Pharmacology of Digestive System
Drugs affecting salivary secretion: Saliva (which contains a digestive enzyme called ptylin or amylase)
is continuously secreted into the oral cavity from salivary glands. The salivary nuclei located in the brainstem are excited by taste and tactile stimuli from the tongue and other areas of mouth. Parasympathetic stimulation causes profused watery salivation whereas sympathetic stimulation tends to
reduce the salivary secretion and enhances its viscosity.
Salivary stimulants/Sialics/Sialagogues: These agents increase the volume and fluidity of saliva and
thus stimulate appetite and even food digestibilty. Gentian, Nux vomica and cholinergic agonists (like
carbachol) can be used to stimulate salivation in hypoptylism (decreased salivary secretion) and xerostomia (dry mouth). Undesirable ptylism is also seen in organophosphate intoxication.
Salivary inhibitors/Anti-sialics/Anti-sialagogues: These drugs are salivary suppressants and have therapeutic significance in many conditions like oral surgery and inhalant general anesthesia (as pre- anesthetics). Anticholinergic drugs like Atropine, Hyoscine and Glycopyrrolate can be used for this purpose but they are not free from unwanted side effects.
Functional anatomy of gastric mucosa: Gastric mucosa is commonly glandular in all animals except horses in which both glandular and non-glandular mucosae are present in the stomach. The glandular mucosa undergoes frequent invaginations, called gastric pits that contain gastric glands at their basal position. On the basis of glandular activity, gastric mucosa is divided into three regions. Cardiac mucosa contains cardiac gastric glands which secrete thick alkaline mucus for providing protection to adjacent esophageal mucosa against gastric acid. Parietal region contains three types of cells; parietal/oxyntic cells which secrete HCl, mucus neck cells (responsible for the release of thin mucus) and chief cells that release pepsinogen (precursor of pepsin). Pyloric mucosa consists of gastrin-producing G cells.
Mechanism of gastric acid production: Acid secretion by parietal cells is a complex process that is made possible through the participation of various receptors and their respective ligands. Carbonic anhydrase (C.A) enzyme (present inside parietal cells) catalyzes the reversible reaction of H2O and CO2 giving rise to the synthesis of H2CO3 (carbonic acid). Further this carbonic acid is cleaved (by the same enzyme) into hydrogen and bicarbonate ions. The hydrogen ion is transported (via proton pump located on the luminal surface of parietal cell) into the gastric lumen to be used for HCl synthesis whereas the bicarbonate ion is moved out of the cell (by counter transport mechanism) in exchange for chloride ion. The potassium and chloride ions which are not so essential for cellular activities are transported into the lumen by another symport/co-transport system.
Four types of receptors (H2, M, Gastrin and Prostaglandin receptors) are found on the apical/basal membrane of parietal cell and three different pathways (paracrine, neurocrine and endocrine) are involved in the regulation of gastric acid production.
Paracrine pathway: It is the most dominant pathway during which histamine is secreted by histaminocytes (its release is also mediated by gastrin and ACh) and it binds with H2 receptors (that are linked with Gs protein). This binding stimulates Gs and then adenyl cyclase (A. C) which converts ATP into cAMP (that is utilized by proton pump (K+-H+-ATPase) to carry out the counter transport of H+ and K+; H+ leaves the parietal cell while K+ enters inside parietal cell. This paracrine pathway is blocked by prostaglandin E (exerts protective effect over gastric mucosa by inhibiting acid secretion) whose receptor are also located on apical membrane of parietal cell and are linked with Gi protein (that inhibits the activity of adenyl cyclase).
Neurocrine pathway: It involves the release of ACh followed by receptor occupancy and then synthesis of cAMP (2nd messenger) which supports the function of proton pump. ACh also enhances the release of histamine (from histaminocytes) and gastrin (from G cells).
Endocrine pathway: Gastrin, released from G cells binds with its respective receptors and promotes proton pump-associated release of H+ into the lumen for incorporation in HCl. Gastrin also enhances the release of histamine (from histaminocytes).
Phases of gastric acid secretion: Gastric acid secretion occurs in following four phases.
1. Cephalic phase: It occurs due to anticipation of food triggering the release of ACh which stimulates
parietal and G cells to secrete HCl and gastrin respectively.
2. Gastric phase: This phase is initiated by the entry of food into stomach; gastric distention is followed by the stimulation of stretch receptors and finally the release of ACh.
3. Intestinal phase: Entrance of acidic food in intestine causes intestinal PH modification that further stimulates acid secretion in stomach.
4. Basal phase: This phase occurs in the absence of any external stimulus.
In case of humans, lowest acid secretion and peak acid secretion can be observed at 7:00 am and midnight respectively.
The following drugs will stimulate gastric acid secretion.
Pentagastrin (Gastrin analogue), Betazole (Histamine analogue), Histamine itself can also be used but it should be co-administered with H1 receptor antagonist to avoid broncho-constriction, hypotension and other signs of allergic reaction. Stomachics, (drugs which assist in digestion by improving gastro-intestinal motility and secretory activity) including Neostigmine and Carbachol can also be used for this purpose.
Acid neutralizing drugs: These are divided into two groups.
1. Systemic agents: Sodium bi carbonate and Sodium citrate are having sufficient water solubility which enables them to get absorbed into blood stream after oral administration and exert a systemic action. These drugs chemically react with HCl and form NaCl (a neutral salt), H2O and CO2. They are used for the symptomatic treatment of gastric hyperacidity and to achieve the alkalization of urine. Rebound acid secretion is the most commonly observed side effect that occurs as a result of excessive CO2 production (as a product during chemical reaction) leading to gastric distension and triggering HCl production. Being alkaline in nature, both Sodium bi carbonate and Sodium citrate have the ability to accelerate the excretion of acidic drugs and to prolong the half life of alkaline drugs.
2. Non-systemic agents: They are unable to get absorbed into systemic circulation due to their hydrophobic nature and therefore they induce local action. Aluminium hydro-oxide acts as a demulcent (exerts soothing effect on mucus membrane) and smooth muscle relaxant activity (it can cause undesirable constipation). It also binds with phosphorus and decreases its absorption that can lead to hypophosphatemia and even osteomalacia. Magnesium hydro-oxide (Milk of magnesia), Magnesium carbonate and Magnesium trisilicate are also used (in the form of suspension). But they cause unwanted laxation due to enhanced release of cholecystokinin (CCK) and hypermagnesemia that can be fatal for patients with renal insufficiency. Chalk (Calcium carbonate) induces antacid and antidiarrheal action when given orally (topical application will provide antiseptic action). Its use is uncommon due to risk of hypercalcemia, hypercalciuria and urolithiasis (formation of stones in urinary tract). Acid neutralizing drugs are commonly used in combinations to minimize adverse effects and to improve efficacy.
Inhibitors of gastric acid secretion (Antacids): Overproduction of gastric HCl gives rise to several pathological conditions like gastritis, gastric ulcer, duodenal ulcer, gastrinoma (a tumor in the pancreas or duodenum that secretes excess of gastrin leading to ulceration in the duodenum, stomach and the small intestine), gastroesophageal reflux disease [GERD, a condition in which the stomach contents (food or liquid) leak backwards from the stomach into the esophagus. This action can irritate the esophagus, causing heartburn and other symptoms], peptic ulcer (erosion in the lining of the stomach or duodenum), Zollinger-Ellison syndrome (G cell tumor leads to excessive gastrin secretion which subsequently enhances acid secretion). Moreover Helicobacter pylori (gram negative bacteria) infection and inadequate use of NSAIDS also results in gastric hyperacidity. Antacids should be used for the treatment (and also prophylaxis in some cases) of above mentioned conditions.
Classification of Antacids: Antacids are classified into following categories.
1. H2 receptor antagonists: Blockage of H2 receptors will inhibit the paracrine pathway of gastric acid secretion. Cimetidine, Famotidine, Ranitidine and Nizatidine are important members of this category. Cimetidine has an apparent immuno-modulating effect by reversing suppressor T-cell mediated immune suppression. It also possesses weak anti-androgenic action which can cause loss of libido (sex drive), hypospermia (reduced sperm count), impotence (sexual dysfunction) and gynecomastia (abnormal enlargement of mammary glands in males due to enhanced plasma prolactin level) in males. Abrupt withdrawl of Cimitidine therapy can lead to rebound acid hypersecretion. It is a potent microsomal enzyme inhibitor and hence it decreases the hepatic metabolism of many drugs. Other are considered as comparatively safe (due to minimum or no side effects).
2. Proton pump inhibitors (PPIS): Omeprazole, Esomeprazole, Pantoprazole (Zopent) and Lansoprazole have the potential to inhibit the action of proton pump. They are more potent than all other antacids. They are formulated in enteric-coated tablets to prevent them from degradation by gastric acid. Prolonged administration of high doses of these agents has been reported to cause hyperplasia of parietal cells. These agents also interfere with the hepatic processing of many drugs by inhibiting the function of microsomal enzymes.
3. Prostaglandin analogues: Misoprostol and othe PGE analogues can be used to block histamine-mediated gastric acid secretion. But they are effective only in the prophylaxis of hyperacidity and should not be used for the treatment of pre-existing hyperacidity.
4. Anticholinergics: Selective M1 receptor blockers like Pirenzepine and Propantheline can reduce gasto-intestinal motility and gastric acid secretion. But they are linked with many side effects like mydriasis, constipation, tachycardia, xerostomia and urine retention.
5. Cytoprotective drugs: Sucralfate (it contains sucrose, Aluminium and Sulphate) is the most common member of this family. In acidic environment of stomach, Sucralfate is broken down into sucrose and sulphate. Sucrose protects the gastric mucosa by assuming a sticky gel like consistency while negatively charged sulphate groups electrostatically bind to positively charged proteins (in ulcerated and necrotic tissue) and inhibit their exudation. It has no direct acid neutralizing action and it is considered the safest drug for hyperacidity due to its minimum side effects.
Mediators of gastric motility: Gastric motility is responsible for the passage of gastric contents into small intestine (called gastric emptying). Gastric motility is regulated by local as well as central mediators. Parasympathetic stimulation increases gastric emptying through the agonistic effect of ACh on muscarinic receptors while sympathetic stimulation delays gastric emptying via adrenergic response (involving norepinephrine). ENS releases dopamine (that acts on D2 receptors) and serotonin (binds with 5HT4 receptors) which cause inhibition and stimulation (by increasing the release of ACh from myenteric plexus) of gastric contraction respectively. Motilin (released from duodenum) also promotes gastric contraction by binding to motilin receptors located in antrum and duodenum. Any interruption in above mentioned regulatory mechanisms can lead to gastric motility disorder that is characterized by chronic vomiting, anorexia, post-prandial discomfort (uneasiness after taking food) and gastro-esophageal reflux (the passage of acidic gastric contents into esophagus that can cause esophagitis).
Prokinetics are drugs that are used to restore gastric contractions in gastric motility disorder. They are divided into following classes.
1. D2 receptor antagonists: Metoclopramide and Domperidone are prokinetics as well as anti-emetics. They increase the force and frequency of gastric contraction, relax the pyloris and have no effect on gastric, pancreatic or biliary secretions. Blockage of D2 receptors in CNS can cause sedation, anti-emesis, behavioral modification and even Parkinsonism (in case of overdosage). Therefore these agents are contraindicated in patients suffering from Parkinsonism.
2. Serotonin (5HT4) receptor antagonists: Cisapride stimulates the motility of stomach, small intestine and colon (colonic stimulation can cause diarrhea that is undesirable). Tegaserod is also a colonic prokinetic. These agents are used to treat delayed gastric emptying, colonic hypomotility, post-operative gastroparesis (gastric paralysis) and grass sickness (in horses).
3. Motilin like drugs: Erythromycin (basically a macrolide antimicrobial drug that is used to treat gram positive bacterial infection) stimulates antral motilin receptors when used in sub-antibacterial dose.
4. H2 receptor antagonists: Ranitidine and Nizatidine (basically used as antacids) decrease parasympathetic stimulation by increasing cholinesterase-mediated degradation of ACh.
5. Misoprostol: This synthetic prostaglandin E1 (also used as antacid) increases the propulsive activity of colon and leads to prokinesis.
Constipation: It is the condition of infrequent defecation or lack of defecation characterized by straining to defecate and retention of hard, dry fecal mass (called scybala) in colon and rectum as a result of excessive water absorption and reduced intestinal motility. Treatment is anticipated by the use of laxatives or purgatives to restore intestinal motility.
Laxatives (Aperients): These agents increase intestinal motility in a mild/moderate manner, leading to excretion of soft fecal material. Laxatives consist of the following types.
(a) Lubricant laxatives: Their mode of action involves the lubrication of dry fecal material as well as intestinal mucosa to facilitate defecation. Liquid paraffin (a residue of petroleum distillation) is an example of such drugs. It can be given orally or as enema (administration of drug through intra-rectal route). Adverse effects include aspiratory pneumonia (due to accidental entry of drug into respiratory tract) and anal leakage/seepage of liquid feces (commonly seen in pets) that can lead to dirtiness of bedding and furniture etc.
(b) Surfactant laxatives (stool softeners): Docusate sodium, Docusate potassium and Docusate calcium are wetting and emulsifying agents which decrease surface tension and allow fats and water to penetrate in fecal mass.
Purgatives (Cathartics): They enhance intestinal motility resulting in watery feces (and may be diarrhea). They are subdivided into following groups;
1. Bulk purgatives: Bran (the outer covering of cereals), Agar (a polysaccharide obtained from algae) and Ispaghul/Psyllium seed (derived from Plantago psyllium) are hydrophilic substances which absorb water and swell up. This action increases the bulk of intestinal contents and exerts pressure on intestinal musculature to stimulate peristalsis.
2. Osmotic purgatives: Being hypertonic in nature, these drugs attract water and retain it in intestinal lumen which removes the hardness of fecal contents. Glycerine [C3H5(OH)3] suppositories can be used for this purpose. Sorbitol and Mannitol (alcohols that are achieved after the reduction of glucose and mannose respectively) are mixed with activated charcoal to facilitate the excretion of some poisons. Excessive use of osmotic purgatives can lead to water deprivation which can be harmful particularly for patients with pre-existing dehydration.
3. Irritant/stimulant purgatives: These are further subdivided into two classes;
Direct acting irritant/stimulant purgatives: Bisacodyl (Dulcolex) is capable to directly stimulate intestinal mucosa and myenteric plexus (which leads to release of ACh) thereby causing increased peristaltic contractions as a result of parasympathetic stimulation.
Indirect acting irritant/stimulant purgatives: Vegetable oils require activation through digestive enzymes in order to be able to induce peristalsis. The hydrolysis of vegetable oils (in small intestine) by pancreatic lipase results in the synthesis of fatty acids that are subjected to saponification by reacting them with sodium and potassium salts. This process also yields glycerine as a by product. Castor oil (obtained from Ricinis communis, Arind) and Linseed oil can be used for this purpose. The active ingredients of Castor oil and Linseed oil are ricinoleic acid and linoleate respectively. Castor oil is contraindicated in pregnant animals as it can stimulate uterine contractions as well.
4. Drastic purgatives: Croton oil or Jamal ghota is a product of Croton tiglium plant. It contains crotinoleic acid as an active constituent. It drastically/harshly increases the intestinal motility and is not commonly used due to its narrow margin of safety.
5. Neuromuscular purgatives: Carbachol and other cholinergic agonists can cause purgation by activating muscarinic receptors located on intestinal smooth muscles. Miosis, bradycardia, frequent urination, salivation and broncho-constriction are their possible side effects. They are contraindicated in all conditions that involve gastrointestinal obstruction.
Diarrhea: Abnormal increase in the frequency, volume and fluidity of fecal contents is termed as diarrhea. Neoplasia, stress, toxins, dietary disturbance, poisoning and enteritis are most common causes of diarrhea. Symptomatic therapy (use of antidiarrheal drugs) combined with etiological treatment (removal of the cause) must be attempted for complete recovery.
Antidiarrheal drugs: These are divided into following categories;
(A) Non-specific drugs: They provide only symptomatic treatment and are further subdivided into following groups.
1. Gastrointestinal protectants and adsorbents: They protect the mucus membrane and reduce irritation by forming protective covering over mucus membrane and adsorbing toxins. Kaolin (Aluminium silicate), Pectin (a carbohydrate polymer), Activated charcoal and Activated attapulgite (Aluminium trisilicate) are examples of such agents. These are used either alone or in combination (e.g. Kao-pectate).
2. Anti-motility agents: Natural opiods (like Codeine, Morphine) and synthetic opiods (like Loperamide and Diphenoxylate) exert anti-motility action by decreasing the release of ACh. Side effects include sedation (stimulation in cats) and dependence.
3. Antispasmodics: Anticholinergic drugs like Atropine, Hyoscine and Propantheline are also used to treat diarrhea by decreasing intestinal motility. Xerostomia, mydriasis, tachycardia, constipation and urine retention are their possible adverse effects.
(B) Specific drugs: They help to specifically eliminate the pathogen involved in the causation of diarrhea. Neomycin (effective against gram negative bacteria), Penicillin (effective against gram positive and gram negative bacteria), Metronidazole (effective against anaerobic bacteria and protozoa like ameoba), Sulphadimidine (anticoccidial and antibacterial) and Furazolidone (anti-giardial) are commonly used to treat infectious diarrhea.
Emesis/Vomiting: Emesis can be defined as the expulsion of gastric contents through mouth as a result of anti-peristalsis. It can be caused by drugs, radiation, infections, motion sickness, metabolic disturbance, emotional disorders and neoplasms. Hyperemesis gravidarum (Morning sickness) is a severe type of vomiting that occurs during first trimester of pregnancy. It exerts deleterious effects on the health of the mother and debilitates her in day to day activities. Although exact cause is unknown however this condition can be attributed to altered level of human chorionic gonadotrophin (HCG) as a result of conception (and associated physiological modifications like absence of menstruation). Nausea is defined as the state of uneasy feelings that precedes emesis. The phenomenon of vomiting is observed only in carnivores and omnivores whereas rabbits, rodents, ruminants and horses are unable to vomit. Emesis is sometimes induced through the application of emetogenic agents (like CuSO4, Na2CO3, Apomorphine) to facilitate the elimination of non-corrosive poisons. Sustained emesis can lead to dehydration, acid-base imbalance, electrolyte disturbance, physical exhaustion and even gastric rupture. Appropriate treatment approach must include the use of anti-emetics, fluid and electrolyte therapy, as well as dietary management. Vomiting is initiated by the stimulation and co-ordination of various organs and body regions (involving different receptors and their associated neurotransmitters) both at peripheral and central level. Different external and internal stimuli can provoke the vomiting pathway.
1. Visual stimuli (e.g. repulsive sight) and olfactory stimuli (e.g. pungent smell) are transmitted to cerebral cortex while head trauma (due to accident etc.) and increased intracranial pressure stimulate limbic system. Cerebral cortex and limbic system are higher centers of the CNS that are having H1 and M receptors and they further transmit these signals to vomiting centre (located in medulla oblongata and provided with H1 and M receptors).
2. Certain stimuli like motion sickness, labyrinthitis and exposure to ototoxic drugs are transmitted to vestibular nuclei (having H1 and M receptors) of CNS by 8th cranial nerve. From there the impulse is transferred to cerebellum which stimulates vomiting centre.
3. Localized pharyngeal irritation is a stimulus for nucleus tractus solitarius (NTS) which comprises of H1, M, D2 and 5HT3 receptors and leads to emesis via stimulating vomiting centre.
4. Toxins and drugs contained in the blood act on chemoreceptor trigger zone (CTZ) that is located outside the blood brain barrier (in the 3rd ventricle) and is supplied with H1, M, D2, 5HT3 and μ (a subtype of opiod receptors) receptors. CTZ can stimulate NTS as well as vomiting centre.
5. M, D2 and 5HT3 receptors located in gastric and intestinal mucosa respond to inflammation, radiation and exposure to cytotoxic drugs (used as anticancer agents) by activating CTZ and NTS.
Various efferent/motor pathways (like vagus, phrenic and spinal nerves) are stimulated by vomiting centre which carry out the relaxation of esophagus, esophageal sphincter and fundus coupled with pyloric and duodenal contraction. Ultimately strong rhythmic contractions of abdominal and diaphragmatic muscles take place which cause the expulsion of gastric contents through mouth (that is known as emesis).
Anti-emetics: These are divided into following categories;
1. Locally acting anti-emetics: They lack the ability to cross blood brain barrier so they cannot act on vomiting centre.
(a) Anti-cholinergic drugs: Scopolamine is commonly used to avoid motion sickness. It is effective only when used for prophylactic purpose. It should not be used for more than three days as it can delay gastric emptying that can cause vomiting.
(b) Prokinetics: Domperidone and Cisapride enhance peristalsis (by increasing the gastric emptying) and thus reverse anti-peristalsis which leads to vomiting.
2. Centrally acting anti-emetics: They induce their anti-emetic effect by acting on vomiting centre and are divided into following groups;
(a) H1-receptor antagonists (Anti-histaminics): Cyclizine, Meclizine, Dimenhydrinate (Gravinate) and Diphenylhydramine (Benadryl) are included in this group. Most common side effect associated with their administration is sedation.
(b) D2-receptor antagonists: These are further subdivided into many classes;
· Phenothiazine derivatives: They include Acepromazine and Chlorpromazine (Largectil) which are used as tranquilizers and anti-emetics.
· Butyrophenone derivatives: Droperidol and Haloperidol are examples of such agents and these are used as anti-emetics and antipsychotics (drugs that are used to treat mental disorders like schizophrenia and mania etc.).
· Benzamides: Metoclopramide (Maxolon, Metoclon) is a member of this class that is exerts prokinetic as well as anti-emetic action.
5HT3-receptor antagonists: Ondansetron and Granisetron are well known members of this group and they are considered safest anti-emetics due to their minimum adverse effects
No comments:
Post a Comment