Gi Pharm.docx

Antiemetics  Many things can cause vomiting – infxn , medicataion , vestibular dysfunction , chemo radiation o Nucleus tractus solitarus (nts) or vomiting center located In medulla , receives inputs from the GI tract , vestibular system , and area postrema and other areas of cns o Nts projects neurons to the other medullary neuclei and coordinates the vomiting response  Gi tract directly communicates with the vomiting center using cranial nerve 10 o Any condition that causes gi irritation such as infxn , chemotherapy or just distension results in increased mucosal serotonin release . o Serotonin activates 5ht3 receptors on vagal afferent nerves – this relays impulse to medullary vomititng center inducing emesis  Vestibular system communicates directly with the nts – via cranial nerve 8 o Vestibular system is responsible for vertigo and motion sickness aka vestibular nausea  The area prostema ( chemoreceptor trigger zone ) is located adjacent to the nts in brain stem . area prostema is located outside the bbb in the 4th ventricle there fore it can respond to many emetogenic substances in the blood and csf esp chemotherapeutic agents Pharm  Ondansetron – a selective antagonist of those 5ht3 serotonin receptors on vagal afferents leading from the gi tract to the brain o Since these affect the gi – these drugs are used to prevent N/V due to gi upset including chemotherapy induced vomiting as well as postoperative vomiting o Usually very well tolerated , but can cause constipation o Can also casue headache and dizziness o Can prolong qt interval and induce torsades – agents that block 5ht3 rec can pprolong qt o Can cause rere but potentially life threataening condition ass with use of 5ht3 rec antagonist – more common with serotenergic drugs like ssri and symp include rigidity , tremor , hyperthermia and confusion  H1 is coupled with Gq – it tuens out the vestibular system is rich in h1 receptor – 1st gen h1 receptor blockers eg diphenhydramine , meclizine cross bbb and treat vestibular nausea ( motion sickness )- can cause significant sedation and also have significanta anti muscarinic properties  The vestibular system contains M1 muscarinic receptors – scopolamine ( muscarinic antagonist) treats vestibular nausea or motion sickness  Motion sickness ( vestibular nausea ) is treated with 1st gen h1 antagonist and scopalmine  The area postrema contains D2 receptors – metoclopramide antagonizes d2 receptors in the area postrema – treats chemotherapy induced vomiting o Remember anti psychotic medications can also act on d2 receptors and can be used for their anti emetic properties o Metoclopramide has upper gi prokinetic effects ( increased esophageal peristalsis , increased lower esophageal sphincter pressure and enhaced gastric emptying ) – useful

for treatment of delayed gastric emptying due to post surgical disorders and diabeteic gastropairesis o Metacloromide (d2 antagonist) is contraindicataed in SBO – activation of gi smooth muscle by antagonizing the effects of dopamine treats an inactive bowel but will not help eith an obstructive bowel. So metaclopromide is contraindicated in small bowel obstruction o Can cause diarrhea – prokientic effects o However the most common adverse effect of metoclopramide are caused by d2 receptor blockade in the cns and they are more common in elderly pt – drowsiness, depression , extrapyramidal effects ( dystonia , akathisia , parkinsonian featurea ) – these are due to central dopamine blockade . metoclopramide can casue tardive dyskinesia with chronic use ( central d2 blockade) – long term use should absolutely avoided until absolutely necessary esp in elderly . o Can cause neuroleptic malilgnant syndrome – symx include fever , rigidity , mental status change , autonomic instability , rhabdomyolysis . this is normally seen with high potency antipsychotic drugs but it can also occur with antiemetic drugs that block d2 receptor o Can cause elevated prolactin ( central d2 blockade )- can cause galactorhea , gynecomastia , impotence and menstrual disorders o Can cause qt prolongation and induce torsades – so should be avoided in pt with long qt syndrome – higher risk of developing torsades  The area postrema contains neurokinin 1 ( NK1 ) receptors- activated by substance P. aprepitant antagonizes the nk1 receptors in the area postrema – treats chemotherapy induces vomiting . aprepitant crosses bbb to occupy the nk1 receptor in the brain and area postrema . this drug is often combined with a 5ht3 antagonist to prevent nausea and vomiting from highly emetigonic chemotherapy . aprepitant may be preffered to other antiemetics because it lacks any effect on serotonin , dopamine and muscarinic receptors – limting adverse effects

Laxatives and antidiarrheals Most people don’t need laxatives , though they are commonly self prescribed . to prevent constipation , all u need is a high fibre diet , hydration , regular exercise . but if lifestyle changes aren’t enough , some kind of a long term laxative regimen maybe considered . Before we begin , we will encounter prompt bowel evavuation – but we are not talking abt the direct stimulation of gi motility , that’s the job of prokinetic agents – bhethanecol (muscarinic agonist ) , neostigmine (anticholinesterase agent ) , metclopromide ( d2 blocker) , erythromycin . laxatives on the other hand work on the stuff that u are trying to get through the gi tract , not on the gi tract itself . its like changing consistencies of feces  Osmotic laxatives – eg magnesium compounds (hydroxide / citrate), lactulose , polyethylene glycol . these are nonabsorbable or poorly absorbable substances that sit inside gi tract and attract water into the lumen(distal small bowel and colon) > distending the intestinal walls and increasing peristalsis. o Magnesium – can be used for the treatment of acute constipation or the prevention of chronic constipation , ehough their efficacy isn’t clear . milk of magnesia – mg OH .  Prolonges use in pt with renal insufficiency can lead to hypermagnesemia . o Polyethylene glycol – non absorbable , osmotically active sugar that draws water into the lumen . lavage solutions containing peg are commonly used for complete colonic cleansing before gi and endoscopic procedures . peg is usually balanced with na , cl , bicarb and k so that there is no significanta electrolyte shift o Lactulose – along with sorbitol is a nonabsorbable sugar that can be used to prevent or treat chronic constipation .  Watch out tho . these sugars are metabolized by colonic bacteria producing severe flatus and cramp - this can be used for cirrhosis related hep encepahalopathy . In this condition too much extra ammonia is bad as your liver cant handle the current laod . a primary source of ammonia comes from intestinal bacteria as they degrade nitrogen products – gi bleeding for example can precipitate hepatic encephalopathy , as hb breakdown by luminal bacteria leads to increased nitrogen products and ammonia . excess diatary intake is another common trigger . intestinal bacteria metabolize lactulose into acid metabolites . the high h+ converts toxic ammonia into ammonium which gets trapped in lumen and excreted . nh4+ is acidic. One more strategy to reduce ammonia is to get rid of these bacteria altogether – rifaximin – poorly absorbed antibiotic , pretty much sits in gi lumen and kills bacteria responsible for all that ammonia production  With any laxative agent excessive diarrhea can lead to dehydration – so imp that pt are adequately hydrated to compensate for fecal fluid loss  Bulk forming laxatives - indigestible , hydrophilic colloid that absorb water forming a bulky emollient gel that distends the colon and promotes peristalsis . common prepirations include natural plant products like psyllium and methyl cellulose and synthetic fibres like polycarbophyl .

o Bacterial digestion of plant fibres in the colon may lead to increased bloating and flatus  Stool surfactant agents – stoof softeners , surfactant agents soften stool by fascilaitating the penetration of stool by water and and lipids . these agents may be administered orally or rectally . common agents include docusate - oral or enema , and glycerin suppository . in hospitalized pt docusate is commonly prescribed to prevent constipation and minimize straining .  Stimulant laxative – cathartics – that induce bowel movement through a number of poorly understood mechanism – these include direct stim of enteric nervous system , in combination with colonic electrolyte and fluid secretion . o Senna – poorly absorbed and after hydrolysis in the colon, it produces a bowel movement in 6-12 hours . chronic use leads to the characteristics brown pigmentation of colon called melanosis coli . Antidiarrheal – can be used safely in pt with mild to moderate acute diarrhea . however these agents should not be used in pt with bloody diarrhea or fever . in this situation the underlying inflammation or traumatic process needs to be managed first .  Opiod agonist - diphenoxylate , loperamide . activate u receptors in the gi . u opiod receptors exist in high density in gi tract and their activation leads to significant constipating effects . o Loperamide – u opoid agonist that does not cross bbb and therefore has no analgesic properties or potential for addiction  Opoid agonist increase the phasic segmenting activity of colon – tract squeezing down on stool instead of pushing it along . this increase colonic transit time as stool just move back and forth . and as the water just sits there , it leads to increased water absorption from the intraluminal contents . o Diphenoxylate is a prescription opiod agonist also used as an antidiarrheal agent – u opoid rec activator but with some ability to cross bbb , so its combined with atropine to avoid abuse . low therapeutic doses of diphenoxylate allow for potent antidiarrheal effect without significant opiotes effect . however at higher doses , it can produce morphine like euphoria and physical dependence thus therapeutic dose of drugs are combined with small doses of atropine and marketed under the name lomotil , as higher doses of these are used , higher doses of atopine will produce adverse symx and discourage abuse  Antidiarrheal agents are contraindicated in pt with bloody diarrhra or fever – unlying pathology can be made worse In genral any opopid agent can cause constipation . pt who aquire prolonged opiod therapy should receive a prophylactic bowel regimen including increased fluid intake , diatary fibre and laxatives

 Vip and carcinoid tumor can cause secretory diarrhea – for pt with advanced symptomatic tumors that cannot be completely resected , ocreotide can be used to reduce secretory diarrhea

and systemic symx theough inhibitioin of hormonal secretion . ocreotide can be useful for managing a variety of syndromes that cause secretory diarrhea , including chemotherapy induced diarrhea , hiv ass diarrhea or short bowel syndrome