GI System Pathophysiology and Drug Absorption

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  • Created by: LBCW0502
  • Created on: 19-10-19 13:07
What does intestinal drug absorption depend on? (1)
The complex process depends on physiological conditions in GIT, pharmaceutical formulation and physicochemical characteristics of the drug. Patients suffering from GI diseases take a variety of medicines for GI condition/other conditions
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What does intestinal drug absorption depend on? (2)
Differences in bioavailability of drugs due to GI disease state can provoke sub-therapeutic or toxic levels of drugs. Impacts on safety and efficacy of drug therapy
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Which factors affect oral drug absorption? (1)
Drug factors - lipophilicity (log P 0-3), molecular size (500 Da), acidic/basic, ionisation
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Which factors affect oral drug absorption? (2)
Other factors - pH of medium, nature of barrier, absorption site, pH membrane surface
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Which factors affect oral drug absorption? (3)
Formulation, CR, passive drug absorption, absorption enhancers, surfactant systems
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What is the primary site of drug absorption?
Small intestine (great absorptive capacity)
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Describe features of the stomach and SI in drug absorption (1)
Stomach act as an organ of digestion (but some drugs are absorbed). SI has high SA. Rate at which stomach empties contents into intestine affects rate at which drugs reach the systemic circulation
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Describe features of the stomach and SI in drug absorption (2)
Slowing rate of stomach emptying decreases overall rate of intestinal absorption. Drug absorption mostly takes place by diffusion (passive). Mwt, structure, pH at absorptive site, water/lipid solubility profile significantly influences absorption
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What are the barriers to pass for drug absorption in the SI?
Mucus, epithelial layer, basement membrane/connective tissue, uptake to capillaries with lymphatics
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What are the types of pathways for drug absorption?
Transcellular, paracellular, passive diffusion, carrier mediated, facilitated diffusion, active transport (change in expression of receptors in disease states can affect drug absorption)
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Give examples of drug transporters expressed on the polarised intestinal epithelia (1)
Multi-drug resistance protein, multi-drug resistance associated protein, breast cancer resistance protein, monocarboxylate transporter protein, peptide transporter protein, organic anion transporting polypeptide, organic cation transporter
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Give examples of drug transporters expressed on the polarised intestinal epithelia (2)
Cartinine/organic cation transporter. Plasma membrane monoamine transporter
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Describe features of bacterial microflora (1)
Large number of bacterial microflora populates in human's distal small and large intestines. No bacterial microflora in stomach and upper intestine due to low pH of human gastric content. As pH decreases, bacterial population increases
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Describe features of bacterial microflora (2)
Presence of intestinal metabolism by bacteria could affect drug absorption
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Describe features of gut bacterial microflora (1)
Roles in metabolism of chemical through hydrolysis, dehydroxylation, deamidation, decarboxylation, reduction of azide groups. More than 40 drug substrates identified in GI microbiota
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Describe features of gut bacterial microflora (2)
Rate/extent of bacterial metabolism is influenced by amounts of xenobiotics reaching distal gut where bacteria concentration is maximal. Pharmacomicrobiomics - effect of microbiome variation on drug disposition and response
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What is the role of gut microbiota on drug metabolism?
Direct mechanisms (e.g. conversions to active or inactive metabolites or toxic metabolites). Indirect mechanisms (microbial metabolism). First pass metabolism. Activation, inactivation, toxicity
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What are the patient and disease factors impacting drug absorption? (1)
GI transit time. Changes in composition/characteristics of GI fluids such as bile salt concentrations, pH, osmolality can affect drug release from formulations and solubilisation of drug. Alterations in GI mucosa can affect drug permeability
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What are the patient and disease factors impacting drug absorption? (2)
Dissimilar expression of transporters can affect oral drug bioavailability. Differences in expression pattern of metabolic enzymes in GI mucosa can influence intestinal first pass metabolism
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What are the patient and disease factors impacting drug absorption? (3)
Alterations in composition and location of GI microbiota can affect exposure of drugs and formulations to bacterial enzymes - may change drug metabolism or release
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What are the effects of disease on drug absorption?
Not well characterised (studies poorly controlled, small patient population, study findings are conflicting). Aware of actual and potential problems that GI disease presents in drug therapy
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Describe features of bowel surgery and drug absorption (1)
Common causes of resection in adults are CD and bowel infarction due to vascular occlusion. Mass resection of SI may result in short bowel syndrome with malabsorption of nutrition, drugs and micronutrients (vitamins, electrolytes and minerals)
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Describe features of bowel surgery and drug absorption (2)
Degree of malabsorption after intestinal resection varies. Depends on extent of resection and patient's age at the time of first resection. Changed in intestinal flora causes further complications
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Describe features of bowel surgery and drug absorption (3)
Important for pharmacists to be aware of variable drug absorption and PK involved in treatment of patients with short small bowel
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Which alterations in IBD influence drug absorption?
Change in GI transit time (affected in UC and GC), change in permeability, change in microbiota and drug metabolism
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What are the further changes in IBD which affect drug absorption? (1)
Intestinal barrier dysfunction plays a key pathogenic in IBD. Altered expression and structural changes in intestinal tight junction proteins linked to development of IBD
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What are the further changes in IBD which affect drug absorption? (2)
Pro-inflammatory cytokines (TNFa) and interferons have been shown to increase TJ permeability and to induce apoptosis of epithelial cells (implications for drug absorption)
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Describe features of paracellular intestinal barrier in health and inflammation (1)
In inflammation, TJ barrier disturbed. Channel forming claudins up regulated, leads to increased permeability for ions and water. Barrier forming TJ proteins down regulated can be shifted into other regions/endosomes, further destabilise TJ barrier
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Describe features of paracellular intestinal barrier in health and inflammation (2)
Occludin involved in regulation of permeability for macromolecules, down-regulated by inflammatory processes (e.g. TNFa, interferon gamma), leads to increased paracellular permeability for macromolecules
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What are the physiological changes in IBD which affect drug absorption? (1)
Different compositional of luminal contents (UC). Differences in transporter expression in IBD. Thickness of colonic and rectal mucus layer reduced in UC. Thickness of colonic and rectal mucus layer increased in CD
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What are the physiological changes in IBD which affect drug absorption? (2)
Expression of metabolising enzymes of LI (UC). Microbiota of patients with IBD decreased in diversity)
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Describe features of coeliac disease (1)
SA for absorption is reduced due to villous atrophy. Rate of gastric emptying increased (delivery of drug to SI results in earlier absorption). Intraluminal pH of small bowel more alkaline (alters ionisation of drug). Drug absorption changed
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Describe features of coeliac disease (2)
Drugs with increased absorption include propranolol, aspirin, methyldopa and simvastatin, reduced absorption seen with digoxin
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Describe features of achlorhydria (1)
Absence of HCl in gastric secretions. Change in gastric pH could be due to - medications that reduce secretion, disease, ethnicity, age. Impair absorption of weakly basic drugs which show low solubility at high pH
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Describe features of achlorhydria (2)
Impaired absorption due to slow/incomplete dissolution of drugs under high stomach pH conditions. E.g. ketoconazole, itraconazole, atazanavir, cefpodoxime, enoxacin and dipyridamole
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What are the strategies to migrate effect of high stomach pH on absorption of weak bases? (1)
Co-administration with acidic beverages (acidic carbonated beverages e.g. Coca-Cola). Pre-treatment of achlorhydric patients with an organic acid supplement such as glutamic acid to reduce gastric pH
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What are the strategies to migrate effect of high stomach pH on absorption of weak bases? (2)
Use of special formulations such as solid dispersions to maximise absorption of poorly soluble drugs
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Describe features of cystic fibrosis (1)
In SI, transit is delayed (consequence of abnormal intestinal mucus blocking normal transit). Low duodenal pH resulting from combined result of gastric hyperacidity and reduced pancreatic bicarbonate secretions
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Describe features of cystic fibrosis (2)
Intestinal microbiome for CF people is less diverse. Pancreatic insufficiency also affects absorption
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Give examples of other diseases where intestinal drug absorption is affected (1)
Parkinson's Disease - prolonged colon transit time. Diabetes - changes in GI physiology. HIV infection - hypochlorhydria and hypoacidity can lead to reduction in absorption and subsequent bioavailability of basic drugs (ketoconazole, itraconazole)
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Give examples of other diseases where intestinal drug absorption is affected (2)
Pain - GI physiology altered by pain owing to gut-brain axis in terms of motility, secretion, intestinal permeability, reduced regenerative capacity of GI mucosa, influence on mucosal blood flow and negative effects on intestinal microbiome
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Give examples of other diseases where intestinal drug absorption is affected (3)
Dysphagia (swallowing difficulties) - patients unable to take some oral formulations. Gastrostomy and jejunostomy feeding - crushing of tablets. Liver disease
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