PHARMACOLOGY MIDTERMS COMPLETE DETAILED STUDY GUIDE GRADED A+ 2022/2023 UPDATE

PHARMACOLOGY MIDTERMS COMPLETE DETAILED STUDY GUIDE GRADED A+ 2022/2023 UPDATE Pharmacokinetics: • Understand the implications of changing renal function on creatinine and drug dosing. Renal disease interacts with drugs in three main ways. Firstly, patients with renal disease may be more vulnerable to a given drug effect (patient susceptibility). Secondly, a drug effect may be exaggerated or attenuated in patients with renal disease (pharmacodynamic change). Thirdly, and most importantly, some drugs have higher steady-state concentrations when given at usual doses to patients with renal disease (pharmacokinetic changes). Serum creatinine is the most commonly used analyte in the evaluation of renal function, and equations using serum creatinine concentration are the basis of most estimates of GFR • What is the impact of the following on drug levels and dosing: o Cirrhosis The liver is the main organ for metabolism and detoxification of endogenous and exogenous substances. Several pathophysiological changes that occur in liver cirrhosis influence this detoxification of exogenous substances, that is, drug pharmacokinetics. o Protein binding Drugs can form reversible bonds with various proteins in the body. Of all the proteins with which drugs can bind, plasma albumin is the most important. Like other proteins, albumin is a large molecule. Because of its size, albumin is too large to leave the bloodstream. Even though a drug can bind albumin, only some molecules will be bound at any moment. The percentage of drug molecules that are bound is determined by the strength of the attraction between albumin and the drug An important consequence of protein binding is restriction of drug distribution. Because albumin is too large to leave the bloodstream, drug molecules that are bound to albumin cannot leave either. As a result, bound molecules cannot reach their sites of action or undergo metabolism or excretion until the drug-protein bond is broken so that the drug is free to leave the circulation. In addition to restricting drug distribution, protein binding can be a source of drug interactions. Each molecule of albumin has only a few sites to which drug molecules can bind. Because the number of binding sites is limited, drugs with the ability to bind albumin will compete with one another for those sites. As a result, one drug can displace another from albumin, causing the free concentration of the displaced drug to rise, thus increasing the intensity of drug responses. If plasma drug levels rise sufficiently, toxicity can result o Drug interactions Drug-drug interactions can occur whenever a patient takes two or more drugs. Some interactions are both intended and desired, as when we combine drugs to treat hypertension. In contrast, some interactions are both unintended and undesired. Consequences of Drug-Drug Interactions When two drugs interact, there are three possible outcomes: (1) one drug may intensify the effects of the other, (2) one drug may reduce the effects of the other, or (3) the combination may produce a new response not seen with either drug alone. o Half-life - Drug half-life is defined as the time required for the amount of drug in the body to decrease by 50%. A few drugs have half-lives that are extremely short—on the order of minutes or less. In contrast, the half-lives of some drugs exceed 1 week. Routes of Administration and Dosage Forms: • Understand the different routes of administration and dosage forms and some of the challenges and benefits associated with these routes and forms. How drugs are administered A drug’s administration route influences the quantity given and the rate at which the drug is absorbed and distributed. These variables affect the drug’s action and the patient’s response. Routes of administration include: • buccal, sublingual, translingual: certain drugs are given buccally (in the pouch between the cheek and gum), sublingually (under the tongue), or translingually (on the tongue) to speed their absorption or to prevent their destruction or transformation in the stomach or small intestine • gastric: this route allows direct instillation of medication into the GI system of patients who can’t ingest the drug orally • intradermal: substances are injected into the skin (dermis); this route is used mainly for diagnostic purposes when testing for allergies or tuberculosis • intramuscular: this route allows drugs to be injected directly into various muscle groups at varying tissue depths; it’s used to give aqueous suspensions and solutions in oil, immunizations, and medications that aren’t available in oral form • intravenous: the I.V. route allows injection of substances (drugs, fluids, blood or blood products, and diagnostic contrast agents) directly into the bloodstream through a vein; administration can range from a single dose to an ongoing infusion delivered with great precision • oral: this is usually the safest, most convenient, and least expensive route; drugs are administered to patients who are conscious and can swallow • rectal and vaginal: suppositories, ointments, creams, gels, and tablets may be instilled into the rectum or vagina to treat local irritation or infection; some drugs applied to the mucosa of the rectum or vagina can be absorbed systemically • respiratory: drugs that are available as gases can be administered into the respiratory system; drugs given by inhalation are rapidly absorbed, and medications given by such devices as the metered-dose inhaler can be self- administered, or drugs can be administered directly into the lungs through an endotracheal tube in emergency situations • subcutaneous (subQ): with the subQ route, small amounts of a drug are injected beneath the dermis and into the subcutaneous tissue, usually in the patient’s upper arm, thigh, or abdomen • topical: this route is used to deliver a drug through the skin or a mucous membrane; it’s used for most dermatologic, ophthalmic, otic, and nasal preparations. Drugs may also be given as specialized infusions injected directly into a specific site in the patient’s body, such as an epidural infusion (into the epidural space), intrathecal infusion (into the cerebrospinal fluid), intrapleural infusion (into the pleural cavity), intraperitoneal infusion (into the peritoneal cavity), intraosseous infusion (into the rich vascular network of a long bone), and intraarticular infusion (into a joint). New drug development In the past, drugs were found by tri • Understand when it is OK to crush (or not crush) certain dosage forms and why. Generally, meds that should not be crushed fall into one of these categories: • Sustained-release tablets, which can be composed of multiple layers for different drug release times, as can beads within capsules. Some of the more common prefixes or suffixes for sustained-release, controlled-release, or controlled-delivery products include: 12-hour, 24-hour, CC, CD, CR, ER, LA, Retard, SA, Slo-, SR, XL, XR, or XT. • Enteric-coated tablets, which are formulated because certain drugs can be irritating to the stomach or are degraded by stomach acid. By enteric-coating tablets or capsule beads, the drug’s release can be delayed until it reaches the small intestine. Prefixes include EN- and EC-. • Which routes of administration have the fastest and slowest rates of absorption? • Know the relative onset, monitoring and appropriate use of various dosage forms including: o Patches (ie; fentanyl, rivastigmine) o Suppositories (ie; acetaminophen) o Sublingual tablets o Tablets o Liquid (know common measures) o Injectables o Sublingual o Nasogastric o Elixir (contains alcohol) (page 85) Route Barriers to Absorption Absorption Pattern Advantages Disadvantages Therapeutics: Gastrointestinal, Cardiac, Respiratory, Neurology, Musculoskeletal Understand the mechanism of action, side effects, appropriate use and contraindications for the classes of drugs and individual drugs listed below. Also, know the key patient education points including cautions, expected effects, and appropriate use (with food, empty stomach, etc.). =================================GASTROINTESTINAL== =============================== • Anti-diarrheals (diphenoxylate HCl with atropine sulfate(Lomotil), loperamide (Imodium ), bismuth subsalicylate[Pepto-Bismol, others]. Antidiarrheal drugs fall into two major groups: (1) specific antidiarrheal drugs and (2) nonspecific antidiarrheal drugs. The specific agents are drugs that treat the underlying cause of diarrhea. Included in this group are antiinfective drugs and drugs used to correct malabsorption syndromes. Nonspecific antidiarrheals are agents that act on or within the bowel to provide symptomatic relief; these drugs do not influence the underlying cause. Opioids are our most effective antidiarrheal agents. By activating opioid receptors in the GI tract, these drugs decrease intestinal motility and thereby slow intestinal transit, which allows more time for absorption of fluid and electrolytes. In addition, activation of opioid receptors decreases secretion of fluid into the small intestine and increases absorption of fluid and salt. The net effect is to present the large intestine with less water. As a result, the fluidity and volume of stools are reduced, as is the frequency of defecation Several opioid preparations—diphenoxylate, difenoxin, loperamide, paregoric, and opium tincture—are approved for diarrhea. Of these, diphenoxylate [Lomotil, others] and loperamide [Imodium, others] are the most frequently employed Bismuth subsalicylate [Pepto-Bismol, others] is effective for the prevention and treatment of mild diarrhea. For prevention, the dosage is two 262-mg tablets 4 times a day for up to 3 weeks. For treatment, the dosage is 2 tablets every 30 minutes for up to eight doses. Users should be aware that the drug may blacken stools and the tongue. • Laxatives (fiber, osmotics, stimulants, other) Laxatives are used to ease or stimulate defecation. These agents can soften the stool, increase stool volume, hasten fecal passage through the intestine, and facilitate evacuation from the rectum. When properly employed, laxatives are valuable medications. However, these agents are also subject to abuse. Misuse of laxatives is largely the result of misconceptions about what constitutes normal bowel function. Before we talk about laxatives, we need to distinguish between two terms: laxative effect and catharsis. The term laxative ef ect refers to production of a soft, formed stool over a period of 1 or more days. In contrast, the term catharsis refers to a prompt, fluid evacuation of the bowel. Hence a laxative effect is slower and relatively mild, whereas catharsis is relatively fast and intense. Traditionally, laxatives have been classified according to general mechanism of action. This scheme has four major categories: (1) bulk-forming laxatives, The bulk-forming laxatives (e.g., methylcellulose, psyllium, polycarbophil) have actions and effects much like those of dietary fiber. These agents consist of natural or semisynthetic polysaccharides and celluloses derived from grains and other plant material. The bulk-forming agents belong to our therapeutic group III, producing a soft, formed stool after 1 to 3 days of use. • Mechanism of Action Bulk-forming agents have the same effect on bowel function as dietary fiber. After ingestion, these agents, which are nondigestible and nonabsorbable, swell in water to form a viscous solution or gel, thereby softening the fecal mass and increasing its bulk. Fecal volume may be further enlarged by growth of colonic bacteria, which can utilize these materials as nutrients. Transit through the intestine is hastened because swelling of the fecal mass stretches the intestinal wall and thereby stimulates peristalsis. • Indications Bulk-forming laxatives are preferred agents for temporary treatment of constipation. Also, they are widely used in patients with diverticulosis and irritable bowel syndrome. In addition, by altering fecal consistency, they can provide symptomatic relief of diarrhea and can reduce discomfort and inconvenience for patients with an ileostomy or colostomy. • Adverse Effects Untoward effects are minimal. Because the bulk-forming agents are not absorbed, systemic reactions are rare. Esophageal obstruction can occur if they are swallowed in the absence of sufficient fluid. Accordingly, bulk-forming laxatives should be administered with a full glass of water or juice. If their passage through the intestine is impeded, they may produce intestinal obstruction or impaction. Accordingly, they should be avoided if there is narrowing of the intestinal lumen. • Preparations, Dosage, and Administration Psyllium (prepared from Plantago seed), methylcellulose, and polycarbophil are the principal bulk-forming laxatives. All three preparations should be administered with a full glass of water or juice. (Dosages and trade names are shown in Table 63.4.) (2) surfactant laxatives, • Actions The surfactants (e.g., docusate sodium) are group III laxatives: they produce a soft stool several days after the onset of treatment. Surfactants alter stool consistency by lowering surface tension, which facilitates penetration of water into the feces. The surfactants may also act on the intestinal wall to (1) inhibit fluid absorption and (2) stimulate secretion of water and electrolytes into the intestinal lumen. In this respect, surfactants resemble the stimulant laxatives (see later). • Preparations, Dosage, and Administration The surfactant family consists of two docusate salts: docusate sodium and docusate calcium. (The dosage for docusate sodium [Colace], the prototype surfactant, is shown in Table 63.4.)Administration should be accompanied by a full glass of water. (3) Stimulant laxatives The stimulant laxatives (e.g., bisacodyl, senna, castor oil) have two effects on the bowel. First, they stimulate intestinal motility—hence their name. Second, they increase the amount of water and electrolytes within the intestinal lumen by increasing secretion of water and ions into the intestine and by reducing water and electrolyte absorption. Most stimulant laxatives are group II agents: they act on the colon to produce a semifluid stool within 6 to 12 hours. Stimulant laxatives are widely used—and abused—by the general public and are of concern for this reason. They have few legitimate applications. Two applications that are legitimate are (1) treatment of opioid-induced constipation and (2) treatment of constipation resulting from slow intestinal transit. o Bisacodyl [Correctol, Dulcolax] is unique among the stimulant laxatives in that it can be administered by rectal suppository as well as by mouth. Oral bisacodyl acts within 6 to 12 hours. Hence tablets may be given at bedtime to produce a response the following morning. Bisacodyl suppositories act rapidly (in 15–60 minutes). Dosages for bisacodyl are shown in Table 63.4. Bisacodyl tablets are enteric coated to prevent gastric irritation. Accordingly, patients should be advised to swallow them intact, without chewing or crushing. Because milk and antacids accelerate dissolution of the enteric coating, the tablets should be administered no sooner than 1 hour after ingesting these substances. Bisacodyl suppositories may cause a burning sensation and, with continued use, proctitis may develop. Accordingly, long- term use should be discouraged. o Anthraquinones act on the colon to produce a soft or semifluid stool in 6 to 12 hours. Systemic absorption followed by renal secretion may impart a harmless yellow- brown or pink color to the urine. o Castor oil is the only stimulant laxative that acts on the small intestine. As a result, the drug acts quickly (in 2–6 hours) to produce a watery stool. Hence, unlike other stimulant laxatives, which are all group II agents, castor oil belongs to group I. Use of castor oil is limited to situations in which rapid and thorough evacuation of the bowel is desired (e.g., preparation for radiologic procedures). The drug is far too powerful for routine treatment of constipation. Because of its relatively prompt action, castor oil should not be administered at bedtime. The drug has an unpleasant taste that can be improved by chilling and mixing with fruit juice. (4) Osmotic laxatives. (Representative drugs are shown in Table 63.2.) o Laxative Salts Actions and Uses The laxative salts (e.g., sodium phosphate, magnesium hydroxide) are poorly absorbed salts whose osmotic action draws water into the intestinal lumen. Accumulation of water causes the fecal mass to soften and swell, thereby stretching the intestinal wall, which stimulates peristalsis. When administered in low doses, the osmotic laxatives produce a soft or semifluid stool in 6 to 12 hours. In high doses, these agents act rapidly (in 2–6 hours) to cause a fluid evacuation of the bowel. High-dose therapy is employed to empty the bowel in preparation for diagnostic and surgical procedures. High doses are also employed to purge the bowel of ingested poisons and to evacuate dead parasites after anthelmintic therapy. Preparations We have two groups of laxative salts: (1) magnesium salts (magnesium hydroxide, magnesium citrate, and magnesium sulfate) and (2) one sodium salt (sodium phosphate). (Dosages for magnesium hydroxide solution (also known as milk of magnesia) and sodium phosphate are shown in Table 63.4.) Adverse Effects Osmotic laxatives can cause substantial loss of water. To avoid dehydration, patients should increase fluid intake. Although the osmotic laxatives are poorly and slowly absorbed, some absorption does take place. In patients with renal impairment, magnesium can accumulate to toxic levels. Accordingly, magnesium salts are contraindicated in patients with kidney disease. Sodium absorption (from sodium phosphate) can cause fluid retention, which in turn can exacerbate heart failure, hypertension, and edema. Accordingly, sodium phosphate is contraindicated for patients with these disorders. Sodium phosphate can also cause acute renal failure in vulnerable patients, especially those with kidney disease and those taking drugs that alter renal function (e.g., diuretics, angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers 1708 [ARBs]). The mechanism involves dehydration and precipitation of calcium and phosphate in renal tubules. Accordingly, sodium phosphate should be avoided in this vulnerable group. o Polyethylene Glycol Polyethylene glycol (PEG) [MiraLax, GlycoLax, Peglax Polyethylene Glycol Polyethylene glycol (PEG) is an osmotic laxative used widely for chronic constipation. Like the laxative salts, PEG is a nonabsorbable compound that retains water in the intestinal lumen, causing the fecal mass to soften and swell. The most common adverse effects are nausea, abdominal bloating, cramping, and flatulence. High doses may cause diarrhea. For management of chronic constipation, PEG is superior to lactulose with regard to relief of abdominal pain and improvements in stool consistency and frequency per week, although side effects are similar. The recommended dosage is 17 g once a day, dissolved in 4 to 8 ounces of water, juice, soda, coffee, or tea. Bowel movement may not occur for another 2 to 4 days. As discussed later, products that contain PEG plus electrolytes can be used to cleanse the bowel before colonoscopy and other procedures. o Lactulose Lactulose [Constulose, Enulose] is a semisynthetic disaccharide composed of galactose and fructoseLactulose. is poorly absorbed and cannot be digested by intestinal enzymes. In the colon, resident bacteria metabolize lactulose to lactic acid, formic acid, and acetic acid. These acids exert a mild osmotic action, producing a soft, formed stool in 1 to 3 days. Although lactulose can relieve constipation, this agent is more expensive than equivalent drugs (bulk-forming laxatives) and causes more unpleasant side effects (flatulence and cramping are common).Accordingly, lactulose should be reserved for patients who do not respond adequately to a bulk-forming agent. In addition to its laxative action, lactulose can enhance intestinal excretion of ammonia. This property has been exploited to lower blood ammonia content in patients with portal hypertension and hepatic encephalopathy secondary to chronic liver disease. o Other Lubiprostone Lubiprostone [Amitiza] is the first representative of a new class of drugs: the selective chloride channel activators. By activating (opening) chloride channels in epithelial cells lining the intestine, lubiprostone (1) promotes secretion of chloride-rich fluid into the intestine and (2) enhances motility in the small intestine and colon. The result is spontaneous evacuation of a semisoft stool, usually within 24 hours. Lubiprostone has three indications: (1) chronic idiopathic constipation in adults, (2) irritable bowel syndrome with constipation (IBS-C) in women at least 18 years old, and (3) treatment of opioid-induced constipation in chronic noncancer pain. Mineral oil is a mixture of indigestible and poorly absorbed hydrocarbons. Laxative action is produced by lubrication. Mineral oil is especially useful when administered by enema to treat fecal impaction. Mineral oil can produce a variety of adverse effects. Aspiration of oil droplets can cause lipid pneumonia. Anal leakage can cause pruritus and soiling. Systemic absorption can produce deposition of mineral oil in the liver. Excessive dosing can decrease absorption of fat-soluble vitamins. (Dosages for adults and children are shown in Table 63.4.) Glycerin Suppository Glycerin is an osmotic agent that softens and lubricates inspissated (hardened, impacted) feces. The drug may also stimulate rectal contraction. Evacuation occurs about 30 minutes after suppository insertion. Glycerin suppositories have been useful for reestablishing normal bowel function after termination of chronic laxative use. From a clinical perspective, it can be useful to classify laxatives according to therapeutic ef ect (time of onset and effect on stool consistency). When these properties are considered, most laxatives fall into one of three groups, labeled I, II, and III in this chapter. Group I agents act rapidly (within 2–6 hours) and give a watery consistency to the stool. Laxatives in group I are especially useful when preparing the bowel for diagnostic procedures or surgery. Group II agents have an intermediate latency (6–12 hours) and produce a stool that is semifluid. Group II agents are the ones most frequently abused by the general public. Group III laxatives act slowly (in 1–3 days) to produce a soft but formed stool. Uses for this group include treating chronic constipation and preventing straining at stool. (Representative members of groups I, II, and III are shown in Table 63.3) Fiber facilitates colonic function in two ways. First, fiber absorbs water, thereby softening the feces and increasing their mass. Second, fiber can be digested by colonic bacteria, whose subsequent growth increases fecal mass. The best source of fiber is bran. Fiber can also be obtained from fruits and vegetables. Ingestion of 20 to 60 g of fiber a day should optimize intestinal function. • Therapy for various gastrointestinal disorders including antiemetics, ulcers, irritable bowel syndrome, Crohn’s ulcerative colitis (ie; alosetron, PPIs like omeprazole, Mesalamine, ranitidine, etc.) IRRITABLE BOWEL SYNDROME (IBS) is the most common disorder of the GI tract, IBS is a GI disorder characterized by crampy abdominal pain—sometimes severe—occurring in association with diarrhea, constipation, or both. Formally, IBS is defined by the presence, for at least 12 weeks in the past year, of abdominal pain or discomfort that cannot be explained by structural or chemical abnormalities and that has at least two of the following features: • Pain is relieved by defecation. • Onset was associated with a change in frequency of stool. • Onset of pain occurred in association with a change in stool consistency (from normal to loose, watery, or pellet-like). IBS has four major forms, characterized as follows: