Diarrhea, Gas, and Hemorrhoids The Role of the Pharmacist Currently, a standard of care does not exist for pharmacists in the United States. However, in Europe, the Royal Pharmaceutical Society has created a set of questions that pharmacists need to ask patients whenever they seek counseling: W- Who? – Who is to be treated? W- What? – What are the current symptoms? H- How long? – How long have the symptoms been present? A- Actions taken/ Allergies? – What is currently being done to alleviate the symptoms? Whenever asking for allergies, always ask what happens. It may not be a true allergy. M- Medications? As a way to keep written documentation of patient encounters, the easiest thing to do would be to email a summary of the patient encounter to yourself on your encrypted UCSF email. DIARRHEA Diarrhea is a result of an imbalance of secretion and absorption in the gastrointestinal tract. Quantitatively, diarrhea can be defined as an abnormal increase in stool frequency and liquidity:

- Having more than three bowel movements per day - Having a stool weight of greater than 200 g

Acute diarrhea lasts for less than 2 weeks. Persistent diarrhea lasts for 2-4 weeks. Chronic diarrhea lasts for more than 4 weeks. *Persons with persistent and chronic diarrhea, and persons with diarrhea lasting for more than 48 hours need to be referred to the MD. Diarrhea is a symptom of an underlying disease, not a disease itself. It is very common in the United States. Children under 5 years old are the most likely to have diarrhea, while adults 65 years and older are the least likely, because of decreased salivation. Because diarrhea is common and often subsides within a few days, it is usually not worth the price of a doctor’s visit and a formal diagnosis. Risk Factors of Diarrhea Daycare centers Food handling Congregate living conditions Consumption of unsafe foods Presence of medical conditions Poisoning Medications Food intolerance Non-GI acute and/ or chronic illnesses

Pathophysiology of Infectious Diarrhea Infectious Causes Non-Infectious Causes Viral Bacterial Protozoal

Drug- Induced Food- Induced AIDS

Viral diarrhea is typically caused by two different classes of viruses: noroviruses and rotaviruses. A vaccine exists for rotaviruses, which has reduced the incidence of deaths from diarrhea in Mexico. Noroviruses (Stomach Flu) Rotaviruses Transmitted by contaminated food/ water Infects all ages Onset 24-48 hours N/V/D, fever, headaches, watery diarrhea Self limiting Lasts 12-60 hours Manage with fluid/ electrolyte replacement

Transmitted by oral-fecal route Infects mostly infants Onset 24-48 hours N/V/D, Fever, acute watery diarrhea Self limiting Lasts 5-8 days Manage with fluid/ electrolyte replacement

Bacterial diarrhea cases are generally more severe than those of viral diarrhea. However, they are also self-limiting. Side Effects: N/V/D, bloody and watery diarrhea Therapy: Fluid and electrolyte replacement (for mild cases), antibiotics (for moderate-severe cases) Common pathogens causing bacterial diarrhea include Clostridium difficile, Campylobacter, Salmonella, Shigella, E. coli, and S. aureus. C. difficile induced diarrhea is difficult to treat and is a huge problem in the hospital setting. People currently taking antibiotics (fluoroquinolones and clindamycin), recently admitted to hospitals, those with a poor immune system, and elderly patients are at the highest risk for it. Protozoal diarrhea is brought on by two protozoa: Giardia lambia and Entamoeba histolytica. Giardia lambia Entamoeba histolytica Infection of small intestine Infects children, travelers, hospitalized patients, and hikers May be transferred via oral-rectal contact 70% are asymptomatic carriers

Occurs in areas of poor sanitation Infects hospitalized/ immunocompromised patients

Pathophysiology of Non-Infectious Diarrhea Drug Induced AIDS Induced Food-Induced Antibiotics Mg2+ containing acids Prokinetic agents Chemotherapy agents

Opportunistic infections HIV medications

Intolerance (e.g. lactose) Allergy Excessively fatty foods

Clinical Presentation Acute diarrhea lasts for less than 14 days. It is associated with the following:

- Loose, watery stools - Flatulence - Abdominal pain - Malaise - Fatigue

This form of diarrhea is usually self-limiting. A fever signals an infectious process or severe dehydration. The main complication of diarrhea is the degree of dehydration. Patients with diarrhea lose a lot of fluids during bowel movents and thus, they are susceptible to dehydration. Mild dehydration is self-manageable. However, moderate to severe dehydration is serious and requires immediate action and medical intervention. Mild dehydration presents as:

- slightly dry mouth - increased thirst - normal urine output

Moderate to severe dehydration presents as:

- poor oral intake - deeply sunken eyes - decrease in tautness of skin - low blood pressure (orthostatic hypotension) - cool extremities - lack of tears when crying - minimal to no urination

Non-Pharmacologic Therapy The main goal of treatment of diarrhea is to prevent or correct fluid and electrolyte loss. In doing so, symptoms are relieved and more serious consequences are avoided. In clinical practice, it is not practical to identify the cause of the diarrhea, if it is acute. Regardless of whether the diarrhea is induced by antibiotics, bacteria, AIDS treatment, etc., the overall therapy strategy is the same. Infectious diarrhea is often self-limiting. Initially, the main focus should be to replace fluids and electrolytes. In select patients, the adverse effects of diarrhea can be achieved with pharmacotherapy. Fluid Management Fluids can be replaced orally (preferred) or via IV, given that the gut is still functional. Oral Rehydration Therapy (ORT) is the preferred method for fluid replacement. Many different formulations of ORT exist, and appropriate ones contain low glucose (which can be food for bacteria) and low osmolarity. Typically, the patient should intake as much fluid as he or she can handle.

Cola, ginger ale, apple juice, and 7-up is not recommended, because its osmolarity is too high, attracting even more water to the lumen. Tea is not recommended because the electrolyte level is too low. Chicken broth is not recommended because the electrolyte level is too high. Foods during diarrhea Food intake does not worsen diarrhea. Bowel rest is also unnecessary. Trends show that early refeeding and ORT improves patient outcomes. Patients should eat normal foods (complex carbohydrates, lean meats, fruits, and veggies). The BRAT (bread, rice, applesauce, toast) diet is inadequate. Foods to avoid include fatty foods, foods with high simple sugars, spicy foods and caffeine. Pharmacologic Therapy The two main over-the-counter pharmacologic agents used to treat diarrhea are (1) Loperamide and (2) Bismuth subsalicylate (BSS). Loperamide is an antiperistaltic agent. Bismuth subsalicylate is an anti-secretory agent. Self-management therapy for diarrhea should not exceed 48 hours. Exclusions for self therapy include: fever, blood/ mucus in stool, being pregnant or breastfeeding, and having symptoms that signal a serious underlying infection like C. difficile. Loperamide (Imodium AD) This is effective in traveler’s diarrhea (TD), non-specific acute diarrhea, and chronic diarrhea. Mechanism of Action: Loperamide works as an agonist at u-opioid receptors in the gut musculature, slowing down peristalsis and reducing GI secretions. Dosage: 4 mg orally, and then 2 mg after each loose stool.

- Do not exceed 8 mg/day for self-treatment - Do not exceed 16 mg/day under MD referral

Pros and Cons of Loperamide Pros Cons - Proven safe and effective for acute, non-

specific diarrhea - Reduces fecal volume, reduces fluid and

electrolyte loss - Increases the viscosity and bulk - Has an onset of 30 minutes - More potent than morphine or

diphenoxylate at u-receptors, but does not cross the BBB

- No significant drug-drug interactions

- Not for use for patients under 6 years old - May worsen invasive bacterial infections - May cause toxic megacolon - Not for patients with liver disease - May cause paralytic ileus - Not for patients taking antibiotics - Side effects include constipation, pain

and distension, N/V, and dry mouth

- Comes in caplets, chewables, liquid Bismuth Subsalicylate (Kaopectate, Pepto-Bismol) BSS treats acute diarrhea and traveler’s diarrhea. Its two active ingredients give it its mechanism of action:

(1) Bismuth is an antimicrobial. (2) Salicylate is an antisecretory, as it inhibits prostaglandin production.

Dosage: 525 mg every 30-60 minutes, and up to 4200 mg/ day (8 doses/day) Pros and Cons of Bismuth Subsalicylate Pros Cons - Reduces frequency, cramping and N/V - Increases stool consistency - Antimicrobial and antisecretory - Also indicated for indigestion and H. pylori - Comes in caplets, chewables, and liquid

- Not for use in children under 12 years old, as it can increase the risk of Reye’s syndrome

- Not for people who are sensitive to aspirin - Neurotoxicity at high doses, indicated by

ringing of ears (tinnitus) - Onset can take ~4 hours - Has anti-platelet effects - Stains the tongue and stool - Not indicated for pregnant women, GI

bleed, and coagulopathy - Not indicated for patients taking anti-

diabetic, anti-gout, and arthritis medicine

As long as the patient is not contraindicated for either BSS or Loperamide, either one will provide similar results.

GAS Gas can manifest itself as:

(1) eructation: swallowed air, resulting in stomach gas (2) flatulence: the release of intestinal air

Gas is a normal product of GI processes. However, sometimes, gas may be excessive. Patients may present with:

- Excessive belching - Gas pains, severe bloating - Uncontrolled flatulence - Colic

At any time, there are 150- 200 mL of gas in our GI tracts. We expel 500-1500 mL daily.

- An average person passes gas 8-20 times a day. Each passage can contain 20-400 mL.

- Gas in our system comes from swallowing air, bicarbonate neutralization, diffusion of gases from the blood to the intestine, and bacterial fermentation.

N2, O2, CO2, H2, and CH4 are odorless gas particles. Skatole, ammonia, hydrogen sulfide, indole, and volatile amines are odorous particles. Triggers of gas Dietary Drug-Induced Medical Conditions Vegetables Legumes Sugars Artificial sweeteners Carbonated drinks Fatty foods Whipped foods Milk

Psyllium Lactobacillus Probiotics PCN, Keflex, quinolones Narcotics Anticholinergics Acarbose Lactulose

Lactose intolerance Irritable bowel syndrome Celiac disease

Non-Pharmacologic Therapy The goals of therapy are to reduce the frequency of gas, its intensity, and its duration. When considering medications, keep in mind any underlying medical conditions, the patient’s eating habits and current pharmacotherapy. The use of pharmacotherapy to treat gas is empiric (try and see). A change in eating habits may alleviate gas.

- Slow down when eating - Eat in a calm environment - Chew food thoroughly - Do not wash solids down with liquid - Do not gulp - Avoid chewing gum and hard candies - Do not induce belching or force flatulence

- Eat smaller meals Changes in diet:

- Avoid foods that cause gas - Avoid foods with air in them - Avoid carbonated beverages

Medications and lifestyle habits:

- Avoid long-term medicines for colds (anticholinergics/ antihistamines) - Avoid tight fitting clothes - Do not lie down after eating - Regular exercise and rest

Pharmacologic Therapy The two main drugs used to treat gas are (1) simethicone and (2) alpha-galactosidase. Simethicone (Gas-X, Mylanta Gas, Mylicon, etc) MOA: Simethicone reduces the surface tension of gas bubbles embedded in the mucus and GI tract, thus reducing the volume of gas passed each time. Pros Cons - No systemic absorption - Well-documented safety - Only anti-flatulent considered safe and

effective by the FDA - Relieves felling of bloating, fullness, or

stuffed feeling - No lower age limit - No adverse reactions reported

- Does not eliminate gas, just makes it easier to pass

- Contraindicated in patients with hypersensitivities to simethicone or silicone

Infants with colic are often recommended to take simethicone. However, no studies show any real benefit in infants from taking simethicone as opposed to the placebo. Alpha-Galactosidase (Beano tablets and liquid) MOA: Enzyme degrades oligosaccharides into digestible sugars (sucrose and glucose) It is a preventative medicine, to be taken in conjunction with trigger foods. Pros Cons - One study shows significant decrease in

flatus - Naturally occurring enzyme

- Not indicated for children under 12 - Derived from A. niger - Drug interaction with penicillin - Inactivated by heat, so hot foods may

inactivate it - Caution with diabetes mellitus patients

HEMORRHOIDS Hemorrhoids are defined as “large or symptomatic conglomerates of blood vessels, supporting tissues, and mucus membranes of the anorectal area.” Over 80% of the population will be affected by hemorrhoids some time in their lifetimes. Depending on the location of the hemorrhoids within the anorectal area, there are different classifications of hemorrhoids. Internal hemorrhoids (A) do not cross the pectinate line, and are not innervated. External hemorrhoids (B) are past the pectinate line and exude from the anus. Mixed hemorrhoids (C) cross the pectinate line. Prolapsing hemorrhoids exude from the rectum to the anal sphincter. Non-prolapsing hemorrhoids remain within the tube. Clinical Presentation Bleeding Patients will experience having blood in the toilet. However, the bleeding is usually self-limiting. In any case, bleeding hemorrhoids must be referred for M.D. evaluation. Pain Pain is not common, and is usually caused by a hemorrhoid that is thrombosed, ulcerated, or gangrenous. Hemorrhoids accompanied with pain must be referred for M.D. evaluation. Pruritus Ani

This is a term meaning anal itch. It may result from inflammation, prolapse, thrombosis, or excessive cleaning. Diets can exacerbate pruritus ani. Trigger foods include caffeine, citrus fruits, beer, carbonated beverages, nuts, dairies and spices. OTC medication can alleviate itching. Non-Pharmacologic Therapy In general, hemorrhoids can be treated with the following:

- Increasing fluid intake - Increasing dietary fiber intake - Increasing exercise - Taking moderate NSAIDs - Defecating for less than 5 minutes - Cleaning the anorectal hygiene with mild, unscented soap - Sitz bath (evidence of efficacy is poor, but may work for some people) - Surgery

o Excising the mass (hemorrhoidectomy) - Non-surgical removal

o Injections, rubber band ligation, cryosurgery, and electrocoagulation Candidate for Self-Treatment Requires MD Referral Itching Discomfort Burning Inflammation Swelling

Acute severe pain Bleeding Drainage Change in bowel pattern Prolapse/ thrombosis

Pharmacologic Therapy Exclusions for self-treatment with OTCs include:

- Being under 12 years old - Diagnosed GI diseases - Family history of colon cancer - Other serious anorectal disorders - Acute onset of severe pain - Black, tarry stools - Severe itching, burning, inflammation, swelling, or discomfort - Minor side effects are not responsive or worsen within 7 days of self-treatment

Seven different classes of medications to treat hemorrhoids are: (1) local anesthetics, (2) vasoconstrictors, (3) protectants, (4) astringents, (5) keratolytics, (6) analgesics/anesthetics/antipruritics, and (7) corticosteroids. Local Anesthetics (Benzocaine, benzyl alcohol, dibucaine, lidocaine, tetracaine, pramoxine, and dyclonine) MOA: They are applied topically to relieve itching, irritation, burning, discomfort and pain, by reversibly blocking nerve impulses. The dose is brand name specific. Pros Cons

May relieve discomfort, pain, soreness, and burning

Systemic absorption Mask pain of severe anorectal disorder For external use only Contact dermatitis Burning and itching

Vasoconstrictors (Ephedrine, Epinephrine, Phenylephrine) MOA: Vasoconstriction via alpha- adrenergic receptors, causing a modest reduction in swelling. Dose: Apply as directed up to QID. Pros Cons May help itching, discomfort and irritation May have an anesthetic effect Phenylephrine has milder effects on the cardiovascular system

May cause cardiovascular effects Not approved for anorectal bleeding May cause contact dermatitis SE: nervousness, tremor, sleeplessness, nausea, loss of appetite, increase in blood pressure, arrhythmia, anxiety, paranoia Contradicated for patients on HTN meds, MAOIs, TCAs, diabetes, thyroid disease, and angina

Protectants (AIOH, cocoa butter, glycerin, hard fat, kaolin, lanolin, minteral oil, white petrolatum, petroleum, shark liver oil, zinc oxide, topical starch, calamine, cod liver oil) MOA: prevents irritation and water loss by forming a physical barrier on the skin. Dose: Apply up to six times a day, except petrolatum and white petrolatum have infinite use. Pros Cons - May help with discomfort, itching, irritation

and burning - May use internally and externally, except

for glycerin (external only) - Prevents drying of anal mucosa - Minimal systemic absorption

- Lanolin allergy is common in people - AIOH and kaoilin cannot be used with

“greasy substances”

Astringents (Calamine, zinc oxide, witch hazel) MOA: Promote coagulation of skin cells, decrease cell volume, protect underlying tissue, decrease secretions, and dry Dose: After each bowel movement, up to 6 times a day Pros Cons

- May help with itching, irritation, and burning

- Calamine and zinc may be used internally or externally

- Adverse events uncommon

- Witch hazel is for external use only - Systemic zinc toxicity with zinc

oxide and calamine if used long-term

Keratolytics (Alcloxa, resorcinol) MOA: Causes desquamination, debraidment, sloughing of epidermal surfaces, stimulate cell turnover, unknown mechanism for decreasing itch and discomfort Dose: Up to six times a day Pros Cons May help with discomfort and itching External use only

Systemic absorption of resorcinol may result in: methemoglobinemia, cardiovascular collapse, syncope, convulsions Must carry warning regarding allergic reactions and open wounds SE: tinnitus, increased heart rate, diaphoresis, shortness of breath

Analgesics/ Anasthetics/ Antipruritics (Menthol, juniper tar, camphor) MOA: Produces cool, warm, or tingling feeling by distracting nociceptors. Dose: Up to 6 times a day. Pros Cons May relieve pain, itching, burning and discomfort

External use only Menthol may lead to allergic reactions Menthol may cause laryngospasms, dyspnea, and cyanosis

Corticosteroids (Hydrocortisone) MOA: Topical antipruritic and vasoconstrictor; lysosomal membrane stabilization, anti-mitotic activity Dose: Up to 3-4 times a day Pros Cons Longer duration of action Only steroid OTC approved for anorectal use Indicated for minor external anal itching

Onset of action is 12 hours May mask symptoms of infection External use only

Many different anorectal products exist, and many come in combinations. Always check active ingredients. Use an intra-rectal applicator or finger for intra-rectal application, when internal use is safe.

LACTOSE INTOLERANCE Our GI tract is lined with the lactase enzyme, which converts lactose into glucose and galactose. As people get older, they may develop lactose intolerance because the concentration of lactase decreases. This is especially true for people who rarely consume lactose. Clinical presentation of lactose intolerance

- Cramps, abdominal pain, increased motility, nausea, borborygmus - Bacterial fermentation, bloating, abdominal pain, flatulence, watery stools,

involuntary leakage, incontinence, and diarrhea When deciding whether a patient has lactose intolerance, consider the following:

(1) It may not be lactose intolerance, but cow milk allergy. This is true if the patient vomits within one hour.

(2) LI symptoms should increase in age, manifesting after 6 years old. (3) Elimination of milk and dairy in the diet may be detrimental, resulting in weak

bones. (4) Before treatment, the patient must be aware of personal lactose tolerance levels. (5) Be aware of lactose used as part of the excipient in certain drug formulations.

Pharmacotherapy Digestive enzymes (Lactase) MOA: Breaks down lactose into galactose and glucose Dose: 1-2 caps taken with meal, based on patient reports Pros Cons No significant SEs No significant DDIs Caplets, chewables, and liquids

Must be taken prior to each meal containing May be degraded by stomach acids