Pharmacology. -Alia Shatnawi
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1 Pharmacology -3 -Alia Shatnawi
2 Gastroesophageal reflux disease (GERD): a digestive disorder that affects the lower esophageal sphincter, characterized by reflux of acids from the stomach to the esophagus causing erosion of the esophageal mucosa. *symptoms: Heartburn (the main symptom), Dysphagia, chronic symptoms which include mucosal damage and metaplasia (produced by abnormal reflux of gastric contents into the esophagus) *affects 10% of US population. Therapy mainly based on decreasing acidity, increasing lower esophageal sphincter tone, enhanced clearance of refluxed material. Treatment: 1)PPI (Proton Pump Inhibitors). 2. Coating agents: like Sulcralfate 3. Promotility/prokinetic agents help tighten the lower esophageal sphincter and promote faster emptying of the stomach. 1)Metoclopramide 2)Bethanechol. **these drugs are not so preferred to be used because they have side effects and are given mainly to patients that show poor response to PPIs Prokinetic agents are used to treat: In terms of the esophagus: they help to treat GERD by increasing the tone of the lower esophageal sphincter tone. In terms of the stomach: they treat gastroparesis; gastroparesis is the condition in which the stomach cannot empty itself and is a result of a damaged vagus nerve. In terms of the small intestines; can be used to treat the postoperative ileus, this is a condition in which the small intestines lose their motility. These prokinetic agents are A) Cholinomimetic Agents: 1) Bethanecol - Stimulates muscarinic receptors on muscle cells and myenteric plexus synapses. - Was used in GERD and gastroparesis. Now it s not being used because of its side effects in the whole parasympathetic nervous system, because it stimulates the whole muscarinic receptors of the body.
3 Side effects such as: (Dizziness, lightheadedness, nausea, vomiting, abdominal cramps/pain, diarrhea, increased saliva/urination, sweating, flushing, watery eyes, or headache may occur, bradycardia) especially the M3 receptors. 2)Neostigmine: - an Acetylcholine esterase inhibitor that increases the Ach concentration in the synapse, resulting in activation of muscarinic receptors so that peristaltic movements in the GIT are stimulated, this is mostly true in ileus. -Not common used because multiple side effects related to increase ach,but neostigmine is still used in Acute Colonic Pseudo-obstruction (Ogilvie s syndrome) : is given IV, has a benefit in rapid evacuation of flatus and feces. B) Dopamine Receptor Antagonists: - 2 DRUGS (Metoclopromide, Domperidone); these agents cause activation of the parasympathetic system; how? Because Dopamine causes inhibition of cholinergic receptors of the GI tract, by antagonizing the Dopamine the more we re stimulating the cholinergic receptors and the parasympathetic system. **these two drugs perform their action mainly on the stomach and esophagus but not on the small or large intestine. **more common used than Cholinomimetic Agents Potential uses 1. GERD: they treat GERD, but these drugs are not effective with erosive esophagitis (because they don't reduce acid secretion), so they are not superior to antisecretory agents like PPI and H2 antagonist. 2. Gastroparesis: the stomach won't be able to empty its content, which result in distention of the stomach. these drugs increase the motility of GIT, So we could use them to solve this problem. **gastroparesis could result from vagotomy Vagotomy: cutting part of the vagus nerve to reduce gastric secretion, this was an operation that d been used to treat peptic ulcer. Diabetes: diabetic neuropathy could affect the nerves that supply the stomach, which results in gastroparesis. 3. In patients who need nasoenteric tubes, because increased peristaltic movement can help to push the tube further through the GI tract.
4 3. Nonulcerative dyspepsia; this is a condition in which patients complain of pain associated with difficulty in digesting food, non-ulcer means that the ulcer is not the cause of it, as a matter of fact, it means that the reason is not known to why it happens. 4. Antiemetic agents. Dopamine receptors also present in the chemoreceptor trigger zone, and their activation cause nausea and vomiting in the medulla oblongata, SO these drugs have a benefit as anti-emetic and anti-nausea agents 5. Postpartum lactation stimulation: the relation between prolactin and dopamine is contrary, when dopamine is released prolactin levels are decreased and vice versa. **This is important in patients who take Dopamine inhibitors because this will stimulate increased prolactin levels and stimulate lactation, this is a problem in males because it evokes the enlargement of the male breast and can promote lactation. **These drugs are used to promote lactation in recently-delivering females. Adverse Effects: 1) CNS adverse effects: these effects are related to Metclopromide only (because it crosses blood brain barrier) and can cause side effects associated with the central nervous system these include: restlessness, drowsiness, insomnia, anxiety and agitation. 2) extrapyramidal symptoms ( ال إرادية فجائية (حكرات like dystonia, akathisia,parkinsonian features and Tardive dyskinesia (these are also related to metclopromide). 3) CVS adverse effects: these drugs can inhibit the heart function by inhibiting the dopamine receptors of the heart, and people with heart conditions must be prescribed lower doses so that they re not affected. **Domperidone does not cross the Blood Brain Barrier, so does not cause CNS side effects. **Both drugs can elevate serum prolactin levels and cause galactorrhea, gynecomastia, and most importantly menstrual cycle disorders. C) Macrolide Antibiotics: These macrolides like erythromycin directly stimulate motilin receptors in the GIT, motilin receptors directly increase the peristaltic movements of the GI tract. Potential Uses: 1) Gastroparesis: here tolerance develops rapidly meaning the body an compensate by reducing the peristaltic activity, these drugs must be given IV and in low dose. NOTE: the tolerance develops by decreasing secretion of motilin hormone from the body.
5 2) Acute upper GIT bleeding: to promote emptying of blood from stomach before endoscopy. Also, the drug here is given IV. D) Chloride Channel Activator: those are prostaglandin analogs; For example: Lubiprostone **they stimulate the opening of the chloride channels in the GI system which increases the liquid secretion in the intestine and delay gastric emptying leading to nausea Constipation - Often caused by a lazy colon or a spastic colon that remains contracted for a prolonged period of time. - Other conditions that can produce a sluggish or poorly contracting bowel include: 1) pregnancy (in pregnancy progesterone level increases, and progesterone relaxes muscles of GIT, so constipation occurs) 2) certain drugs. 3) thyroid hormone deficiency 4) travel and stress 5) the chronic abuse of laxatives: some people use Herbs to decrease their weight, these Herbs like " سنا مكي " increase the motility of GIT so preventing good absorption of food. However, abuse of these Herbs causes lazy colon which leads to constipation. Life style Treatment; trying to treat such condition non-pharmacologically by drinking enough fluids, diet rich in fibers like fruits and vegetables, exercise. Laxatives; what are laxatives? They are used to treat and/or prevent constipation, there are so many agents that vary a lot in their mechanism of action, examples of such agents: 1- Bulk-Forming Laxatives: Are indigestible, hydrophilic colloids that absorb water forming a bulky, emollient gel in the colon; such as natural plant products like Psyllium, Sterculia, Methylcellulose mechanism of action: these fibers absorb water => distending the intestine => stretching => induction of the myenteric receptors => increases the motility in the intestine and decrease constipation. Side effect: Can cause bloating (نفخة) and flatus (gas in the stomach and intestine)
6 2- Stool Surfactant Agents (Softeners): They permit water and lipids to penetrate the stool, making it easier to move through the GIT. Given orally, or rectally as suppository. Examples: 1- Glycerin suppository which is given to children. 2- Mineral oil (like castor oil) **Castor oil causes irritation of the intestinal mucosa and can enhance the peristaltic movement (these points about mineral oils were read quickly from the doctor): **They re clear viscous oil that lubricates fecal material, retarding water absorption from stool. **They re used to prevent and treat fecal impaction. **aspiration of the oil during ingestion can cause pneumonia. **they could cause impairment of the absorption of FAT soluble vitamn ( A,K,E,D ) 3- Osmotic Laxatives (Purgatives): Agents that cause strong fast evacuation of the contents in the intestine. Soluble nonabsorbable compounds that result in increased stool liquidity due to an obligate increase in fecal fluid. Examples a. Magnesium oxide (Milk of Magnesia) **If good absorption of these drugs occurs, they could increase magnesium concentration levels in the blood, magnesium is involved in activation of multiple enzymes in the body, so we need to be careful with these drugs. **Large doses of magnesium citrate and sodium phosphate: can cause Purgation which is rapid bowel evacuation within 1-3 hours. This might cause volume depletion, hypotension and dehydration, so we need to give patients supplements like electrolyte and water if this occurs. b. Sorbitol c. Lactulose: **Lactuloses are sugars metabolized by bacteria producing severe flatus and cramps. **This is a disaccharide (double-sugar) formed from one molecule each of the simple sugars (monosaccharides) fructose and galactose. Lactulose is not normally present in raw milk but is a product of heat-processing. **Lactulose is not absorbed in the small intestine nor broken down by human enzymes, thus stays in the digestive bolus through most of its course, causing retention of water through osmosis
7 leading to softer, easier to pass stool. It has a secondary laxative effect in the colon, where it is fermented d. Balanced Polyethylene Glycol: by the gut flora, producing metabolites which have osmotic powers and peristalsis-stimulating effects Balanced Polyethylene Glycol: Safe solution: no intravascular fluid or electrolyte shifts. Does not cause cramps or flatus. Used for complete colonic cleansing before endoscopy 4hours before operation. PEG is an inert, nonabsorbable, osmotically active sugar. Sodium sulfate, chloride, bicarbonate and potassium chloride. For colonic cleansing, it should be ingested rapidly (4 L over 2-4hs). For chronic constipation, PEG powder is mixed with water or juice. 4- Stimulant Laxatives (Cathartics): a cathartic is a substance that accelerates defecation. This contrasts with a laxative, which is a substance that eases defecation, usually by softening feces. It is possible for a substance to be both a laxative and a cathartic Direct stimulation of the enteric system. Colonic electrolyte and fluid secretion. Can lead to dependence and destruction of the myenteric plexus resulting in colonic atony and dilation. Note: (atonia) is a condition in which a muscle has lost its strength. It is frequently associated with the conditions atonic seizure May be needed in neurologically impaired patients and in bed-bound patients in long term care facilities. Anthraquinone Derivatives: - Aloe. - Senna. - Cascara. They are: Poorly absorbed. After hydrolysis, produce bowel movement in (6-12) hours. Cause brown pigmentation of the colon Melanosis Coli. Not carcinogenic. Castor Oil: **Hydrolyzed in upper intestine into ricinoleic acid which is a local irritant. **Was used as purgative to clean the colon before procedures. Review of peptides that control the activity of the GI tract: Tegaseroid:
8 Is a serotonin 5-HT4 partial agonist, which are presynaptic receptors of the submucosal intrinsic primary afferent nerves which enhance the release of their neurotransmitters, particularly acetylcholine. These neurons stimulate proximal bowel contraction (via ACh and substance P) and distal relaxation (via nitric oxide and VIP). The drug promotes gastric emptying and small and large bowel transit but has no effect on esophageal motility. Also stimulates camp-dependent chloride secretion leading to increased stool liquidity; which increase ease of evacuation. Clinical Uses: Chronic constipation. Nonulcer dyspepsia. Gastroparesis. Treatment of Irritable bowel syndrome. Adverse Effects: Extremely safe drug. Diarrhea occurs in 9% of patients but resolves within days. Expensive. **Antidiarrheal Agents Can be used in mild to moderate acute diarrhea. Should not be used in the presence of infective diarrhea, because these agents will preserve the toxins of the microorganisms that caused the infection and will not wash them out, this will cause a prolonged period of infection and pain, in such case antibiotics are used to treat the infection, this the expose the toxins and will stimulate the peristaltic movement and caused diarrhea to wash the intestines **Toxins prevent the absorption of water and electrolytes and sugars from the small intestines, sugars will stay in the small intestines and bacteria that metabolizes them there will cause cramps and gas. **In diarrhea patients, they will lose large amounts of water and electrolytes, these patients will need to be supplemented by water and electrolyte solutions. Can be used to control chronic diarrhea, like in irritable bowel syndrome or inflammatory bowel disease. Diarrhea causes hypovolemia, so patients need electrolytes and water to prevent it Opioid Agonist Morphine, the prototypic opioid agonist, these agents work on the opioid receptors, the opioid receptors are found in the central nervous system and the GI Tract, in the GI tract these agents cause to enhance peristaltic movements, however taking these agents can cause activation of opioid receptors in the central nervous system and can cause addiction. Have significant constipating effects:
9 Inhibit presynaptic cholinergic nerves, leading to increased colonic transit time and increased fecal water absorption. Decrease mass colonic movements and gastrocolic reflex. Can have CNS effects and addiction potential. Usually combined with atropine to reduce dependence, because atropine causes an unpleasant effect and that prevents addiction. 1- Does not cross BBB, so no analgesic or addiction potential. 2- Diphenoxylate: Can have CNS effects and dependence. Kaolin and Pectin (they re natural products) Kaolin is a naturally occurring hydrated magnesium silicate. Pectin is an indigestible carbohydrate derived from apples. Both act to absorb bacteria, toxins and fluid. Usually combined, e.g. Kaopectate. Are not taken in combination with other medications, because they these can enhance the absorption and reduce the therapeutic window for the other medications. Bile salt-binding resins: 1- Cholestyramine 2- Colistipol. Malabsorption of bile salts (e. g. after surgical resection), can cause diarrhea. These drugs can bind bile salts. Can cause bloating, flatulence, constipation and fecal impaction. Also, drug and fat malabsorption. Octreotide: Is a synthetic octapeptide with actions like somatostatin, somatostatin is a hormone that is secreted from the hypothomes to control the pituitary gland. Somatostatin is a 14 amino acid peptide released in the GIT and pancreas as well as from the hypothalamus: 1. Inhibits release of many hormones. 2. Reduces intestinal fluid and pancreatic secretions. 3. Slows GIT motility and gallbladder contraction. 4. Causes contractions of blood vessels. 5. Inhibits secretion of some anterior pituitary hormones. Clinical Uses: 1. Inhibition of endocrine tumor effects: Carcinoid and VIPoma can cause secretory diarrhea and systemic symptoms like flushing and wheezing. 2. Diarrhea due to vagotomy or dumping syndrome or short bowel syndrome and AIDS. 3. In small doses can stimulate motility in small bowel bacterial overgrowth or intestinal pseudoobstruction secondary to scleroderma. 4. Pancreatic fistula, pituitary tumors and GI bleeding. Adverse Effects: Steatorrhea; which is a lipid rich diarrhea which can cause fat-soluble vitamin deficiency. Nausea, pain, flatulence. Sludge or gall stones. Hyper or hypoglycemia due to pituitary gland hormonal imbalance. Hypothyroidism and Bradycardia.
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