Pharmacology of the lower GI tract Flashcards
Opiate Agonists
Treat Diarrhea
Prototype: Loperamide
o Others: Diphenoxylate, codeine
MOA (Mechanism of action)
Opiates
Loperamide and diphenoxylate are piperidines, structurally related to opiates such as meperidine. As such they are classed as μ-agonists, although they have less propensity for eliciting the euphoric effect typically seen with opiate analgesics.
Side Effects:
Constipation
Bulk
Treat Diarrhea
Fibre (Physillium, Metamucil)
Bulk:
• Fibre promotes intestinal motility by increasing the bulk of the stool. This is accomplished by increasing the bacterial content of stool by fermentation of fibre (‘fermentable’ fibres) or simply by drawing water into the stool (‘non-fermentable’ fibre). Many substances in the diet perform a combination of the two. Fibre, and specifically the short chain fatty acids produced by fibre, may also have a direct stimulatory effect on the gut.
Osmotic Laxatives (2 Types)
Sugars: lactulose, PEG (polyethalene glycol)
Sugar SE: bloating / gas
Salts: Magnesium Hydroxide
Salts SE: Electrolyte Problems
Osmotic:
• There are two types of osmotic laxatives, those made of sugars/alcohols and those that are salts of electrolytes.
• A shared mechanism of both types is that they create an osmotic force, pulling water into the stool and creating additional bulk, in a manner analogous to that seen with the
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bulk agents. The sugars are typically poorly absorbed, such as polyethylene glycol, sorbitol, and lactulose.
• Additional mechanisms may contribute to the efficacy of the electrolyte salts, and these agents are generally considered to be more potent than the sugars. For example, magnesium-containing laxatives may stimulate cholecystokinin release, which in turn leads to increased fluid and electrolytes within the gut lumen, and increased motility.
Loperamide
Opiod Agonist
Physillium
Another product name is Metamucil (Fibre Bulking Agent)
Magnesium Hydroxide
Salt Osmotic Laxative
PEG
Another product name is Lactulose (Sugar Bulking Agent)
Stimulants
Sennosides
- Stimulant laxatives, as the name suggests, work by stimulating the intestinal wall, which leads to an accumulation of fluid and electrolytes and increased motility.
- The method by which stimulate laxatives stimulate the intestinal wall has not been clearly defined, although likely mediators include the activation of cAMP and cGMP pathways, inhibition of Na/K ATPase and increased platelet activating factor production
Sennosides
Stimulants
Softeners
Docusate
As the name suggests, softeners are emollients that soften the stool, making defecation easier. They accomplish this in a variety of ways.
• Docusate salts are surfactants that allow mixing of aqueous and fatty substances in the stool. The docusate salts also increase intestinal fluid secretion.
Docusate
Softeners
Opioid Antagonist
Opioid antagonists
• Constipation is a significant adverse effect of opioid use. Stimulation of opioid mu-receptors in the gut inhibits peristalsis and reduces intestinal secretions, resulting in constipation. The constipation can be severe and patients are unlikely to develop tolerance to the constipation and the severity of constipation increases with increasing dose.
• The opioid antagonists block mu-receptors peripherally, in the gut, and have only minimal penetration of the CNS. Therefore the opioid antagonists reduce the constipating effects of opioids without significantly interfering with their analgesic effects
Aminosalicyaltes (IBD)
Prototype and common drugs
Aminosalicylates: 5-ASA (mesalamine)
Others: sulfasalazine, olsalazine, balsalazide, mesalamine
MOA (Mechanism of action)
- The aminosalicylates are primarily anti-inflammatories. The precise mechanism of their anti-inflammatory effects is unknown, however they appear to exert a number of effects that would be expected to reduce inflammation.
- Aminosalicylates appear to inhibit inflammatory cytokines. This is likely to be the main mechanism by which they exert their anti-inflammatory effects. Among the cytokines they inhibit is tumour necrosis factor (TNF), a key mediator of inflammation that is the molecular target of a number of powerful anti-inflammatories.
- They also inhibit the cyclo-oxygenase (COX) pathway. This is the main mechanism for the anti-inflammatory effects of NSAIDs like the salicylates (ASA). Although the aminosalicylates are closely related to ASA, COX inhibition is not thought to play as important a role in the anti-inflammatory effects of the aminosalicylates.
- Aminosalicylates may also have immunosuppressive effects, although this is likely not as important as their anti-inflammatory effects in treating IBD.
Side Effects
- gastrointestinal (worse with sulfasalazine)
- headache
- also a number of rare but serious harms
Aminosalicyaltes (IBD) strategies of administration
There are several strategies employed to preserve the structure of the active drug during its passage through the gastrointestinal tract. These include:
- Attaching the drug to a chemical that is then cleaved in the colon
- Prodrug: Sulfasalazine
- R-ASA + sulfapyridine
- 2 separate molecules separated in colon by bacteria
- Efficacy largely due to 5 ASA
- AE mainly due to sulfapyridine - Enteric coating that does not dissolve until the distal small intestine
- Asocol, Solfalk
- Delayed release of 5-ASA based on PH
- Begin releasing drug in terminal ileum, continuing through rectum - Microspheres that slowly release drug beginning in the duodenum.
- 5 ASA ER
- Release 5-ASA throughout the small intestine to rectum - Rectal
- suppositories (suppositories effects may extend to the upper rectum 10 to 15 cm)
- Enemas can reach further
TNF Inhibitors (IBD)
Prototype and common drugs
Monoclonal Antibodies (MAbs):
• Prototype: infliximab
• adalimumab, certolizumab, golimumab
MOA (Mechanism of action)
• TNF-α is mostly produced by macrophages, but is also produced by other inflammatory cells. It binds to TNF receptors (TNFR) which are present on many different cells of the immune system. It promotes inflammation and is believed to play important roles in both inflammatory reactions to infections and also in the pathogenesis of autoimmune diseases.
• TNF-α is believed to exert its pro-inflammatory actions via promoting:
o the acute phase response which occurs early in the inflammatory response and is mediated in part by the release of other pro-inflammatory cytokines, including interleukin (IL)-1, IL-6, and IL-8, resulting in fever, loss of appetite, vasodilation, and tachycardia
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o increased expression of endothelial adhesion molecules which results in increased migration of leukocytes into target organs
o apoptosis
• The monoclonal antibodies typically bind to soluble TNF-α and/or transmembrane TNF-α, thus preventing TNF-α from interacting with its receptor. Through inhibition of TNF-α, the inflammatory response is blunted
Side Effects:
- Opportunistic infections (reactivation of TB)
- Hypersensitivity Reactions (acute or delayed, infiximab is chimeric (animal/human) while other are human mabs).
- Malignancies (due to immune survellance being reduced as TNF lyses tutor cells)
