Diphenoxylate antidiarrheal

Diphenoxylate Hydrochloride. l-(3-Cyano-3,3-diphenylpropyl)-4-phenyl-4-piperidinecarboxyhc acidmonohydrochlorhydrate [3810-80-8] (Lomotil) (13) is a white, odorless, crystalline powder that melts at 220—226°C. It is soluble ia methanol, spariagly soluble ia ethanol and acetone, slightly soluble ia water and isopropyl alcohol, freely soluble ia chloroform, and practically iasoluble ia ether and hexane. The method of preparation for diphenoxylate hydrochloride is available (11). Diphenoxylate hydrochloride [3810-80-8] (13) is an antidiarrheal that acts through an opiate receptor. It has effects both on propulsive motility and intestinal secretion. Commercial forms are mixed with atropiae to discourage abuse. 

Antidiarrheals decrease intestinal peristalsis, which is usually increased when the patient has diarrhea. Examples of these drug s include difenoxin with atropine (Motofen), diphenoxylate witii atropine (Lomotil), and loperamide (Imodium). 

Antidiarrheal medications that reduce GI motility, such as loperamide, diphenoxylate/atropine, or codeine should be avoided in patients with active IBD due to the risk of precipitating acute colonic dilation (toxic megacolon). 

HT3 antagonist, prochlorperazine for emesis (avoid corticosteroids), H2 blocker for gastritis, antidiarrheal as needed (loperamide, diphenoxylate/atropine, codeine). 

Opioids. Activation of opioid receptors in the enteric nerve plexus results in inhibition of propulsive motor activity and enhancement of segmentation activity. This antidiarrheal effect was formerly induced by application of opium tincture (paregoric) containing morphine. Because of the CNS effects (sedation, respiratory depression, physical dependence), derivatives with peripheral actions have been developed. Whereas diphenoxylate can still produce clear CNS effects, loperamide does not Lullmann, Color Atlas of Pharmacology... 

A not uncommon side effect observed with morphine and some of the other narcotic analgesics is constipation due to decreased motility of the gastrointestinal tract. It proved possible to so modify pethidine as to retain the side effect at the expense of analgesic activity. Relief of diarrhea, it will be realized, is a far from trivial indication. Alkylation of the anion from diphenylacetonitrile (95) with ethylene dibromide gives the intermediate, 96. Alkylation of normeperidine (81) with that halide affords diphenoxylate (97), an antidiarrheal agent. 

Diphenoxylate + Atropine (Lomotil, Lonox) [C V] [Opioid Antidiarrheal] Uses D Action Constipating m CTidine congener, X GI motihty Dose Adults. Initial, 5 mg PO tid—qid until controlled, then 2.5-5 mg PO bid 20 mg/d max Peds >2 y. 0.3-0.4 mg/kg/24 h (of diphenoxylate) bid-qid, 10 mg/d max Caution [C, +] Contra Obstructive jaundice, D d/t bacterial Infxn children <2 y Disp Tabs, Liq SE Drowsiness, dizziness, xCTostomia, blurred vision, urinary retention, constipation Interactions T Effects W/ CNS depressants, opioids, EtOH, T risk HTN crisis W7 MAOIs EMS Monitor for Sxs of electrolyte disturbances and hypovolemia d/t D OD May cause Szs, hypotension, and anticholinergic effects (xerostomia [dry mouth], urine retention, flushed skin) activated charcoal may be effective for OD... 

Diphenoxylate Lomotil) is a meperidine derivative used as an antidiarrheal. It exhibits no morphinelike effects at low doses, but it produces mUd opioid effects, such as sedation, euphoria, and dependence, at higher doses. Its salts are highly insoluble in water, which reduces recreational use. Preparations often include atropine. 

Difenoxin is a metabolite of diphenoxylate with antidiarrheal effects similar to the parent drug. Loperamide Imodium) is a piperidine derivative of diphenoxylate, which acts both at the level of the gut and also in the CNS to reduce GI motility. Its use as an antidiarrheal and its potency are similar to those of diphenoxylate. 

The dangers of dependency and addiction clearly preclude the use of such compounds as morphine, meperidine, and methadone as treatment for diarrhea. Antidiarrheal specificity therefore is of paramount importance in choosing among the synthetic opioids and their analogues (e.g., diphenoxylate and loperamide). 

Niemegeers, C.J., Lenaerts, F.M., Janssen, P.A. Difenoxine (R 15403), the active metabolite of diphenoxylate (R 1132). 2. Difneozine, a potent, orally active and safe antidiarrheal agent in rats, Arzneimittelforschung 1972, 22, 516-518. 

Aluminum Hydroxide Magnesium Trisilicate (Gaviscon) Aluminum Hydroxide (Amphojel, ALtemaGEL) Aluminum Hydroxide + Magnesium Carbonate (Gaviscon Extra Strength, Liquid) Antidiarrheals Bismuth Subcitrate/ Metronidazole/ Tetracycline (Pylera) Bismuth Subsalicylate (Pepto-Bismol) Diphenoxylate w/ Atropine (Lomotil, Lonox)... 

Opiate preparations, usually given as paregoric, are effective and fast acting antidiarrheal agents. These agents are also useful postoperatively to produce solid stool following an ileostomy or colostomy. A meperidine derivative, diphenoxylate, is usually dispensed with atropine and sold as Lomotil. The atropine is added to discourage the abuse of diphenoxylate by narcotic addicts who are tolerant to massive doses of narcotic but not to the CNS stimulant effects of atropine. 

Diphenoxylate and its metabolite, difenoxin, are not used for analgesia but for the treatment of diarrhea. They are scheduled for minimal control (difenoxin is schedule IV, diphenoxylate schedule V see inside front cover) because the likelihood of their abuse is remote. The poor solubility of the compounds limits their use for parenteral injection. As anti diarrheal drugs, they are used in combination with atropine. The atropine is added in a concentration too low to have a significant antidiarrheal effect but is presumed to further reduce the likelihood of abuse. 

Diphenoxylate Hydrochloride/Atropine Sulfate Brand name Lomotil Class Antidiarrheals... 

Diphenoxylate is a synthetic compound designed to have the antidiarrheal effects of the opiates, but it also retains some less desirable opiate effects. It is generally combined with atropine, as co-phenotrope, which was originally added to the formulation in the hope of preventing misuse, although it can itself cause problems, especially if the combination is intentionally or accidentally used to excess. 

In addition to modifications of the morphine molecule, many purely synthetic analgesics have been produced, the first of these, pethidine (meperidine), having been synthesized in 1939 in an attempt to make a substitute for atropine (276). As in the case of heroin, pethidine was at first thought to be nonaddictive. It has been followed by a hundred or so other compounds of several different types, but, as with the morphine derivatives, none, with the possible exception of pentazocine, has been found to have analgesic without addictive properties. However, it seems that the two effects may not be entirely inseparable, as diphenoxylate, which has come into use as an antidiarrheal drug, has been found to possess the power to cause addiction but no analgesic action at all (277). 

Diphenoxylate is an opiate (schedule V) with antidiarrheal properties. It is usually dispensed with atropine and sold as Lomotil. The atropine is added to discourage the abuse of diphenoxylate by narcotic addicts who are tolerant to massive doses of narcotic but not to the CNS stimulant effects of atropine. Diphenoxylate shonld be used cautiously in patients with obstructive jaundice because of its potential for hepatic coma, and in patients with diarrhea cansed by pseudomembranous colitis because of its potential for toxic megacolon. In addition, it should be used cautiously in the treatment of diarrhea caused by poisoning or by infection by Shigella, Salmonella, and some strains of E. coli because expulsion of intestinal contents may be a protective mechanism. Diphenoxylate should be used with extreme caution in patients with impaired hepatic function, cirrhosis, advanced hepatorenal disease, or abnormal liver function test results, because the drug may precipitate hepatic coma. Because diphenoxylate is structurally related to meperidine, it may cause hypertension when combined with monoamine oxidase inhibitors. As a narcotic, it will augment the CNS depressant effects of alcohol, hypnotic-sedatives, and numerous other drugs, such as neuroleptics or antidepressants that cause sedation. 

Diphenoxylate is an antidiarrheal agent. Diphenoxylate, related to meperidine, decreases motility of the GI tract. Atropine discourages deliberate overdosage of diphenoxylate. The combination is indicated as adjunctive therapy in the treatment of diarrhea. 

OPIOIDS Opioids continue to be widely used in the treatment of diarrhea. They act principally through either p- or 5-opioid receptors on enteric nerves, epithelial cells, and muscle (see Chapter 21). These mechanisms include effects on intestinal motility (p receptors), intestinal secretion (5 receptors), or absorption (p and Preceptors). Commonly used antidiarrheals such as diphenoxylate, difenoxin, and loperamide act principally via peripheral /t-ofrioid receptors and are preferred over opioids that penetrate the CNS. 

Treatment of diarrhea Selective antidiarrheal opioids include diphenoxylate and loperamide. They are given orally. 

Kappa receptor activation does not appear to be responsible for dependence, euphoria, or effects on smooth muscle. Increases in cerebral blood flow and (possibly) increased intracranial pressure result from the respiratory depressant actions of opioid analgesics. The latter effects are due to increased arterial PrOj, which results from mu receptor inhibition of the medullary respiratory center. However, the activation of kappa receptors contributes to analgesia at the spinal level and is probably responsible for sedative actions of the opioids. The answer is (D). Codeine and possibly nalbuphine could decrease gastrointestinal peristalsis but not without marked side effects (and a prescription). Dextromethorphan is a cough suppressant. The other two drugs listed are opioids with antidiarrheal actions. Diphenoxylate is not available over-the-counter since it is a constituent of a proprietary combination that includes atropine sulfate (Lomotil). Loperamide is available over-the-counter. The answer is (D). 

E. Antidiarrbeal Agents The most effective antidiarrheal drugs are the opioids and derivatives of opioids that have been selected for maximal antidiarrheal and minimal CNS effect. Of the latter group, the most important are diphenoxylate and loperamide, meperidine analogs with very weak analgesic effects. Difenoxin, the active metabolite of diphenoxylate, is also available as a prescription medication. Diphenoxylate is formulated with antimuscarinic alkaloids to reduce the already minimal likelihood of abuse loperamide is formulated alone and sold over the counter as such. 

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