1. Drugs acting on the gastrointestinal tract
2015

2. Drugs used to inhibit or neutralise gastric secretion
to reduce acid secretion and peptic ulceration (both duodenal and gastric), reflux oesophagitis (in which gastric juice causes damage to the oesophagus)
Etiology:
- increased mucosal irritation - mucosal-damaging mechanisms - acid, pepsin,stress, alcohol, cigarette smoking…)
- decreased mucosal-protecting mechanisms of the stomach - NSAIDs consumption - PGS synthesis is diminished (PGE1-2 stimulates mucus and bicarbonate secretion, decreases acid secretion and causes vasodilation), PGI2 inhibits acid, stimulates mucus and bicarbonate secretion
- infection of the stomach mucosa with Helicobacter pylori (chronic gastritis)

3. Regulation

4. GASTRIC PARIETAL CELL intersticial fluid bazolaterall membrane apical
M - muscarinic receptor
PGR - prostaglandin E2 receptor
ECHB –enterochromaffin cells
Gs a Gi - G-proteins
cAMP - cyclic AMP
Ac - adenylyl cyclase
PK - proteinkinase
PGE - prostaglandins E
C - synport carrier for Cl- a K+
P = antiport, which exchanges
Cl- and HCO-3
PP = proton-pump
bazolaterall
membrane
Regulation of acid secretion by parietal cells is important in peptic ulcer. The secretion is an isotonic solution of HCl (150 mmol/L) with a pH less than 1. The Cl- is actively transported into canaliculi in the cells which communicate with the lumen of the gastric glands and thus with the lumen of the stomach.
This Cl- secretion is accompanied by K+, which is than exchanged for H+ from within the cell by a PP.
Carbonic anhydrase catalyses the combination of carbon dioxide and water to give carbonic acid, which dissociates into H+ and bicarbonate ions. The latter exchanges across the basal membrane for Cl-
Three main stimuli act on the parietal cells:
- gastrin (a hormon)
- ACH (a neurotransmitter)
- histamine (a local hormone)
apical
membrane

5. Treatment of peptic ulcers
ANTACIDS HISTAMINE H2-RECEPTOR ANTAGONISTS PROTON-PUMP INHIBITORS TREATMENT OF HELICOBACTER PYLORI INFECTION DRUGS THAT PROTECT THE MUCOSA

6. Drugs used to inhibit or neutralise gastric secretion - ANTACIDS
symptomatic relieve in peptic ulcer - act by neutralising gastric acid and thus raising the gastric pH. This has the effect of inhibiting peptic activity, which practically ceases at pH 5. They vary widely in their potency
The antacids in common use are salts of magnesium and aluminium - magnesium trisilicate, aluminium hydroxide, alginates
given 1 and 3 hours after each meal and at bedtime used in dyspepsia,
can be effective in promoting healing of duodenal ulcers, their benefit in gastric ulcers is less clear
oesophageal reflux

7. Histamine H2-antagonists
competitively inhibit histamine action at all H2 –receptors - reduce gastric acid secretion.
They inhibit histamine - gastrin - and ACH-stimulated acid secretion: both basal and food stimulated by 90% and promote healing of duodenal ulcers
Relapses are likely to follow when treatment with H2 –receptors antagonists is stopped
(cimetidin - a CYP450 inhibitor) ranitidine famotidine
Adverse effects: diarrhea, dizziness, muscle pain, transient rashes

8. Proton-pump inhibitors
Inhibit the terminal step in the acid secretory pathway – the proton pump which results in marked inhibition of both basal and stimulated gastric acid secretion
i.v./p.o. - given orally (as capsules containing enteric-coated granules) they are absorbed and distributed into the parietal cells and then accumulate in the canaliculi (a single daily dose affects acid secretion for 2-3 days)
weak bases - accumulate in the acid environment of the canaliculi of the stimulated parietal cells where they are activated. This preferential accumulation in areas of very low pH, such as occur uniquely in the secretory canaliculi of gastric parietal cells, results in a specific effect on these cells

9. Proton-pump inhibitors
omeprazole, esomeprazole, lanzoprazole, pantoprazole
Adverse effects (not very common) - headache, diarrhea, rashes…
used in:
peptic ulcer
reflux oesophagitis
as one component of therapy for Helicobacter pylori infection
Zollinger-Ellison syndrome (a rare condition caused by gastrin-secreting tumours)

10. Treatment of Helicobacter pylori infection
H.pylori is implicated in the production of gastric and, more particularly, duodenal ulcers and is a risk factor for gastric cancer
Combination therapy with three drugs is employed to eradicate H.pylori like:
omeprazole + amoxicillin+ metronidazole or
omeprazole + clarithromycin + amoxicillin (tetracycline) + bismuth chelates
Elimination of the bacillus can produce long-term remission of ulcers but reinfection can occur

11. Drugs that protect the mucosa
enhance the mucosal protection mechanisms
and/or provide a physical barrier over the surface of the ulcer
Bismuth chelate - out
mucosal-protecting effects - coating the ulcer base, adsorbing pepsin, enhancing local PG synthesis, stimulating bicarbonate secretion
Adverse effects - nausea, vomiting, blackening of the tongue and faeces
toxic effects on the Hellicobacter - used as one component of therapy for H.pylori infection

12. Drugs that protect the mucosa
Sucralfate
a complex of aluminium hydroxide and sulfated sucrose
in the presence of acid acquires a strong negative charge and binds to positively charged groups in protein forms complex gels with mucus - decreasing mucus degradation and H+ ions diffusion - stimulates bicarbonate secretion and PGs production
Adverse effects - constipation (in 15% of patients treated), less common: dry mouth, headache, rashes
Reduces the absorption of a number of other drugs including fluorochinolone antibiotics, theophylline, tetracycline, digoxin…

13. Drugs that protect the mucosa
Misoprostol
A stable analogue of PGE1 which inhibits gastric acid secretion, both basal and stimulated by food or histamine by a direct action on the parietal cells. It increases mucosal blood flow and augments the secretion of mucus and bicarbonate
Adverse effects - diarrhea, abdominal cramps, uterine contractions
used to prevent gastric damage that can occur with chronic use of NSAIDs

14. PROKINETICS drugs increasing GIT motility
These drugs increase:
Tonus of the lower oesophageal sphincter (inhibition of gastro-intestinal reflux)
Gastric emptying (improve gastroparesis and functional dyspepsia)
intestinal motility (increased peristalsis)
Mechanisms of Action
Antagonism at D2 receptors – desinhibition of myenteric motor neurons leads to the increased ACh release
Modulation of 5-HT receptors (5-HT4, 5-HT1) – complex effects resulting in increased ACh release (among others)

15. Prokinetics Domperidon
Mechanism of action: predominantly a D2-antagonist
It does not cross the blood-brain barrier ! But it affects those CNS areas which lack the barrier area postrema (antiemetic action )
- hypophysis ( prolactin secretion )
Adverse reaction: galactorrhea, gynecomastia, amenorrhea
Metoclopramide
Mechanism of action is more complex: D2-antagonism,
5HT4 receptor agonism, sensitisation of M receptors
- antiemetic action
- CNS adverse effects: extrapyramidal (parkinsonian-like symptomes)

16. Prokinetics (Cisaprid) Just for your information:
Mechanism of action: an agonist on 5-HT4 receptors
It was quite potent and often used drug!
It was recently withdrawn in number of countries due to the increased risk of arrhythmias - „torsades de pointes“
It is uncommon polymorphous ventricular tachyarrhythmia with potentially fatal outcomes (associated with long QT-interval)
Itopride - D2-antagonist/Acetylcholinesterase inhibitor

17. ANTISPASMODICS (SPASMOLYTICS)
Drugs used to relieve spasms of smooth muscle in the GIT
Two main groups of drugs:
A) drugs affecting autonomic innervations – (anticholinergics and parasympatolytics)
B) drugs directly affecting smooth muscle function
Combination with analgesics (pethidine, codeine, tramadol, metamizol) = spasmo-analgesic preparations
Indications and therapeutical use:
Irritable bowel syndrome, flatulent distension of the abdomen (meteorism), smooth muscle spasms
Spasmo-analgesics: in biliary, renal and intestinal colics (also in spastic dysmenorrhoea etc.)

18. Antispasmodics 1. affecting autonomic innervations
Parasympatolytics (antimuscarinics)
Antagonists on M – receptors
Spasmolytic effect on smooth muscle but they tend to have rather opposite effects on sphincters (e.g. Oddi)
Drugs: atropine, trospium, tolterodine
Adverse effects (relatively frequent): xerostomia, mydriasis, cycloplegia, increased ocular pressure, urinary retention and
Anticholinergics
Antagonists on both M and N types of cholinergic receptors
Spasmolytic effects on both smooth muscle and sphincters
Often in combination with other drugs
Quarternary amines – low/slow absorption (low adverse effects on the CNS)
Drugs: otilonium, fenpiverine, pitophenone, buthylscopolamine

19. Antispasmodics 2. directly affecting smooth muscle
Different mechanisms of action are involved: inhibition of Ca2+ channels, activation of K+ channels, stimulation of NO synthesis
Drugs: papaverine (opiate) and drotaverine,
mebeverine, alverine, pinaverine