ANTIDIARRHEAL DRUGS Objectives: By the end of this lecture the student should be able to know: - Definition of diarrhea - General

causes of diarrhea - Management of diarrhea including drug therapy - Drug management of ulcerative colitis Diseases affecting the GIT: - Infections ( Bacterial, Fungal, Viral, Parasiticetc ) - Tumors ( Benign, Malignant ) - Inflammatory Diseases - Peptic Ulcer Disease Normal bowel movement: An average, healthy person has anywhere from three bowel movements a day to three a week, depending on that person's diet. Normally the stool (the material that is passed in a bowel movement) has a texture something like clay Diarrhea Diarrhea is not a disease, but a symptom of some other problem characterized by either more frequent bowel movement and/or the texture of the stool is thin and sometimes watery . Diarrhea may be classified into: - Acute ( sudden onset ): Food induced ( travelers ) - Chronic ( 2 weeks or longer ): IBD, Stress or Irritable bowel syndrome

**Antidiarrheal drugs help control or relieve diarrhea and some of the symptoms that go along with it e.g abdominal pain or cramps Goals of treatment: Control the loss of fluids Identify and treat cause Provide symptomatic relief ( antidiarrheal drugs )

Description Antidiarrheal drugs work in several ways: 1. Locally acting agents ( Adsorbents ): Kaolin often combined with Pectin ( Kaopectate )

Most widely used preparation available in powder dosage form. This product adsorbs bacterial toxins, binds water and decreases mucus secretion. Bismuth subsalicylate ( Pepto-Bismol; oral tablets ) Also adsorbs bacterial toxins, decreases the secretion of fluid into the intestine and inhibits the activity of bacteria 2. Centrally acting agents (Inhibit defecation reflex ): Codeine: Has limited use because it leads to tolerance, addiction and withdrawal manifestations. Diphenoxylate (+ Atropine= Lomotil ) : Opium-like drug with less addictive properties. Widely used combined with Atropine (an Anticholinergic ) Loperamide ( Imodium ):Produces rapid and sustained inhibition of the peristaltic reflex slowing the passage of stools through the intestines which will allow more time for water and salts in the stools to be absorbed back into the body. 3. Octreotide It is a synthetic somatostatin analog. Highly effective in relieving diarrhea of Carcinoid Syndrome Given SC or in an IV infusion. Can cause constipation (major side effect), Low back pain, headache, distension, rash, abdominal pain, dizziness, dry mouth. Ulcerative Colitis ( UC ) Ulcerative colitis is an inflammatory bowel disease (IBD) that causes chronic inflammation of the digestive tract. It is characterized by abdominal pain and diarrhea. Like Crohn's disease, another common IBD, ulcerative colitis can be debilitating and sometimes can lead to life-threatening complications. Ulcerative colitis usually affects only the innermost lining of the large intestine (colon) and rectum. It occurs only through continuous stretches of the colon, unlike Crohn's disease, which occurs in patches anywhere in the digestive tract and often spreads deep into the layers of affected tissues. Treatment of UC: There's no known cure for ulcerative colitis, but therapies are available that may dramatically reduce the signs and symptoms of ulcerative colitis and even bring about a long-term remission Ulcerative colitis treatment usually involves either drug therapy or surgery. The goal of medical treatment is to reduce the inflammation that triggers the signs and symptoms. A. Anti-inflammatory drugs Anti-inflammatory drugs are often the first step in the treatment of IBD. They include: - Sulfasalazine: It is a sulfa drug, in the gut is converted to sulfapyridine and 5-ASA (5-amino salicylates Sulfapyridine has no anti-inflammatory effect, absorbed to systemic circulation and responsible for most of the side effects to sulfasalazine including allergy. anti-inflammatory effect. 2 5-ASA remains in the colon and has good

Mesalamine and olsalazine These medications tend to have fewer side effects than sulfasalazine has. - Balsalazide This drug is similar to sulfasalazine, but produces fewer side effects Corticosteroids Corticosteroids can help reduce inflammation, but they have numerous side effects, including a puffy face, excessive facial hair, night sweats, insomnia and hyperactivity, high blood pressure, type II diabetes, osteoporosis, bone fractures, cataracts and an increased susceptibility to infections. Long-term use of steroid drugs is not advised

LAXATIVES There are several types of laxatives, listed below. Some laxatives combine more than one type of active ingredient to produce a combination of the effects mentioned. Laxatives may be oral or in suppository form. Constipation with no known organic cause, i.e. no medical explanation, exhibits gender differences in prevalence: females are more often affected than males. Bulk-producing agents Site of Action: Small and large intestine Onset of Action: 12 - 72 hours Examples: psyllium husk (Metamucil), methylcellulose (Citrucel), polycarbophil, dietary fiber, apples Also known as bulking agents or roughage, these include dietary fiber. Bulk-producing agents cause the stool to be bulkier and to retain more water, as well as forming an emollient gel, making it easier for peristaltic action to move it along. They should be taken with plenty of water. Bulk-producing agents have the gentlest of effects among laxatives and can be taken just for maintaining regular bowel movements. Stool softeners / Surfactants Site of Action: Small and large intestine Onset of Action: 12 - 72 hours Examples: docusate (Colace, Diocto) These cause water and fats to penetrate the stool, making it easier to move along. Many of these quickly produce a tolerance effect and so become ineffective with prolonged use. Their strength is between that of the bulk producers and the stimulants, and they can be used for patients with occasional constipation or those with anorectal conditions for whom passage of a firm stool is painful.

Lubricants / Emollient Site of Action: Colon Onset of Action: 6 - 8 hours These simply make the stool slippery, so that it slides through the intestine more easily. An example is mineral oil, which also retards colonic absorption of water, softening the stool. Mineral oil may decrease the absorption of fat-soluble vitamins. Glycerin suppositories lubricate the inside of the anus (the outside opening to the intestine) to make it easier to pass hard stools. Hydrating agents (osmotics) These cause the intestines to hold more water within, softening the stool. There are two principal types, saline and hyperosmotic. a. Saline Site of Action: Small and large intestine Onset of Action: 0.5 - 6 hours Examples: Dibasic sodium phosphate, magnesium citrate, magnesium hydroxide (Milk of magnesia), magnesium sulfate (which is Epsom salt) , monobasic sodium phosphate, . Saline laxatives attract and retain water in the intestinal lumen, increasing intraluminal pressure and thus softening the stool. They will also cause the release of cholecystokinin, which stimulates the digestion of fat and protein. Saline laxatives may alter a patient's fluid and electrolyte balance. Sulfate salts are considered the most potent. b. Stimulant / Irritant Site of Action: Colon Examples: Bisacodyl/dulcolax, castor oil, sennacort, Onset of Action Laxative Name6 - 8 hours These stimulate peristaltic action and can be dangerous under certain circumstances. Long term use can lead to 'cathartic colon'. Stimulant laxatives act on the intestinal mucosa, or nerve plexus; they also alter water and electrolyte secretion. They are the most severe among laxatives and should be used only in extreme conditions. Castor oil may be preferred when more complete evacuation is required.

CYTOTOXIC AGENTS Chemo strategies Intermittent chemotherapy Combination chemotherapy Regional drug delivery Intra-arterial solid tumors Intrathecal CNS delivery (non-BBB drugs) Intracavity pleural, peritoneal, bladder Portal Vein Liver Brain Implants Combination chemotherapy Suppression of Drug Resistance Increased Cancer kill rates Reduced systemic toxicity Selection Criteria Each drug effective alone Different mechanism of action Minimal overlapping toxicities Cytotoxic drugs Classes Alkylating agents Antimetabolites Antitumor antibiotics Mitotic inhibitors Nitrogen mustards Mechanism of action Disrupt DNA synthesis Block mitosis Disrupt protein synthesis Target cell replication High Growth Fraction most affected Cell cycle specific vs. nonspecific Cell cycle specific drugs Toxic to cells in a specific phase Vincristine - causes mitotic arrest 5

 Only effective in M-Phase Require long presence Prolonged infusions Multiple doses Known as Schedule Dependent Drugs Classes Antimetabolites (S) Mitotic Inhibitors (M) Asparaginase (G1 & S) Bleomycin (G2) Etoposide (G2) Cell cycle non specific drugs Act during any phase (even G0) Synergistic w/cell cycle specific drugs More toxic to proliferating cells Cells use G0 for repair Toxicity apparent during proliferation Include Alkylating Agents Most antitumor antibiotics a. Alkylating agents They are cell cycle non specific agents. They kill tumor cells by alkylating the DNA. Results in miscoding or breaking of DNA. Inhibits DNA replication. Cells most susceptible during S and G1. Can be given in a single bolus. Examples: Procarbazine, streptozocin, dacarbazine, temozolomide b. Antimetabolites Mimic structures of normal metabolic molecules. Kill cells in S phase Three main groups Folate antagonists Pyrimidine analogs Purine analogs

Examples: methotrexate, fluorouracil, gemcitabine, 6-mercaptopurine, pentostatin, fludarabine.

c. Cytotoxic antibiotics Substances of microbial origin that prevent mammalian cell division 6

Examples: doxorubicin, dactinomycin, bleomycin.

d. Plant alkaloids Work at mitosis. Affect tubulin, therefore microtubule activity Examples: vincristine, vinblastine, vindesine.

e. Nitrogen mustards Example: cyclophosphamide

f.

Hormones Tumors derived from tissues responding to hormones may be hormone-dependent Growth inhibited by hormone antagonists OR other hormones with opposing actions OR inhibitors of relevant hormone o Glucocorticoids

Inhibitory on lymphocyte proliferation. Used against leukemias, lymphomas o Estrogens Block androgen effects (ex: fosfestrol). Used to recruit cells in G0 G1, so better targets for cytotoxic drugs Progestogens (ex: megestrol, medroxyprogesterone)

Used in endometrial, renal tumors o Hormone antagonists Tamoxifen impt in breast cancer treatment Competes with endogenous estrogens for receptor Inhibits transcription of estrogen-responsive genes