GIT PDF - Drugs for Inflammatory Bowel Disease

Chapter Three: Gastro-intestinal System 3.1-Drugs for inflammatory bowel disease. Notes: 1-Chronic inflammatory bowel diseases (IBD) include crohn’s disease (CD) and ulcerative colitis (UC) (1). UC is confined to the rectum and colon, while CD can involve any part of the gastrointestin...

Chapter Three: Gastro-intestinal System 3.1-Drugs for inflammatory bowel disease. Notes: 1-Chronic inflammatory bowel diseases (IBD) include crohn’s disease (CD) and ulcerative colitis (UC) (1). UC is confined to the rectum and colon, while CD can involve any part of the gastrointestinal (GI) tract (2). 2-The major drug therapies used in IBD are aminosalicylates; corticosteroids; immunomodulators (azathioprine, mercaptopurine, and methotrexate); immunosuppressive agents (ciclosporine and tacrolimus); antimicrobials (metronidazole and ciprofloxacin) monoclonal antibodies (infliximab, adalimumab, golimumab, certolizumab, natalizumab, ustekinumab, and vedolizumab) or Janus kinase function (tofacitinib) (2). 3.1.1-Aminosalicylates 1-Aminosalicylates include Sulfasalazine [a combination of 5-aminosalicylic acid, (‗5-ASA‘) and sulfapyridine (acts as a carrier and believed to be responsible for many of the adverse reactions to sulfasalazine)], and the safer sulfa-free compounds [mesalazine (mesalamine)(5-ASA), balsalazide (a pro-drug of 5-ASA) and olsalazine (a dimer of 5-ASA)] (1-3). 2-The aminosalicylates are among the most commonly used drugs for inducing and maintaining remission in patients with mild to moderate IBD (4). 3-Enemas are appropriate for patients with left-sided disease because the medication will reach the splenic flexure. Suppositories deliver mesalamine up to approximately 20 cm and are most appropriate for treating proctitis (4). 4-Oral and topical mesalamine preparations may be used together for maximal effect. Oral mesalamine may also be used for patients who are unwilling or unable to use topical preparations (4). 5-The extent of disease should be considered when choosing the route of administration. If the inflammation is distal, a rectal preparation is adequate but if the inflammation is extended, systemic medication is required (1). 6-Enemas or suppositories (when given once daily) are preferably administered at bedtime, preferably after a bowel movement (1). 7-Oral aminosalicylates for the treatment of ulcerative colitis are available in different preparations and release forms. The preparation and dosing schedule should be chosen taking into account the delivery characteristics and suitability for the patient (1). 27 8-Unlike sulfasalazine, sulfa-free compounds are safe to use for patients with sulfonamide allergies (3). 9-Blood count should be performed and the drug stopped immediately if there is suspicion of a blood dyscrasia (1). 10-Patients receiving aminosalicylates, and their carers, should be advised to report any unexplained bleeding, bruising, purpura, sore throat, fever or malaise that occurs during treatment (Blood disorders) (1). 11-Olsalazine is associated with a higher incidence of secretory diarrhea than other aminosalicylates (4). 12-Aminosalicylates are contra-indicated in salicylate hypersensitivity (1). 13-Balsalazide and olsalazine are taken after food (1). 14-Note: sulfasalazine is also used for rheumatoid arthritis [it is one of the Disease-Modifying Antirheumatic Drugs (DMARDs)] (1). Aminosalicylates Scientific name Trade names Dosage form(s) 1 2 3 4 Any extra notes: 3.2-Proton pump inhibitors (PPIs) 1-Drug action: Proton pump inhibitors inhibit gastric acid secretion by blocking the H+/K+-ATPase (the ‗proton pump‘) of the gastric parietal cell (1). 2-PPIs are the most potent inhibitors of gastric acid secretion. PPIs include omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole (2). 3-PPIs are used for the treatments of gastric and duodenal ulcers; they are also used in combination with antibacterials for the eradication of Helicobacter pylori (a bacteria that is common cause of ulcer). PPIs can be used for the treatment of dyspepsia and gastro-oesophageal reflux disease. They are also used for the prevention and treatment of NSAID-associated ulcers (1). 28 4-PPIs are most effective when taken 30 to 60 minutes before meals (3).The once daily dose usually given in the morning before meals. Large doses should be given in 2 divided doses (1) (for divided dosing, give evening dose before evening meal instead of at bedtime) (5). 5-PPIs are formulated as delayed-release enteric-coated dosage forms that have pH-sensitive granules contained in gelatin capsules (omeprazole, esomeprazole, and lansoprazole), rapidly disintegrating tablets (lansoprazole), and delayed-release enteric-coated tablets (rabeprazole, pantoprazole, and nonprescription omeprazole). Omeprazole is also available in a delayed-release tablet and in a combination product with sodium bicarbonate in an immediate-release capsule and oral suspension (Zegerid®) (2). The sodium bicarbonate raises intragastric pH, permitting rapid absorption of omeprazole from the duodenum (6). 6-PPIs are generally considered interchangeable; selection of agent is usually based on cost and formulary considerations (7). PPIs Scientific names Trade name Dosage form Any extra notes: 3.3-Histamine-2 receptor antagonists (H2RAs) 1-Drug action: H2RAs reduce gastric acid output as a result of histamine H2- receptor blockade (1). 2-H2RAs include cimetidine, ranitidine, famotidine, and nizatidine (2). 3-H2RAs are used for the treatments of gastric and duodenal ulcers. They can be used for the treatment of dyspepsia and gastro-oesophageal reflux disease (1). 4-Cimetidine inhibits several CYP450 isoenzymes, resulting in numerous drug interactions (e.g., theophylline, warfarin, and clopidogrel) (2). Avoidance of the combination, or a reduction in the dosage of these drugs may be required (8). 29 5-Ranitidine has less potential for hepatic CYP450 drug interactions, while famotidine and nizatidine do not interact with drugs metabolized by the hepatic CYP450 pathway (3). 6-Cimetidine has demonstrated weak antiandrogenic effects, and its use in high doses has been associated with gynecomastia and impotence in men. This effect is reversible with discontinuation of the medication or by switching to another H2RA (3). H2RAs Scientific names Trade name Dosage form Any extra notes: 3.4-Treatment of H. pylori–associated ulcers 1-H. pylori is a common cause of both gastric and duodenal ulcer. General recommendations, are to include an antisecretory agent (preferably a PPI) plus at least two antibiotics in the eradication regimen (5). (5) 2-Therapy duration is usually 10–14 days. 3-Several first-line therapies are recommended, but bismuth quadruple therapy (bismuth subsalicylate, metronidazole, tetracycline, and a PPI ) for 10-14 days should be used preferentially (2). (Table 3-1) 4-Another recommended first line therapy is concomitant therapy (PPI, clarithromycin, with amoxicillin and metronidazole) for 10 to 14 days (2). 5-Clarithromycin triple therapy is no longer recommended in areas where H. pylori resistance exceeds 15% (2). 6-Sequential therapy: Sequential therapy involves administration of a PPI and amoxicillin given for the first 5 days, followed by a PPI, clarithromycin, and tinidazole for an additional 5 days (5). 7-Quadruple-based therapy: A-Bismuth subsalicylate, metronidazole, tetracycline, and a PPI (5). B-Nonbismuth quadruple therapy (also called ―concomitant‖ therapy) contains a PPI, amoxicillin, clarithromycin, and metronidazole taken together at standard doses for 10 -14 days (2). 31 8-Hybrid therapy (combines the strategies of concomitant and sequential therapy) involves 7 days of dual therapy (PPI and amoxicillin) followed by 7 days of quadruple therapy (PPI, amoxicillin, clarithromycin, and metronidazole) (2). 9-Levofloxacin-Based Therapy Levofloxacin has been studied as first-line therapy and (after initial treatment failure) for H. pylori eradication. Three regimens using levofloxacin have been suggested (levofloxacin triple therapy, levofloxacin sequential therapy and Quadruple therapy) (Table 3-1). Concerns about using fluoroquinolones to treat H. pylori include development of resistance and adverse effects (e.g., tendonitis and hepatotoxicity) (2). Table 3-1. Recommended Treatment Regimens for Helicobacter pylori Infection (5). 31 BID: twice daily; PPI : proton pump inhibitor; QID : four times daily; TID : three times daily. 3.5-Antacids: 1-Antacids are basic compounds that neutralize hydrochloric acid in the gastric secretions. They are used in the symptomatic management of gastrointestinal disorders associated with gastric hyperacidity such as dyspepsia, GERD, and peptic ulcer disease (8). 2-Antacid agents include a variety of aluminum, magnesium, and calcium products available as single and combination therapy preparations in multiple dosage forms (7). 3-Antacids are best given when symptoms occur (i.e. when required) or are expected, usually between meals and at bedtime (1). When taken 1 h after a meal, antacids may act for up to 3 h compared with only 30 min–1 h if taken before meals (9). 4-Liquids and powders generally provide faster relief and have greater neutralizing capacity than tablets. Advantages of tablets over liquids include ease of portability and administration (10). It might be appropriate for the patient to have both; the liquid could be taken before and after working hours, while the tablets could be taken during the day for convenience (9). 5-Tablets should not be swallowed whole; they should be chewed to initiate disintegration or sucked to provide a relatively slow but sustained delivery of antacid to the stomach (10). 32 6-Interactions: A-Antacids can affect the absorption of a number of drugs (via chelation and adsorption) (11). This interactions can usually be avoided when potentially interacting drugs are separated by at least 2 hours (7). B-Antacids also interact with enteric-coated tablets, capsules and granules (Enteric coatings may be disrupted prematurely in the presence of antacids, causing unwanted release of the drug in the stomach) (10). 7-Side effects of antacids: A-AL-containing antacids tend to be constipating. Mg-containing antacids tend to cause osmotic diarrhea and are useful in patients who are slightly constipated. Thus combination products of AL and Mg salts cause minimum bowel disturbances (9). B-Antacids containing sod. Bicarbonate: The high sodium content may cause fluid overload in patients with congestive heart failure, renal failure, cirrhosis, or pregnancy, and in those on sodium restricted diets (6). C-Calcium carbonate: It acts quickly, has a prolonged action and is a potent neutralizer of acid. It can cause acid rebound and, if taken over long periods at high doses, can cause hypercalcaemia and so should not be recommended for long-term use (9). 8-Other drugs that may be combined with antacid formulations include simeticone, which acts as a defoaming agent to reduce excess gas in the stomach, and alginates, which form a gel or foam on the surface of the stomach contents thereby impeding reflux and protecting the oesophageal mucosa from acid attack (8). Antacids (including those combined with simethicone, and alginate) Scientific names Trade names Dosage form 1 2 3 4 5 6 Any extra notes: 33 3.6-Laxatives: 1-Laxatives (purgatives or cathartics) promote defecation and are used in the treatment of constipation and for bowel evacuation before investigational procedures such as endoscopy or radiological examination, or before surgery (8) to ensure the bowel is free of solid contents (1). (10) 2-Laxatives can be classified into groups depending on their mode of action (Table 3-2). Table 3-2: types of laxatives Type of laxative Example(s) Approximate onset of action Senna, Bisacodyl, Sodium Oral:6-12hours (9) 1-Stimulant laxative picosulfate, and Glycerin (supp.) Rectal: within 1 hour (9) Methylcellulose, Bran , Sterculia 12 -24 hours, but 2-Bulk-forming and Ispaghula (Metamucil®) onset may be laxative delayed as long as 72 hours (6) 4-Osmotic laxative Lactulose 1-2 days (9) 3.6.1-Stimulant laxatives: 1-Stimulant laxatives are thought to act mainly by stimulating the intestinal mucosa to secrete water and electrolytes (12). 2-The main adverse effects of stimulant laxatives are griping and intestinal cramps. Prolonged use may result in loss of colonic smooth muscle tone (10). However, many experts now believe that the risk of long-term use of stimulant laxatives use have been overestimated and they are safe for daily use) (13). 3-Bisacodyl tablet is enteric-coated; therefore, it should be swallowed whole and should not be taken within one hour of antacid or milk as this will lead to dissolution of the coating and release of the drug into the stomach and cause gastric irritation (10). 4-Senna is excreted via the kidney and may color the urine a yellowish-brown to red color depending on its PH (12). 5-Senna is secreted in breast milk, and large dosages may cause increased gastric motility and diarrhea in breastfed infants. Breastfeeding mothers should, therefore, avoid this laxative (12). (However BNF-81 states that specialist sources indicate suitable for use in breast-feeding in infants over 1 month (1)). 6-Usual doses: Bisacodyl 5 mg tab. Adult dose: usually 1-2 tablets (dose to be taken at night). While the dose of supp. Is one supp. (usually in the morning) (1). Senna tab. Adult dose: usually 2 tablets (preferably at bedtime) (11). Glycerin suppositories: Glycerol suppositories are normally used when a bowel movement is needed quickly. The patient should experience a bowel movement in 34 15 to 30 minutes. Varying sizes are made to accommodate use for different ages. The 1-g suppositories are designed for infants, the 2-g for children and the 4-g for adults. (11). 3.6.2-Bulk-forming laxative: 1-Bulk laxatives are those that most closely resemble the normal physiological mechanisms involved in bowel evacuation. Bulk laxatives work by swelling in the gut and increasing faecal mass so that peristalsis is stimulated. The laxative effect can take several days to develop (9). 2-Bulk laxatives should not be taken immediately before going to bed, because there may be a risk of oesophageal blockage if the patient lies down directly after taking them (10). 3-When recommending the use of a bulk laxative, the pharmacist should advise that an increase in fluid intake would be necessary (9). 4-Adverse effects and disadvantages are relatively minor. They include:  Risk of oesophageal and intestinal obstruction if preparations are not taken with sufficient water.  Abdominal distension and flatulence.  They may not be suitable for patients who must restrict their fluid intake severely (12). 5-Bulk-forming drugs are useful in controlling diarrhea associated with diverticular disease (1). 3.6.3-Lactulose: 1-It can be taken by all age group, have no drug interactions and can be safely used in pregnancy (11). However, there are some factors that may deter patients from using lactulose: It may take 72 hours of regular dosing to produce an effect. It is intensely sweet in taste which makes it more palatable for children, to whom it can be given safely (10). Adult laxative dose (1): 15 ml twice daily. 2-Serious adverse effects with lactulose are rare. Relatively minor side-effects occur in about 20% of patients taking full doses and include flatulence, cramp and abdominal discomfort, particularly at the start of treatment (12). 3-Lactulose syrup should be used with caution in diabetic patients because it contains lactose and galactose (14). 3.6.4-Product selection guidelines (Table 3-3). Table 3-3:Product selection guidelines Patient Preferred laxative Pregnant women Bulk-forming laxative. Lactulose may be used (13) Breast-feeding mother Bulk-forming laxative, lactulose (13) Children Glycerin(supp.), lactulose (13) Advanced age(elderly) Bulk-forming laxative, also lactulose and glycerin (supp.) are safe (6, 11). 35  Laxatives (try to include the different types of laxatives ) Scientific name Trade names Type Dosage form(s) 1 2 3 4 5 6 7 Any extra notes: 3.7-Antidiarrheals The priority in acute diarrhea is the prevention or reversal of fluid and electrolyte depletion. This is particularly important in infants and elderly patients. Oral rehydration preparations are used in the prevention or reversal of fluid and electrolyte depletion. Severe depletion of fluid and electrolytes requires immediate admission to hospital and urgent replacement treatment with an intravenous rehydration fluid is recommended (1). 3.7.1-Antimotility drugs [Loperamide , Co-phenotrope (Diphenoxylate+Atropine)] Note: Atropine is included at a subtherapeutic dose to discourage abuse (unpleasant antimuscarinic effects will be experienced if higher than recommended doses are taken)] (12). 1-Antimotility drugs are not recommended for acute diarrhea in young children (1). In the UK, diphenoxylate hydrochloride is not licensed for children under 4 years of age. In the UK, loperamide is not licensed for children under 4 years of age. In the USA, loperamide is not recommended for children under the age of 2 years (8). 2-Adult doses : Loperamide: Initially 4 mg (2 tablets or capsules) , followed by 2 mg (1 tablet or capsule) to be taken after each loose stool; usual dose 6–8 mg daily; maximum 16 mg per day (1). Co-phenotrope: Initially 4 tablets, followed by 2 tablets every 6 hours until diarrhea controlled (1). 36 3.7.2-Adsorbents (pectin +kaolin) 1-There is insufficient evidence to recommend adsorbent preparations (such as kaolin) in acute diarrhea (1). 2-Kaolin can form insoluble complexes with some drugs in the gastrointestinal tract and reduce their absorption; oral doses should not be taken at the same time (8). 3.7.3-Oral rehydration solution (ORS) 1-A premixed solutions (6) or sachets of powder for reconstitution are available; these contain sodium as chloride and bicarbonate, glucose and potassium (9). 2-Only water should be used to make the solution and that boiled and cooled water should be used for children < 1 year (9). 3-To avoid risk of possible exposure to further infection, the solution should be discarded not later than 1 hour after reconstitution, or it may be kept for up to 24 hours if stored in a refrigerator (10). Table 3-4:Amount of rehydration 4-Table 3-4 provides the volumes solution to be offered to patients (9). required per watery stool (9). Age Quantity of solution (per 3.7.4-Probiotics (dietary watery stool) supplement): Under 1 year 50 mL (quarter of a glass) Probiotics are dietary supplements 1–5 years 100 mL (half a glass) containing bacteria (including 6–12 years 200 mL (one glass) several Lactobacillus species) that Adult 400 mL (two glasses may promote health by enhancing the normal microflora of the GI tract while resisting colonization by potential pathogens (4). Probiotics have been shown to decrease the duration of infectious and antibiotic-induced diarrhea (AAD) in adults and children (2). 3.7.5-Use of zinc in children with diarrhea: Several large studies performed in developing countries have shown that daily zinc supplementation in young children with acute diarrhea reduces both the duration and severity of diarrhea. The WHO/UNICEF recommends that children with acute diarrhea also receive zinc (10 mg of elemental zinc/day for infants younger than 6 months; 20 mg of elemental zinc/day for older infants and children) for 10 to 14 days (6). Antidiarrheals Scientific name Trade names Dosage form 1 2 3 37 Any extra notes: 3.8-Antispasmodics 1- Antispasmodics are drugs used for their relaxant action on smooth muscle. They play a role in the management of gastrointestinal spasm and irritable bowel syndrome (IBS) as well as other disorders associated with smooth muscle spasm (8). 2-Antispasmodics include antimuscarinics (e.g. hyoscine butylbromide). Other antispasmodics (mebeverine, alverine citrate, and peppermint oil) are used to relieve pain in irritable bowel syndrome (1). 3-Conerning IBS (1): A-Laxative (excluding lactulose as it may cause bloating) can be used to treat constipation in IBS. B-Loperamide is the first-line choice of anti-motility drug for relief of diarrhea in IBS. C-A low-dose tricyclic antidepressant, such as amitriptyline, can be used for abdominal pain or discomfort as a second line option in patients who have not responded to antispasmodics. A selective serotonin reuptake inhibitor may be considered in those who do not respond to a tricyclic antidepressant. Antispasmodics Scientific name Trade names Dosage form 1 2 3 Note: antichloinergics may be combined with benzodiazepine (librax®) or phenothiazine (stelabid®). Also they may be combined with an analgesics. They areused for GIT disorders associated with smooth muscle spasm (8). Compound anticholinergics Trade names Scientific name Dosage form Librax® Stelabid® Antispasmine- co® Riabal-co® 38 Any extra notes: 3.9-Nausea and vomiting 1-Prochlorperazine, metoclopramide and domperidone are used to treat or prevent nausea and vomiting (1). 2-Cinnarizine is used to prevent motion sickness where the dose is taken 2 hours before travel then every 8 hours if required (1). 3-Domperidone has the advantage over metoclopramide and the prochlorperazine of being less likely to cause central effects such as dystonic reactions (a tetanus-like reaction) because it does not readily cross the blood- brain barrier (1). 4-Granisetron, ondansetron and palonosetron (5HT3-receptor antagonists) are of value in the management of nausea and vomiting in patients receiving cytotoxics and in postoperative nausea and vomiting (1). 5-Dexamethasone has antiemetic effects and it is used in vomiting associated with cancer chemotherapy. It can be used alone or with metoclopramide, prochlorperazine, lorazepam, or a 5HT3-receptor antagonist (1). 6-Doxylamine (antihistamine ) with pyridoxine (B6) combination is used for nausea and vomiting in pregnancy (1). 7-Side effects: A-Cinnarizine may cause drowsiness which may affect performance of skilled tasks (e.g. cycling, driving) (1). B-Domperidone is associated with a small increased risk of serious cardiac side-effects (arrhythmia). Patients and their carers should be told how to recognize signs of arrhythmia and advised to seek medical attention if symptoms such as palpitation or syncope develop (1). C-Metoclopramide can induce acute dystonic reactions involving facial and skeletal muscle spasms and oculogyric crises. These dystonic effects are more common in the young (especially girls and young women) and the very old; they usually occur shortly after starting treatment with metoclopramide and subside within 24 hours of stopping it (1). Antiemetics Scientific name Trade names Dosage form(s) 1 2 3 39 4 5 Any extra notes: 3.10-Anti-obesity drugs 1-An anti-obesity drug should be considered only for those with a BMI of ≥ 30 kg/m2, in whom diet, exercise and behavior changes fail to achieve a realistic reduction in weight. In the presence of associated risk factors, it may be appropriate to prescribe an anti-obesity drug to individuals with a BMI of ≥28 kg/m2 (1). 2-Orlistat is a gastric and pancreatic lipase inhibitor that reduces the absorption of dietary fat. Other drugs used for obesity is liraglutide (1). 3-Orlistat is given in a usual dose of 120 mg orally three times daily, immediately before, during, or up to 1 hour after meals. If a meal is missed or contains no fat, the dose should be omitted (1). 4-Treatment with orlistat may also be used to maintain weight loss rather than to continue to lose weight (1). 5-Discontinuation of treatment with orlistat should be considered after 12 weeks if weight loss has not exceeded 5% since the start of treatment (1). 6-Orlistat may reduce the absorption of fat-soluble vitamins (A, D, E, and K) and patients should take a multivitamin supplement that contains these vitamins. The supplement should be taken once a day at least 2 hours before or after the administration of orlistat, such as at bedtime (3). 7-Because orlistat‘s main effect is to prevent dietary fat from being absorbed, the fat is excreted unchanged in the feces and so the stool may become oily or loose (steatorrhoea) (9). 8-Increased flatulence is also common. Bowel movements may become frequent or urgent, and cases of fecal incontinence have been seen (9). 9-To minimize these effects, foods with high fat content should be avoided. Taking drugs for diarrhea (such as loperamide) will not control these symptoms (9). 10-It is important to have adopted the low fat diet a few days before introducing orlistat. Oily stools and flatulence can be controlled by reducing the dietary fat content to somewhere in the region of 15 g per meal, and it has been suggested 41 that the decrease in side effects over time may be associated with long-term acceptance and adoption of a low fat diet (9). 11-Liraglutide (Saxenda®) [a glucagon-like peptide-1 (GLP-1) receptor agonist]. A-Liraglutide, is an injectable medication, FDA-approved for long-term obesity management as an adjunct to lifestyle modification. When used for obesity, the dose is titrated to 3 mg daily (3). Scientific name Trade names Dosage form Orlistat Liraglutide Any extra notes: 3.11-Local preparations for anal and rectal disorders 1-These products are used mainly for hemorrhoids, pruritus ani and anal fissure (1). 2-They are usually formulated as ointments and creams or suppositories. Ointments and creams can be used for internal and external hemorrhoids while suppositories are used for internal hemorrhoids. However both are used twice daily (morning and evening) and after each bowel movement (9). 3-Many people prefer suppositories, but these products are often not effective because they tend to slip into the rectum and melt, thus bypass the anal canal where the medication is needed. In general ointments and creams are preferred over suppositories (13). 4-When used intrarectally, the ointment may be inserted using an applicator or finger but the applicator is preferred because it can reach an area where the finger cannot reach. The applicator should be lubricated by the ointment before insertion (6). 5-Topical preparations that contain a combination of local anaesthetics, corticosteroids, astringents, lubricants, and antiseptics are available. They can offer symptomatic relief of local pain and itching (1). 6-Long-term use of corticosteroid creams can cause ulceration or permanent damage due to thinning of the perianal skin and should be avoided (1). Local preparations for anal and rectal disorders Scientific name Trade names Dosage form 1 41 2 3 Any extra notes: References 1-BNF-81 (2021) 2-Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach, 11th Edition. 2021. 3-Zeind, Caroline S and Carvalho, Michael G. Applied Therapeutics: The clinical use of drugs, 11th ed., 2018. 4-Marie A. Chisholm-Burns.Pharmacotherapy Principles & Practice. 5th edition. 2019. 5-ACCP Updates in Therapeutics® 2021: The Pharmacotherapy Preparatory Review and Recertification Course. 6-American pharmacists association. Handbook of Non-prescription drugs: An Interactive Approach to Self-Care. 18th edition. 2016. 7-Michael AM, Jason. Frequently prescribed medications. Third edition 2019. 8-Martindale: The Complete Drug Reference, 38th Edition. Pharmaceutical Press 2014. 9-Alison Blenkinsopp, Paul Paxton and John Blenkinsopp. Symptoms in the pharmacy. A guide to the managements of common illness. 8th edition. 2018. 10-Nathan A. Non-prescription medicines. 4th edition. London: Pharmaceutical Press. 2010. 11-Paul Rutter. Community Pharmacy. Symptoms, Diagnosis and Treatment. 5 th edition. 2021. 12-Nathan A. fasttrack. Managing Symptoms in the Pharmacy. Pharmaceutical Press. 2008. 13-Canadian pharmacists association (CPhA). CTMA: Compendium of Therapeutics for Minor Ailments. 2018. 14-Virginia P A. Pharmacotherapeutics for Advanced Practice A Practical Approach. 3rd edition. 2013. 42