gastric acid secretion

Deurali-Janta Pharmaceuticals Pvt. Ltd.

Presented by:Asad KamranTechnical Consultant, MPDDeurali-Janta Pharmaceuticals Pvt. Ltd.

Gastric Acid SecretionPhysiology

INTRODUCTION

• An intricate balance of chemotransmitters delivered to the gastric mucosa by several pathways.

• Stimulatory and inhibitory mechanisms.• Remarkable ability of normal gastro-duodenal

mucosa to defend itself against injury – Several mechanisms.

• Neural, endocrine, paracrine, and autocrine control pathways.

INTRODUCTION

• There is limited understanding of the actual physiologic and pathophysiologic importance of most of these pathways and chemotransmitters.

• Gastric acid is not essential for life.• The benefits of gastric acid are to facilitate

digestion of proteins and the absorption of calcium, iron, and vitamin B12.

INTRODUCTION

• Gastric acid suppresses growth of bacteria, which can help prevent enteric infections and small intestinal bacterial overgrowth.

Phases of Gastric Secretion

Phases Of Gastric Secretion

• Three interrelated phases: cephalic, gastric, and intestinal.

• Cephalic phase is activated by the thought, taste, smell and sight of food, and swallowing, mediated mostly by cholinergic/vagal mechanisms.

• Gastric phase is due to the chemical effects of food and distension of the stomach.

Phases Of Gastric Secretion

• Gastrin appears to be the major mediator since the response to food is largely inhibited by blocking gastrin action at its receptors.

• Intestinal phase accounts for only a small proportion of the acid secretory response to a meal; its mediators remain controversial.

Phases Of Gastric Secretion

Secretion Of Acid & Pepsin

Secretion Of Acid & Pepsin

• Gastric acid secretion from parietal cells is regulated by redundant, overlapping pathways:– endocrine (gastrin),– paracrine (locally delivered histamine and

somatostatin),– neural (acetylcholine),– and probably autocrine (transforming growth

factor-alpha) factors.

Mechanism Of Acid Secretion

Mechanism Of Acid Secretion

• The hydrogen ion concentration in parietal cell secretions is roughly 3 million fold higher than in blood.

• Chloride is secreted against both a concentration and electric gradient.

• Ability of the parietal cell to secrete acid is dependent on active transport.

• The key player in acid secretion is an H+/K+ ATPase or "proton pump" located in the cannalicular membrane.

Mechanism Of Acid Secretion

• Hydrogen ions are generated within the parietal cell from dissociation of water.

• The hydroxyl ions formed in this process rapidly combine with carbon dioxide to form bicarbonate ion, a reaction catalyzed by carbonic anhydrase.

• Bicarbonate is transported out of the basolateral membrane in exchange for chloride.

Mechanism Of Acid Secretion

• The outflow of bicarbonate into blood results in a slight elevation of blood pH known as the "alkaline tide".

• This process serves to maintain intracellular pH in the parietal cell.

• Chloride and potassium ions are transported into the lumen of the cannaliculus by conductance channels, and such is necessary for secretion of acid.

Mechanism Of Acid Secretion

• Hydrogen ion is pumped out of the cell, into the lumen, in exchange for potassium through the action of the proton pump; potassium is thus effectively recycled.

• Accumulation of osmotically-active hydrogen ion in the cannaliculus generates an osmotic gradient across the membrane that results in outward diffusion of water.

Mechanism Of Acid Secretion

• The resulting gastric juice is 155 mM HCl and 15 mM KCl with a small amount of NaCl.

Mechanism Of Acid Secretion

Control Of Acid Secretion

Control Of Acid Secretion

• Parietal cells bear receptors for three stimulators of acid secretion.– Acetylcholine (muscarinic type receptor)– Gastrin– Histamine (H2 type receptor)

• When low levels of each i.e. Acetylcholine, Gastrin & Histamine are present, acid secretion is strongly forced.

Control Of Acid Secretion

• Additionally, pharmacologic antagonists of each of these molecules can block acid secretion.

• Histamine's effect on the parietal cell is to activate adenylate cyclase, leading to elevation of intracellular cyclic AMP concentrations and activation of protein kinase A (PKA).

Control Of Acid Secretion

• One effect of PKA activation is phosphorylation of cytoskeletal proteins involved in transport of the H+/K+ ATPase from cytoplasm to plasma membrane.

• Binding of acetylcholine and gastrin both result in elevation of intracellular calcium concentrations.

Control Of Acid Secretion

The Parietal Cell

The Parietal Cell

• In the resting state, parietal cells are filled with secretory vesicles that coalesce with stimulation to form channels (canaliculi) that drain to the apical lumen.

• The secretory membrane lining these structures contains the hydrogen-potassium-ATPase acid-secreting pump.

The Parietal Cell

• This pump is always active, but exists in a short-circuited state in resting vesicles because the pathway necessary for transporting potassium to the apical surface for exchange with hydrogen is not present or active.

• With stimulation, this pathway for potassium-chloride cotransport becomes active, allowing hydrogen-potassium exchange to occur.

The Parietal Cell

• Parietal cell activation involves an increase in cytoplasmic calcium or generation of cyclic AMP, followed by activation of a cAMP-dependent protein kinase cascade that triggers translocation of proton pump containing membranes to the apical surface.

• The cessation of acid secretion is associated with the re-internalization of the hydrogen-potassium-ATPase pump.

The Parietal Cell

Gastrin

Gastrin

• Gastrin is the major endocrine regulator of the secretory response to a protein meal.

• It is released from gastrin-expressing cells (G cells) localized to the antrum.

• Gastrin enhances gastric acid secretion from parietal cells primarily by stimulating the synthesis and release of histamine from oxyntic mucosal enterochromaffin-like (ECL) cells.

Gastrin

• However, gastrin also has direct actions on parietal cells.

• Acid secretion is tightly controlled by a second hormone, somatostatin, which is a potent inhibitor of both gastrin and histamine synthesis and release, and, therefore, of gastric acid secretion.

• Gastrin is the best identified trophic regulator of parietal cell mass in humans.

Gastrin Receptors

• Gastrin acts via activation of the cholecystokinin CCK2 receptor (also known as the CCK-B or gastrin receptor), which has equal affinity for cholecystokinin (CCK) and gastrin.

• These receptors have been localized to parietal and ECL cells, but it is likely that the ECL cell gastrin receptor is of greater importance in regulating acid secretion.

Gastrin Receptors

• Gastrin "receptors" have also been found on somatostatin-secreting D cells.

• However, this receptor is a CCK1 or CCK-A receptor that has much greater affinity for CCK than for gastrin.

• This difference in receptor affinity may explain why gastrin is so much more effective as a stimulant of acid secretion, while CCK induces greater release of the inhibitor somatostatin.

Gastrin Receptors

• CCK1 receptors exert inhibitory effects on acid secretion in vivo, mediated by release of endogenous somatostatin.

Regulation Of Gastrin secretion

• Complex mechanisms control gastrin release from the antral G cells.

Regulation Of Gastrin secretion

• Two meal-related factors stimulate gastrin secretion: gastric distention and amino acids.

• Low grade distention activates vasoactive intestinal peptide neurons which stimulate somatostatin release and therefore inhibit gastrin secretion.

• Higher grade distention causes cholinergic activation which reverses the pattern to one of increased gastrin and reduced somatostatin secretion.

Regulation Of Gastrin secretion

• Amino acids induce gastrin release; direct actions on the G cell have been demonstrated but amino acids also activate both cholinergic neurons and bombesin neurons.

• The release of bombesin (also called gastrin-releasing peptide) from mucosal nerves directly stimulates the G cell.

• Somatostatin is the major inhibitory paracrine regulator of gastrin release.

Regulation Of Gastrin secretion

• Gastrin itself contributes to this process by enhancing the secretion of somatostatin.

• Cholinergic activation after gastric distention or in response to a meal promotes acid secretion by shifting the balance of stimulatory and inhibitory mechanisms toward the stimulatory side, directly activating the parietal cell and stimulating gastrin release while suppressing somatostatin release.

Gastrin Summary

Histamine

Histamine

• Histamine is the major paracrine stimulator of acid secretion.

• It is localized both in mucosal mast cells and in endocrine cells, the latter called enterochromaffin-like (ECL) cells because of the silver-staining properties of their granules.

• The ECL cells are localized to the acid-secreting oxyntic or body mucosa, in direct proximity to the parietal cell.

Histamine

• Gastrin is the primary stimulus to histamine release from ECL cells.

• ECL cells are also directly stimulated by pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP).

• Somatostatin is a major direct inhibitor of histamine release; calcitonin gene-related peptide (CGRP), peptide YY, prostaglandins, and galanin also inhibit release.

Histamine

• Stimulated ECL cells promptly degranulate, with release of histamine and pancreastatin from the vesicles; this is followed by an increase in histamine synthesis.

• Although gastric mast cells outnumber ECL cells, gastrin has only been demonstrated to release histamine from ECL cells.

• Several lines of evidence indicate that ECL cell histamine is the major physiological mediator of acid secretion.

Histamine

• Inhibitors of the histamine-forming enzyme, histidine decarboxylase (HDC), block the acid secretory response to gastrin, but not to histamine.

• The effects of histamine are largely mediated by the H2 receptors, which explain the efficacy of H2 receptor blockers in the treatment of acid-peptic disease.

Histamine

• These drugs inhibit acid secretion in response to gastrin, meal, and neural stimulation, clearly establishing that histamine plays a role as a universal mediator or modulator of the acid secretory response.

• Histamine may also act at H3 receptors to increase acid secretion via inhibition of somatostatin release.

Somatostatin

Somatostatin

• Somatostatin is a potent inhibitor of acid secretion.

• It is released from D cells, which are present throughout the gastric mucosa.

• Although somatostatin has some effects on parietal cells, its major effects are exerted on the inhibition of histamine release and to a lesser extent on gastrin release.

Somatostatin

• The secretion of somatostatin is increased by gastric acid and by gastrin itself, suggesting that a major function of somatostatin is to modulate the feedback inhibition of the acid secretory response to gastrin.

• Somatostatin primarily acts by suppressing gastrin-stimulated release of histamine from ECL cells.

Somatostatin

• Somatostatin secretion is also affected by neural inputs. It is suppressed by cholinergic activation and increased by vasoactive intestinal peptide activation.

Acetylcholine

Acetylcholine

• Neural input may serve as an important integrator of secretory function.

• The mucosal nerves, containing acetylcholine, bombesin, VIP, and PACAP mediate the response to the cephalic phase of acid secretion and to gastric distention and amino acids.

• Acetylcholine is the major stimulatory mediator.

Acetylcholine

• The major effects of muscarinic receptor activation are to increase gastrin release, stimulate parietal cells, and inhibit somatostatin secretion.

• Vasoactive intestinal peptide release has a dual effect: a weak transient increase in acid secretion, possibly due to direct effects on ECL cells; and a sustained reduction due to enhanced release of somatostatin.

Acetylcholine

• Vasoactive intestinal peptide release has a dual effect: a weak transient increase in acid secretion, possibly due to direct effects on ECL cells; and a sustained reduction due to enhanced release of somatostatin.

• Orexin, nitric oxide, and galanin may also contribute to the neural regulation of acid secretion.

Components Explained

Prostaglandins

Prostaglandins

• Prostaglandins are autocrine factors that inhibit acid secretion, histamine-stimulated parietal cell function, and gastrin-stimulated histamine release.

• The effect on gastrin release is less clear as both inhibitory and stimulatory mechanisms have been described.

• They are generated from cells in the epithelium and lamina propria.

Prostaglandins

• Macrophages and capillary endothelial cells appear to be the primary source.

• The mechanisms regulating their release in vivo are not well-understood.

Other Secretory Regulators

Other Secretory Regulators

• Transforming growth factor-alpha (TGF-alpha) is an autocrine factor that is present in parietal cells and inhibits gastric acid secretion.

• Peptide YY (PYY) is released postprandially from cells in the ileum and colon and inhibits the cephalic and gastric phases of acid secretion via central and peripheral effects.

• PYY binds to receptors on ECL cells and inhibits gastrin-stimulated histamine release.

Pepsin

Pepsin

• Acid plus pepsin is much more ulcerogenic than acid alone, leaving little question that the "peptic" label appropriately reflects the critical role in ulcer formation of the proteolytic activity in gastric juice.

• The potentiating effect of pepsin may be due in part to its mucolytic activity.

• Peptic activity is closely linked to acid secretion and gastric pH.

Pepsin

• This relation is partly due to peptic digests of dietary protein (primarily amino acids), which are potent stimulants of gastrin release and acid secretion.

• In addition, pepsinogen is converted to the active protease pepsin at low gastric pH; on the other hand, pepsin is inactivated when the pH is increased above 4.

Pepsin

• This pH dependence probably accounts for the requirement for elevating the intraluminal pH above 4 to heal refractory ulcers.

• Pepsinogen secretion is enhanced by acetylcholine and peptides of the CCK/ gastrin family.

• In addition, agents that raise cyclic AMP, such as secretin and vasoactive intestinal peptide, increase pepsinogen secretion in vitro.

Acid Secretory Regulationin Human

In Human

• Aspiration of gastric contents via a nasogastric tube is the easiest method of measuring acid secretion, if collections are complete.

• Basal acid secretion can also be reliably measured through an endoscope during a 15-minute collection period.

• Alternatively, intragastric titration allows the actual level of acid secretion to be measured by the quantity of base required to hold the gastric pH at a predetermined level.

In Human

• Placement of a gastric pH probe allows hydrogen ion concentration to be measured over a 24-hour period, but measuring hydrogen ion concentration provides only an indirect indicator of the rate of acid secretion.

• Basal acid output (BAO) is the level of acid secretion when the subject is unstimulated; measurements are widely variable among individuals.

In Human

• Physiologic factors enhancing secretion are vagal activation, food (particularly amino acids), and gastric distention.

• Histamine release from enterochromaffin-like (ECL) cells plays a major role since the acid secretory in response to food, gastrin, and vagal stimulation is inhibited by H2 receptor antagonists.

• In contrast, carbohydrates and fat inhibit acid secretion.

In Human

• Intestinal exposure is required for the carbohydrate effect, but the mechanisms are uncertain.

• Fat stimulates the release of cholecystokinin (CCK), which is a potent inhibitor of acid secretion; fat also releases other potential mediators and it activates neural responses.

Effect OfHelicobacter Pylori Infection

H. Pylori

• Acute H. pylori infection induces a short period of hypochlorhydria.

• In contrast, chronic infection can lead to increases in basal and stimulated acid output, particularly in patients who develop duodenal ulcer.

• H. pylori eradication reduces basal and stimulated acid output by 50 percent at one month, and to normal levels by one year.

H. Pylori

• One mechanism by which H. pylori may enhance gastric acid secretion is via increased release of gastrin.

• Patients with H. pylori infection have elevated basal and stimulated concentrations of serum gastrin, and a decreased concentration of somatostatin.

Gastric Acid Hypersecretion

Hypersecretion

• Gastric acid hypersecretion (characterized by a basal acid output >15 mEq/hour) is observed in approximately 30 percent of patients with duodenal ulcers.

• H. pylori infection is a contributing factor, but some patients have acid hypersecretion independent of H. pylori.

Hypersecretion

• Other uncommon conditions associated with acid hypersecretion include the Zollinger-Ellison syndrome (due to a gastrinoma), mastocytosis, and a retained antrum following partial gastrectomy.

Phr. Asad KamranTechnical Consultant, MPD

Deurali-Janta Pharmaceuticals Pvt. Ltd.