GI Tract 1 Powerpoint Lecture.pptx

Drugs and the GI Tract - I Drugs used in the treatment of:- A. Vomiting B. Constipation & Diarrhoea C. Irritable Bowel Syndrome (IBS) Dr J Haylor, Department of Medicine, U...

Drugs and the GI Tract - I Drugs used in the treatment of:- A. Vomiting B. Constipation & Diarrhoea C. Irritable Bowel Syndrome (IBS) Dr J Haylor, Department of Medicine, UCLan UM1010 2023 The first session on drugs and the GI tract is divided into 3 bitesize recordings and will deal with drugs used in the treatment of vomiting, diarrhoea & constipation and irritable bowel syndrome.  Nausea and Vomiting Nausea is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It may precede vomiting, but a person can have nausea without vomiting. When prolonged it is a debilitating symptom. disease motion sickness (infection, migraine) drugs pregnancy (opioids, digoxin, anti-cancer agents) Nausea is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. Nausea which may precede vomiting and present without vomiting can be a debilitating condition when prolonged and is a common drug adverse effect. Common causes of nausea and vomiting include motion or travel sickness and obviously pregnancy. It can also be induced by disease such as infection or migraine. Drug-induced vomiting is a common property of opioid analgesics and the cardiac glycoside digoxin. The ability to control vomiting induced by cancer chemotherapy is of particular importance.  Vomiting The act of vomiting itself requires signals from the vomiting centre, activated by high centres, to provide abdominal pressure with contraction of the diaphragm and abdominal muscles. Respiration is stopped, oesophageal sphincter opens with squeezing of the stomach and closure of the glottis to allow the cascade of vomit.  Neurotransmitters – CTZ & VC Histamine (H1) Acetylcholine (M) Dopamine (D2) 5-hydroxytryptamine (5HT3) Substance P (neurokinin) (NK1) Enkephalins (∂/µ) Afferent Efferent nerves nerves Chemoreceptor Trigger Zone Vomiting Centre (CTZ) (VC) Brain - medulla Many different neurotransmitters are involved in signalling through the CTZ and vomiting centre including histamine at its H1 receptor, acetylcholine at its muscarinic receptor, dopamine at its D2 receptor and serotonin at its 5HT3 receptor. Two additional pathways to consider are the opiate receptors for endogenous enkephalins/endorphins and neurokinins also known as substance P. Substance P is a ubiquitous 11 amino acid peptide present in the vomiting centre in the medulla and sensory nerves now defined in the class of  Antiemetics : Receptor Antagonists Receptor Antagonists of:- acetylcholine (M) histamine (H1) dopamine (D2) serotonin (5HT3) neurokinin (NK1) Anti-emetic drugs work at three potential sites in the vomiting centre, the chemoreceptor trigger zone and the GI tract. The transmitter pathways involved maybe divided into two groups. Vestibular stimuli are mediated through histaminergic and cholinergic pathways while visceral stimuli use dopaminergic and serotonergic systems. Antiemetic drugs can be divided into 5 groups, all of which involve antagonism of neurotransmitters receptors which mediate transmission through the chemoreceptor trigger zone and vomiting centre and GI tract. In terms of drug access it is important to note that the CTZ is outside of the blood brain barrier. The major advance in this area, comparable to the development of PPI to treat GI tract ulcers, was the introduction of antagonists of 5HT3 receptors.  1. Cholinergic Muscarinic Antagonists Hyoscine Hydrobromide (0.15-0.3mg) patches Unwanted Effects anticholinergic symptoms dry mouth, blurred vision. less drowsiness than anti-histamines (poorer CNS penetration) Cochrane : The use of HYOSCINE versus placebo in preventing MOTION SICKNESS has been shown to be effective. No conclusions or recommendations can be made on the comparative effectiveness of scopolamine and other agents such as antihistamines and calcium channel antagonists. In addition, no randomised controlled trials were identified that examined the effectiveness of scopolamine in the treatment of established symptoms of motion sickness. Travel sickness is a common disorder which can be effectively prevented using hyoscine, a muscarinic cholinergic antagonist. Hyoscine is available as both tablets and patches. The patches are placed behind the ear. The evidence on the effectiveness of hyoscine is however based on prevention not on treatment. Unlike the anti-histamines, sedation is less of a problem, but the anticipated muscarinic side effects of dry mouth and blurred vision may develop. Please remember there are two major forms of hyoscine. To inhibit vomiting, hyoscine hydrobromide, the more lipid soluble form of hyoscine is employed at much lower doses than the hyoscine butylbromide  2. Histamine (H1) Antagonists Cinnarizine Cyclizine Promethazine (+ calcium channel (+ muscarinic antagonism)(+ muscarinic antagonism) block) Therapeutic Use motion sickness, stomach irritants, pregnancy (if severe, promethazine) Adverse effects drowsiness, sedation Three of the most commonly used antihistamines as antiemetics are cinnarizine, cyclizine and promethazine. All of these drugs have an additional mechanisms of action, cinnarizine for example blocks calcium channels while cyclizine and promethazine are also muscarinic antagonists. As with all older anti-histamines, they may induce drowsiness and sedation. The sickness of pregnancy is obviously a major cause of concern, with thoughts of the teratogenic tragedy induced by thalidomide. This raises the question - are there any safe antiemetics to use in pregnancy. The absolute answer would be no, but of all of the over the counter medicines available, promethazine (Phenergan) would probably be the one associated with the lowest risk. Cyclizine is probably the commonest antiemetic used in secondary care where the importance of having an injectable rather than oral preparation should be recognised.  3. Dopamine (D2) Antagonists Non-selective dopamine antagonists Phenothiazines – ie chlorpromazine, trifluoperazine Antagonise dopamine (D2) receptor in CTZ Additional mechanisms – antagonist for acetylcholine/histamine Adverse effects - sedation, hypotension, tardive dyskinesia Selective dopamine D2 Antagonists Metoclopramide - central action in CTZ, peripheral increase motility - blockade of other CNS dopamine receptors results in fatigue, prolactin↑ Domperidone has similar properties though fewer CNS unwanted effects - less penetration of B/B barrier (CTZ more accessible). The introduction of the phenothiazines such as chlorpromazine in the 1950’s introduced a new antiemetic mechanism - dopamine antagonism. Phenothiazines have the potential added benefit of also being both histamine (H1) and cholinergic (M) antagonists. However, the non-selective effect on central dopamine receptors may lead to major adverse effects such as the development of movement disorders such as tardive dyskinesia. Two dopamine antagonists, metoclopramide and domperidone, have a more selective action on the D2 receptor subtype involved in the vomiting reflex. Domperidone, unlike metoclopramide, does not cross the blood brain barrier and therefore has few CNS adverse effects. Remember the CTZ can be accessed from the peripheral circulation.  4. 5-Hydroxytryptamine (5-HT3) Antagonists Ondansetron Peripheral : Blocks effect of 5HT on visceral afferent fibres CNS : Blocks effect of 5HT onto Chemoreceptor Trigger Zone Therapeutic Use vomiting post-operative and due to radiotherapy, vomiting due to cytotoxic drugs including cisplatin (high emetic potential).Effective in all forms of emesis (acute, delayed, anticipatory) Adverse effects constipation, headache, flushing Alternatives : granisetron, palonosetron One major advance in the development of anti-emetic drugs, has been antagonism of the 5HT3 receptor. Although 5HT-3 receptors are present centrally, the major effect of 5HT3 antagonism is thought to result from antagonism peripherally in visceral afferent fibres following the release of serotonin from enterochromograffin cells. Ondansetron was the first in class, introduced in 1990 and by the end of its patent life was the 20th highest selling drug in the US. For the first time, a drug was available which effectively inhibited vomiting associated with the chemotherapy and radiotherapy treatments for cancer.  5. Neurokinin (NK1) Antagonists Aprepitant Neurokinin (NK1) antagonist peripherally in GI tract and centrally in both CTZ and VC Neurokinin (substance P) is an 11 amino acid peptide neurotransmitter activating G/I vagal afferents and VC Effective in both acute and delayed emesis Oral dosage form - IV prodrug available (Fosaprepitant) Vomiting more likely :- 50 years old↓, female, anxious, suffer from motion sickness, repeated exposure to cytotoxic therapy. acute (24h), anticipatory (lorazepam) Neurokinin antagonists, such as aprepitant may be employed when 5HT3 antagonists lack efficacy particularly under conditions when vomiting is delayed. An injectable form is available called fosaprepitant, an intravenous prodrug. Vomiting itself can be divided into 3 groups related to the efficacy of drug treatment , as acute within 24h, delayed after 24h and anticipatory prior to anticancer drug administration The anticipatory form, ie vomiting prior to drug treatment is more effectively treated with anti-anxiety agents such as  BNF 8.1 Cytotoxic drugs : nausea and vomiting Mildly Emetogenic Mildly Emetogenic fluorouracil, etoposide, methotrexate dopamine antagonist (low dose), vinca alkaloids, abdominal radiotherapy Moderately Emetogenic Moderately Emetogenic * dexamethasone or lorazepam taxanes, doxorubicin, cyclophosphamide (low dose), Highly Emetogenic mitoxantrane, methotrexate (high dose) 5HT3 antagonists neurokinin antagonist Highly Emetogenic cisplatin, dacarbazine, * There is some evidence to suggest cyclophosphamide (high dose) that steroids are both non-competitive 5HT antagonists and may inhibit 5HT release. For the treatment of vomiting due to cytotoxic drugs, the BNF divides cytotoxic drugs into 3 categories dependent on their ability to stimulate vomiting. It is mild with the low dose of methotrexate used in autoimmune disease but high with the platinum containing drugs such as cisplatin used to treat solid tumours. Treatment ranges from dopamine antagonists for mildly emetogenic agents upto the combined use of 5HT3 and neurokinin antagonists for platinum induced toxicity.. Interestingly for moderate agents, steroids or lorazepam are recommended. And here is some evidence that steroids, in addition to all their other properties, may also inhibit the release and activity of 5HT.  For TOP 100 Drugs 3rd edition 2023 See pages 64-69 for antiemetic drugs Lecture Content 1. Anti-emetics 2. Treatment of constipation & diarrhoea 3. Irritable Bowel Syndrome (IBS) Please refer to the TOP 100 Drugs book for further information where there are 3-4 sections on anti-emetic drugs. The second bitesize recording will consider the treatment of constipation and diarrhoea.  Drugs and GI Tract I Drugs used in the treatment of:- A. Vomiting B.Constipation & Diarrhoea C. Irritable Bowel Syndrome Dr J Haylor, Department of Medicine, (IBS) UCLan UM1010 2023 This second bitesize recording considers drugs and the treatment of constipation and diarrhoea. This includes both drugs which stimulate GI motility in the treatment of constipation, drugs which inhibit GI motility in the treatment of diarrhoea. An overuse of drugs to treat constipation may have diarrhoea as an adverse effect while the over use of drugs to treat diarrhoea may induce constipation.  1.Bulk 2.Osmotic Laxatives Faecal Softeners : docusate sodium 3.Stimul Increased faecal water ant (stimulates fluid secretion) avoids pain on straining to defaecate arachus oil (enema), Laxatives are used to treat constipation or to clear the bowel when investigational procedures such as colonoscopy are being used. The weakest agents are faecal softeners administered either orally or rectally in the form of an enema or suppository, they include docusate sodium and arachus oil enemas. Laxatives are divided into 3 groups based on their mechanism of action generally increasing in effectiveness from firstly, bulking agents which retain water, secondly, osmotic agents which draw fluid into the bowel lumen and thirdly, stimulants which increase peristalsis.  Laxatives : Constipation/Bowel Clearance 1.Bulk 2. Osmotic 3. Stimulant ispaghula husk lactulose Senna glycosides (Fybrogel), sterculia Not IBS – bloating stimulates peristalsis (Normacol) Hepatic myenteric plexus (colon) methylcellulose (Celevac) Encephalopathy Caution if bowel (mucilagenous gel (macrogols, obstruction, absorbs 10x weight in magnesium salts, (muscle cramping) water) phosphate enemas) Ispaghula husks (Fybrogel) is a natural fibre drink which contains a bulk laxative, while methycellulose (Celevac) forms a mucilagenous gel which absorbs upto 10 times its weight in water. Lactulose is a non-absorbable disaccharide sugar which draws fluid into the bowel by osmosis. Lactulose however, is also used to treat high levels of ammonia in the blood in hepatic encephalopathy by trapping ammonia in the GI Tract, producing ammonium ions, acidifying colon fluid. However, a potential to produce bloating means lactulose is not a suitable laxative to treat the constipation of IBS. Senna is the most powerful of the 3 major types of laxatives. Senna contains plant glycosides which stimulate the myenteric plexus in the bowel to enhance peristalsis causing defaecation. However, care must be taken  Drugs which increase G/I motility Serotonin (5HT4) Agonist Dopamine Antagonists 5HT stimulates acetylcholine release at lower oesophageal sphincter myenteric plexus (5HT4 receptor) pressure↑ gastric emptying ↑ Prucalopride enhance duodenal peristalsis↑ 150-fold selectivity GI tract vs. CVS, prokinetic properties Therapeutic Use Therapeutic Use : Licensed for chronic gastro-oesophageal reflux, constipation in women when other disorders gastric emptying, laxatives fail chronic gastric reflux Adverse Effects : diarrhoea, headache * cisapride withdrawn - CVS effects metoclopramide & domperidone increased stroke/heart attack. * Better known as antiemetics Subtyping of 5HT receptors, has identified a 5HT4 subtype in the myenteric plexus which stimulates the release of acetylcholine and therefore stimulates peristaltic activity. Initial use of the 5HT4 agonist, cisapride had to be withdrawn due to adverse cardiovascular effects. However its successor, prucalopride, with a much greater selectivity for the GI tract is licensed for the treatment of chronic constipation in women when other laxatives, such as senna, fail to work. Drugs which increase GI motility in the upper GI tract can also be used in disorders of gastric emptying and gastric reflux. These include the dopamine antagonists, metoclopramide and domperidone, which are perhaps better known as anti-emetics. They can be used increase gastric emptying and enhance duodenal peristalsis.  Drugs which Decrease G/I Motility Loperamide µ-opioid receptor agonist (pethidine analogue) Decreases activity in myenteric plexus (50x morphine) Decreases G/I motility - slow transit time, enhancing water/ion absorption No analgesic activity Doesn’t cross blood brain barrier (extruded by P-glycoprotein) Therapeutic Use - Treats diarrhoea - acute, travel sickness, IBS, bowel re-section Adverse effect – constipation Loperamide * enterohepatic re-cycling proposed The major agent used to treat diarrhoea is the u-opioid agonist, loperamide (Imodium). The myenteric plexus in the GI tract contains u- opioid receptors which inhibit the parasympathetic stimulation of peristalsis. There are 2 important differences between loperamide and morphine. Firstly loperamide does not cross the blood brain barrier and therefore his no analgesic activity. Secondly, the affinity of loperamide for the myenteric plexus is some 50x than that of morphine. Inhibition of GI tract motility, slows the transit time through the bowel, indirectly enhancing water/ion absorption which aids the treatment of diarrhoea. However, too great an effect means that  Opioid-Induced Constipation Palliative Care (BNF p20-24) opioid-induced constipation is a major problem laxative plus a peristaltic stimulant peripheral opioid antagonist is available - methylnaltrexone As might be expected from the adverse effects of loperamide, constipation is an important adverse effect of opioid analgesics. Propulsive activity in the GI tract is slowed muscle tone increasing and sphincters closing. This can be a major problem when opioid analgesics are used chronically in palliative care. Treatment with both laxatives and peristaltic stimulants such as senna are recommended. In addition, a peripheral opioid antagonist, methylnaltrexone is available which, since it doesn’t cross the blood brain  Irritable Bowel Syndrome Recurrent abdominal pain Abnormal bowel movements Constipation/diarrhoea Hypersensitive muscle tone Before considering the treatment of irritable bowl syndrome it would be useful to discover a little more about the pathology of IBS. It is important to distinguish IBS from the inflammatory bowel disorders of ulcerative colitis and Crohn’s disease, the treatment of which will be considered in year 2. Although the etiology of IBS is largely unknown, symptoms include recurrent abdominal pain, abdominal bowel movements associated with either constipation or diarrhoea. Hypersensitivity of muscle tone would appear to be an important component of this condition.  Drugs and GI Tract I Drugs used in the treatment of:- A. Vomiting 1 B. Constipation & Diarrhoea C.Irritable Bowel Syndrome (IBS) Dr J Haylor, Department of Medicine, UCLan UM1010 2023 This third bitesize recording considers the treatment of irritable bowel syndrome. (IBS) Irritable bowel syndrome (IBS) is a common disorder affecting the large intestine with symptoms of recurrent abdominal pain, bloating and either constipation or diarrhoea. Although the etiology of IBS is largely unknown, hypersensitivity to muscle tone would appear to be an important component.  Antispasmodics Muscarinic Antagonists Muscarinic Antagonists propantheline hyoscine butylbromide (Buscopan) quaternary ammonium compounds reduces systemic absorption anti-muscarinic side effects - dry mouth, blurred vision, urinary retention Antispasmodics form the first line of treatment for IBS. They include muscarinic cholinergic antagonists such as atropine, propatheline and hyoscine. These are used in the form of quaternary ammonium salts which, being highly ionised, are poorly absorbed and do not cross the blood brain barrier. Hyoscine butylbromide marketed as Buscopan is probably one of the most well known, but all maybe associated with  Antispasmodics Mebeverine Mebeverine (Colofac 1965) Musculotropic antispasmodic - direct action on the smooth muscle of the GI tract, without affecting normal gut motility Mechanism uncertain - possible decrease in ion channel permeability, blockade of noradrenaline reuptake, anaesthetic , weak anti-muscarinic Systemic adverse effects as seen with typical anti-cholinergics are absent. The most commonly used antispasmodic, mebeverine (Colofac) however has little muscarinic antagonist activity and therefore no antimuscarinic adverse effects. Its mechanism of action involves a direct relaxing effect on intestinal smooth muscle without influencing the neural control of GI motility. Although a number of actions have been proposed such as inhibition of ion channels or noradrenaline  Peppermint Oil Menthol (40%) Menthone (25%) Suppresses painful spasms, bloating and constipation (suppressing hypersensitivity) Cold and Menthol Receptor 1 (CMR1) Menthol activates CMR1 in primary afferent cold neurones Na+ depolarises, Ca2+ influx also k-opioid weak agonist (also known as TRPM8 – anti pain channel) Peppermint oil can suppress painful spasms and bloating and relieve constipation in IBS and is available in gastro-resistant, modified- release capsules. Peppermint oil contains a number of biologically active compounds, the major active constituent being menthol. The ability of menthol to produce a cold, anti-irritant effect in lozenges and vapo-rub is well known. Menthol activates an ion channel in sensory afferent neurones called the cold and menthol receptor 1 (CMR1), also known as the anti-pain channel. Menthol induces  Linaclotid Linaclotide e Guanylin (intestinal natriuretic peptide analogue, 14 amino acids) Activates cell membrane guanylate cyclase 2C - cGMP↑ cGMP - stimulates the chloride channel enhancing fluid secretion cGMP - inhibits local sensory pain fibres It is effective for both the pain and constipation of IBS (IBS-C) Few systemic effects - entirely metabolised in GI tract. Undetectable in the systemic circulation at therapeutic doses. More recently a 14 amino acid peptide, linaclotide has been developed to activate the cell membrane enzyme guanylate cyclase, elevating the intracellular levels of the cyclic nucleotide, cGMP. cGMP opens the chloride channel (CFTR better known in cystic fibrosis) to stimulate a chloride rich watery secretion. In addition however, the cGMP elevated by linaclotide also appears to inhibit peripheral pain fibres. It is an increase in the sensitivity of such fibres which is thought to be an important component of the pain associated with IBS.  Antidepressants amitryptyline Neuronal Uptake Inhibitors x N E 1. Tricyclic antidepressants inhibit the NE↑ uptake of noradrenaline/5HT enhancing neuronal activity. 2. Low dose amitriptyline 3. Not due to antidepressant fluoxetine x effect. 4. Unlicensed application - use in non- responders 5HT 5. Adverse effects – sedation, anticholinergic properties 5HT 6. If ineffective – try selective ↑ serotonin reuptake inhibitor (SSRI). If treatments such as antispasmodics and linaclotide are ineffective, low dose amitryptyline, a tricyclic antidepressant, may be employed. Tricyclic antidepressants inhibit the neuronal reuptake of noradrenaline and serotonin, increasing their synaptic concentrations, enhancing neurotransmission in these pathways. The benefit of amitryptyline is thought to be due to a local effect on the GI tract, not due to its antidepressant or anxiolytic activity. Unlike its antidepressant effect, the benefit of amitriptyline in IBS has a rapid onset of action at dose levels well below the antidepressant range. Potential adverse effects include sedation, postural hypotension and anticholinergic properties such as dry mouth, urinary retention. This is an unlicensed application for tricyclic antidepressants although, if ineffective, a  Drugs and the GI Tract Nausea/Vomiting Learning Outcomes Antiemetic (antihistamine) (2S) - Cyclizine Antiemetic (5HT antag) (3S) - Ondansetron 1. Outline the mechanism of action and therapeutic use of GI Tract Motility Bulk forming laxatives (7P) - Ispaghula anti-emetic drugs Osmotic laxatives (14) - Lactulose Stimulant laxatives (16) - Senna 2. List the mechanism of action Antimotility (69) - Loperamide Antispasmodics (53) - Mebeverine and therapeutic use of drugs that treat peptic ulcer disease, Gastric Acid Secretion diarrhoea, constipation and Proton pump inhibitors (1) - Omeprazole gastrointestinal infection H2 antagonists (44) - Ranitidine Chronic GI Tract Disease 1/10 of all NHS prescription items Aminosalicylates (68) - Sulphasalazine Drugs acting on the GI tract form 10% of all NHS prescription items. A second session on drugs and the GI tract will discuss the therapeutic use and adverse effects of drugs working on the stomach to influence gastric acid secretion and ulcer formation. This will include the use of some antibiotics, a subject further discussed in pharmacology in the core block of year 2.  Important Drugs for GI Tract 1 Antiemetics GI Motility IBS Hyoscine Docusate Hyoscine Isphagula (butylbromide) (hydrobromide) husk Mebeverine Promethazine Lactulose Peppermint oil Cyclizine Senna Linaclotide Metoclopramide Prucalopride Amitryptyline Ondansetron Loperamide Morphine