4. Gastric Acid Secretion GORD

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PHAY2004: Control of the gastro intestinal system

•Enteric system

•Control of gastric secretion

- This is a complex process involving number of different cell types and chemical signalling

molecules (neurotransmitters, hormones, local mediators, ions and the product of

digestion)



Vagus Nerve

Pelvic Nerve

Innervation of gastric secretion



Enteric nervous system

The arrangement of neurones in the

enteric nerve plexi.

•The gastrointestinal tract is innervated

by both the sympathetic and

parasympathetic branches of the

autonomic nervous system.

• Autonomic nerves form synapses

directly on smooth muscle and

secretory cells,

•However, the gastrointestinal system

possesses a nervous system of its own-

the enteric nervous system, which alsoreceives autonomic innervation.

•The enteric nervous system comprises

various types of neurones organised

into the myenteric (Auerbach's ) and

mucosal (Meissner's ) plexuses.

•Auerbach’s- situated between the

longitudinal and circular muscle layers

•Meissner’s - situated in the mucosal

layer.



Enteric nervous system



Enteric nervous systemThe arrangement of ENS

Synaptic connections are made with:

•the enteric neurones with one another,

•and with autonomic nerves

This is somewhat complex and can be designated as:•Motoneurones- excitatory

•interneurones –inhibitory

As a result act to regulate muscle contraction/relaxation and secretions.

•Sensory neurones-

Sensory neurones are activated by:-mechanoreceptors (which detect stretching of the muscle)

-chemoreceptors (which detect irritant substances in the gut lumen).

Although some of these neurones use acetylchol ine as a transmitter, many do not- termed non-

adrenergic non-chol inergic (NANC) and use variety of transmitters:

• ATP ,

•5-hydroxytryptamine (5-HT),•substance P ,

•vasoact ive intest inal polyp ept ide (VIP)

•nit r ic oxide (NO)

Overall function of the ENS is to control contraction/relaxation of the gut and mediate release of

local mediators.



Summary of ENS modulation



Acid Secretion

A major constituent of gastric secretion is HCl which is secreted from parietal (oxyn tic)

cel ls together with in t r insic factor (important for the absorption of vitamin B12).

Human parietal cells -

stomach



Schematic illustration of the mechanism of the secretion of hydrochloric acid by the gastric

parietal cell. Secrection involves a proton pump (blue) which is a H+/K+ -ATPase, a symport carrier (C)

for K+ and Cl−, and an antiport (pink), which exchanges Cl─ and HCO3─. A Na+/H+ antiport at the

interface with the plasma may also have a role (not shown).

• Acid secretion- Carbonic

anhydrase in the parietal cell

cytoplasm catalyses the

conversion of CO2 and H2O to

H2CO3 which dissociates into H+and HCO3−

•The H+ ions are then actively

pumped into the lumen of the

stomach via H+/K+ ATPases

(proton pumps) which also move

K+ ions in the opposite direction.

•The HCO3− ions are transported

into the bloodstream by antiporters

in exchange for Cl− ions which are

then carried by symporters into the

lumen together with K+ ions.

Acid Secretion



Gastric Phases

3 main phases:

• Cephalic phase – sight, taste and smell (30% of total acid

produced)

• Gastric phase –stimulated by contact of food with gastric

mucosa, (60% of total acid produced)

• Intestinal phase – stimulated as food enters duodenum (10%

of total acid produced)



Summary of the mechanisms of stimulation of acid secretion from the oxyntic

cell by gastrin, histamine and neurotransmitters.

.

Acid Regulation-How?

Vagus nerve activity

and gastrin are also

involved in the

activation of chiefcells to produce

pepsinogen



Mechanisms of feedback inhibition

of acid secretion by somatostatin

released in response to low pH in

the antrum. Somatostatin inhibits

both the release of gastrin from G

cells and release of histamine

from the entrochromaffin like cells.

Acid secretion is inhibited by somatostatin released from the D cells in response to high

acidity. For clarity this is illustrated in a separate diagram. (Ach, acetylcholine,; GRP,

gastrin releasing peptide; CCK-BR, cholecystokinin B receptor.)

Acid Secretion-Control



Drugs that inhibit or neutralize acid

secretion and their targets:

• histamine H2 receptor

• CCK cholecystokinin-B receptor

• PG, prostaglandin receptor.

Acid Secretion-Control



Summary-Control of gastric acid secretion

Summary diagram illustrating the direct and indirect and mechanisms involved in the

control of acid secretion and sites of action of drugs.

Acetylcholine (ACh) (from the

vagus nerve) and gastrin (from

the stomach) may act directly on

the parietal cell or indirectly by

releasing histamine.



Summary of innervation and control of gastric secretion

Parasympathetic

• vagus (mainly afferent, but ~20% efferents

• vagal efferents convey info from dorsal vagal

complex, which integrates sensory

information from gut and taste receptors and

from higher centres to set overall level of

gastric function

sympathetic innervation is sparser

ENS encircles walls of stomach

-allows for some degree of autonomous function,

in addition to transmitting effects of central input



*Dyspepsia:

Peptic ulcersGastro - oesophageal reflux disease (GORD)

*Vomiting

•Constipation and diarrhoea

Gastrointestinal function and disorders



Dyspepsia is a general term used to describe the symptomsassociated with upper gastrointestinal tract disorders.

Symptoms include heartburn, abdominal pain, nausea and

belching.

These can sometimes be indicative of an underlying disease,such as gastric or duodenal ulceration, but are often of unknown

origin.

Dyspepsia

Peptic ulcersGastro - oesophageal

reflux disease (GORD



Peptic ulcers

Left: Endoscopic view of gastric ulcer. Right: X-ray of barium visualized gastric ulcer

can occur in the stomach or duodenum

Risk factors associated with the condition; family history, heavy smoking and alcohol

consumption

Symptoms of ulceration: epigastric pain, nausea and vomiting

*Weight loss and anorexia- common in those with gastric ulcers

*pain associated duodenal ulceration often experienced at night and resolves overnight

or by the consumption of food.

An ulcer is a wound, a discontinuity or break in a bodily membrane that

impedes the organ of which that membrane is a part from continuing its

normal functions



Gastric ulceration is also associated with long-term use of

non -steroidal ant i - inf lammatory drug s (NSAIDs).

These interfere with the integrity of the mucus layer which

protects the gastric lining from the acidic environment in the

stomach. NSAIDs block the synthesis of prostaglandins byinhibiting the enzyme cyclooxygenase .

Causes ofgastr ic ulcers

Increasing evidence that the presence of Hel icobactor

py lor i (H. Pylori) in the gut may also be a predisposing

factor.

An imbalance betweenthe pepsin and stomach

acids.



H. Pylori

spiral-shaped micro-organisms instomach mucosa

described almost 100 years ago

presence was not really taken

seriously until the late 1970s, when

John Warren, a pathologist in Perth,Western Australia, noted the

appearance of spiral bacteria

overlaying gastric mucosa, and

chiefly over inflamed tissue.

The link between H. pylori and thepathogenesis of peptic ulcers was

established in the mid 1980s.



H. Pylori H. pylori survives the acidic conditions present in the stomach by growing within

the mucus layer.

synthesizes large amounts of urease which catalyses the liberation of ammonia

from urea. The ammonia serves to buffer the acid in the bacteria's environment.

1.H. pylori penetrate the mucus

layer of host stomach and

adhere the surface of gastric

mucosal epithelial cells.

2.produce ammonia from ureaby the urease, and the

ammonia netralize the gastric

acid to escape from

elimination.

3. prolifirate, migrate, and

finally form the infectious focus.

4. The gastric ulcerization is

developed by destruction of

mucosa, inflammation and

mucosal cell death.



Treatment of Peptic Ulcers

H2 antagonists and proton pump inhibitors-classed as ulcer-healing drugs are

used in the treatment of gastric and duodenal ulceration

cimet idine the pro totypical H2-receptor antagon is

http://en.wikipedia.org/wiki/Cimetidine

http://en.wikipedia.org/wiki/Cimetidine



Treatment of Ulcers

Proton pump inhibitors are also used in combination with antibacterials for the

eradication of H. Pylori:

One week, triple therapy regime is successful in about 85% of cases.

Two week therapy periods can be affected by adverse side-effects which

reduce patient compliance.

Typically regime: administration of omeprazole (20 mg, twice daily) together with

amoxici l l in (1 g, twice a day) plus clar i thromycin (500 mg, twice a day).

If the patient has received clarithromycin for another infection, metronidazole (400 mg,

three times a day) may given with amoxicillin (500 mg, three times a day).

Resistance to clarithromycin and metronidazole is common, hence the combination of

antimicrobials.

Prostaglandin analogue: misoprosto l

•They exert antisecretory and cytoprotective properties

•This can prevent NSAID-induced ulceration, used when NSAID treatment cannot be

withdrawn.



Proton Pump Inhibitors



Proton pump inhibitors - mechanism of action

The proton pump inhibitors are generally considered to be better than H2 receptorantagonists in the treatment of peptic ulcers and GORD.

They target the final step in acid secretion (H+/K+ ATPase) their effects cannot be overcome by food-induced acid secretion mediated by theactivation of muscarinic or CCK receptors.

These drugs are substituted benzimidazoles- weak bases, and as a result,accumulate in the acidic compartment of the parietal cells close to the H+/K+ ATPases.

The acid environment catalyses their conversion to a sulphenamide intermediatewhich interacts covalently with the sulphydryl groups on the cysteine residues in theextracellular domain of the H+/K+ ATPase

thus blocking its activity.

Omeprazole's duration of action is about 24 h, its dissociation from the proton pumpis probably mediated by glutathione which releases the omeprazole sulphide andallows re-activation of the pump.



Gastro - oesophageal reflux disease (GORD)

heartburn, difficulty in swallowing and regurgitation of gastric contents into the

mouth.

Reflux is associated with reduced peristaltic activity in the oesophagus and

transient relaxation of the oesophageal sphincter allowing gastric acid, pepsin andbile to come into contact with the oesophageal epithelium.



Drugs

Antacids: aluminium

hydroxide,

magnesiumcarbonate,

magnesium

trisi l icate

Alginates: gaviscon

Antacids are used overcome the symptoms of the conditions listed above:

• they neutralise gastric acidity and are more effective if taken after food

• but do not, however, treat the underlying disease

Some antacid preparations contain simeticone, an anti-foaming agent that prevents

flatulence, others contain alginates which form a 'raft' on the surface of the stomach

contents, thus reducing reflux.

Histamine H2

antagonists:

cimetidine,

famotidine,

ranit idin e, nizatidine

Proton pump

inhibitors:

omeprazole,

esomeprazole,

lansoprazole,

pantoprazole,

rabeprazole



Other types of Ulcers

Ulcerative colitisCrohn's disease

Inflammatory bowel disease

•Chronic disease that causes inflammation in

the rectum, colon and the last part of the small

ileum.•The inflammation affects the inner lining of the

colon, causing ulcers.

•Chronic disease that can cause

inflammation anywhere along the

digestive tract from the mouth to theanus.

Abdominal pain and cramps

Bloody stool

Diarrhea

Fever

Loss of appetite

Symptoms



Treatment of IBDs

Drugs commonly used to treat ulcerative colitis include:

Azulfadine (sulfasalazine) Asacol (mesalamine)

Immunosuppressants

Methotrexate

TNF-alpha inhibitors

Corticosteroids

Surgery: Surgery is also used as a treatment for IBDs.

Medicat ion : A variety of medications may be used to treat IBDs.

Medications typically fall into two categories: Maintenance drugs,

which are taken continuously to prevent flare-ups, and fast-acting

drugs, which are taken to stop a flare-up.

http://ibdcrohns.about.com/cs/prescriptiondrugs/a/methotrexatefaq.htm

http://ibdcrohns.about.com/cs/prescriptiondrugs/a/methotrexatefaq.htm



Non-invasive Breath Tests Can Detect Ulcer-Causing Bacteria

Diagnostic Tests for peptic ulcers

and IBDs

Upper endoscopy may be done if disease in the upper digestive tract is

suspected.

Colonoscopy may be used to look inside the colon to see if inflammation is

present for IBDs

Blood tests are also commonly done to provide helpful information about thestatus of IBDs, especially red blood cell and white blood cell counts.

Other blood tests can measure electrolyte levels, such as sodium and potassium,

to determine if they are depleted from persistent diarrhea.

Other types: x-rays, barium enema, upper gastrointestinal series



Ejection of the gastric contents through

the mouth

protective role of the stomach as it results

in the removal of toxic substances from the

body.

It is controlled by the vom it ing centre

and the chemo receptor tr igg er zone(CTZ) situated in the brain stem

CTZ- is relatively permeable in BBB

consequently it can be affected by various

circulating mediators and by drugs that do

not cross the blood brain barrier

The main neurotransmitters involved in

this reflex are ACh, 5-HT, histamine,

dopamine and substance P and it is the

receptors they act on that provide the

targets for the most commonly used anti-

emetic drugs.

Vomiting (emesis)





Drugs affecting vomiting

Muscarinic

antagonists:

hyoscine

Histamine H1

antagonists:

promethazine,

cinnarizine,

cycl iz ine

The above are used in the treatment of motion sickness and nausea associated

with vertigo and labyrithine disorders. They have no effect on the CTZ.

Dopamine D2 antagonists: metaclopramide,

domper idone

5-HT3 antagonists: ond ansetron, dolasteron,granisetron, tropisetron

Neurokinin 1 antagonists: arepitant

Cannabinoids: nabi lone



Constipation

• Constipation is the passage of small, hard stools less frequently than is usual

• Often caused by a diet low in fibre and/or inadequate fluid intake

• However, it can also be a symptom of an underlying disease, for example colonic

cancer, or a side-effect of certain drugs, such as opioid analgesics• Treatment involves the use of either bulking agents, osmotic or stimulant

laxatives.



Constipation

Lactobacillus fermentum

Efficacy: The Lactobacillus fermentum

is lack of intestinal Lactobacillus A&C

active probiotic, high unit

Intestinal bacteria can complement

good, improve in appetence, indigestion,constipation and diarrhoea

Effective treatment collapse-Abscess

colitis and other diseases.

Constipation Bulking agents

http://lactic-acid-bacteria.net/

http://lactic-acid-bacteria.net/



Constipation-Bulking agents

Examp les: Wheat bran , ispaghula husk , stercul ia and methylcel lu lose

Increase faecal mass, thus promoting perstalsis by stimulating mechanoreceptors in the colon wall.

In addition, they cause the retention of water in the lumen of the colon which softens the faeces.

These agents take approximately 24 h to work, and should be accompanied by a liberal intake of

fluid.Osmotic laxatives include lactu lose and magnesium s alts .

Lactulose:disaccharide which is broken down by bacteria in the colon to its constituent parts

(fructose and galactose) which release osmotically active lactic and acetic acids upon fermentation.

This process results in lactulose taking approximately 48 h to have an effect. In addition to their

osmotic effects, magnesium salts also stimulate CCK release in the small intestine which promotes

motility.



Bisacody l , danthro n, senna and sodium picosulph ate are examples of stimulantlaxatives.

• Exactly how these agents work is unknown, however, it is believed that they stimulatemyenteric nerve plexuses thus promoting gut motility and reducing fluid reabsorption.

Senna is the most gentle of these and acts within 8 - 12 h. It is metabolised by colonicbacteria to senosides A and B (anthracene glycoside derivatives) which irritate the gutthus stimulating faecal movement.

Danthron is carconogenic, and only used in elderly terminally ill patients, either in aformulation with the wetting agent poloxamer 188 (co-danthramer ) or with the detergentdocusate sodium (co-danthrusate ).

Faecal softeners are useful in less severe cases of constipation. Glycerol, arachis o il

and l iquid p araff in are examples, although the latter is not rarely used.

Constipation-Treatments



Diarrhoea

Gastrointestinal infections (bacterial and/or viral) are the usual cause of acute diarrhoea,

however, this can also be a side effect of certain drugs, broad spectrum antimicrobials,



Diarrhoea-Treatments

Opioids- such as cod eine, diphenox ylate and loperamide are used to treat this condition

• Codeine , is a morphine congener, whilst other two are congeners of pethidine

• Their therapeutic effects are due to their action on opioid receptors (μ and κ) on enetric

neurones, resulting in : reduced gut motility, allowing more time for fluid reabsorption and

increasing the transit time of intestinal contents.

In addition, both codeine and loperamide have anti-muscarinic properties which, in turn,decreases peristalsis.

Diphenoxylate does not have this quality, and is therefore formulated with a small dose of

atropine as co-phenotrope .

Adequate hydration and electrolyte balance should also be maintained when treating acute

diarrhoea, particularly in children and frail or elderly individuals.

Chronic diarrhoea may be the result of conditions such as colonic cancer, inflammatorybowel disease or coeliac disease.-In these cases, the underlying condition must be treated in

addition to the diarrhoea.



• Constipation and/or diarrhoea together with abdominal pain, bloating, anddiscomfort is associated with i rr i table bowel disease (IBS) .

• The underlying cause(s) of this condition usually remain unidentified, although it isgenerally believed to involve a psychological component which may requiretreatment.

• The therapeutic agents listed above are often used to treat the constipation ordiarrhoea as appropriate, however antispasmodic agents are of benefit inovercoming the abdominal pain which is caused by smooth muscle spasms.

• Drugs of this class: atropine sulphate , diclover inehydrochlor ide , hyoscinebuty lbromide and prop anthel ine brom ide , all of which are anti-muscarinics, andalverine citrate , mebeverine hydroc hlor ide and peppermint oi l which arethought to be direct intestinal smooth muscle relaxants.

IBS (irritable bowel syndrome)

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4. Gastric Acid Secretion GORD