GI Conditions Study Guides

What are some upper GIT conditions (mouth, oesophagus, stomach)? Dry mouth or excess saliva (hyposalivation and hypersalivation) Dysphagia Gastritis Delayed gastric emptying Ulcers Gastro oesophageal reflux disorder (GORD) Dyspepsia/ functional dyspepsia How is saliva secretion regulated? • Saliva secretion is regulated by the ANS. Secretion is stimulated mainly by acetylcholine, released by the parasympathetic NS, and inhibited by noradrenaline, released by the sympathetic NS (fight or flight) • A small amount of saliva is continuously secreted, and this amount is increased due to ANS stimulation • Presence of food in the mouth induces saliva secretion, which is an extrinsic reflex - food chemicals stimulate taste receptors in the mouth - this sends a sensory impulse to the brainstem salivary nuclei - this leads to parasympathetic activity being initiated - parasympathetic fibres (from the cranial nerve) terminate on the smooth muscle fibre that surround the salivary acini What is the cause of dry mouth? • Hyposalivation, which is reduced production of saliva by the salivary glands • Dehydration (the GI plays a role in thisfluid is secreted into the stomach and small intestine during digestion, and if this is not absorbed then there is potential risk of dehydration) • ADR of drugs with anticholinergic ac1 / 64 tivity, eg antidepressants, antihistamines (in particular, H1 receptor antagonists). These drugs stop acetylcholine acting on its receptors, reducing salivary secretion • Radiotherapy to head and neck, which can damage nerves or the salivary glands themselves to reduce salivary secretion What is the treatment of dry mouth? Usually treated with artificial saliva substitute eg sprays What is the cause of excess saliva? • Hypersalivation, which is increased production of saliva by the salivary glands • Inhibition of swallowing due to neurological damage eg through stroke or neuromuscular disease eg motor neuron disease Some cases of excess saliva eg those caused by hypersalivation can be treated What is the treatment of excess saliva? with anticholinergics, where the effects of acetylcholine at the salivary glands are blocked • Referral to SLT, if the excess saliva is What are some red flags for excess sali- caused by decreased swallowing of saliva that warrant referral? va rather than increased saliva production 2 / 64 What is dysphagia? • Difficulty, discomfort and/or pain on swallowing food or liquids • It is a disruption of the normal physiological events of swallowing - chewing and moving food to the throat - food moving through the throat and oesophagus - peristalsis in the oesophagus in the bottom 2/3rds of smooth muscle, regulated by the nervous system, causes contraction and relaxation to push food down the oesophagus - the lower oesophageal sphincter relaxes (circular muscle) as the peristaltic wave hits the bottom of the oesophagus, allowing the material to enter the stomach • It can occur at any point during the swallowing process • It can occur in two regions 1. The oropharyngeal region (the throat) 2. The oesophageal region • It prevents - eating, which can lead to malnutrition - taking oral medication - material being digested normally, so leads to aspiration of material into the lungs, resulting in infection and pneumonia - comfort, since the stretching of the oesophagus activates pain receptors 3 / 64 What is the cause of dysphagia? • Neurological disorders eg stroke, Parkinson's disease, dementia - this affects smooth muscle tone • Structural abnormalities in the oesophagus • Cancer, such as mouth or oesophageal cancer - the presence of the tumour disrupts swallowing • Radiotherapy - this causes inflammation • Heartburn and acid reflux, especially in those who have GORD • Chronic oesophagitis (long-term inflammation) - this leads to scarring of the oesophagus, where the tissue is replaced by new cells that do not have the normal physiological properties, causing loss of function • Some medicines eg antipsychotics • Age - natural loss of smooth muscle tone What is oropharyngeal dysphagia? • Difficulty swallowing, which initiates in the orophargngeal region (the throat) • This region initiates the process of swallowing • It is commonly a consequence of a neuromuscular disease It is difficult to treat with pharmacotherapy so is instead treated with • Swallowing therapy to develop the reWhat is the treatment of oropharyngeal flex back dysphagia? • Dietary changes (more liquids as they are easier to swallow) • Feeding tubes 4 / 64 What is oesophageal dysphagia? • Difficulty arises after the swallow, when trying to move food down the oesophagus • It is commonly a consequence of a structural or mechanical obstruction (majority of cases) eg damage to the oesophagus, which affects swallowing of solids only • It can also be caused by motor disorders (minority of cases), which affects signalling in the oesophagus, causing disrupted peristalsis - this can be caused by systemic diseases - or due to oesophageal spasms, caused by rare neurodegenerative disorders of the oesophagus What is the treatment of oesophageal dysphagia? • Surgery • Pharmacotherapy to relax the lower oesophageal sphincter and reduce its pressure to facilitate emptying via gravity • Long acting nitrates (isosorbide dinitrate) which activate guanylate cyclase in the muscle cell, increasing cyclic GMP, causing dephosphorylation of myosin, ultimately inhibiting contraction of the oesophageal muscle • Calcium channel blockers (nifedipine) which block the dihydropyridine chanWhat pharmacotherapy is used to treat nels, and this leads to reduced calcium oesophageal dysphagia? entry into the smooth muscle cells and reduces contraction amplitude (since calcium entry into the smooth muscle is what causes the muscle to contract) • Injection of type A botulinum toxin (from clostridium botulinum), which contains a protease that targets and destroys a protein (SNAP25) involved in the cal5 / 64 cium dependent exocytosis of acetylcholine from presynaptic nerve muscles, so acetylcholine isn't released, preventing smooth muscle contraction These all reduce oesophageal muscle contraction which reduces pain when swallowing What is a functional disorder? • Symptoms in the absence of mucosal, structural or biochemical disease (does not imply that there is no physiological basis) • It can be triggered by - previous inflammation - post-infective state - psychological disturbances eg stress, anxiety - dysmotility - visceral hypersensitivity, which is an exaggerated or heightened perception of pain and discomfort in the internal organs, which occurs when the brain is more sensitive to what is happening in the body organs, causing the brain to respond to these movements and processes inappropriately • Examples include - functional (non-ulcer) dyspepsia - irritable bowel syndrome - constipation What is functional dysphagia? • Difficulty swallowing that occurs without an identifiable structural or mechanical cause - no obvious physical obstructions, no inflammation or infection etc • Characterised by a sensation of abnormal bolus transit through the oesophagus 6 / 64 • Peristaltic dysfunction What is the cause of functional dyspha- • Dysfunction in the sensory perception gia? of what is happening in the oesophagus (viseral hypersensitivity) It is difficult to know what exactly is causing it, so treatment involves mainly management eg • Avoid precipitating factors and triggers • Careful mastication of food- chew the What is the treatment of functional dys- food properly so that it is in small pieces phagia? before swallowing • Address psychological factors and the brains response to what's happening in the gut eg through antidepressants • Use smooth muscle relaxants eg type A botulinum toxin • Very severe difficulty swallowing, to the point where food or drink cannot be swallowed at all • Feeling like something is stuck in the throat after eating, causing coughing or choking • Food not staying down, and being What are some red flags for dysphagia brought back up, sometimes through the that warrant referral to the GP? nose • Babies will cry a lot or arch their back when feeding • Shortness of breath after eating or drinking • When the patient has frequent chest infections • Inflammation of the gastric mucosa leading to discomfort and tenderness • Inflammation causes release of molecules that increase our sensitivity to pain • Acute gastritis is the injury/ damage of the protective mucosal barrier, which causes the acid in the stomach to reach 7 / 64 What is gastritis? the epithelial cells and the nerve endings beneath them • Chronic gastritis commonly occurs in the elderly and is usually due to the thinning or breakdown of the stomach wall. This can lead to chronic fundal or anstral gastritis (gastritis that occurs in separate regions of the stomach) What is the cause of acute gastritis? • Drugs eg NSAIDs - NSAIDs reduce prostaglandins, reducing secretion of mucus and bicarbonate which form the protective barrier, increasing risk of acid reaching the gut wall • Chemical eg histamine - histamine increases acid release, increasing risk of damage to the gut wall • Infection • Alcohol, digitalis and uremia can all be contributing factors What is the treatment of gastritis? • Remove the trigger • Decrease stomach acid, as the acid coming into contact with the epithelial cells causes the pain, through proton pump inhibitors What is oesophagitis? • Inflammation of the oesophagus • Oesophagitis can develop into Barrett's oesophagus which can lead to oesophageal cancer • It is treated similarly to gastritis, using a PPI What is delayed gastric emptying? Food in the stomach for more than 8 hours It results in pain, nausea and vomiting 8 / 64 What is the cause of delayed gastric emptying? • Eating too many fat-rich meals as lipids take longer to be emulsified so remain in the stomach for longer. • Eating too large meals as there is more material in the stomach which takes longer to be emptied, and you are more likely to experience symptoms associated with delayed gastric emptying • Mechanical obstruction • Gastroparesis, which is delayed gastric emptying due to changes in neuronal regulation of the stomach, caused by - diabetes mellitus where the vagus nerve was damaged - past surgery in the GIT, as regions of the gut can communicate and lead to disturbance of whole gut activity, preventing motility (post-operative gastric stasis) - idiopathy, where there is no known cause of gastric emptying - ADR of medicine use eg medicines that slow activity in the stomach What can cause mechanical obstruction? • Acute peptic ulcer disease, where inflammation causes the stomach lining to swell (oedema), affecting how food moves through • Chronic peptic ulcer disease, where scarring (fibrosis) to the stomach wall makes the muscle less able to contract, affecting how food moves through • Cancer, where the presence of a tumour in the gut wall impacts contraction • Amyloidosis, where amyloids (insoluble protein aggregates) are deposited in the smooth muscle layers of the GIT, affecting motility 9 / 64 Treatment of gastroparesis • Correct or treat the reversible factors - optimise diabetes management - reduce dose, or discontinue aggravating medications - CBT (cognitive behavioural therapy) due to the visceral hypersensitivity, to relax the person and make them less bothered about what is happening in the What is the treatment of delayed gastric stomach emptying? • Increase gastric emptying - using prokinetic agents - by stimulating the third stage of the migrating motor complex (motor pattern of the fasting state, where the third stage includes neuronal activity, signalling and contraction to move material along) through octreotide and erythromycin What are prokinetic drugs? • Drugs that increase the strength and coordination of muscular contractions in the gut to help push the material food contents through the GIT • However these cannot be used long term due to ADRs • In the past, domperidone and metoclopramide were bought OTC to treat gastroparesis and manage the feeling of fullness, but both have ADRs that limit their use • They both act on receptors involved in nausea and vomiting to reduce these effects • Domperidone has cardiovascular risks and is contraindicated in those with underlying cardiac conditions, and is no longer available without a prescription and should not be used long term • Metoclopramide has a risk of neuro10 / 64 logical side effects, and is now given a reduced dose and a maximum of 5 days use • Domperidone cannot cross the blood brain barrier but metoclopramide can • They are both used in an acute hospital setting for 2-3 days eg intestine care treatment of gastroparesis induced nausea and vomiting How do prokinetic drugs work? • The aim of prokinetic drugs is to increase the release of acetylcholine, which acts on smooth muscle cells to enhance stomach motility without purgation • The motor neuron releases acetylcholine • Serotonin activates 5HT4 receptors (G-protein coupled receptors) on the motor neuron, which leads to the depolarisation of the motor neuron, causing it to release acetylcholine. • A dopaminergic neuron releases dopamine which is inhibitory. Dopamine activates D2 receptors and hyperpolarises the motor neuron, preventing release of acetylcholine. • Serotonin can also activate 5HT3 receptors (ligand gated ion channel) causing the release of non-adrenergic and non-cholinergic substances eg ATP, NO, which leads to hyperpolarisation of the motor neuron, preventing release of acetylcholine. • Therefore an agonist is needed at the 5HT4 receptors and an antagonist is needed at the D2 and 5HT3 receptors. • Domperidone and metaclopramide are D2R antagonists • Prucalopride is a 5HT4R agonist 11 / 64 What is octreotide? • It is a somatostatin analogue (a molecule that is similar to somatostatin) to induce phase 3 of the MMC in the duodenum, to move contents through • However this prolongs the overall transit time through the intestines, which could cause constipation - hence why this drug is useful for individuals with a stoma who have a net secretor phenotype, where they produce a lot of fluid, so constipation would be less likely, and increasing transit time also allows for more reabsorption of fluid for the patient A stoma is a surgically created opening in the body to allow for bodily waste and fluid to be excreted when normal excretory pathways are disrupted due to damage in the gut that causes a part of the gut to not work, eg in those with cancer of the lower GI tract or IBS. An inability to reconnect parts of the bowel means that the rectum cannot be used to excrete faeces. Therefore an opening (a stoma) is made to the external surface of the body, and a cholestomy bag is attached to allow for excretion What is erythromycin? • It is an antibiotic, so contributes to antibiotic resistance as no bacteria is involved in gastroparesis • It activates the motilin receptor, which helps move material through the upper GIT • It stimulates gastric and small intestine contractions so induces MMC phase 3 activity • It increases lower oesophageal sphincter pressure • It is used in a specialist setting eg inten12 / 64 sive care for 3-4 days, in those who have had surgery What are ulcers? • Erosion of the stomach or intestinal lining • They can occur in the stomach, duodenum (most common) or oesophagus (rare) • Normally, mucus cells in the neck of the gastric glands secrete mucus and bicarbonate ions to create a chemical barrier to protect the stomach. Ulcers are formed when acid and pepsin destroy the mucosa and form holes through the submucosa into the muscularis. • Ulcers account for around 13% of cases of dyspepsia • Ulcers can erode the gut wall until it reaches a blood vessel, which can lead to life threatening bleeding • They are caused by an imbalance between the protective factors in the stomach and the amount of acid secreted Gastric ulcers • Pain, due to action of acid on sensory nerve endings • Loss of appetite and weight loss • Bloating or nausea after eating What are symptoms of ulcers? Duodenal ulcers • Pain, which worsens when fasting at night and is relieved by food. Food buffers the acid, so less acid enters the duodenum, lessening pain. The type of pain is common to all locations- it is a burning, aching, gnawing pain between the navel and the breastbone, sometimes extending to the back. 13 / 64 Bleeding of the ulcer can lead to black, tar-like stools (described as coffee grounds). Bleeding of the ulcer is shown through low blood pressure (which could be due to vasodilation or dehydration) and low haemoglobin and haematocrit levels What are causes of ulcers? • NSAIDs • Smoking, which reduces nitric oxide and therefore reduces angiogenesis, which is needed to heal the ulcer • High alcohol intake, which causes an increase in acid release • Zollinger-Ellison syndrome, which is when gastrin-secreting tumours in the pancreas cause unopposed secretion of gastrin, which isn't reduced by the normal physiological processes of the body. This leads to hyperacidity and ulcers • Bacterial infection, which is usually by H.pylori, as some strains are immunogenic and can cause inflammation to cause an ulcer How do NSAIDs cause ulcers? • They inhibit cyclooxygenase leading to a reduction in production of prostaglandins. Reduction in prostaglandins causes - a decrease in release of mucus and bicarbonate, reducing protective factors, so you are more likely to get erosion of the gut wall - a decrease in its inhibition effect on stomach acid release, as there is more cAMP, more activation of protein kinase A, and more translocation of proton pumps, so more stomach acid is released • Hence why strong NSAIDs are pre14 / 64 scribed with PPIs, so the PPI can help reduce the acid to prevent ulcers The main aim of treatment is to resolve the pain, by • Healing the ulcer • Preventing it's recurrence • Avoidance of complications eg bleeding What are treatments of ulcers? How is drug therapy used to treat the ulcer? This is done by • Drug therapy • Lifestyle modifications - avoid alcohol - avoid smoking - avoid NSAIDs Drugs can be used to • Eradicate the bacterial infection causing the ulcer • Decrease acid secretion • Neutralise the acid • Antibiotics • Proton pump inhibitors • Bismuth Chelates 1. Triple therapy- two antibiotics and a PPI, to reduce acid levels and manage the infection What drugs can be used to eradicate the - two antibiotics are used to ensure combacterial infection? plete destruction of the bacteria to avoid resistance - eg amoxicillin and clarithromycin/ metronidazole along with lansoprazole 2. If the antibiotics do not work because of resistance, then second/third line therapy includes Bismuth Chelates 15 / 64 What are Bismuth Chelates? • They physically bind to the bacteria to prevent them binding to the surface of the gut wall (bactericidal effect on bacteria) • They strongly adhere to proteins • They can form a complex gel with mucus, which forms a barrier to prevent acid getting to the surface of the stomach to cause damage, and also to prevent the penetration of H.pylori into the mucosa itself • They promote prostaglandin release to increase mucus and bicarbonate release • Examples include bismuth subsalicylate or bismuth subcitrate (brand names include Pepto-Bismol, Pepti-Calm and BisBacter) • They are not used very commonly due to ADRs of nausea and abdominal pain • Proton pump inhibitors • Histamine H2 receptor antagonists • Prostaglandin analogues could potentially be used to increase the inhibition of What drugs can be used to decrease the acid release by preventing the translocaamount of acid released? tion of the proton pump to the cell membrane, and to increase the production of mucus and bicarbonate for protective factors. They are not used clinically now because of ADRs What are proton pump inhibitors? • The PPI will reduce basal acid secretion and acid secretion stimulated by food, by around 90% • They are enteric coated to ensure they are not dissolved in the stomach, but reach the duodenum from where they can enter the circulation • They have a high specificity for the stomach • There is no effect on the release of 16 / 64 pepsin or intrinsic factor • Proton pumps are constantly synthesised to replace inactivated or degraded ones, so PPIs irreversibly binding to the proton pumps is convenient because it blocks their activity for an extended period of time, making the dose normally only once a day • Examples include Lansoprazole, Omeprazole What is the dose of PPIs? • The dose differs for the condition being treated • The dose usually lasts for 4-8 weeks • The dose is taken in the morning before breakfast, before acid secretion is stimulated. But it should not be taken too long before, because an acidic environment is required to protonated the PPIs, so half an hour before food is recommended. • Due to ADRs, the dose of the PPI should be reduced gradually, and they should be prescribed for the shortest possible duration. • However some people stay on it for much longer because the reduced amount of acid allows them to continue with their lifestyle they had that led to them getting the ulcer, and it helps relieve symptoms of dyspepsia How do proton pump inhibitors work? • They enter the circulation from the duodenum, and arrive at the stomach where they move through parietal cells to the canaliculi, which are invaginations of the membrane in the parietal cell to give it a large surface area. • Here, the PPI becomes protonated by the acid, trapping it. • In its protonated form, it can form a 17 / 64 disulfide bridge (covalent bonding) with the proton pump, causing irreversible binding, and this irreversibly inhibits the proton pump. • For more info, see Proton Pump Inhibitors set What are dosage forms of PPIs? • Tablets, which are enteric coated • Capsules - if tablets or capsules cannot be swallowed, then the capsules can be opened and the granules inside are enteric-coated and are smaller so can be swallowed. The patient should be advised to swallow the granules with water, or mix the granules into a slightly acidic fluid eg fruit juice or apple sauce, or in non-carbonated water, stir it, and then swallow this immediately or within 30 minutes, and then rinse down with half a glass of water. The enteric coated granules must not be chewed • Oral suspensions, which are usually very expensive Why are PPI tablets ineffective when crushed? • PPIs have an enteric coating that allow it to withstand the acidic conditions in the stomach and be absorbed in the bloodstream • If the tablet is crushed, the enteric coating is broken so omeprazole would become protonated in the stomach lumen. Once omeprazole is protonated in the lumen, it cannot move to the parietal cells through the cell membranes therefore it will not be able to bind with and inhibit the proton pump, rendering it ineffective. 18 / 64 • On demand dosing, so only take when you have symptoms • Move to OTC antacids • Remove the drug altogether, and focus on lifestyle modifications What are different ways of deprescribing • Remain on the dose since it is appropriPPIs? ate for the individual patient Overall, speak to the patient and come to a shared decision. Consider side effects of PPIs, interactions and the ongoing need for it. • Headaches • Dizziness • Nausea or vomiting • Diarrhoea • Constipation • Stomach ache • Flatulence • Dry mouth or throat What are some common side effects of • Fundic gland polyps (benign- not harmusing PPIs short-term? ful), which are small masses of cells in the upper part of the stomach (the fundus). Large polyps which have a diameter larger than around 1cm can carry a small risk of cancer • Itching or rash • Urticaria/ hives, which are itchy, raised rashes • Fatigue 19 / 64 • They impact absorption of drugs that require an acidic environment to absorb, due to achlorhydria, which is a lack of hydrogen ions • It's use has been linked to - increased risk of bone fractures, because the reduced stomach acid can decrease solubilisation of calcium salts in the stomach, which can reduce the absorption of calcium in the intestines - hypomagnesameia (low magnesium levels) - vitamin B12 deficiency, because vitamin B12 is released from dietary proteins What are ADRs of PPIs (uncommon but by the action of HCl and pepsin, so reserious)? duced stomach acid impairs the release of B12, decreasing its availability to (bind to intrinsic factor and) be absorbed - increased risk of infection, because reduction in acid means less microbes are killed - drug interactions via CYP inhibition, because there is metabolism of PPIs by CYP • Epidemiological studies have linked the long-term use of PPIs with chronic kidney disease, cardiac disease, and dementia in some cases • Reduced acid secretion can cause acid rebound 20 / 64 What is acid rebound? • Hypersecretion of acid (a lot of acid is secreted) • This occurs when PPI use is suddenly terminated (so the dose of PPIs should be reduced gradually) • It occurs because inhibiting acid release removes the negative feedback control of gastric secretion by HCl, so less acid increases the amount of gastrin. Gastrin can increase the growth of the stomach lining (hypertrophy), increasing the number of cells in the lining - more parietal cells increase acid secretion - more ECL cells means more histamine is released, which has a greater effect on parietal cells to secrete acid • It can also occur by increased sensitivity or upregulation of histamine receptors so there are more histamine receptors, so more acid is secreted. This occurs because the cell tries to compensate for the lack of acid secretion. • They block histamine receptors to prevent the release of stomach acid • They are not as effective as PPIs because it only blocks histamine, so acetylcholine and gastrin would still cause acid secretion - However, because acid secretion isn't completely reduced, it allows the acid to maintain its normal physiological role • Examples include ranitidine • Ranitidine is a competitive inhibitor of the H2 receptor, so reduces stomach acid secretion (both basal and food-stimulated) by around 60%, and also reduces pepsin levels. This leads to healing of duodenal ulcers (around 80% of healing 21 / 64 What are histamine receptor antagonists? within 4 weeks) • However, Ranitidine, a H2 receptor antagonist, would have been used to reduce stomach acid however Ranitidine medicines have been suspended in the EU due to the presence of low levels of an impurity called NDMA (above levels considered to be acceptable), which is a probable human carcinogen • Instead of Ranitidine, PPIs are being used, or an alternative H2 receptor antagonist can be used • Relapse is likely when the drug is stopped, especially if there is incomplete eradication of infection • There is evidence of acid rebound after therapy, as there are more receptors to be acted upon by histamine PPIs, since they irreversibly bind to proton pumps to stop acid secretion Histamine receptor agonists only stop the effect of histamine, and not the other substances that stimulate acid secretion, so acid levels do not completely decrease What drug is the most effective in reducHence, usually only PPIs are prescribed ing stomach acid? without H2 receptor agonists, as only one or the other is needed. However, if there are symptoms at night (when levels of the PPI have decreased a bit) then a H2 receptor antagonist can be taken at night (when the PPI is used in the morning) to help nocturnal reflux. 22 / 64 • Anti-cholinergics are not used to decrease acetylcholine to reduce stomach acid secretion, because of its adverse effects, since anti-cholinergics cannot specifically target the receptors on the parietal cell so affect the rest of the body • Drugs are not used to target gastrin What drugs are not used to decrease the receptors to reduce stomach acid, beamount of acid released? cause gastric receptors are structurally similar to other receptors in the body so achieving high selectivity for the gastrin receptors is difficult, and the drug could bind to other receptors to have unintended ADRs. Also the drug cant specifically target the receptors on the parietal cell so affect the rest of the body • Dry mouth, because acetylcholine stimulates secretion of saliva • Constipation What are adverse effects of anti-cholin- • Bowel obstruction ergics? • Blurred vision • Drowsiness • Urinary retention, due to reduced contraction What drugs are used to neutralise stomach acid? Antacids What are antacids? • They neutralise gastric acid by increasing the pH to e4, but a good antacid will keep pH rise to d4 • This helps to alleviate ulcer pain and inactivate pepsin • A higher pH above 4 poses a risk of acid rebound due to gastrin secretion • The effectiveness of an antacid is governed by - dosage form dissolution - reactivity with acid - physiological effects of the cation 23 / 64 - individual tolerance of the formulation • A good antacid will be fast-acting and long-acting • In calcium-containing antacids with nothing else in it, the calcium stimulates gastrin release, causing increased release of acid. This is not a problem while the antacid is being used but can be a problem after it has stopped • Antacids can come in solid or liquid dosage forms What are the main types of antacids? Aluminium compounds Magnesium compounds Sodium bicarbonate based What are aluminium antacids? • An example is aluminium hydroxide • They react slowly with HCl so they have prolonged action • They form a protective coat over the ulcer • They adsorb pepsin • They are non-systemic, so a very small amount of around 0.12% is absorbed • They have constipation as a side effect • They form complexes with phosphates in the intestines, causing increased phosphate excretion. This can be useful in those with chronic renal failure who struggle to excrete phosphates • They form complexes with tetracycline, which is an issue when used with antibiotics as they reduce antibiotic absorption 24 / 64 What are magnesium antacids? • Examples include magnesium trisilicate, magnesium hydroxide, magnesium oxide, magnesium carbonate • They react slowly with HCl so they have prolonged action • They form a protective coat over the ulcer • They adsorb pepsin • Very little is absorbed systemically (around 5%) • It stimulates the gut by causing secretion of CCK, having a laxative effect and causing diarrhoea • Magensium trisilicate is one of the best magnesium antacids because it reacts slowly with HCl and gives a pH rise to about 4. Other magnesium salts give a pH rise to around 9 What are sodium bicarbonate based antacids? • They have a rapid reaction with gastric acid • They rapidly cause a pH rise to around 7.4 • There is a danger of acid rebound • They produce carbon dioxide in the stomach, which initiates belching and stimulates gastrin secretion. However some sodium bicarbonate-containing antacids contain other excipients eg sodium alginate which is a gel-forming agent and can form a barrier over the food contents to trap the CO2 and stop belching • There is systemic absorption, which poses a risk of alkalosis (higher than normal concentration of bicarbonate ions), and also sodium retention aggravates hypertension 25 / 64 • Antacids can decrease the absorption of other medications • Antacids neutralise pH however some Why is it important to give advice on how drugs require low gastric pH to release to take antacids with other prescribed the drug medications? • If antacids interfere with the medicine, then the antacid can be taken for a longer period before or after taking the medicine • Tums- calcium carbonate • Gaviscon advance chewable tabletssodium alginate, calcium carbonate and sodium hydrogen carbonate • Pepto-Bismol- bismuth subsalicylate • Magnesium Trisilicate Compound Tablets BP- magnesium trisilicate and aluminium hydroxide • Maalox Plus Tablets- aluminium hydroxide mixture, magnesium hydroxide and simeticone - Maalox tablets have a slower onset of What are examples of antacids in solid action than the oral suspension dosage form seen in practice and what • Rennie Extra tablets- calcium carbonare their active ingredients? ate, magnesium carbonate and alginic acid • Rennie Deflatine- calcium carbonate, magnesium carbonate heavy and simeticone • Bisodol Indigestion Relief tablets- calcium carbonate, magnesium carbonate light and sodium bicarbonate • Boots Pharmaceuticals Indigestion Relief tablets- calcium carbonate • Andrews Original Salts- sodium hydrogen carbonate, magnesium sulphate and citric acid 26 / 64 • Maalox Plus suspension- aluminium hydroxide mixture, magnesium hydroxide and simeticone • Mucogel suspension- aluminium hydroxide gel BP and magnesium hydroxide BP • Altacite Plus suspension- hydrotalcite (aluminium magnesium carbonate hydroxide hydrate) and simeticone • Boots Pharmaceuticals Heartburn Relief- sodium alginate, sodium bicarbonate and calcium carbonate • Kolanticon Gel- dicycloverine hydrochloride, aluminium hydroxide, light magnesium oxide and simeticone • Gaviscon Cool Liquid- sodium alginate, What are examples of antacids in liquid sodium bicarbonate and calcium carbondosage form seen in practice and what ate are their active ingredients? • Gaviscon Advance Aniseed suspension- sodium alginate and potassium bicarbonate • Gavison Double Action Oral suspension- sodium alginate, calcium carbonate and sodium bicarbonate • Milk of Magnesia- magnesium hydroxide • Magnesium Trisilicate mixture BPmagnesium carbonate light, magnesium trisilicate and sodium hydrogen carbonate • Pepto-Bismol oral suspension- bismuth subsalicylate • Rennie Liquid Heartburn Relief Oral suspension- sodium bicarbonate, sodium alginate and calcium carbonate 27 / 64 What are alginates? • Active ingredients added to antacids • They are naturally occurring hydrophilic carboxylated polysaccharides, extracted from the cell wall of brown algae • Upon acidification of alginate salts eg sodium alginate, calcium alginate, alginic acid is obtained • They are found in sodium bicarbonate-containing antacids • They react with stomach acid to form a floating viscous gel of pH7 on the surface of gastric contents which acts as a barrier to prevent reflux into the oesophagus, protects the oesophageal mucosa and traps carbon dioxide to avoid belching • They are taken after meals • They are commonly available as compound preparations also including antacids • Examples of antacids that contain alginates include Gaviscon, Peptac What is simethicone? • An active ingredient added to antacids • It acts as an antiflatulent What is dicycloverine? • An active ingredient added to antacids • It is a muscurinic receptor antagonist which reduces spasms What is bismuth subsalicylate? • An active ingredient added to antacids • It coats the stomach mucosa to ease symptoms Sodium bicarbonate and calcium carbonate both react with stomach acid to Why does a patient belch when using produce carbon dioxide, which is a gas antacid products containing sodium bi- so causes belching carbonate or calcium carbonate? CaCO3 + 2HCl -> CaCl2 + H2O + CO2 NaHCO3 + HCl -> NaCl + H2O + CO2 28 / 64 What is GORD? • Gastro-oesophageal reflux disorder • Symptoms and/or mucosal damage resulting from reflux of gastric contents into the oesophagus • Reflux into the oesophagus is completely normal, but the problem occurs when the symptoms occur more frequently or for a longer duration • It is a common disorder • It is a chronic disorder that requires long term treatment • It accounts for around 20% of dyspepsia cases • Excess reflux into the oesophagus is normally prevented by - the lower oesophagus sphincter (LOS), which is circular smooth muscle between the oesophagus and stomach - the diaphragm, which has a pinching effect on the oesophagus - secondary peristalsis in the oesophagus, which are peristaltic waves that occur after the first wave of peristalsis, to push down any material into the stomach that wasn't removed the first time • The oesophagus doesn't have as much of a protective layer compared to the stomach, as there is mucus secreted here but not bicarbonate What are categories of GORD? • Uncomplicated GORD, where there are sporadic episodes, no more than 2-3 per week. • Moderate GORD (with or without oesophagitis) where there are more frequent episodes, more than 3 a week • Severe GORD where there is chronic, unrelenting symptoms which relapses once therapy is completed, and is more likely to have complications 29 / 64 What are the symptoms of GORD? • Restrosternal pain around the breastbone, which can extend upwards towards the mouth • Heartburn, which is caused by the exposure of oesophageal mucosa to the gastric acid or bile • Epigastric pain, in the region of the stomach • Hoarse voice/ cough • Regurgitation • Waterbrash, where the mouth is filled with dilute saliva • Dysphagia, if there is damage to the oesophagus over time • Tooth decay and bad breath due to the acid • Oesophagitus, which is caused when repeated presence of acid in the oesophagus over time causes inflammation. It occurs in up to 2% of patients. • Chronic ulceration, which is rare. It causes increased pain and bleeding, which can give rise to anaemia. • Fibrosis/ stenosis where over time, scar tissue is laid down, causing progressive dysphagia • Barrett's oesophagus, where metaplasWhat are the long term effects of GORD? tic columnar epithelial cells replace the normal stratified squamous cells. There is a 30-50% risk of adenocarcinoma. Individuals with Barrett's oesophagus have a reduced oesophageal pain threshold to acid, but they generally have few symptoms, unless it's complicated by the presence of an ulcer, hence it's quite difficult to determine if someone has it, but important to diagnose since it can be a pre-cancerous condition. 30 / 64 What are the causes of GORD? • Hiatus hernia, which is where part of the stomach extends through an opening of the diaphragm into the chest • Transient relaxations or defective basal tone of the LOS • Ineffective oesophageal motility, which involves a lack of primary peristalsis moving material into the stomach • Food- spicy and fatty foods which cause delayed gastric emptying so increased acid, and caffeine relaxes the LOS • Pregnancy - physical pressure from the uterus pushes acid upwards - relaxation of muscle tones d ur to hormones, so the LOS is more easily open, causing reflux What is the treatment of GORD? • Lifestyle modifications • Phamacotherapy • If pharmacotherapy fails, surgery can be used to enhance and tighten the lower oesophageal sphincter • Alginates to prevent acid or bile reflux into the oesophagus • Antacids to neutralise acid • Proton pump inhibitors or H2 receptor antagonists to reduce gastric acid production What phamacotherapy is used to treat • For uncomplicated GORD eg mild GORD? symptoms of infrequent heartburn, antacids are mainly used, or H2 receptor antagonists. PPIs are avoided here due to its side effects • For moderate or severe GORD, PPIs are used • Ranitidine, a H2 receptor antagonist, 31 / 64 would have been used to reduce stomach acid however Ranitidine medicines have been suspended in the EU so instead, PPIs are being used, or an alternative H2 receptor antagonist can be used eg Famotidine * Complete inability of swallowing- severe dysphagia that has been getting worse over time * Frequent, forceful projectile vomiting - Suggests hypertrophic pyloric stenosis in infants up to 2 months old. * Bile-stained (green or yellow-green) vomit - Suggests intestinal obstruction * Abdominal distension, pain, tenderness, or palpable mass - Suggests intestinal obstruction or another acute surgical condition eg gallstones, appendicitis * Blood in vomit (not caused by swallowed blood from a nosebleed or ingestWhat are some red flags for GORD that ed from a cracked maternal nipple). Old warrant referral to the GP? blood is seen as coffee ground and fresh blood is seen as bright red - Suggests an important and potentially serious bleed from the oesophagus, stomach, or upper gut. * Altered responsiveness (eg lethargy or irritability) - Suggests raised intracranial pressure (for example caused by meningitis) * Rapidly increasing head circumference (more than 1 cm each week) with a persistent morning headache and vomiting worse in the morning - Suggests raised intracranial pressure (eg caused by hydrocephalus or a brain tumour) 32 / 64 * Blood in the stool/ black or dark stool - Suggest a variety of conditions, including bacterial gastroenteritis and infant cows' milk protein allergy * Chronic diarrhoea - Suggests cows' milk protein allergy * With, or at high risk of, atopy - Suggests cows' milk protein allergy * Dysuria - Suggests a urinary tract infection (UTI), especially when accompanied by featured such as fever irritability, lethargy, jaundice, haematuria, and offensive urine. * Appearing unwell or fever - Suggests infection * Onset of regurgitation and/or vomiting after 6 months of age or persisting after 1 year of age - Suggests a cause other than reflux, for example UTI. What is dyspepsia? • Indigestion • Pain or an uncomfortable feeling in the upper middle part of the stomach area What are symptoms of dyspepsia? After eating or drinking: • Heartburn - a painful burning feeling in the chest, often after eating • Feeling full and bloated • Nausea • Burping and farting • Bringing up food or bitter-tasting fluids into your mouth What are causes of dyspepsia? • Acid reflux • Inflammation of oesophagus due to certain medicines eg ibuprofen and aspirin • Hiatus hernia • Stomach ulcers or cancer of the stomach 33 / 64 • Lifestyle factors eg smoking, stress, certain foods or drinks, being overweight, pregnancy • Functional dyspepsia has no underlying cause What are treatments of dyspepsia? • Pharmacotherapy - antacids, PPIs or H2 receptor antagonists - avoid OTC painkillers eg aspirin and ibuprofen • Lifestyle advice - changing diet, eating less fatty and fried meals and avoiding caffeine and alcohol - eat slowly and chew properly - not eating large meals within 3-4 hours before sleeping - reduce smoking Anything that may suggest cancer • Unexplained appetite loss • Unexplained weight loss • Vomiting blood • Dark stools What are some red flags for dyspepsia • Pain in upper abdomen that is severe, that warrant referral to the GP? persistent (longer than 3 weeks), worsening and unexplained • Feeling faint • Swallowing problems • Jaundice in someone over 40 • Iron deficiency anaemia Malabsorption Irritable bowel syndrome (IBS) Constipation Diarrhoea What are some lower GIT conditions? 34 / 64 What is malabsorption? • Failure of normal absorption of nutrients by the GIT (different from malnutrition) • Prolonged malabsorption can result in malnutrition and vitamin deficiencies • Causes by deficient digestion or deficient absorption • There are two types of malabsorption: specific and general • Leads to a deficiency in - amino acids for proteins - conversion of food for energy - enzymes What is specific malabsorption? • Failure to absorb one class or type of nutrient • Examples include - lactose intolerance, where there is a lactase deficiency that causes an inability to digest lactose, therefore it cannot be broken down into its monosaccharides to be absorbed - vitamin B12 malabsorption, where auto-antibodies against cells within the stomach release intrinsic factor - 2-abetalipoproteinemia The lactase deficiency causes an accumulation of lactose in the intestinal lumen. The undigested lactose molecules draw water into the intestine through osmosis to dilute the higher concentration of lactose in the lumen, therefore fluid What happens in someone with a lactose accumulates in the lumen. This fluid itintolerance? self, along with luminal distension and enhanced peristalsis as a cause of the fluid, leads to watery diarrhoea. Luminal distension can also cause cramps. It can also lead to symptoms of colic which is repeated spasms of the gut wall. 35 / 64 What is general malabsorption? • Failure to absorb several classes of nutrients • There is a tendency to not see symptoms unless it involves digestion or absorption of fat • If malabsorption is severe and involves fats, then symptoms appear, including - steatorrhoea, which is the production of stools with a high fat content (yellow/pale stool that floats and smells bad) - symptoms due to effects of deficiencies of micronutrients or macronutrients eg fat-soluble vitamins eg vitamin A, D, E and K cannot be absorbed Specific malabsorption is caused by • Genetics, in most cases • An autoimmune condition What is the cause of malabsorption? General malabsorption • Pancreatic enzyme deficiency • Bile salt deficiency • Reduction of absorptive mucosa • Increased rate of intestinal transit • It affects amylase, protease and lipase secretions, leading to impaired digestion of carbohydrates, proteins and fats • Lipase deficiency is most important in causing symptoms of malabsorption: chronic abdominal pain, spasms (due to increased osmotic load), steatWhat is pancreatic enzyme deficiency? orrhea, flatulence (due to bacteria in the colon acting on the lipids and producing waste products which releases methane), weight loss (due to nutrition deficiency) • It is caused by chronic pancreatitis (inflammation), cystic fibrosis, pancreatic cancer or pancreatic surgery 36 / 64 What is bile salt deficiency? • Lack of bile salts interferes with absorption of fats and fat-soluble vitamins. Bile salts have hydrophilic and hydrophobic regions to physically attach to the lipids to allow the lipase to digest the fats. • Symptoms include steatorrhoea and weight loss • It is caused by reduced secretion of bile salts due to - intrahepatic cholestasis, which is a lack of production of bile salts due to liver damage eg hepatitis, drug-induced damage - extrahepatic cholestasis, which is a mechanical impairment in bile flow, so bile salts are produced but they are not secreted, and this can be due to presence of gallstones • It is also caused by inhibition of reabsorption, as bile salts recirculate in the body but if they are not reabsorbed then there is less bile salts • A reduction in surface area for efficient absorption of nutrients • It can be caused by - an anatomical reduction in small intesWhat is reduction of absorptive mucosa? tine length (short bowel syndrome) eg due to surgery - a reduced surface area of villi, due to abnormal villous surface eg caused by chronic inflammation, IBS • Material moving too quickly through the intestines • Digestion and absorption can require a certain amount of time, and so material moving too quickly through the small intestine reduces the amount of time for absorption to happen 37 / 64 What is an increased rate of intestinal transit? • It involves increased gut motility (due to drugs, infection, functional disorders etc) which can lead to fat malabsorption, causing steatorrhoea and fat-soluble vitamin deficiency • It can be caused by - chronic diarrhoea - functional disorders eg IBS - hyperthyroidism, where excess circulating hormone reduces colon transit time General malabsorption caused by pancreatic enzyme deficiency is treated using • A fat restricted diet (less than 20g per day) • Enzyme supplements taken with meals to replace the missing pancreatic secretions - these supplements are enteric-coated to withstand the acidic environment • If these are ineffective on its own, then a proton pump inhibitor or H2 antagonist can be used alongside the enzyme supplements What is the treatment of malabsorption? • Fat-soluble vitamins supplements General malabsorption caused by bile salt deficiency is treated using • Limitation of saturated and long-chain fatty acid intake (unsaturated fats and short chain fatty acids are easier to digest and absorb) • Bile acid supplements taken with meals General malabsorption caused by reduction of absorptive mucosa can be treated using supplemental parenteral nutrition, to bypass the GIT 38 / 64 General malabsorption caused by increased rate of intestinal transit is treated by reducing transit time through Loperamide (an opioid receptor agonist) • A functional disorder, so it is caused by changes to normal body functioning rather than a disease affecting the body • It affects about 10% of the population • It can be a life-long condition • It is assumed to be a colon motility disorder, as this is the main area where symptoms are experienced • It involves recurrent abdominal pain/ cramping, and altered bowel habit What is irritable bowel syndrome (IBS)? - it can be constipation predominant (IBS-C) - diarrhoea predominant (IBS-D) - or alternating between constipation and diarrhoea • Triggers include food eg wheat, dairy products, citrus foods, beans, milk etc, intolerances (eg foods you cannot digest) , stress, alcohol, caffeine, drugs that act on the gut flora eg antibiotics, infection and inflammation How is irritable bowel syndrome diagnosed? • It is diagnosed by eliminating other conditions. Tests are used to exclude any other conditions that could be affecting the GIT eg blood tests that check for inflammation in the body. IBS does not involve inflammation but other GIT conditions eg IBD, do • The absence of certain alarm signs is seen: unintended weight loss, rectal bleeding, abdominal pain that worsens over time, changes in bowel habits in individuals aged 50+ • The presence of certain symptoms are 39 / 64 looked for (ABC): - Abdominal pain - Bloating - Change in bowel habit OR - Altered bowel habit - Bloating - Cramps • Altered/over processing by the CNS of visceral pain, and increased visceral sensitivity - neurotransmitters that mediate VH: serotonin, bradykinin, tachykinins • Altered motility - neurotransmitters and neuromodulators that mediate motility: serotonin, acetylcholine, CCK, motilin, nitric oxide, somatostatin, substance P, VIP • Serotonin/ 5HT plays a role in both altered visceral sensitivity and motility. Serotonin stimulates motility through What is the cause of irritable bowel syn- peristalsis and acts on visceral sensory drome? neurons by binding to its receptors to increase visceral hypersensitivity - those with IBS-D have a higher circulating concentration of serotonin, increases motility - those with IBS-C have a decrease in serotonin-immunoreactive cells, decreasing motility - individuals who have had post-dysenteric IBS have an increase in enterochromaffin cells for up to 12 weeks after the inflammation or infection has gone. This increases serotonin release which increases motility • Serotonin 5HT-3 receptor antagonists • Other pharmacological treatments 40 / 64 What is the treatment of irritable bowel syndrome? which are directed at the symptoms experienced • Lifestyle modifications • Dietary advice How are 5HT-3 receptor antagonists used to treat IBS-D? They block serotonin receptors to reduce motility to treat IBS-D. These receptors can be • excitatory ligand-gated ion channels on sensory neurons, so blocking them means the serotonin cannot bind to the receptors so signals cannot be sent to be central nervous system • on the surface of enterochromaffin cells, so blocking them means that when serotonin is released, it cannot act on the enterochromaffin cells to cause further release, preventing larger release of serotonin • excitatory receptors on motor neurons in the colon, so blocking them can prevent release of serotonin No 5HT-3 receptor antagonists are available currently in the UK for the gut due to ADRs, but some can be used under specialist supervision in particular circumstances What drugs are given to those with IBS-D? • Anti-diarrhoeal drugs eg opioids- Loperamide 41 / 64 What drugs are given to those with IBS-C? • Macrogol is recommended (over lactulose) as it is gentler on the GIT, as they are completely inert so can increase osmotic load with no additional symptoms or side effects experienced • Lactulose is a semi-synthetic disaccharide that cannot be digested, so bacteria in the gut digests it. This can lead to overgrowth of bacteria, and bacteria can produce gas as a byproduct, increasing symptoms. • Stimulant laxatives that are very fast acting are not recommended eg bisacodyl, picasulfate, as someone with IBS-C potentially has visceral hypersensitivity • Bulking agents are not recommended, as they can push the symptoms from one extreme to the other (constipation to diarrhoea) and they can irritate the gut lining None of these medications effectively treat all of the symptoms of IBS (as it is a syndrome, it involves a collection of symptoms) and they may exacerbate individual symptoms eg anti-diarrhoeal treatments can promote constipation • Analgesia eg paracetamol • Antispasmodic/ antimuscurinics/ antiWhat drugs are given to those with pain/ cholinergic drugs bloating symptoms with IBS? • Antidepressants eg tricyclic antidepressants What are antispasmodic drugs? • They reduce intestinal motility and so relieve the pain associated with abdominal cramps. • Two types of antispasmodics can be used: 42 / 64 - antimuscarinics which block the action of acetylcholine - direct relaxants on intestinal smooth muscle What are antimuscarinics? • Muscarinic acetylcholine receptor antagonists • They inhibit parasympathetic activity and block the effect of the acetylcholine at muscarinic receptors at the smooth muscle to relax the muscle • Side effects include the typical anticholinergic effects of constipation, sedation, dry mouth and blurred vision • Examples include dicycloverine hydrochloride and hyoscine butylbromide What are direct relaxants on intestinal smooth muscle? • They directly relax the smooth muscle by - prevent acetylcholine acting at its receptors - prevent excitation of the smooth muscle cell directly - reducing ion channel activity eg to reduce calcium levels in the smooth muscle cell, making it less able to contract • Examples include - mebeverine, which inhibit sodium channels - peppermint oil, which inhibit calcium channels • Direct relaxants have fewer side effects than muscarinic receptor antagonist 43 / 64 What are antidepressants (in terms of GIT)? • They can be used to treat abdominal pain and discomfort associated with IBS • They are usually given as a second line treatment after anti-diarrhoeal medications/ laxatives/ antispasmodics • The mechanism of action is unclear, but they can reduce visceral hypersensitivity • In particular, tricyclic antidepressants (TCAs) eg amitriptyline, are used, as - they can reduce visceral hypersensitivity by reducing the perception of what is happening the gut - they have anti-muscarinic properties which is useful in IBS-D to decrease gut motility to slow down movement of stool through the intestines - they have constipation as an adverse effect which can help in those with IBS-D • It is important, when giving an antidepressant for IBS, to inform the patient that the antidepressant is for pain relief associated with IBS, to avoid them being confused and thinking you gave them something for depression when they do not have depression. • Stop any anti-diarrhoeal medicines given • Provide an osmotic laxative eg Movicol, but NOT lactulose - lactulose is fermented in the bowel so can increase bloating and make sympIf someone with IBS's symptoms toms worse changed from diarrhoea to constipation, - Movicol is a good choice because it is how would their treatment change? inert so doesn't aggravate symptoms • If visceral hypersensitivity has a role in the patients IBS, then the patient is likely to be prescribed amitriptyline, a TCA. This has anti-muscurinic effects so decreases motility which would make con44 / 64 stipation worse, so this would have to be stopped. Instead, an SSRI can be prescribed for the visceral hypersensitivity. • Hydration - impacts stool formation - impacts the ability of the food to move What lifestyle modifications can be given through the GIT for those with IBS? • Exercise - reduces stress - stimulates GI motility What dietary advice can be given for those with IBS? • Ear regularly and do not leave long gaps between meals • Increase soluble fibre eg isphagula husk, oats • Reduce insoluble fibre eg bran, and resistant starches (starches that have been cooked, cooled and cooked again, changing its configuration and making it more difficult to digest) • Reduce intake of caffeine, alcohol and fizzy drinks • Avoid foods/ medicines containing sorbitol • Avoid food that are not tolerated well and cannot be digested well eg lactose • Avoid certain foods (FODMAP) that could be triggers causing the diarrhoea, by having an exclusion diet, where foods (and everything containing that food) are eliminated from the diet one at a time, to find out what foods can and can't be tolerated. This is done under the supervision of a dietician or medical specialist. 45 / 64 What is FODMAP? • Fermentable, oligosaccharides, disaccharides, monosaccharides and polyols • These foods are poorly absorbed • F: fermentable foods, which have the same effect as lactulose • O: garlic, onions, wheat-based products • D: certain dairy products eg milk, yoghurt and soft cheeses • M: certain fruits eg apples, pears, stone-fruits, honey, high-fructose corn syrup • P: stone fruits, sweeteners in sugar-free gum and candies What are some red flags for IBS that warrant referral to the GP? • Refer to GP/ hospital (gastroenterology) if there is uncertainty in the diagnosis, or if the symptoms are atypical, severe or cannot be treated/ managed in primary care • Refer to mental health services for psychological support if symptoms are ongoing for at least 12 months and/ or psychological comorbidities are identified What is constipation? • Infrequent or difficult defecation • It is a consequence of increased water reabsorption. It is caused by impaired colon function, as the longer the material is present in the colon, the more time there is for reabsorption of water • It is diagnosed if - bowel movements occur less than 3x a week - there may be daily bowel movements but associated symptoms eg excessive straining - a passage of stool is less frequent than the persons normal pattern - the presence of symptoms for around 3 months: infrequent bowel movement, 46 / 64 straining, hard, dry or lumpy stools, sensation of incomplete evacuation after bowel movements, abdominal discomfort or bloating What is the cause of constipation? • Disturbed daily routine • Dietary inadequacy - not eating well, so there is no food in the gut to stimulate peristalsis - inadequate water intake - lack of fibre • Immobility/ lack of exercise/ prolonged bed rest (hence why constipation is common in the elderly or those who have just had surgery) • Habitual denial (not going to the toilet when you need to, meaning material is present in the colon for longer and there is more time for reabsorption) • Organic obstruction, where the impaction of faeces within the colon makes it difficult to remove • Disease • Pregnancy • Drugs • Stress • Other conditions eg IBS, hypothyroidism, diabetes, Parkinson's disease, coeliac disease What drugs can cause constipation? • Opioids eg morphine, codeine, diphenoxylate, loperamide • Anti-cholinergic agents eg atropine • Antispasmodics eg hyoscinebutylbromide • Tricylic antidepressants eg amlodipine • Antihistamines • Parkinson's drugs • Antacids • Iron supplements 47 / 64 • Calcium supplements • Diuretics • Calcium channel blockers • NSAIDs eg ibuprofen, aspirin How do opioids cause constipation? They activate opioid receptors which reduces peristalsis and forward propulsion, increases segmentation, reduces secretions and increases sphincter tone How do anticholinergics, antispasmodThey act at muscurinic receptors in the ics, TCAs and some antihistamines gut to reduce motility cause constipation? They affect dopamine levels or mimic it's effects, and this can disrupt the norHow do Parkinson's drugs cause constimal functioning of the GI tract, leading pation? to slower movement of food through intestines How do antacids cause constipation? Some antacids contain aluminium or calcium compounds as active ingredients. Aluminium can inhibit muscle contractions in the GI tract to slow down bowel movements. Calcium can decrease bowel motility Iron is an essential cofactor for bacteria within the gut, so iron can change the gut flora and lead to decreased peristalsis. How do iron supplements cause consti- Iron can also irritate the GI lining which pation? causes inflammation and slows down movement of food. Iron can draw water into the intestines to harden the stool Calcium can bind to other substances in the GI tract, forming insoluble complexes that slow down the movement of food How do calcium supplements cause conthrough the intestines stipation? Calcium also competes with other minerals such as magnesium in the gut, and this imbalance can lead to reduced gut 48 / 64 motility High levels of calcium in the gut can reduce smooth muscle contraction How do diuretics cause constipation? They increase urine production and promote fluid loss from the body, causing dehydration and making stools harder They can disrupt the balance the electrolytes in the body, which can lead to slow GI motility, as electrolytes play a role in muscle function (including muscles that move food through the GI tract) How do NSAIDs cause constipation? They inhibit cycloxygenase, reduces prostaglandins. This reduces release of bicarbonate and mucus, reducing the slip of stool, and can reduce motility. They reduce motility, which increases transit time. This means that food remains in the gut for longer so there is more reabsorption of water. This hardens How does reduced motility caused by the stool so it is more difficult to pass these drugs actually cause constipation? and also makes it smaller so there is less stretch of the intestines, reducing any propulsion of food through the gut, causing constipation. • Laxatives, which accelerate the passage of food through the intestine. There are 4 types: - bulk forming - osmotic - faecal softeners - stimulant laxatives What is the treatment of constipation? • Suppositories and enemas • Drugs for chronic constipation in those who aren't responding to laxatives: - prucalopride - linaclotide - lubiprostone • Lifestyle modifications/ dietary advice 49 / 64 • They contain fibre, which are not digested but retain water within the colon to increase faecal mass and increase distension to promote peristalsis. • They have a slow onset of action (days) so are a good first choice laxative What are bulk forming laxatives? • Isphagula husk, which is dietary fibre. Examples include Fybogel, which takes What are examples of bulk forming laxa1-2 days to work tives? • Sterculia • Methylcellulose What are osmotic laxatives? • Hyperosmolar solutions which contain poorly-absorbed solutes to lead to - an increased osmotic load. This increases distension and motility to increase the rate of transfer of contents through the small intestine, and an increased volume of material enters the colon. - retention of fluid in the bowel lumen. This softens the faeces and makes it liquid • Disadvantages include - the distension of the colon can cause abdominal cramps and bloating - the by-products of the agents used can cause flatulence What are examples of osmotic laxatives? • Magnesium salts • Lactulose • Macrogols What are magnesium salts? • Eg magnesium sulphate, magnesium hydroxide • The dose needs to be controlled because it causes increased motility in the lower GI at the lower doses, and causes vomiting at high doses, and it should only be for occasional use 50 / 64 • There is minimal systemic absorption • It has a rapid onset of action (hours) What is lactulose? • It is a synthetic disaccharide used to treat constipation by working in a similar way to when there is a lactose intolerance in the body. • Lactulose cannot be digested by our normal body enzymes. It is acted upon by the bacteria in the colon, to release lactic acid and acetic acid. The bacteria reproduces and increases biomass in the colon, to increase the osmotic load. This causes luminal distension and enhanced peristalsis, leading to watery diarrhoea • It has a slow onset of action (days) • Side effects include - cramps, due to distension - flatulence, as the bacteria in the colon release methane - diarrhoea What are macrogols? • Complexes of polyethylene glycol (PEG) with electrolytes. Polyethylene glycol acts like glycerol in solution to increase the amount of water absorbed into the gut to soften stool, and electrolytes pull fluid into the gut. • It can be used for constipation, and for bowel cleansing and purgation pre-surgery or pre-colonoscopy to ensure the bowel is clear (rapid onset of action of 1 hour) • PEG is an inert polymer, non-absorbable and non-metabolised, which prevents fluid in the bowel from being absorbed • Side effects include: flatulence, abdominal discomfort, nausea, vomiting • Systemic reviews have found macro51 / 64 gols to be more effective than lactulose • Examples of macragols are Laxido and Movicol. - They take around 1-2 days to work - Movicol is inert so doesn't aggravate existing symptoms. What are faecal softeners? • It is a surface active compound so reduces surface tension of the stools, making them easier to pass • It alters consistency and softens the faeces • It also act as a stimulant laxative • It can reduce consistency to the extent of faecal leakage, which usually occurs in the elderly • Docusate. Examples include DulcoEase, which takes around 1-2 days to work What are examples of faecal softeners? • Paraffin oil could also be used however there is more of a risk of steatorrhoea so is less recommended What are stimulant laxatives? • They stimulate activity of the gut wall to increase mucosal secretion of water and electrolytes • They increase peristalsis through enteric plexus stimulation • Fast onset of action so can be used for bowel cleansing prior to surgery/ endoscopy • Side effects include - abdominal cramps - dehydration, caused by prolonged use, due to stimulating secretion of water - reduced reabsorption of potassium, leading to low potassium levels (hypokalemia) - reduced reabsorption of sodium, leading to low sodium levels (hyponatraemia) 52 / 64 What are examples of stimulant laxatives? • Bisacodyl, which can be administered orally or rectal. They are very fast acting(minutes) • Sodium picosulphate, which is administered orally, and is fast acting • Senna (sennosides) preparations, which is taken orally. It has slower action (around 8 hours so overnight), and it contains anthracene glycosides. It is activated within the colon by bacteria which hydrolyse the glycosidic bond, and the end products of the metabolism of Senna stimulate the myenteric plexus. Senna is the best overall laxative to use due to the slower onset of action • Suppositories are inserted into the body where it dissolves or melts to exert local or systemic effects. They act as lubricants to irritate the anal area to allow stools to be passed. They are usually fast acting, around 15-60 minutes, so it What are suppositories and enemas? is recommended that the patient is at home when it is taken. Examples include gycerin suppositories • Enemas involve inserting liquids directly into the rectum to cleanse or stimulate the emptying of the bowels What is Prucalopride? • Serotonin 5-HT4 receptor agonist • It is used for chronic constipation in women only in the UK (as it doesn't work in men) including in IBS-C, where two previous treatments have failed • It binds to receptors on excitatory interneurons in the gut wall • It increases release of acetylcholine to increase intestinal motility and reduce transit time 53 / 64 • ADRs include headache, nausea, abdominal pain, diarrhoea What is Linaclotide? • Guanylate cyclase-C agonist • It is used for moderate to severe IBS-C that has not responded to normal laxatives • It binds to receptors in the small intestine and colon • It is a peptide agonist • It has minimal bioavailability and cannot cross into the circulation well • It increases the amount of cGMP in the cells which activated pkG to increase activity of the cystic fibrosis transmembrane conductance regulator (chloride channel) to promote chloride and bicarbonate secretion. When chloride ions are transported into the intestinal lumen, water follows passively through osmosis, which makes stool easier to pass • It reduces nociceptor sensitivity to stimuli and decreases pain fibre activity • It increases secretions to increase fluidity of material in the gut • ADRs include abdominal distension, abdominal pain and diarrhoea • It is a prostaglandin E1 derivative, so mimics the action of prostaglandin in the gut • It activates chloride ion channels located in the apical intestinal membrane (cystic fibrosis transmembrane conductance regulator and voltage gated chloride channel) to increase secretion of chloride ions. When chloride ions are transported into the intestinal lumen, water follows passively through osmosis, which makes stool easier to pass 54 / 64 What is Lubiprostone? • Activation could occur - directly and/or downstream of EP4 receptor activation, stimulating adenylate cyclase activity - indirectly through prokinetic activity on smooth muscle via action on EP1 prostanoid receptors, increasing amount of calcium • It is recommended for chronic idiopathic constipation • ADRs include nausea and diarrhoea, due to increased amount of fluid in the gut Prescribe an osmotic laxative like macrogols and a stimulant laxative like Senna Avoid bulk-forming laxatives, because How would you treat opioid-induced con- they work by increasing the bulk of the stipation? stool to promote peristalsis, however opioids work to reduce peristalsis, so this opposing action will worsen abdominal pain and contribute to bowel obstruction. • Drink more water, which leads to softer stools and increases the ability of the food to move through the GIT • Exercise, which stimulates GI motility and reduces stress What lifestyle modifications can be given • Deep breathing exercises or meditation for those with constipation? to reduce stress and relax the mind and body • Increase fibre intake to add bulk to stools, which encourages the body to increase motility 55 / 64 • Persistent constipation that has not responded to self care measures for more than 2 weeks • Sudden change in bowel habit • Rectal bleeding or bloody stools that is not related to haemorrhoids • Black coloured stools (not related to medication) • Unexplained weight loss (that is not due to diet change) • Severe abdominal pain, that makes it What are some red flags for constipation difficult to move, think or talk (indicates that warrant referral to the GP? bowel obstruction) • Iron deficiency anaemia • Constant vomiting and inability to keep fluids down • Vomiting blood • Severe dehydration, which is seen as dark coloured urine, urinating less, feeling of thirst, and dizziness. In children, this is seen as less than 6 wet nappies a day and no tears when crying. • Confusion or feeling disorientated • Family history of colon cancer What is diarrhoea? • Decreased consistency and increased liquidity of faeces • It can be acute or chronic • There is disordered water and electrolyte transport, which is caused by increased gut motility, increased gut secretions, or decreased fluid reabsorption • It is a major cause of childhood mortality, due to the dehydration associated with diarrhoea 56 / 64 What is the cause of diarrhoea? • Chronic disease eg inflammatory bowel disease, irritable bowel syndrome, malabsorption diseases • Infection of the GIT eg cholera, gastroenteritis, C. difficile infections • Diet eg foods that are triggers for IBS • Drugs • Bacterial endotoxins - they increase secretions by inhibiting a regulatory protein within the cell, so there is activation of channels from which ions and water can flow out from • Diabetic neuropathy - this increases motility, due to damage to the nerves that regulate the inhibitory actions What drugs can cause diarrhoea? • Some laxatives eg lactulose • Drugs for chronic constipation eg prucalopride, linaclotide, lubiprostone • Antibiotics • Antidepressants • Antacids • PPIs eg omeprazole • Chemotherapy • Magnesium hydroxide - it draws fluid and increases osmosis • Xylitol - this increases osmosis so stool is more liquidy • Drugs containing the artificial sweetener sorbitol • Oral rehydration solutions • Use of anti-infective agents depending on the cause • Reduce symptoms using - anti-motility agents and opiods - adsorbents and bulk forming agents - agents that modify fluid and electrolyte 57 / 64 What is the treatment of diarrhoea? transport - antispasmodics if spasms are present However these medicines shouldn't be used in all cases of diarrhoea. For example, the use of anti-diarrhoeal agents is discouraged to treat diarrhoea caused by norovirus • Lifestyle advice What is oral rehydration therapy? • It is the first line treatment for all patients in cases of acute diarrhoea • It is a mix of water and electrolytes eg sodium, potassium, chloride and citrate, and glucose, to maintain fluid and electrolyte balance - citrate provides a source of bicarbonate - glucose aids reabsorption of electrolytes • The electrolytes are present at a concentration to enable them to gain entry to the gut without having a high concentration of them left in the gut, as this can pull water out rather than in • This treatment is often sufficient in itself to treat the diabetes if there is no infection present • It is a very important treatment for babies, young children and the elderly due to their ability to become dehydrated faster There is a sodium-glucose transporter on the apical membrane, and a glucose How does reabsorption work in oral re- transporter and the Na+/K+-ATPase on hydration therapy? the basolateral membrane. Glucose and sodium enter into the cell and exits into the ECF. 58 / 64 What are anti-motility agents? • They slow down the movement of the GIT • They cause - decreased stomach emptying - increased sphincter tone, which tightens the sphincter to reduce their relaxation and inhibit movement of material from one part of the gut to another - inhibited peristalsis, to prolong transit time and allow for reabsorption of water and electrolytes - increased segmentation and rhythmic contractions - reduced intestinal secretions, to reduce the volume of stool, create less distension and therefore less motility • Opiods can act as anti-motility agents by acting at ¼ opioid receptors which causes everything mentioned in the list above. They are useful when diarrhoea is accompanied by pain • Examples include Loperamide, morphine, codeine, diphenoxylate How do opiods reduce diarrhoea? • They bind to opioid receptors • They reduce peristalsis • They increase segmentation • They reduce secretions • They increase sphincter tone, making it harder to open so there is less movement of material through the gut, helping to reduce liquidity and consistency of stool and also reduce peristalsis What is morphine and codeine? •¼ opioid receptor agonists which binds to ¼ opioid receptors and activates them to decrease motility • They have a low specificity for the gut, so it is not a particularly good treatment for diarrhoea 59 / 64 • They cross the blood brain barrier • This means there is a risk of dependence and tolerance, and this risk is greater in morphine than codeine, therefore they are unsuitable for prolonged use What is diphenoxylate? •A¼ opioid receptor agonist which binds to ¼ opioid receptors to slow gastric motility • It has reduced uptake across the blood brain barrier but still has CNS effects at high doses, so there is still a risk to dependency, addiction and tolerance • It is commonly formulated with atropine as a co-phenotrope, to get the anti-muscurinic side effects, to prevent abuse, so people are less inclined to take it What is loperamide? •A¼ opioid receptor agonist which binds to ¼ opioid receptors to decrease motility and increase anal sphincter tone to help control bowel movements • The opioid of choice for treatment of diarrhoea, because it doesn't readily cross the blood brain barrier so there is no CNS activity. However there is still the ability for it to get across the BBB so there is potential for abuse • It can be used by adults who - want to treat the diarrhoea quickly - have IBS-D (along with mebeverine or peppermint oil for the spasm pain) • It has a long half-life as there is significant entero-hepatic cycling (it is absorbed in the gut, goes to the liver, is excreted in bile and goes back to the gut, and it keeps circling and being recycled) • It is not readily absorbed from the GI tract 60 / 64 • Side effects include nausea and vomiting • More serious ADRs include serious cardiac reactions with high doses of loperamide associated with abuse/ misuse (MHRA Yellow Card Scheme) therefore dose should be controlled • They help form stool better and improve faecal consistency to make them less watery • Used more for chronic diarrhoea rather than acute diarrhoea What are adsorbents and bulk forming • ADRs are generally minimal as they are agents? not absorbed • Examples include - Kaolin (adsorbent) - Methyl cellulose (bulk forming) - Ispaghula husk (bulk forming) - Sterculia (bulk forming) • Rest at home • Manage stress • Drink plenty of fluids • Manage diet - avoid spicy and fatty foods - avoid alcohol - avoid caffeine - avoid fizzy drinks What lifestyle modifications can be given - eat bland foods like pasta, rice or crackfor those with diarrhoea? ers • For infants, keep breast-feeding/ giving formula milk, if the child is not vomiting • For pregnant women, inform a pharmacist to help figure out the cause of the diarrhoea, as some causes like food poisoning could lead to complications during pregnancy 61 / 64 How does treatment for some GI conditions differ in those with short bowel syndrome? • Someone with short bowel syndrome has part of their small intestine missing (due to surgery) or damaged • This means that there is a lower transit time in the intestines so less time for drugs to be absorbed in the circulation, so less of the actual drug is absorbed. • Therefore the same treatment this used but much higher doses of the drugs are required to exert the desired effect compared to the dose that would be used to treat a healthy individual with a normal length intestine How is Loperamide used in someone with short bowel syndrome? pt1 • Loperamide is not readily absorbed from the GI tract so high doses are required in those with short bowel syndrome to be able to have the desired anti-motility effect. • Loperamide has a long half-life as there is significant entero-hepatic cycling (it is absorbed in the gut, goes to the liver, is excreted in bile and goes back to the gut, and it keeps circling/ being recycled). In someone with a shorter bowel, less of the drug will be recycled with a normal dose, so a higher dose is required How is Loperamide used in someone with short bowel syndrome? pt2 • There is a risk of serious cardiac ADRs with high doses of Loperamide. A patient with short bowel syndrome is given much higher doses of Loperamide, and even though much less of it is absorbed, it is still being used off-license (by giving a much higher dose than recommended). This means we need to make an informed decision and weigh up benefits and risks. If the patient isn't given the Loperamide, he will continue to suffer so the medication is in his best interest. We 62 / 64 need to establish any existing cardiac conditions or events before continuing to supply it, and we need to make sure we are monitoring the patient more, specifically their heart. What are some red flags for diarrhoea that warrant referral to the GP? • Sudden change in bowel habit • Rectal bleeding or bloody stools • Unexplained weight loss • Severe abdominal pain, that makes it difficult to move, think or talk • Iron deficiency anaemia • Constant vomiting and inability to keep fluids down • Vomiting blood • Severe dehydration, which is seen as dark coloured urine, urinating less, feeling of thirst, and dizziness. In children, this is seen as soft spots on the head, less than 6 wet nappies a day and no tears when crying. • Confusion or feeling disorientated • Full blood count (FBC) - inflammation/ infection - increased RBC, haemoglobin and haematocrit can indicate IBS-D, due to fluid loss • Erythrocyte sedimentation rate (ESR) - a fast ESR shows inflammation, because the increased presence of proWhat tests are used to help with differenteins in the body cause substances to be tial diagnosis of GI conditions? attached to the red blood cells, so they are denser and fall faster within a tube • C reactive protein (CRP) - inflammation- C reactive protein is released into the blood a few hours after a tissue injury in response to inflammation • Tissue transglutaminase (TTG) - Celiac disease 63 / 64 • Faecal calprotectin - a high level shows inflammation, because calprotectin is a protein released by neutrophils in response to inflammation in the GI, and this is released in the stool, so a high level shows increased WBCs and inflammation Most of these tests see if there is inflammation eg in inflammatory bowel disease, however IBS is a non-inflammatory bowel condition so negative tests for inflammation could indicate IBS 64 / 64