Module 8 - Gastrointestinal Drugs
N609

Ingestion or administration of substances or drugs
Gastrointestinal (GI) disorders
Neurologic processes
Metabolic disorders
Presence of noxious stimuli
Supratherapeutic digoxin (Lanoxin) and theophylline
Chemotherapy

Emetic complex (EC)
Stimulatory centers: chemoreceptor trigger zone (CTZ)
GI tract
Central nervous system
Limbic system

Nausea: unpleasant physical sensation of impending retching or vomiting; symptoms include flushing, pallor, tachycardia, and hypersalivation
Retching: involuntary synchronized labored movement of abdominal and thoracic muscles before vomiting
Vomiting: coordinated contractions of the abdominal and thoracic muscles to expel the gastric contents

Evaluate and correct possible causes
Treat infectious cases
Change patient diet
Consider hypnosis, behavior modification, and imagery

To alleviate nausea's subjective feeling
The objective act of vomiting and its associated complications

Phenothiazines are a commonly used class of drugs to treat nausea and vomiting.
Prochlorperazine (Compazine) and promethazine (Phenergan) are the most frequently used drugs in this class.

There is a wide variety of agents available in the antihistamine-anticholinergic drug class.
These agents are most useful for mild nausea, such as motion sickness.
Hydroxyzine (Vistaril, Atarax), meclizine (Bonine, Antivert), dimenhydrinate (Dramamine), and scopolamine (Transderm Scop) are some of the more common agents of this class.

Often used for other indications, benzodiazepines offer useful qualities to the treatment of nausea.
Not only do these agents treat and prevent emesis, but they can also cause anxiolysis and amnesia.
These latter effects are particularly beneficial in anticipatory nausea and vomiting associated with chemotherapy.
Lorazepam (Ativan) is the most frequently used benzodiazepine for nausea and vomiting.

The serotonin antagonists are another class of antiemetics. Ondansetron (Zofran), granisetron (Kytril, Sancuso), palonosetron (Aloxi), and dolasetron (Anzemet) are available in the United States.

Metoclopramide (Reglan) has been used to treat nausea and vomiting caused by several different stimuli.
It is a highly useful agent in the treatment of diabetic gastric stasis, postsurgical gastric stasis, and gastroesophageal reflux, which may be associated with some degree of nausea.

Corticosteroids are usually reserved for chemotherapy-induced nausea and vomiting and have been shown to create an additive effect in chemotherapy-induced nausea and vomiting's (CINV's) prevention.

Cannabinoids are indicated only for nausea and vomiting associated with chemotherapy.
In the 1970s, it was observed that patients on chemotherapy who smoked marijuana experienced a lower incidence of nausea and vomiting. Investigators then determined that tetrahydrocannabinol (THC) has antiemetic properties.

Over-the-counter (OTC) antacid preparations may provide relief to patients experiencing mild nausea and vomiting.
The general mechanism by which these agents exhibit their effects is by coating the stomach and neutralizing gastric acid.
Most preparations contain one or several of the following: calcium carbonate, magnesium hydroxide, aluminum hydroxide, or aluminum carbonate.

First-Line Therapy: An antiemetic is selected based on patient-specific factors. Initially, a phenothiazine is used for mild to moderate nausea and vomiting. Promethazine and prochlorperazine are usually sufficient.
Second-Line Therapy: If the above treatment is not effective, an antihistamine or anticholinergic preparation can be used. These are usually not as effective as phenothiazines but may be useful in mild nausea.
Third-Line Therapy: If the first two therapies are not successful, the patient should be re-evaluated for a physiological cause that has not been treated and therapy based on patient data.

Acute emesis is vomiting occurring within 24 hours of treatment.
The onset of acute emesis is usually within 1 to 2 hours after the start of chemotherapy.
It peaks within 4 to 10 hours and resolves within 24 hours, but these factors vary from agent to agent.
This most common type of chemotherapy-induced nausea and vomiting is associated with a higher frequency and severity than the other two classifications.

Delayed nausea and vomiting are defined as emesis that begins or persists more than 24 hours after chemotherapy completion.
Some investigators suggest that because there is a "peak" in incidence at 18 hours after cisplatin-based chemotherapy, a revised definition of delayed emesis should include this timetable.
The new-found, reliable control of acute emesis from highly to moderately emetogenic chemotherapy regimens has unveiled delayed nausea and vomiting as a more vexing problem.
Many chemotherapy agents produce mild delayed nausea and vomiting, but cyclophosphamide, cisplatin, and the anthracyclines are particularly noted for their delayed emesis.

Anticipatory nausea and vomiting occur in up to 20% to 30% of patients receiving chemotherapy (Molassiotis, et al., 2016).
It is usually associated with a history of uncontrolled nausea and vomiting with prior chemotherapy and is a conditioned response.

A practitioner is treating a patient for nausea and vomiting not related to chemotherapy. What therapy would be used if phenothiazines fail to work?
A. Serotonin antagonist
B. Dexamethasone
C. Metoclopramide
D. Antihistamine

D. Antihistamine
Rationale: The second-line of therapy for nausea and vomiting not related to chemotherapy is an antihistamine. Serotonin antagonists, dexamethasone, and metoclopramide are commonly used to treat chemotherapy-induced nausea and vomiting.

Congenital obstructive GI malformations
Atresias or webs of esophagus or intestine
Meconium ileus or plug; Hirschsprung disease
Inborn errors in metabolism

Acquired or milder obstructive lesions
Pyloric stenosis; malrotation and volvulus
Intussusception
Metabolic diseases, milder inborn errors of metabolism
Nutrient intolerances
Functional disorders: gastroesophageal reflux
Psychosocial disorders: rumination, injury due to child abuse

The best measure of nausea control is how the patient feels.
It can be rated as none, mild, moderate, or severe to evaluate nausea more objectively.
Another method is to ask the patient to rate nausea on a scale from 0 to 10, with 0 equal to no sickness and 10 equals severe nausea.
These methods may compare nausea from day to day or week to week in the same patient.
Episodes per day and volume easily quantify vomiting.
If the vomit volume exceeds 200 to 500 mL/d, the patient should be evaluated for electrolyte abnormalities.

It is pivotal to identify the cause of nausea and vomiting and educate the patient about lifestyle actions that help.
Many cases of mild nausea and vomiting can be alleviated without additional medications.

Nausea and vomiting are common complaints in humans. The severity of the event can range from a slight discomfort or queasiness to uncontrollable, forceful vomiting.
All are perceived to be uncomfortable and troublesome and should be treated in a proper and timely manner.
Practitioners must be aware of the different causes of nausea and vomiting and treatment options available to manage the complications associated with this disorder.

Definition: infrequent or difficult evacuation of stool
Causative factors: diet, lifestyle, medications, and many disease states
Preferred therapy: dietary and lifestyle modifications

Onset and duration of symptoms
Patient's definition of constipation
Presence of abdominal cramping relieved by defecation (if yes, think irritable bowel syndrome [IBS])
Presence of blood in the stool

Evaluation of the perianal area for scars, fistulas, fissures, and external hemorrhoids
Observe the perineum at rest and while patient is bearing down
Digital rectal examination-check for fecal impaction, stricture, or rectal masses

Lifestyle modifications are preferred over pharmacologic therapy for treating constipation. Diet, exercise, and bowel habit training are usually targeted.
One additional lifestyle modification includes establishing a regular pattern for bathroom visits especially with the elderly. Patients should also be counseled not to ignore the urge to defecate, because this delay increases the time for absorption of fluid from the stool.
Biofeedback, a method of retraining the pelvic floor muscles to relax during defecation, may be effective in selected patients.

The goal of therapy for constipation is to increase the water content of the feces and increase motility of the intestines to promote comfortable defecation, using the lowest effective dose of a laxative for the least amount of time possible.

Bulk forming
Hyperosmotic
Saline
Stimulant
Surfactant
Lubricant

Secretagogues-Chloride Channel Activators
Gunaylate Cyclase-C Agonist
Peripherally acting Mu-opioid Receptor Antagonist (PAMORA)
Serotonin-4 (5-HT4) Receptor Agonist

A practitioner is prescribing third-line treatment for a patient with constipation that did not respond to first- and second-line treatment. What is a recommended agent?
A. Bulk-forming agents
B. Milk of magnesia
C. Stimulant laxatives
D. Glycerin

C. Stimulant laxatives
Rationale: The third-line treatment for constipation consists of stimulant laxatives (senna, cascara sagrada, casanthranol, bisacodyl); mineral oil, sodium biphosphates, magnesium citrate, and castor oil.

Monitoring patient response
Patient education
Patient oriented information sources
Nutrition/Lifestyle changes
Complementary and alternative medications/treatments

Antacids (magnesium containing); antibiotics
Antidepressants (selective serotonin reuptake inhibitors [SSRIs])
Cholinergic agents; colchicine
Digoxin
GI stimulants (metoclopramide)
Laxatives, prostaglandin analog (misoprostol)
Quinidine; metformin; prostaglandins (dinoprostone)

Aeromonas species
Bacillus cereus
Campylobacter
Chlamydia trachomatis
Clostridium difficile
Cryptosporidium
Escherichia coli
Entamoeba histolytica

Giardia
Mycobacterium avium-intracellulare
Salmonella
Shigella
Staphylococcus aureus
Viral agents
Yersinia

Osmotic
Secretory
Exudative
Altered intestinal motility

Laboratory evaluation for ova and parasites should be performed in the following:
A person not previously treated with empiric antiparasitic therapy
A person with persistent diarrhea for more than 7 days
A person who recently traveled to mountainous regions, Russia, or Nepal
A person who was exposed to infants at day care centers or who was exposed through a community waterborne outbreak
A person with bloody diarrhea with few or no fecal leukocytes
Homosexual men or patients with acquired immunodeficiency syndrome (AIDS)

The goals of drug therapy are to reduce the symptoms of diarrhea and to make the patient as comfortable as possible. Causative factors should be identified and eradicated. Fluid and electrolyte replacement is particularly important to avoid serious complications from dehydration.

Antimotility agents
Atypical Antidiarrheals
Adsorbents and Absorbents
Semisynthetic antibiotic

First line: Loperamide: easy to use, tablet or liquid; Rifaximin (TD): well tolerated, 3-day course
Second line: Adsorbents or antisecretory agent: selection based on drug-drug interactions or allergies (e.g., aspirin sensitivity and bismuth subsalicylate)
Third line: Diphenoxylate: side effect profile, especially with atropine added, lowers the utility of this agent

Drug information
Patient oriented information sources
Nutrition/Lifestyle changes
Complementary and alternative medications

IBS as recurrent abdominal 1 day per week in the last 3 months related to defecation, change in stool frequency and form with the onset at least 6 months prior to diagnosis (Lacey et al., 2016).

IBS with constipation (IBS-C)-hard or lumpy stools >=25% and loose (mushy) or watery stools <=25%
IBS with diarrhea (IBS-D)-loose (mushy) stools or watery stools >=25% and hard or lumpy stools <=25%
IBS mixed (IBS-M)-hard or lumpy stools >=25% and loose (mushy) or watery stools >=25%
IBS unclassified (IBS-U)-insufficient abnormality of stool, consistency to meet criteria for other classifications

Mild IBS: usually shows a sporadic pattern; symptoms are worsened by stress and dietary factors; there is no alteration in the patient's daily activities.
Intermittent IBS: the symptoms are worse and begin to affect the patient's daily life; it is more difficult to relate symptoms to specific precipitants, and a psychological component to the syndrome may be developing.
Continuous IBS: the symptoms affect every aspect of the patient's daily routines; an inability to pinpoint precipitants still exists, and there is a definite psychological component to the syndrome.

The goal of pharmacotherapy for IBS is to alleviate or control the specific symptoms

Bulk-forming laxatives
Hyperosmotic laxatives
Stimulant laxatives
Surfactant laxatives
Antidiarrheal agents
Antispasmotic agents
Antidepressants
Serotonin 3 receptor antagonists

Secretagogues
Chloride channel activators
Guanylate cyclase C agonist
Semisynthetic antibiotic

A practitioner is prescribing an antidiarrheal for a patient newly diagnosed with diarrhea. What is the recommended agent of choice?
A. Loperamide
B. Adsorbent
C. Antisecretory agent
D. Diphenoxylate

A. Loperamide
Rationale: The first line of therapy for diarrhea is loperamide and rifaximin (TD). The second line is an adsorbent or antisecretory agent, and the third line is diphenoxylate.

Predominant constipation (IBS-C): osmotic laxative-lactulose syrup, magnesium citrate, magnesium hydroxide, linaclotide or lubiprostone
Predominant diarrhea (IBS-D): antidiarrheal-loperamide; hydrochloride (Imodium), rifaximin
Abdominal bloating/gas: antispasmodics-dicyclomine hydrochloride (Bentyl)
Psychological symptoms: antidepressants (SSRIs)

Drug Information
Patient-oriented information sources
Nutrition/Lifestyle changes
Complementary and alternative medications

Functional bowel disorders of the lower GI tract can include symptoms of hypogastric cramping, abdominal pain, diarrhea, or constipation.
IBS and chronic idiopathic constipation (CIC) are two of the most common GI complaints globally (Ford et al., 2014).
Similar pharmacologic agents are used to treat the symptoms of IBS, CIC, opioid-induced constipation (OIC), or diarrhea, whether self-limited or chronic.

Dysregulation of immunologic mechanisms
Defect in the GI mucosal barrier that results in enhanced permeability and increased uptake of proinflammatory molecules and infectious agents
Bacterial and viral causative organisms
Complex genetic disorder
Psychological well-being
Environmental triggers

Complete history focusing on recent use of antibiotics, recent international travel, diet history, use of laxatives or antidiarrheals, frequency and quality of daily bowel movements, history of peptic ulcer disease (PUD), and family history of inflammatory bowel disease (IBD) to rule out similar presenting conditions.
Physical examination should include assessment of vital signs and weight loss, a thorough abdominal examination, and special attention to extraintestinal complications.

Resume normal daily activities
Restore general physical and mental well-being
Attain appropriate nutritional status
Maintain remission of disease
Decrease the number and frequency of exacerbations
Decrease side effects related to medications
Increase life expectancy

Ambulatory patients
Able to tolerate oral alimentation
No evidence of:
Dehydration, high fevers, rigors, prostration, abdominal tenderness, painful mass, abdominal obstriction
10% weight loss

Failed treatment for mild to moderate disease OR have:
High fever
>10% weight loss
Abdominal pain/tenderness
Intermittent nausea or vomiting (without obstructive findings)
Significant anemia

Have persistent symptoms despite outpatient steroid therapy OR have:
High fever
Persistent vomiting
Intestinal obstruction
Rebound tenderness
Cachexia
Abscess

Mild UC: <four stools daily (with or without blood); no presence of anemia, fever, or tachycardia; normal erythrocyte sedimentation rate (ESR)
Moderate UC: >four stools daily; minimal anemia, fever, or tachycardia
Severe UC: >six stools daily; positive fever, tachycardia, anemia, or elevated ESR
Fulminant UC: 10 stools daily; continuous bleeding, abdominal tenderness and distention, anemia requiring blood transfusion, colonic dilation

A patient presents with severe ulcerative colitis. What is one criterion for this category of UC?
A. >four stools daily
B. Minimal anemia, fever, or tachycardia
C. >six bloody stools daily
D. Anemia requiring blood transfusion

C. >six bloody stools daily
Rationale: The criteria for severe UC is >six bloody stools daily, positive fever, tachycardia, anemia, or elevated ESR. >four stools daily and minimal anemia, fever, or tachycardia, are symptoms of moderate UC, and anemia requiring blood transfusion is a criterion for fulminant UC.

Aminosalicylates
Corticosteroids
Immunosuppressive agents
Antibiotics
Biological agents

A practitioner is prescribing an immunosuppressive for a patient with inflammatory bowel disease. Which drug is in this classification?
A. Prednisone
B. Sulfasalazine
C. Metronidazole
D. Oral methotrexate

D. Oral methotrexate
Rationale: Oral methotrexate is an immunosuppressive prescribed for IBS. Prednisone is a corticosteroid, sulfasalazine is an aminosalicylate, and metronidazole is an antibiotic.

A patient is diagnosed with mild distal UC. What is the recommended therapy for this condition?
A. Antibiotic therapy
B. Oral/rectal aminosalicylate
C. IV infliximab
D. IV corticosteroid

B. Oral/rectal aminosalicylate
Rationale: The recommended therapy for mild distal UC is oral/rectal aminosalicylate or rectal corticosteroid.

Sigmoid colostomy: distal end of large intestine
Descending colostomy: descending colon and rectum
Transverse colostomy: small portion of transverse colon
Proctocolectomy/ileostomy: entire rectum and large intestine

Drug information
Patient-oriented information sources
Preventive care
Nutrition
Vaccination
Cancer screening
Complementary and alternative therapies

IBD is a generic term used to describe two main chronic inflammatory conditions of the GI tract: Crohn disease (CD) and UC.
IBD affects approximately 1 million Americans. In 2004, the prevalence of CD was estimated to be approximately 359,000, and for UC, it is estimated to be 619,000.
Although the mortality rate is low for the diseases, they significantly affect the patient's overall mental status, physical health, and quality of life.

Definition
"Troublesome symptoms and/or complications" resulting from the abnormal reflux of gastric contents into the esophagus or beyond, including the oral cavity or lungs
Two categories
Symptoms present but without erosions seen on endoscopic exam
Those with esophageal tissue injury

Foods
Fatty foods, chocolate, peppermint/spearmint, garlic, onions, chili peppers, alcohol, coffee/caffeinated drinks
Drugs
Anti-cholinergic agents, benzodiazepines, caffeine, calcium channel blockers (dihydropyridines), dopamine, estrogen/progesterone, nicotine, nitrates, theophylline, tricyclic antidepressants

Foods
Spicy foods, citrus juices, tomato products, coffee, tobacco chew
Drugs
Aspirin, bisphosphonates (e.g., alendronate), iron, nonsteroidal anti-inflammatory drugs (NSAIDs), potassium chloride

Esophagitis: inflammation of the lining of the esophagus
Erosive esophagitis: erosion of the squamous epithelium of the esophagus
Peptic stricture development: narrowing or tightening of the esophagus
Barrett's esophagus: squamous epithelium of the esophagus is replaced by specialized columnar-type epithelium
Esophageal adenocarcinoma: cancer of the esophagus

Typical
Acid regurgitation, heartburn
Atypical symptoms
Epigastric fullness, epigastric pressure, epigastric pain, dyspepsia, nausea, bloating, belching
Extraesophageal symptoms
Chronic cough/throat clearing, asthma/bronchospasm, wheezing, hoarseness, sore throat, chronic laryngitis

Peptic ulcer disease (PUD) is characterized by discontinuation in the inner lining of the gastrointestinal (GI) tract because of gastric acid secretion or pepsin.
It extends into the muscularis propria layer of the gastric epithelium.
A peptic ulcer often reoccurs, and like GERD, PUD can significantly impair quality of life.

Helicobacter pylori-positive ulcers,
NSAID-induced ulcers
Stress ulcers

Normally, the gastric and duodenal environments can maintain a state of homeostasis where food digestion can occur without compromising gastric tissue integrity.
There are five components including hydrochloric acid, pepsin, and intrinsic factor. Pepsin is the enzyme most involved with protein digestion.
Additionally, hydrochloric acid plays a role in creating the correct pH environment to convert pepsinogen to pepsin.
Several defense mechanisms exist to prevent tissue injury from acid and digestive functions of the GI tract. H. pylori and NSAIDs can disrupt these processes, leading to the formation of ulcers.

Though not all patients with PUD present with symptoms, the most common complaints include epigastric pain described as burning, fullness, discomfort, gnawing, cramping, or aching.
The severity and frequency of the pain can fluctuate, and some patients report worsening at night.
Often, heartburn, belching and bloating accompany the pain.

Relieve symptoms
Decrease the frequency and duration of reflux
Heal the esophageal mucosa
Prevent complications

Relieve symptoms
Reduce acid secretion
Promote epithelial healing
Prevent recurrence
Prevent complications

Calcium-, magnesium-, and aluminum-containing formulations: dosing ranges from hourly to as needed
Adverse effects
Rebound hyperacidity, diarrhea with magnesium-containing antacids, constipation with aluminum-containing antacids
Monitor for drug interactions; use magnesium-aluminum combination to avoid diarrhea or constipation

Cimetidine (Tagamet), famotidine (Pepcid), nizatidine (Axid), ranitidine (Zantac)
Adverse events: generally well tolerated, may experience headache, dizziness, confusion
Contraindication: hypersensitivity to H2RAs
Take without regard to meals, monitor for drug interactions, consider dose reduction in elderly and renal impairment, may be scheduled or used on an as needed basis

Omeprazole (Prilosec, Zegerid), lansoprazole (Prevacid), pantoprazole (Protonix), esomeprazole (Nexium), dexlansoprazole (Dexilant), rabeprazole (AcipHex)
Adverse events: diarrhea, constipation, abdominal pain, headache
Contraindications: hypersensitivity to PPIs
Take 30 to 60 minutes before meals, do not crush, chew, or split delayed-release tablets

Amoxicillin (Amoxil), clarithromycin (Biaxin), metronidazole (Flagyl), tetracycline
Adverse events: amoxicillin: diarrhea, nausea, vomiting; clarithromycin: diarrhea, abnormal taste, nausea, vomiting; metronidazole: headache, metallic taste, nausea, peripheral neuropathy; tetracycline: GI upset, diarrhea, photosensitivity
Contraindications: amoxicillin: allergy to penicillin or other beta-lactams; clarithromycin: allergy to macrolides, QT prolongation, use with astemizole, cisapride, pimozide, simvastatin, or lovastatin

Metoclopramide: allergy to metoclopramide; tetracycline: allergy to tetracycline
Take without regard to meals, except tetracycline should be taken on empty stomach; avoid clarithromycin in retreatment for those who fail initial clarithromycin-containing regimen; avoid alcohol with metronidazole; avoid dairy, antacids, and iron products within 2 hours of tetracycline administration

Misoprostol (Cytotec)
Adverse events: diarrhea, abdominal pain, cramping, nausea; contraindications: hypersensitivity to misoprostol, pregnancy; take with food; reduce dose if diarrhea is intolerable
Sucralfate (Carafate)
Adverse event: constipation; contraindication: hypersensitivity to sucralfate; take on empty stomach; monitor for drug interactions

Bismuth subsalicylate (Pepto Bismol)
Adverse events: black stools, darkened tongue, constipation, tinnitus
Contraindication: hypersensitivity to salicylates
Avoid in pregnancy and lactation

A practitioner is prescribing a drug for a pregnant woman with severe GERD symptoms. What drug is contraindicated for this patient?
A. Antacids
B. Cimetidine
C. Omeprazole
D. Misoprostol

D. Misoprostol
Rationale: Drugs for GERD that should be avoided during pregnancy include misoprostol and bismuth subsalicylate.

Pediatric
Geriatric
Women
Patient Educations
Drug information
Nutritional and lifestyle changes
Complementary and alternative medicine

GERD and PUD are two disorders of the GI tract that can cause tissue damage and unpleasant symptoms.
Several pharmacologic agents are available for the treatment of PUD, and many overlap with the drugs used in the treatment of GERD. The choice in treatment depends on the etiology, presentation, and presence of complications.

Cirrhosis is most commonly identified in patients aged 45-64, predominantly due to hepatitis C virus (HCV).
This cohort of the population has been found to be at particularly high risk because of their possible exposure to blood products prior to widely available screening viral screening.
Intravenous drug users, and those participating in high-risk sexual activity, also have an elevated risk of transmitting HCV and ultimately cirrhosis.

Cirrhosis is most commonly identified in patients aged 45-64, predominantly due to what type of hepatitis?
A. A
B. B
C. C
D. D

C. C
Rationale: Cirrhosis is most commonly identified in patients aged 45-64, predominantly due to hepatitis C virus (HCV), not A, B, or D.

Acute liver injury describes an episode of abrupt liver dysfunction and should also be further classified as hepatocellular or cholestatic liver injury that may be identified by the presence of an elevated alkaline phosphatase in addition to AST and ALT .
Drug-induced liver injury is a frequently encountered medical problem that can lead to acute liver failure.
Cirrhosis is a chronic condition that develops after repeated episodes of injury to the hepatocytes leading to replacement of healthy liver cells with non-functional scar tissue.

Cirrhosis is a progressive disease that develops after repeated episodes of liver injury.
The pathophysiology of the cirrhosis complications is complex but can be traced back to activation of hepatic stellate cells.
As fibrosis progresses, hepatic portal venous pressure simultaneously increases. As portal hypertension (PH) evolves, it causes enlargement of splanchnic vessels in the esophagus and stomach, which are termed varices.

A buildup of fluid in the peritoneum is also a hallmark complication of cirrhosis.
As ascites develop, patients are at an increased risk of spontaneous bacterial peritonitis (SBP), an infection of the peritoneal space.
In the late stages of cirrhosis, despite increasing amounts of fluid being retained, it escapes the vasculature and can lead to profound reduction of blood flow to the kidneys.

Various objective imaging studies may be helpful in confirming a diagnosis of cirrhosis, but often a thorough patient history and evaluation of signs and symptoms is the first step to identifying the likelihood of cirrhosis in a patient.
Once the diagnosis of cirrhosis is confirmed, several additional tools may be implemented to evaluate the severity of cirrhosis.
Depending on the underlying etiology of cirrhosis, risk factors should be identified and addressed. Alcohol abstinence is pivotal in patients with alcoholic liver disease.

PH nearly directly correlates with the progression of liver fibrosis. The primary diagnosis of clinically significant PH is based on the hepatic portal venous gradient (HPVG) of >10 mmHg. An HVPG of >12 mmHg is associated with variceal rupture and hemorrhage and development of ascites.
Because liver fibrosis and PH develop concurrently, there has been recent interest in using ultrasound elastography to measure the presence of clinically significant PH.

Identification of patients with varices is a crucial step in the assessment and evaluation of patients with cirrhosis.
Most patients diagnosed with cirrhosis should undergo evaluation for gastroesophageal varices via esophagogastroduodenoscopy (EGD).

Because PH is the first consequence of cirrhosis, it is also the first opportunity to initiate pharmacologic therapy.
Three non-selective beta-blockers (NSBB), propranolol, nadolol, and carvedilol, are used to cause reduced blood flow through the portal vascular system.
Clinically, the goal of drug therapy for PH is to prevent variceal hemorrhage and reduce mortality.

All three NSBBs are indicated for primary prophylaxis of variceal hemorrhage.
Due to multiple daily doses required for propranolol and carvedilol, patients may benefit from a once-daily dosing of nadolol.
Despite the ease of dosing with nadolol, it is generally more expensive and may lead to additional out-of-pocket costs for patients.

Unfortunately, for many patients with advanced cirrhosis, acute variceal hemorrhage can be one of the first physical manifestations of cirrhosis.
Although variceal hemorrhage is ultimately diagnosed via an EGD, the initial clinical signs and symptoms are similar to that seen in patients with upper gastrointestinal bleed (i.e., decreased hemoglobin and hematocrit, hematochezia, coffee-ground emesis, altered mental status, elevated BUN, hypotension, and tachycardia).

The primary goal of drug therapy for variceal hemorrhage is to reduce the risk of mortality at 6 weeks post-event.
Acutely, the clinician should ensure hemodynamic stability with intravenous fluids, maintain adequate oxygenation with supplemental O2, maintain hemoglobin between 7 and 9 g/dL with packed red-blood cell transfusion, and control bleeding.
In patients with known or suspected ascites, administration of antibiotics is of upmost importance to further reduce the incidence of SBP and mortality.
Vasoactive agents have been shown to reduce short-term mortality and transfusion requirements in patients presenting with variceal hemorrhage.

Ascites, although most frequently associated with cirrhosis, can develop due to additional causes such as heart failure, neoplasm, and nephrotic syndrome.
A thorough physical exam in patients with a distended or protuberant abdomen will assist the clinician in identifying patients with ascites.

The primary goal of therapy for ascites is to mobilize and excrete fluid by administration of diuretics, while minimizing intravascular volume depletion.
Additionally, drug therapy is used to prevent the re-accumulation of fluid.
Although the mainstay of treatment is diuretic agents, occasionally, paracentesis is required in patients with large volume ascites and/or ascites refractory to treatment.
The aldosterone antagonist spironolactone is considered the gold standard initial therapy for the treatment of ascites.

Which is considered the gold standard initial therapy for the treatment of ascites?
A. Spironolactone
B. Furosemide
C. Potassium replacement
D. Spironolactone and furosemide

A. Spironolactone
Rationale: The aldosterone antagonist spironolactone is considered the gold standard initial therapy for the treatment of ascites. It is preferred over furosemide monotherapy as it targets the underlying hyperaldosteronism that occurs in patients with ascites and has been shown to be more effective in mobilizing fluid. Due to the frequency of hyperkalemia that occurs with high-dose spironolactone and the longer time to mobilization of fluid, the combination of spironolactone and furosemide is recommended for most patients.

In patients with known cirrhosis and ascites, the ascitic fluid can become infected, leading to SBP. SBP is diagnosed when an elevated ascitic fluid polymorphonuclear cell count or neutrophil count is >=250 cells/mm3 without an intra-abdominal source of infection (i.e., perforation).
SBP is most commonly caused by enteric gram-negative pathogens (e.g., E. coli and K. pneumonia) as well as S. pneumonia, and thus empiric therapy should adequately cover those isolates until sensitivities are available.

Eradication of active peritoneal infection and improving survival is the primary goal of therapy in SBP.
Furthermore, certain patients presenting with SBP are at higher than normal risk of mortality as well as kidney injury, which requires additional non-antimicrobial therapies.
In most cases, the 3rd generation cephalosporins should be used as first-line therapy for the treatment of SBP.

Patients should become afebrile and begin to clinically improve within 24-48 hours after antibiotic initiation; thus, repeat diagnostic paracentesis is not required unless the patient clinically deteriorates or demonstrates a lack of improvement.
If an additional paracentesis is required, additional causes of infection should be evaluated, and surgical intervention may be required.

Like the treatment of SBP, primary and secondary prophylaxis should target typical infecting organisms.
Regardless of the agent chosen, daily administration should be used to prevent the development of antimicrobial resistance.

Hepatorenal syndrome (HRS) is a complex problem encountered in patients with cirrhosis and ascites, characterized by either an acute or a sub-acute rise in acute kidney injury.
Treatment of HRS is often delayed because of the lack of formal diagnostic criteria but should be implemented as soon as possible, as short-term mortality is significant.
Because HRS is most frequently triggered by infection, a careful infectious workup and prompt antimicrobial therapy should be implemented.

The primary focus of treatment is to successfully bridge the patient to liver transplant. During the bridge period, renal function can be maintained either through pharmacologic therapy or with renal replacement therapies.
If a reversible cause of acute liver dysfunction is identified, treatment should also be initiated to reverse the cause.
Due to the lack of formalized diagnostic criteria, randomized control trials are lacking, but a combination of albumin, octreotide, and midodrine has been shown to be effective in increasing mean arterial blood pressure, which may improve renal blood flow and may also improve short-term mortality.

Hepatic encephalopathy (HE) is a wide-ranging constellation of possible signs and symptoms displayed in patients with cirrhosis. In its most mild forms, patients may display inattention, agitation, and general confusion. As HE progresses, dyskinesia, parkinsonian tremors, and loss of deep tendon reflexes may become apparent.
Initiation of drug therapy is the last step in the management of overt HE.
Although serum ammonia levels are not used for the initial diagnosis of OHE, a decrease in their level may correlate with drug therapy efficacy. Ultimately, treatment should provide a return to baseline mental status.

Lactulose is considered the standard of care for OHE.
Rifaximin works by inhibiting the growth of organisms in the bowel that produce ammonia.
For acute episodes of OHE, close monitoring is required to ensure drug therapy targets are achieved and progression into more severe grades of OHE do not occur. Clinical evaluation of mental status through the Glasgow Coma Scale (GCS) is the most reliable assessment of patient response to therapy and can be used at the bedside without additional resources.

Drug Information
Nutrition/Lifestyle Changes
Complementary and Alternative Medications

Hepatitis B (HBV) and C (HCV) are blood-borne pathogens and are spread via transmission of infected blood and body fluids.
Risk factors for HBV and HCV are similar and include exposure to blood or blood-contaminated body fluids; injection drug use; unprotected sexual intercourse with an infected person; men who have sex with men; household contacts or sexual partners of known persons with chronic HBV or HCV infection; hemodialysis; infants born to infected mothers.

Hepatitis viruses replicate preferentially in the hepatocytes of the liver.
In general, acute and chronic hepatitis can be differentiated based on the duration of inflammation in the liver.
Patients with acute HBV or HCV may be asymptomatic or may exhibit non-specific symptoms, including right upper quadrant pain, fatigue, myalgia/arthralgia, fever, nausea, jaundice, pruritis, dark urine.
When HBV or HCV becomes chronic, hepatic symptoms and extrahepatic manifestations may occur.

HBV include suppression of viral replication, to the point of undetectable HBV DNA, loss of HBsAG, prevention of cirrhosis and related complications of ESLD, prevention of hepatocellular carcinoma, and minimization and mitigation of drug therapy adverse effects and toxicity.
Similar goals of preventing liver-related morbidity and mortality exist in the treatment of patients with HCV.
Peginterferon, entecavir, or tenofovir are preferred first line options.
The direct acting antivirals have revolutionized HCV care since their introduction to the market in 2011.