhibition of the gastric (H+, K+)-ATPase by proton pump inhibitors. J Am Chem Soc 2004; 126:7800.
The pKas of PPIs range from approximately 4 to 5, and drugs that have higher pKas have a more rapid and more complete activation, particularly as the pH of the canalicular space rises above 1 to 2.
This slide demonstrates the differences in activation times of the various PPIs. The pKas of the PPIs range from 5.0 for rabeprazole (Aciphex) down to about 3.8 for pantoprazole (Protonix). At a pH of 1.2, which would occur in the canalicular space during eating, all of the PPIs are very rapidly activated. However, once the patient stops eating, the pH in the canalicular space rises. At a pH of 5.1, notice that rabeprazole, with a pKa of 5, is still rapidly activated. Look instead at pantoprazole, which has a pKa of 3.8. When the pH in the canalicular space is 5, the activation time of pantoprazole has slowed down to nearly 300 minutes.The differences we see between the PPIs and their activation time are most important when one considers the onset of effect of the drugs. These differences might be especially important if one is trying to get symptoms under control very quickly. In addition, short-duration therapy, for example the treatment of H. pylori with PPIs, also might benefit from a rapid onset of action The differences we see between the PPIs and their activation time are most important when one considers the onset of effect of the drugs. These differences might be especially important if one is trying to get symptoms under control very quickly. In addition, short-duration therapy, for example the treatment ofH. pyloriwith PPIs, also might benefit from a rapid onset of action.
DC LC HC
The half-life of all the PPIs is relatively short, a half hour to 2 hours. Oral administration is relatively irrelevant. We're interested in the duration of effect, so the elimination half-life has little to do with it. P.P.I - Irreversible inhibitors of H+K+ATPaseAbility to maintain intragastric pH > 4 in 10-14 hrsSingle PPI will not inhibit all pumps. Second dose could be taken before evening mealNocturnal acid breathrough*
CHUYN HA THUC
Omeprazole, esomeprazole (Nexium), and pantoprazole are predominantly metabolized by enzyme 2C19. Lansoprazole is about equally metabolized by 2C19 and 3A4; rabeprazole is somewhat unique in that most of its metabolism does not go down a cytochrome P450 pathway.
CYP2C19*2in exon 5119bp93bp169bp120bp1M23456CYP2C19*3in exon 4Homozygous extensive metabolizer = Extensive metabolizer (EM)Heterozygous extensive metabolizer -= Intermediate metabolizer (IM)Poor metabolizer (PM)*1/*1*1/*2*1/*3*2/*3*2/*2*3/*3PCR-RFLP patterns for CYP2C19 genotyping. CYP2C19 genotyping pattern are determined by the combination of cleavage patterns for CYP2C19*2 and CYP2C19*3.KIU GEN V KIU HNH CYP2C19
There are two genes that code for 2C19; having both genes makes you a homozygote extensive metabolizer. Having one functional and one nonfunctional gene makes you a heterozygote extensive metabolizer, and having two nonfunctional genes makes you a poor metabolizer for 2C19.
PHN B KIU HNH CA CYP2C19Yamada S. J Gastroenterol. 2001, 36: 669-672Hong-Guang Xie et al. Pharmacogenetics 1999; 9: 539-549
nEMIMPMTrung Quc12126,4%49,6%24%Nht Bn9636,5%45,8%17,7%Thi Lan12137,2%47,1%15,7%Vit Nam9040%40%20%Da trng1.35672,6%25,3%2,1%
A compilation of clinical data of CYP genotype distribution among different ethnic groups clearly showed that the incidence of extensive metabolisers in Asians is much lower than Caucasian population. In addition, it is also clear that in the Asian population, there is greater variability and hence it is likely that efficacy of drug metabolized by CYP2C19 would be unpredictable.
80% benh nhn ngi chu A cha u lieu v ho co kieu hnh di truyen EM, IM. Neu tng lieu, * 20% nguy c qua lieu, * Tac dung phu caoRapid metabolizers have lower blood concentration of PPIs; slow metabolizers have relatively higher concentration of PPIs. Of course, the response to PPIs varies with the amount of drug present in the patient. Notice that most Caucasians are extensive metabolizers of 2C19, with only about 3% being poor metabolizers. Asians are more often slow metabolizers of 2C19, about 20%, due to a higher occurrence of dysfunctional gene
PPI c CH cng nhanh
clearance cng tng nng thuc cng gim nhanh gim hiu qu khng tit *PM: c tc CH chm hiu qu mnhEM: c tc CH nhanh hiu qu km c th gy tht bi dit tr H. Pylori, lot/ GERD khng tr
PPI no c CH t ph thuc vo CYP2C9 c :Hiu qu T n nh, t b nh hng bi kiu hnh CYP2C19t tng tc thuc KIU HNH CYP2C19 V HIU QU T CA PPI* Krisztina Hagymsi; Pharmacogenomics.2011;12(6):873-888.
KIU HNH CYP2C19 NH HNG LN pH D DY
Omeprazole: Nhm mang kiu hnh EM cho t l cn lot cao hn nhiu so vi PM, IM (Hiu qu iu tr ph thuc kiu hnh CYP2C19) Rabeprazole: Khng c khc bit c ngha v t l cn lot sau 2 tun 3 dng kiu hnh PM, IM & EM (Hiu qu iu tr khng ph thuc kiu hnh CYP2C19)
CHUYN HO ESOMEPRAZOLE Andersson T, et al. Aliment Pharmacol. Ther. 15(10), 15631569 (2001).Krisztina Hagymsi; Pharmacogenomics.2011;12(6):873-888.
The explanation for this lies in the alteration in metabolism and clearance with repeated dosing of esomeprazole. After the first dose, there is metabolism by CYP2C19 and CYP3A. This leads to esomeprazole sulphone, and this esomeprazole sulphone inhibits the CYP2C19 pathway; therefore, almost the entire metabolism goes free