FINAL BOOKLET PHD 223 - Group 7

IRRITABLE BOWEL DISEASE (IBD) PREPARED FOR: DR. SURAYA SULAIMAN

NURIRDINA AMANI BINTI RIZALMAN 2019269682 A2 NURSYAFIQAH IZZATI BINTI AHMAD 2019237154 A2 SABIRIN 2019232306 A2 RAFIQAH RAFIA BINTI RAMLI 2019274966 B1 EMYLIA ERINA BINTI ROSLAN



INTRODUCTION Irritable bowel disease (IBD) is defined as a chronic disorder that affects the large intestine in body. IBD can be diagnosed through the symptoms and signs experienced by the patients. For instance; abdominal pain, rectal bleeding, diarrhea at night, and anemia. In addition, people with stressful life are more prone to experience the symptoms and signs of IBD and cause them to develop IBD. Moreover, age, gender, and family history of IBD can be the major factor in developing IBD. Irritable bowel disease (IBD) takes a long period of time to treat it. Hence, these drugs are used in order to help in reducing IBD which is Rifaximin, Ispaghula husk, Loperamide, and Diphenoxylate hydrochloride.

LOPERAMIDE Drug for Irritable Bowel Disease (IBD) WHAT IS LOPERAMIDE? Loperamide was chosen as choice of drug for treatment of Irritable Bowel Disease (IBD) because it is the first line treatment for this disease. Loperamide is an opioid agonist that binds to its receptors on the circular and longitudinal intestinal muscles straight in the gut wall. Then it decreases propulsive peristalsis and prolonged transit time and increasing water and electrolyte resorption. Loperamide is classified as anti-diarrheal agent. This medication can be obtained by prescription and non-prescription which Over- The-Counter (OTC) but it depends on the strength and brand as well. Loperamide is in capsules and soft gels which are solid dosage form and semi-solid dosage form.

Mechanism Of Action Loperamide can decrease peristaltic activity. This could affect the stimulation of opiate receptors in the periphery. Then, it binds to the mu-opiate receptor in the gut and controls serotonin release and its effects on the neurokinin NK3- receptor. Lastly, loperamide antagonizes the NK2 receptors at micromolar concentrations. Loperamide could also alter anti-secretory activity. It influences pro-absorptive or secretory peptides hence it affects enteric 5-HT. This lead to hinder calmodulin function in the gastrointestinal tract and hinders L-type calcium channels at sub-micromolar concentrations.

Drug-drug Interactions 01 Ritonavir Lead to higher concentration of 02 Quinidine plasma & rises Loperamide serum concentration when it is combined with Ritonavir. Lead to higher concentration of plasma & increase the arrhythmogenic activities of Quinidine. 03 Gemfibrozil Lead to higher concentration of plasma. 04 Ketoconazole Lead to higher concentration of plasma & lower down Ketoconazole & Itraconazole & Itraconazole metabolism when it is combined with Loperamide.

Pharmacodynamics Loperamide slows the flow of food into the intestines. It decreases daily faecal volume, improves viscosity and bulk density, and reduces fluid and electrolyte loss. There has been no evidence of tolerance to the antidiarrheal effect. Pharmacokinetics Absorption: After intake 2 mg capsule of loperamide, unchanged drug concentrations in the blood are less than 2ng/mL. Plasma concentrations of loperamide are at peak around 5 hours after capsule administration and 2.5 hours after liquid administration. Both formulations had identical peak plasma concentrations of loperamide. Distribution: Loperamide binds to plasma proteins at a rate of about 95%. Loperamide is a substrate for P-glycoproteins. Metabolism: In vitro, the cytochrome P450 (CYP450) isoenzymes CYP2C8 and CYP3A4 metabolise loperamide to form N-demethyl loperamide. Quercetin (a CYP2C8 inhibitor) and ketoconazole (a CYP3A4 inhibitor) blocked the N-demethylation mechanism by 40% and 90%, respectively, in an in vitro sample. Furthermore, CYP2B6 and CYP2D6 tend to play a minor role in the N-demethylation of loperamide. Excretion: The constant loperamide and its metabolites are mostly excreted in the faeces.

Contraindication Pediatric patients who are age < 2 years old have possibilities of respiratory depression and serious cardiac effect. Patients who have abdominal pain without presence of diarrhea. Patients who have bacterial enterocolitis mainly by invasive organisms including Salmonella, Shigella, and Campylobacter. Patients who have pseudomembranous colitis such as Clostridium difficle related with the use of broad-spectrum antibiotics. Side Effects 01 03 VOMITTING CONSTIPATION 02 04 DIZZINESS FLATULENCE 05 ABDOMINAL PAIN

DIPHENOXYLATE HYDROCHLORIDE What is diphenoxylate hydrochloride (HCL)? Diphenoxylate hydrochloride, often known as diphenoxylate HCL, was chosen as a medicine for the treatment of irritable bowel disease (IBD) because it is an anti-diarrhea agent. This medication is used as an additional therapy for the treatment of IBS. Diphenoxylate is the generic name for diphenoxylate hydrochloride. Diphenoxylate hydrochloride is indeed the hydrochloride salt version of diphenoxylate, a piperidine derivate having antidiarrheal efficacy but no central nervous system (CNS) action. Diphenoxylate reduces gastrointestinal motility by acting on opioid receptors throughout the gastrointestinal tract. Diphenoxylate often used in combination with atropine sulfate. It is because it can prevent drug abuse or overdose in patients. Lomotil® is the most common brand name that had been used widely in Malaysia. It contains diphenoxylate and also atropine. This drug can be obtained only with prescription because diphenoxylate is a controlled substance. Lomotil® drug can be in tablet form and in a liquid form.

MECHANISM OF ACTION Diphenoxylate is an opioid receptor agonist that stimulates the enteric nervous system’s mu (μ) opioid receptors. The enteric nervous system is made up of two parts which are the myenteric plexus and the submucosal plexus. Diphenoxylate directly impacts the myenteric plexus, which governs segmental contraction and is located between the circular and longitudinal smooth muscle of the intestinal wall. Meanwhile, the submucosal plexus regulates fluid and electrolyte release in the gut lumen. It inhibits the movement and secretory function of the enteric nervous system by acting on presynaptic opioid receptors. It thereby restricts the neurotransmitter in the synaptic cleft. This activity may result in segmentation and lengthening of gastrointestinal transit time. Besides, it allows moisture to be drawn out of the intestines which will stop the formation of loose and liquid stools.



DRUG-DRUG INTERACTION Topiramate The likelihood or severity of Monoamine undesirable outcomes can be raised. oxidase inhibitors Can cause hypertension Diphenhydramine Side effects such as dizziness, tiredness, disorientation, and Barbiturates & difficulties concentrating, may be Tranquilizer exacerbated. Some persons, particularly the elderly, may also Benzphetamine develop cognitive, judgment, and motor coordination deficits. Clopidogrel May potentiate CNS depressant effects. May increase the analgesic activities of Diphenoxylate. Diphenoxylate can cause a decrease in the absorption of Clopidogrel resulting in a reduced serum concentration and potentially a decrease in efficacy.

PHARMACODYNAMICS As an additional therapy for diarrhea, diphenoxylate, an antidiarrheal, is beneficial. In humans, diphenoxylate is quickly and fully converted to diphenoxylic acid (difenoxine), a physiologically active metabolite that is the main constituent in the bloodstream, by ester hydrolysis. PHARMACOKINETICS Absorption Well absorbed from the GI tract. Bioavailability is around 90%, and the duration to peak plasma concentration is around 2 hours. Distribution It can enter breast milk. Plasma protein binding: 14-22%. Metabolism It is quickly and widely converted in the liver to diphenoxylic acid, an active form, and hydroxydiphenoxylic acid through ester hydrolysis. Excretion Mostly via feces (49% as unaltered drug and compounds) and urine (around 14% as unaltered drug) The elimination half-life is 2.5 hours.

CONTRAINDICATION The component in diphenoxylate can cause an allergic reaction. Diarrhea sufferers from certain problems like pseudomembranous colitis, enterotoxin-producing bacteria, and a foodborne illness. Patients with obstructive jaundice. Patients suffering from stomach or bowel obstructions, angle-closure glaucoma, myasthenia gravis, urinary blockage, or excessive acid inside the stomach or esophagus. Patients receiving sodium oxybate (GHB) Patients underneath the age of six should avoid it since it might induce shortness of breath and neurotoxicity. SIDE EFFECT Common side effects Serious side effects Abdominal Hallucination discomfort Pancreatitis Nausea and Toxic megacolon vomiting Anaphylaxis (severe Dizziness and allergic reaction) headache Somnolence (sleepiness) Euphoria Malaise Loss of appetite

ISPAHGUSHKULA INTRODUCTION OF ISPAGHULA HUSK Ispaghula husk is the common name for the numerous species of the Plantago genus that can relieve irritable bowel disease. It's available in plain or fruit-flavored granules that mix with water to make a high-fiber beverage. Prescription sachets containing granules of ispaghula husk are available as non-prescription sachets, in pharmacies and other shops (over-the-counter) Ispaghula husk is categorized as bulk-forming laxatives and is also known as psyllium or psyllium husk.

MECHANISM OF ACTION The dietary fiber contained in the ispaghula husk forms a gel-like material or mucilaginous mass that acts as a moderate laxative when combined with water. This gel-like material travels down the patient’s gastrointestinal system, softening the feces by increasing the water content in feces. Ispaghula husk also can help to lubricate the intestine and allowing feces to move more easily. Other than that, the presence of the mucilaginous mass can cause the increase of feces size and also increase the intestinal wall tension or stretch stimuli which helps to induce bowel motions.

INDTREURGA-CDTRIOUGNS CARDIAC Medications' GLYCOSIDES absorption in the DRUG, gastrointestinal tract COUMARIN may be delayed or DERIVATIVES DRUG reduced SODIUM The combination of the SULFATE sodium sulfate with AMANTADINE ispaghula husk increase the severity of side FUROSEMIDE effect. When used with amantadine, the therapeutic efficacy of ispaghula husk can be lowered The combination of furosemide with ispaghula husk can increase the severity of side effects.

PHARMACODYNAMICS The ispaghula husk is notably high in alimentary fibers and mucilages where it has a higher concentration than the other Plantago. The ispaghula husk can absorb up to forty times its weight in water. Ispaghula husk contains 85 percent of water-soluble fiber and works in the bowel by hydrating it. Ispaghula husk can change the motility and transit rate of the gastrointestinal tract by mechanically stimulating the gut wall. Resulting in the increased intestinal volume caused by water and decrease the viscosity of the luminal contents. PHARMACOKINETICS ABSORPTION: In the stomach, less than 10% of the mucilage is hydrolyzed, resulting in the generation of free arabinose. The free arabinose is absorbed between 85 and 93 percent in the intestine. As a result, ispaghula husk is primarily found in the gastrointestinal system as a 'bulk' agent that travels through the gut relatively unmodified. DISTRIBUTION: Has a low absorption rate in the body and plasma. METABOLISM: There is limited chance for significant absorption into or metabolism by the body because psyllium remains mostly in the gut as a 'bulk' agent that passes mostly unchanged throughout the gastrointestinal tract EXCRETION: Excreted in the feces

CONTRAINDICATIONS - Patients who have had an abrupt change in bowel habits for more than two weeks. - Rectal bleeding that goes undiagnosed and failure to defecate after using a laxative. - Patients with swallowing difficulties or other throat issues. ADVERSE EFFECTS HYPERSENSITIVITY ABDOMINAL DISTENTION GASTROINTESTINAL CUTANEOUS IMPACTION SYMPTOMS

Rifaximin is one of the medicine that help in reducing Irritable Bowel Disease (IBD). It is defined as semisynthetic, rifamycin-based non-systemic antibiotic in which, it will not enter the circulatory system via the gastrointestinal wall. In addition, Rifaximin is a medication that belongs to a class of drugs known as antibiotics. This medicine has the ability to reduce the overgrowth of bacteria in the gastrointestinal (GI) tract that can lead to IBD. It is taken by oral. Moreover, Rifaximin is not over-the-counter (OTC) drug at pharmacy. Thus, it requires a prescription from doctor before it can be dispensed by pharmacist to the patient.

Rifaximin has been chosen as drug that can decrease the overgrowth of bacteria in GI tract. It works by binding to the beta-subunit of the bacterial deoxyribonucleic acid (DNA)- dependent ribonucleic acid (RNA) polymerase enzyme. Hence, it inhibits RNA synthesis in sensitive bacteria. As a result, translocation is blocked due to this binding that lead to stop the transcription. As a result, translocation is blocked due to this binding as well as stops the transcription.

R DICOUMAROL Increase the risk of severity I bleeding. F A ISONIAZID Hepatotoxic activities of X OLICERIDINE Isoniazid can be inceased. I M Decrease the concentration I of oliceridine serum. N LACTULOSE Decrease the therapeutic efficacy of lactulose.

Rifaximin is used to reduce Irritable Bowel Disease (IBD) symptoms. It acts by reducing the overgrowth of bacteria in large intestine. Rifaximin only can be used to treat bacteria infections, not effective to treat viral infections such as flu. Thus, Rifaximin has been proven to treat IBD effectively. ABSORPTION : Low absorption in gastrointestinal tract. Bioavailability is 0.4 %. Approximately 1 hour is required to reach the peak of plasma concentration. DISTRIBUTION : Volume of plasma protein binding is 67.5% for healthy patients. Thus, the percentage of plasma protein binding decreased to 62% for patients with hepatic impairment. METABOLISM : This drug extensively metabolised by enzyme cytochrome P450 3A4 (CYP3A4) in the liver. EXCRETION : Excrete 96.6% of Rifaximin via faeces as unchanged drug. 0.32% of the drug was excreted in urine as metabolites.

Patients with a hypersensitivity towards Rifaximin such as anaphylaxis, angioneurotic edema and dermatitis. Contraindicated in patients with intestinal obstruction, diarrhoea with fever and blood in stool. Patients with severe liver disease. Pregnant patients in which can affect the fetus. ANEMIA DIARRHOEA WITH BLOODY STOOL FEVER ABNORMAL LIVER ABDOMINAL FUNCTION TESTS PAIN PERIPHERAL OEDEMA

CONCLUSION In conclusion, there are many drugs that can be used as a treatment for irritable bowel disease (IBD). Among them are, loperamide, diphenoxylate hydrochloride, rifaximin, and ispaghula husk. As we already know that, IBD is a disease that is difficult to treat and these existing medications only work to reduce the symptoms of IBD from occurring on a regular basis. If the patient follows all the doctor's instructions in taking these drugs, of course, IBD can be prevented from occurring.

REFERENCES LOPERAMIDE 1.List of 76 Irritable Bowel Syndrome Medications Compared - Drugs.com from https://www.drugs.com/condition/irritable- bowel-syndrome.html 2. IMODIUM CAPSULES Rx. (2016) from https://www.accessdata.fda.gov/drugsatfda_docs/label/2016 /017690s005lbl.pdf 3.IMODIUM. Rxlist.com. (2020) from https://www.rxlist.com/imodium-side-effects-drug- center.htm. RIFAXIMIN 1.Rifaximin. Uses, Interactions, Mechanism of Action | DrugBank Online. (n.d.). https://go.drugbank.com/drugs/DB01220. 2. RxList. (2020, October 7). Xifaxan (Rifaximin): Uses, Dosage, Side Effects, Interactions, Warning. RxList. https://www.rxlist.com/xifaxan-drug.htm 3.Team, C. by M. I. M. S. O. (n.d.). Rifaximin. Rifaximin: Indication, Dosage, Side Effect, Precaution | MIMS Malaysia. https://www.mims.com/malaysia/drug/info/rifaximin? mtype=generic 4.WebMD. (n.d.). Rifaximin Oral: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing. WebMD. https://www.webmd.com/drugs/2/drug-91339/rifaximin- oral/details 5.Mayo Foundation for Medical Education and Research. (2020, October 15). Irritable bowel syndrome. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/irritable- bowel-syndrome/symptoms-causes/syc-20360016 1.

REFERENCES DIPHENOXYLATE HCL 1.Barbara Bolen, P. (2020, June 11). Lomotil for IBS Diarrhea. Retrieved from verywell health: https://www.verywellhealth.com/lomotil-for-diarrhea-1945159 2.Jain, M., & Wylie., W. P. (2021.). Diphenoxylate and Atropine. In T. I. (FL), StatPearls [Internet]. USA: StatPearls Publishing. 3.Vrinda Rio, P. (2019). Lomotil (diphenoxylate/atropine). Medical News Today. 4.Wishart DS, K. C. (2005, June 15). DrugBank: Diphenoxylate. Retrieved from Educe ISPAGHULA HUSK 1.Fybogel Orange Granules - Summary of Product Characteristics (SmPC) - (emc). Medicines.org.uk. (2020). Retrieved 3 June 2021, from https://www.medicines.org.uk/emc/product/1447/smpc#gref\\ \\. 2.Ispaghula husk: Indication, Dosage, Side Effect, Precaution | MIMS Malaysia. Mims.com. Retrieved 6 June 2021, from https://www.mims.com/malaysia/drug/info/ispaghula%20husk /. 3.Plantago seed: Uses, Interactions, Mechanism of Action | DrugBank Online. Go.drugbank.com. Retrieved 1 June 2021, from https://go.drugbank.com/drugs/DB11097.