Drugs affecting GIT secretions.

 

     Drugs affecting GIT secretions.

1.1   Drugs affecting salivary secretions.

I.      Salivary stimulants/sialagogues/sialics-are the drugs that increase the volume and fluidity of saliva.

II.     Salivary inhibitors/salivary suppressants/antisialics – are the drugs that decrease the volume and fluidity of saliva.

These drugs oftenly affect respiratory and digestive secretions.

I. Sialagogues:– On the basis of mechanism of action these are of two types, A.        Indirect acting sialagogues and

B.     Direct acting sialagogues.

A.     Indirect acting salagogues:These stimulate the taste buds on tongue due to their bitter taste and mild irritant action and reflex enhance flow of saliva so commonly called as bitters. These agents take some time to produce their action, therefore given 15-30 min. before meal.

Agents:Gentian, Nuxvomica, Quassia.

Gentian:Dried rhizome and roots of Gentiana lutea. It Contains major bitter glycoside – Gentiopicrin(2%).

Doses               Dogs: 0.3-1.2g gentian powder, p.o. (total dose),

Large animals : 30-60g, p.o.

Sheep and goats: 4-8g, p.o.

Nux vomica:Powder of dried and ripe seeds of Strychnos nuxvomica:

Major alkaloids are: Strychnine (1.25%) and Brucine (1.5%). These are bitter in taste and act as sialagogues, and stomachic.

Dose: Nux vomica powder is adjusted to contain 1.2% of strychnine,

Catte : 4-8g (total), p.o. 1.3-4g (total), p.o.

Quassia:Dried stem wood of Picroena excelsa which is commonly known as Jamaica quassia. Quassia contain a bitter called quassin. (terpine nature)

Ipecacuanha (Ipecac): It is obtained from Cephaelis ipecacuanha.

B. Direct acting sialics:Directly stimulate salivary gland to enhance flow of saliva.

Agents: 1. Parasympathamimetic agents: stimulate muscasinic receptors and there is increase in flow of serous saliva.

2. α-adrenoceptor agonists: promotes secretion of scanty amount of viscous saliva.

Therapeutic Uses: As such these agents are not used for treating the condition of hypoptyalism (decreased flow of saliva). Indirect acting sialics are used in indigestion and are part of digestive tonics.

II)     Antisialagogues:

Agents: Antimuscarinic agents – atropine, hyoscine, glycopyrronium.

Atropine– used as preanaesthetic agent when irritant gases or irritant volatile anaesthtics are used. Dogs and cats: 0.03-0.1 mg/kg, i.m/s.c., Cattle and horses: 0.03-0.06 mg/kg.

Hyoscine(Scopolamine): Causes more CNS sedation in comparison to atropine. Dogs and cats: 0.01-0.02 mg/kg, i.m.

Glycopyrronium: Longer acting synthetic quarternary atropine substitute: Does not cross BBB so no central effects, Does not cross placental barrier, Better drug for horses.

Dose:

Dogs and cats : 0.01-0.02 mg/kg, s.c., i/m or i/v. route.,

Horses: 0.001-0.003 mg/kg, i.v.

1.2.   Drugs affecting gastric secretions:

Physiology of gastric secretion.

Gastric acid secretion is a complex, continuous process in which multiple peripheral and central factors contribute to a common endpoint: the secretion of H⁺by parietal cells.

Peripheral factors.

-      Neuronal (acetylcholine, ACh), paracrine (histamine), and endocrine (gastrin) factors all regulate acid secretion through their specific receptors (M₃, H₂, and CCK₂ receptors, respectively) are on the basolateral membrane of parietal cells in the body and fundus of the stomach and are part of  GPCR.

-      The H₂receptor signals through cyclic AMP-dependent pathway. ACh and gastrin signal through Ca²⁺-dependent pathway in parietal cells. These pathways activate H⁺,K⁺-ATPase (the proton pump), which exchanges hydrogen and potassium ions across the parietal cell membrane. This pump generates the largest known ion gradient in vertebrates, with an intracellular pH of about 7.3 and an intracanalicular pH of about 0.8.

Central factors.

-      These are the dorsal motor nucleus of the vagal nerve, the hypothalamus, and the solitary tract nucleus.

-      Efferent fibers originating in the dorsal motor nuclei descend to the stomach via the vagus nerve and synapse with ganglion cells of the enteric nervous system. ACh release from postganglionic vagal fibers directly stimulates gastric acid secretion through muscarinic M₃ receptors on the basolateral membrane of parietal cells. The CNS predominantly modulates the activity of the enteric nervous system via ACh, stimulating gastric acid secretion in response to the sight, smell, taste, or anticipation of food (the "cephalic" phase of acid secretion). ACh also indirectly affects parietal cells by increasing the release of histamine from the enterochromaffin-like (ECL) cells in the fundus of the stomach and of gastrin from G cells in the gastric antrum.

-      ECL cells, the source of gastric histamine secretion, usually are in close proximity to parietal cells. Histamine acts as a paracrine mediator, diffusing from its site of release to nearby parietal cells, where it activates H₂ receptors. The critical role of histamine in gastric acid secretion is dramatically demonstrated by the efficacy of H₂-receptor antagonists in decreasing gastric acid secretion.

-      Gastrin, which is produced by antral G cells, is the most potent inducer of acid secretion. Gastrin release is stimulated by CNS activation, local distention, and chemical components of the gastric contents. Gastrin stimulates acid secretion indirectly by inducing the release of histamine by ECL cells; a direct effect on parietal cells also plays a lesser role.

-      Somatostatin (SST), which is produced by antral D cells, inhibits gastric acid secretion. Acidification of the gastric luminal pH to <3 stimulates SST release, which in turn suppresses gastrin release in a negative feedback loop. SST-producing cells are decreased in patients with H. pylori infection, and the consequent reduction of SST's inhibitory effect may contribute to excess gastrin production.

-      Prostaglandins E₂and I₂, directly inhibit gastric acid secretion by parietal cells Mucus production is stimulated by PGs. Gastric mucus is soluble when secreted but quickly forms an insoluble gel that coats the mucosal surface of the stomach, slows ion diffusion, and prevents mucosal damage by macromolecules such as pepsin. Thus, alcohol, aspirin, and other drugs that inhibit prostaglandin formation decrease mucus secretion and predispose to the development of acid-peptic disease.

I       Drugs stimulating gastric secretions

        A) Gastrin analogues, B) Histamine and analogues, C) Stomachics-cholinergic agents and bitters.

acid secretion is stimulated by three receptors- gastrin receptors, H₂-histamine receptors, M₃-mAChRs.

II     Drugs inhibiting gastric secretions

A) H₂ – receptor antagonists, B) Proton-pump inhibitors, C) Muscarinic receptor antagonist, D) Prostaglandin analogues.

EP₃-prostaglandin stimulation inhibits HCl production.

I. Drugs stimulating gastric secretions:

A) Gastrin analogues: Pentagastrin – Synthetic pentapeptide having all physiological actions of endogenous gastrin

Actions:

- Secretion of gastric acid, pepsin and intrinsic factor, stimulation of pancreatic secretion, inhibition of absorption of water and electrolyte and increase blood flow in gastric mucosa.

Clinical Use: :

 As diagnostic agent for evaluation of gastric acid secretary functions, Dogs: Dose for diagnosis: 6 µg/kg, s.c.

B)  Histamine and analogues: Histamine acid phosphate, Betazole.

Both are used for clinical testing of gastric secretions in suspected cases of hypochlorhydria or achlorhydria.

Betazole is preferred as it has less marked effect on blood pressure and smooth muscles than histamine as betazole is selective H₂ against.

When histamine is used, H₁ histamine receptors should be blocked by using H₁-blockers. Dogs: Histamine acid phosphate = 0.04 mg/kg, s/c

Betazole – 1.7 mg/kg, s.c.

C) Stomachics: agents that promote functional activity of stomach by increasing secretions and motility

i) Cholinergic agents: Neostigmine, bethanecol produce stomachic effect of stimulating gastric muscarinic receptors

ii) Bitters: included in tonic formulations.

 

II Drugs inhibiting gastric secretions: Used in conditions like – hyperacidity, peptic ulcers, reflex oesophagitis, Zollinger-Ellision syndrome (gastrin producing tumors), abomasal ulceration in cattle.

A)         H₂–receptor antagonists – Cimetidine, ranitidine famotidine, zimatidine, roxatidine, loxatidine,

Cimetidine – block H₂ – receptors which mediate gastric secretions.

Inhibit P450 in liver.

Dog and Cats – 5-10 mg/kg, p.o., s.c. i.m. or slow i.v. Suppress acid for 3-5 hours.

Cattle (Abomasal ulceration): 8-16 mg/kg, 3x daily

Foals (Gastric ulceration):  20 mg/kg, p.o. 2 x daily and 5 mg/kg, i.v., 4-6 x daily

Swine 330 mg (total), 2 x daily.

Ranitidine: 2mg/kg, b.wt. i/v, i/m or oral. Suppress acid for upto 8 hours.

B)          Proton pump inhibitors: Omeprazole, lansoprazol, pantoprazol, rabeprazole, esomeprazole.

MOA of omeprazole: After absorption in blood through intestine, get partitioned into parietal cells and diffuse into acidic envonrment of secretory canaliculi.

Drug is then protonated and rearranges to form a sulphenic acid and sulphenamide, Sulphenamide group reacts with sulph hydril group (-SH group) of the H⁺-K⁺-ATPase enzyme and inactivate it irreversibly àH⁺ ion secretion.

Lansoprazole and Pantoprazole – enzyme inhibition is reversible and other side effects are lesser.

C)     Muscarinic receptor antagonists:

i) Non selective inhibitors: Atropine, glycopyrronium, aminopentamide, isopropamide, propantheline, oxyphenomium etc. These reduce gastric motility and basal secretion. These delay gastric emptying so allow other antacids given concomitantly to act for longer duration.

ii) Selective M₃ muscarinic receptor antagonists: M₃ receptor found possibly on histamine secretory cells and gastric parietal cells.

iii) Selective M₁ muscarinic receptor antagonists pirenzepine and telenzepinecan reduce basal acid production by 40% to 50% and long have been used to treat patients with peptic ulcer disease. These drugs are believed to suppress neural stimulation of acid production via actions on M₁ receptors of intramural ganglia.

D)          Prostaglandin analogues: i) PGE₂and I₂ act as cytoprotective by inhibiting gastric acid production and secretion and by enhancing production of mucus.      

ii) Misoprostol (Methyl ester analogue of PGE₁) generally indicated alongwith NSAIDS to prevent NSAIDS induced ulcers. Other congeners are: iii) Arbo prostil, iv) Enprostil, v) Trimoprostil.

 

ANTACIDS AND CYTOPROTECTIVE AGENTS:

Neutralizes preformed HCl in stomach.

1.     Fast acting antacids/systemic antacids– sodium bicarbonate. Onset of action fast and can be absorbed systemically.

2. Modest to slow acting antacids/Non-systemic antacids: - Salts of Aluminum, magnesium and calcium

-Onset of action slower than fast acting, absorption from GIT poor. Their acid neutralizing ability further benefit patient by

-decreasing pepsin activity.

-binding to bile salts.

-stimulating local prostaglandin (PGE₂) synthesis.

1.      Fast acting:

i) Sodium bicarbonate: Neutralization of preformed gastric acid is fast. Duration of action short. Produce rapid relief from pain due to hyperacidity.

1g neutralizes about 12 mEq of HCl. Causes acid rebound due to production of CO₂ gas.

Dose:

Cattle : 15-30g (total), p.o. 2-3x daily,

Horses: 8-15g, p.o., 2-3X daily,

Dogs: 0.3-1.0g, p.o., 2-3x daily,

2.     Modest to slow acting:

i) Aluminum salts – Aluminum hydroxide, Alum. hydrate, hydrated alumina. Non absorbable, slow onset of action, low neutralizing capacity, Neutralization of HCl is further slowed by presence of food in the stomach  

Al (OH)₃ + 3 HCl àAlCl₃ + 3H₂O

Inactivates pepsin (side effect), Protects and coats the m.m/ulcers and acts as demulcent.

Decrease GIT motility (side effect)

Doses:

Dogs:200-500 mg (total) p.o. 4-6 x daily,

Cats : 100-200 mg (total), p.o. 4-6 x daily,

Cattle : 15-30g (total), p.o. 2-3 x daily,

ii)     Magnesium salts – a) Mag. hydroxide, low water solubility, low concentration of OH^- ions and low alkalinity in aqueous suspensions,

Mg(OH)₂+ 2 HCl àMgCl₂ + 2H₂O, 1 g neutralizes about 30 mEq. HCl, MgCl₂so produced is soluble, Mg+2 ions are poorly absorbed from GIT so render osmotic pressure and act as osmotic purgative,

b) Magnesium trisilicate (hydrated magnesium silicate)

2MgO.3SiO₃x H₂O + 4HCl à2 MgCl₂ + 3 SiO₃ + (x+2) H₂O,

c) Magnesium carbonate: Cattle 16g (total) p.o.

Mg salts Increase GIT motility (side effect).

iii)    Calcium salts: a) Calcium carbonate (chalk, creta) 1 g = 20 m Eq HCl, CaCO₃ + 2HCl à CaCl₂ + CO₂ + H₂O, Calcium absorption may occur upto 30% which results in hypercalcaemia, hypercalciuria, alkalosis and formation of calcium stones in kidney.

Dose

Cattle: 60-360 g (total), p.o.

Sheep : 10-20g (total), p.o.

Antacid combinations:

1.           Magnesium salts (Laxative effect) + Alum salts (constipating effect) – gut movement least affected.

Mag. hydroxide (moderately acting) + Alum. Hydroxide (slow acting) àProduce rapid and sustained effect. Antacid combination decrease dose of individual drugs and reduce systemic toxicity.

iv) Magaldrate: hydrated complex of hydroxy magnesium aluminate. On reaction with acid releases aluminium hydroxide

v) Prostaglandin E₁ (Misoprostol): Inhibits HCl secretion and increases mucus secretion.

vi) Rebamipide: is used for ulcer therapy in parts of Asia. It appears to exert a cytoprotective effect both by increasing prostaglandin generation in gastric mucosa.

vii) Carbenoxolone, a derivative of glycyrrhizic acid found in licorice root, has been used with modest success for ulcer therapy in Europe. Its exact mechanism of action is not clear, but it may alter the composition and quantity of mucin.

viii) Sucralfate – Sucrose aluminium hydroxide product. Dissociates in acidic environment of stomach to sucrose octasulphate and polymerises to a viscous, sticky substance which protects the ulcerated site from HCl, bile and pepsin activity, stimulate PG synthesis.

ix) Colloidal bismuth subcitrate: Effective against Helicobacter pylori in gastroduodenal mucosa. It causes enhanced secretion of mucus and HCO₃^-and inhibits pepsin activity. It heals 60% of ulcers in 4 weeks and 80-90% in 8 weeks in human beings.