Beta 2 Receptor Agonists Exam Questions PDF

Beta 2 Receptor Agonists Bind to β2 smooth muscle cells in the airway - Stimulates smooth muscle cell relaxation causing bronchodilation via cyclic AMP pathway - Inhibits release of hypersensitivity mediators -- especially from mast cells All have some β1 receptor activity which caus...

Beta 2 Receptor Agonists Bind to β2 smooth muscle cells in the airway - Stimulates smooth muscle cell relaxation causing bronchodilation via cyclic AMP pathway - Inhibits release of hypersensitivity mediators -- especially from mast cells All have some β1 receptor activity which causes many of the side effects Beta 2 Receptor Agonists Pharmacokinetics - Absorbed from the bronchi - Metabolized in the liver - Excreted in the urine Come in multiple forms and delivery systems Side effects -- tachycardia, tremors Precautions -- monitor when used in patients with arrythmias, cardiovascular disease, hyperthyroidism - Beta 2 Receptor Agonists Short Acting Beta Agonists (SABA) - 4-6 hours - Albuterol -- Proair, Ventolin, Proventil - Levalbuterol - Xopenex - Pirbuterol - Maxair - Tirbutaline -- Brethine Long Acting Beta Agonists (LABA) -- 12 hours - Salmeterol - Serevent - Fomoterol - Foradil - Arfomoterol -- Brovana Ultra Long Acting Beta Agonists (ULABA) -- 24 hours - Indacaterol -- Arcapta Neohaler - Olodaterol -- Striverdi Respimat - Vilanterol -- Breo Ellipta (in combination with ICS only) - Inhaled Anticholinergics Block muscarinic cholinergic receptors by antagonizing acetylcholine - Decreases formation of cyclic GMP → decreased contractility of smooth muscle of the lungs Pharmacokinetics - Poorly absorbed from lungs and GI tract - 90% of dose is swallowed and excreted in feces - 10% is metabolized by hydrolysis - Inhaled Anticholinergics Side effects -- dry mouth, cough, headache Precautions - Avoid in patients with urinary retention or BPH and closed-angle glaucoma - Should not be used for acute bronchospasm unless in combination with albuterol Inhaled Anticholinergics Short Acting Muscarinic Antagonists (SAMA) -- 4 -- 6 hours - Ipratropium bromide -- Atrovent - Ipratropium bromide/albuterol -- Combivent Long Acting Muscarinic Antagonists (LAMA) - Tiotroprium bromide -- Spiriva Handihaler and Spiriva Respimat -- 24 hours - Aclidinium bromide -- Tudorza Pressair -- 12 hours - Umeclidinium bromide -- Incruse Ellipta -- 24 hours - Revefenacin -- Yupelri -- 24 hours + - first long acting nebulized LAMA - Inhaled Anticholinergics Long Acting Muscarinic Antagonists - Glycopyrrolates - Preferentially bind to M3 receptors which are the primary muscarinic receptor involving bronchoconstriction in COPD - Glycopyrronium bromide - Seebri Neohaler -- 12 hours - Breztri (in combination with LABA and ICS) - Methylxanthines Theophylline - Inhibit phosphodiesterases that lead to an increase in cyclic AMP - Bronchial smooth muscle relaxation - Pulmonary vessel relaxation Pharmacokinetics - Well and fully absorbed orally - Very little first pass effect - Metabolized in liver - Methylxanthines Side effects -- headache, irritability, gastric irritation, n/v Multiple drug interactions Requires monitoring with serum drug levels to prevent toxicity - Inhaled Corticosteroids - Inhibit IgE and mast cell mediated migration of inflammatory cells into bronchial mucosa - Late-phase allergic reaction - Pharmacokinetics - Rapidly absorbed from lungs and GI tract - Less than one-fourth of dose is deposited in the lungs - Swallowed portion undergoes extensive first pass metabolism - Excreted in urine and feces - Inhaled Corticosteroids - Come in multiple forms and delivery systems - Side effects -- xerostomia, hoarseness, mouth irritation, dysgeusia, oral candidiasis - Precautions -- - HPA suppression - High-dose ICS in children may inhibit growth - Contraindicated in status asthmaticus - Inhaled Corticosteroids - Highest to Lowest Potency - Fluticasone furoate DPI -- Arnuity Ellipta - Mometasone furoate DPI -- Asmanex Twisthaler - Fluticasone propionate DPI -- ArmonAir Digihaler and generic diskus formulation - Beclomethasone dipropionate -- QVAR RediHaler - Ciclesonide MDI -- Alvesco Inhalation Aerosol - Budesonide DPI -- Pulmicort Flexhaler - Leukotriene Modifiers - Leukotrienes are inflammatory mediators produced by eosinophils and mast cells that can lead to bronchospasm, airway hyperresponsiveness and vascular leakage - Leukotriene Receptor Agonists - Montelukast (Singulair) - Inhibits the cysteinyl leukotriene receptor → blocks action of LTD4 -- a component of SRS-A - 5-Lipoxygenase Pathway Inhibitors - Zileuton (Zyflo) - Inhibits 5-Lipoxygenase -- enzyme responsible for the formation of leukotrienes from arachidonic acid - Leukotriene Modifiers - Pharmacokinetics - Both groups are rapidly absorbed from the GI tract and highly protein bound - Both groups are extensively metabolized in the liver and excreted in the urine - Montelukast -- metabolized by CYP3A4 & CYP2C9 - Zileuton -- metabolized by CYP1A2, CYP2C9 & CYP3A4 - Side effects - Montelukast -- headache, sore throat - Zileuton - dyspepsia - Leukotriene Modifiers - Precautions/Contraindications -- both groups associated with neuropsychiatric events post-marketing including irritability, agitation, tremors, insomnia, depression and suicidality - Leukotriene Receptor Agonists - Should be avoided in patients with severe liver disease - Montelukast chewable tablets contain phenylalanine so are contraindicated in individuals with PKU - 5-Lipoxygenase Pathway Inhibitors - Contraindicated in patients with active liver disease - Antihistamines - Block the action of histamine by binding to H1 receptors - Decrease respiratory, vascular and GI smooth muscle constriction - Decrease capillary permeability - First generation -- bind non-selectively to central H1 receptors - Second generation -- selective for peripheral H1 receptors - Antihistamines - Pharmacokinetics - Well absorbed orally with wide volume of distribution - Metabolized in liver - Excreted in urine - Side effects -- sedation, dry mouth, blurred vision, tremors - Precautions - First generation - All on Beer's Criteria list - Can cause paradoxical CNS stimulation in young children - Contraindicated in patients with BPH, narrow angle glaucoma, newborns and premature infants - convulsions - Antihistamines - First generation - Diphenhydramine -- Benadryl - Chlorpheniramine -- Chlor-Trimeton - Hydroxyzine -- Atarax - Second generation - Cetirizine -- Zyrtec - Levocetirizine -- Xyzal - Loratadine -- Claritan - Desloratadine -- Clarinex - Fexofenadine - Allegra - Intranasal Antihistamines - Used for the treatment of seasonal allergic rhinitis and vasomotor rhinitis - Pharmacokinetics - Systemic oral bioavailability of 40% with high levels of protein binding - Metabolized into active metabolites and excreted in the feces - Side effects -- somnolence, nasal irritation, bitter taste - Azelastine (Astelin, Astepro) - Olopatadine (Patanase) - Nasal Corticosteroids - Mechanism of action and pharmacokinetics same as ICS - Side effects -- Nasal irritation, itching, sneezing, dryness, epistaxis - Fluticasone -- Flonase - Budesonide -- Rhinocort Aqua - Triamcinolone -- Nasacort AQ - Ciclesonide -- Omnaris - Mometasone - Nasonex - Decongestants - Used to relieve nasal congestion - Oral and topical (nasal spray) forms - Alpha-adrenergic receptor agonists - Stimulate alpha receptors of vascular smooth muscle, constricting dilated arterioles within the nasal mucosa - Pharmacokinetics - Oral - Pseudoephedrine - Well absorbed from GI tract - Widely distributed -- crosses blood-brain barrier - Partially metabolized in liver - Excreted in urine with up to 75% as an active metabolite - Topical - Unknown - Decongestants - Side effects - Oral -- anxiety, restlessness, tremors - Topical -- burning, stinging, dryness, sneezing - Contraindications -- Oral - Severe HTN, cardiovascular disease - Absolute contraindication -- patients on MAOIs - Should not be used/prescribed to children younger than 4 years of age - Precautions -- Topical - Should not be used in children younger than 6 years of age - Decongestants - Oral - Pseudoephedrine - Phenylephrine - Topical - Phenylephrine - Oxymetazoline - Tetrahydrozoline - Antitussives - Used to suppress cough -- but should be used judiciously - Nonopioids -- benzonatate, dextromethorphan - Dextromethorphan -- d isomer of codeine analogue that acts in medulla to increase cough threshold - Benzonatate -- chemically related to tetracaine that acts by anesthetizing the cough receptors in the lungs - Opioids - Codeine -- directly acts on receptors in the cough center of the medulla - Antitussives - Pharmacokinetics - All absorbed well from GI tract - Codeine widely distributed including CNS, distribution of others is unknown - Dextromethorphan -- extensively metabolized by liver and excreted in urine as metabolites - Codeine -- metabolized in liver and excreted in urine - Metabolism and excretion of benzonatate is unknown - Antitussives - Side effects/Precautions - Drowsiness, dizziness, nausea - Codeine and dextromethorphan -- may cause dependence - Antitussives should not be used in patients with respiratory disease who have chronic cough - Benzonatate is contraindicated in individuals who are allergic to any "caine" compound - Expectorants - Used to reduce the viscosity of thick sputum in the symptomatic treatment of cough due to respiratory infections - Guaifenesin -- only FDA approved expectorant - Thick bronchial secretions are composed of substances called mucins which are produced by goblet cells and submucosal glands located in the airways - Guaifenesin decreases mucin production from goblet cells and indirectly stimulates GI vagal afferent nerves that trigger reflex parasympathetic glandular secretion from submucosal glands and goblet cells increasing hydration of mucus layer for more effective mucociliary clearance. - Expectorants - Side effects/Precautions - GI upset -- n/v, diarrhea - Not recommended for coughs due to asthma, COPD, heart failure or ACE inhibitor therapy - Diuretics - First-line therapy in the management of HTN and HF → increased sodium and water retention resulting in ECF volume. - Diuretics reduce cardiac output by decreasing plasma volume - Over time these effects are reduced, but they do decrease peripheral resistance → decreased afterload and BP - Diuretics - Several classes of diuretics - Carbonic anhydrase inhibitors - Osmotic diuretics - Aldosterone antagonist/potassium-sparing diuretics - Loop diuretics - Thiazides - Diuretics - Side Effects/Precautions - Electrolyte imbalances -- hypokalemia, hypercalcemia, hyponatremia, hypomagnesemia - High sodium dietary intake exacerbates the potassium loss - Hypokalemia may cause metabolic alkalosis - Elevated uric acid - Glucose intolerance -- most likely with loop and thiazide diuretics - Directly linked to the potassium level - Diuretics - Side Effects/Precautions - Hypotension related to decreased fluid volume - Drug Interactions - multiple - Loop Diuretics - Inhibit sodium reabsorption in the ascending loop of Henle - Increases potassium excretion - Short acting but powerful diuretic - Large natriuresis - Pharmacokinetics - Well absorbed orally - Widely distributed - Metabolized by liver and excreted unchanged in urine - Thiazide Diuretics - Inhibit sodium reabsorption in the distal renal tubule - Increases potassium excretion - Longer lasting with less diuresis - Pharmacokinetics - Well absorbed orally - Widely distributed -- only diuretic to enter intracellular spaces so can be used in refractory edema - Metabolized by liver and excreted unchanged in urine - Thiazide Diuretics - Side Effects/Precautions - Hyperlipidemia -- elevations are transient - Photosensitive reactions -- can last years after discontinuing drug - Aldosterone Antagonists - Inhibit excretion in the distal tubule of the kidney - Weak diuretics - Most often used in combination with thiazide diuretics to decrease potassium loss - Pharmacokinetics - Absorption rates vary - Widely distributed - Metabolized by liver and excreted unchanged in urine - Aldosterone Antagonists - Side Effects/Precautions - Gynecomastia -- occurs in 50% of patients taking spironolactone - Impotence - Diuretics - Loop Diuretics - Furosemide - Bumetanide - Thiazide Diuretics - Chlorthalidone - Hydrochlorothiazide - Indapamide - Metolazone - Aldosterone Antagonists - Spironolactone - Triamterene - Amiloride - Eplerenone - References - **Laxatives** - **Stimulants** -- cascara, senna, bisacodyl, castor oil - **Osmotics** -- magnesium hydroxide, magnesium citrate, sodium phosphate, polyethylene glycol (PEG) 3350 - **Bulk-producing** -- psyllium, methylcellulose, polycarbophil - **Lubricants** -- mineral oil - **Surfactants** -- docusate medications (sodium, calcium, and potassium - **Hyperosmolar** -- glycerin, lactulose - **Chloride channel activators** -- lubiprostone - **Opioid receptor antagonists** -- methylnaltrexone **Notes re all laxatives:** - **Abuse potential/dependency** re the laxative (except for the bulk-producing laxatives) can lead to electrolyte alterations, fluid alterations, steatorrhea, osteomalacia, vitamin and nutrient deficiencies - **Tartrazine sensitivity** -- tartrazine can cause hypersensitivity reactions that may include bronchospasm (association with aspirin sensitivity) - All are contraindicated when nausea, vomiting, and/or abdominal pain of unknown cause are present, especially if bowel obstruction might be the cause - Some laxatives are contraindicated in pregnancy - **Laxatives (cont.)** - **Stimulants** - **Clinical uses:** constipation due to prolonged immobility or drug-caused constipation (such as with chronic opioid use), conditions causing reduced motility of the GI tract, neurogenic bowel (spinal cord injury), constipation-predominant IBS, and bowel prep for procedures - **Actions:** - Thought to possibly cause stimulation/irritation of the myenteric nerves along with irritation of intestinal smooth muscle increase in peristalsis - Increased prostaglandin release and an increase in cAMP concentration electrolytes undergo increased secretion peristalsis is stimulated - **Adverse effects:** - Diarrhea, flatulence, abdominal cramping, and bloating - Uterine contractions with castor oil do not use in pregnancy - Diarrhea in lactating infants due to cascara - **Important to remember:** - Cardiovascular disease is a relative contraindication to the use of bisacodyl - Cascara should not be used if the patient cannot ingest alcohol -- cascara contains some alcohol - Bisacodyl can be used in pregnancy - **Laxatives (cont.)** - **Osmotics** - **Clinical uses:** constipation and bowel prep - **Actions:** - Increased intraluminal pressure due to water being drawn more inside the intestines increase in peristalsis - **Adverse effects:** diarrhea, flatulence, abdominal cramping, and bloating - **Important to remember:** - Avoid the use of magnesium-containing laxatives in the setting of renal dysfunction since the kidneys may not be able to excrete the magnesium adequately hypermagnesemia may develop - Do not use magnesium-containing laxatives in the setting of cardiac dysrhythmias or conduction disturbances and do not use if the patient is hypocalcemic - PEG 3350 -- cautious use in the pediatric population - For all, caution re the use in pregnancy or lactation -- benefit to risk ratio should be positive - **Laxatives (cont.)** - **Bulk-producing** - **Clinical uses:** long term therapy for simple, chronic constipation; use in chronic, watery diarrhea to bulk the stool - **Actions:** act physiologically like increased fiber in the diet would by combining with water in the intestines mechanical distention of the intestinal wall increased peristalsis - **Adverse effects:** diarrhea, flatulence, abdominal cramping, and bloating -- these dissipate with time, usually - **Important to remember:** - Some may be contraindicated in clinical settings where either salt or sugar is restricted since some preparations contain these substances - Cautious use in settings where there may be strictures or other narrowing of the esophagus or intestine - Contraindicated if there is a bowel impaction (feces cannot get around the impacted stool) - Pregnancy -- can be used safely - **Laxatives (cont.)** - **Lubricants** - **Clinical uses:** used to soften impacted stool (mineral oil the main component of these laxatives) - **Actions:** more water is retained in the stool stool softening occurs; lubrication to help stool move more easily via the presence of mineral oil - **Adverse effects:** - Diarrhea, flatulence, abdominal cramping, and bloating - Decreased absorption of fat-soluble vitamins if used chronically - Lipid pneumonia if aspirated -- avoid in the very young and in any patient who is at risk of aspiration (e.g., someone who has had a stroke that affected swallowing) - **Important to remember:** - Avoid use in pregnancy since fat-soluble vitamins may not be absorbed as well deficiencies in the newborn such as those related to vitamin K that may cause hypoprothrombinemia - **Laxatives (cont.)** - **Surfactants -- stool softeners** - **Clinical uses:** used to soften stool and prevent constipation, especially stool that is dry and difficult to evacuate and when straining at stool must be stopped - **Actions:** assist with lipids and water being mixed into stool stool becomes softened - **Adverse effects:** - Diarrhea, flatulence, abdominal cramping, and bloating but usually well-tolerated and are without precautions or contraindications - **Important to remember:** - Okay to use in pregnancy - **Laxatives (cont.)** - **Hyperosmolar laxatives** - **Clinical uses:** fecal impaction and those with neurogenic bowel (glycerin); chronic constipation and increased excretion of ammonia in the stool \[therapy for hepatic encephalopathy re the latter\] (lactulose) - **Actions:** - Glycerin -- local colonic irritation and more water is drawn into the stool stool becomes more fluid - Lactulose -- bacteria the gut transform this disaccharide into lactic, acetic, and formic acids water is drawn into the stool stool becomes more fluid - **Adverse effects:** - Diarrhea, flatulence, abdominal cramping, and bloating - Fluid losses which can be particularly significant in older patients - Hyperglycemia with lactulose - Avoid glycerin in pregnancy; use lactulose only when benefits outweigh any risks to fetus or mother - Avoid use in lactating mothers - **Important to remember:** - Older patient population most at risk for dehydration due to intravascular volume depletion with these drugs - Monitor blood sugars in those taking lactulose chronically and monitor acutely in those with diabetes mellitus - **Laxatives (cont.)** - **Chloride channel activators** - **Clinical uses:** chronic constipation due to unknown cause and due to IBS; opioid-induced constipation - **Actions:** - Activation of CIC-2 chloride channels of the intestinal epithelium more chloride is secreted this increased chloride then helps to soften the feces and improve intestinal movement - **Adverse effects:** - Diarrhea, flatulence, abdominal cramping, and bloating - Nausea -- avoid by giving the drug with a meal - Dyspnea - **Important to remember:** - Avoid use in pregnancy - **Laxatives (cont.)** - **Opioid Receptor Antagonists** - **Clinical uses:** chronic constipation due to opioids - **Actions:** - Antagonist at the mu-opioid receptors in the gut speeds up peristalsis - No analgesia -- does not cross the blood-brain barrier (BBB) to exert any effects - **Adverse effects:** - Diarrhea, flatulence, abdominal cramping, and bloating - Can cause an opioid withdrawal syndrome, especially if alterations of the BBB have occurred - **Important to remember:** - Monitor for opioid withdrawal if indicated - Monitor for abdominal pain since some patients with constipation might experience bowel rupture - **Antidiarrheals** - **Absorbent drugs** -- kaolin and pectin, bismuth subsalicylate - **Opiates** -- diphenoxylate with atropine, difenoxin with atropine, loperamide - **Drugs used to treat chronic diarrhea in inflammatory bowel disease (IBD)** -- Crohn disease and ulcerative colitis antidiarrheal drugs used include loperamide and anticholinergics - **Drugs used to treat IBS with chronic diarrhea** - We will focus on the first two classes of drugs **Clinical uses for antidiarrheals:** uncomplicated acute diarrhea; chronic diarrhea due to IBD; chronic diarrhea associated with pancreatic insufficiency; diarrhea-predominant irritable bowel syndrome (IBS); chronic infantile diarrhea; traveler's diarrhea - **Antidiarrheals (cont.)** - **Absorbent drugs** - **Actions:** - Kaolin and pectin -- pectin absorbs liquid in the stool and thus thickens the stool usually used for uncomplicated acute diarrhea - Bismuth subsalicylate -- antisecretory (salicylate portion), antiinflammatory, and antimicrobial (bismuth portion) actions - **Adverse effects** - Rebound constipation which can progress to serious impaction, especially in older adults - Discoloration of stool and tongue with bismuth - **Important to remember:** - Avoid bismuth subsalicylate (especially in pediatrics) in febrile viral conditions such as suspected influenza salicylate portion can precipitate Reye syndrome which can be life-threatening - Bismuth causes gray/black stools and black tongue advise patients, so they do not think they are undergoing GI bleeding - No significant data for safe use in pregnancy and lactation - Extremely cautious use in children under the age of 2 guidelines emphasize oral rehydration therapy and the avoidance of all antidiarrheals in the setting of diarrhea - **Antidiarrheals (cont.)** - **Opiates** - **Actions:** - Diphenoxylate and difenoxin (main active metabolite of diphenoxylate) with atropine -- no analgesia; atropine portion is antisecretory and slows peristalsis; risk of physical dependence with chronic use - Loperamide -- slowing of peristalsis by binding of the drug to opioid receptors in the intestines; bulking and increased thickness of the stool; reduction in fecal volume; prevention of fluid and electrolyte loss in the GI tract; used in mild cases of Crohn disease that is without any serious complications - **Adverse effects** - Rebound constipation which can progress to serious impaction, especially in older adults - Anticholinergic effects due -- dry mouth and eyes, urinary retention, etc. children esp. prone - Dizziness and drowsiness; headache - Toxic megacolon - **Important to remember:** - Cautious use in the older population (sedation and other anticholinergic effects with diphenoxylate and difenoxin) and avoid use in children, especially those with Down syndrome -- see above also - Avoid use in narrow angle glaucoma and any urinary obstruction (e.g., BPH) - Do not use diphenoxylate and difenoxin in intestinal infections can worsen the conditions - **Antidiarrheals (cont.)** - **Drugs used to treat chronic diarrhea in IBS** - Loperamide - Eluxadoline -- mu and kappa opioid receptor agonist and delta opioid receptor antagonist; avoid use in those with a history of biliary disorders, pancreatitis, severe liver impairment, and heavy alcohol use - Alosetron -- selective 5-HT3 receptor antagonist decreased intestinal motility and secretions and a decrease in any associated abdominal pain; for females with diarrhea-predominant IBS not responsive to other therapies - **Antiemetics** - **Antihistamines** -- dimenhydrinate, diphenhydramine, hydroxyzine, meclizine - **Phenothiazines** -- prochlorperazine, perphenazine, promethazine - **Sedative-hypnotics** - **Cannabinoids** - dronabinol - **5-HT3 receptor antagonists** -- palonosetron, ondansetron, dolasetron mesylate, granisetron - **Anticholinergics** - scopolamine - **Substance P/neurokinin 1 (NK1) receptor antagonist** -- aprepitant - **Miscellaneous** - trimethobenzamide - **Antiemetics (cont.)** - **Antihistamines** - **Clinical uses:** most useful for motion sickness N/V due to slowing of neuronal communication in the vestibulocerebellar areas - **Actions:** - Bind to histamine-1 receptors decreased secretions in the mouth and eyes - Bind to central cholinergic receptors which causes decreased N/V - **Adverse effects** - Anticholinergic effects -- avoid in the older adult population - Unexpected agitation in the pediatric population as opposed to sedation in adults - **Important to remember** - Avoid in hepatic dysfunction (liver metabolism) - Assess benefit to risk ratio in pregnancy and lactation (true for all antiemetics) - **Antiemetics (cont.)** - **Phenothiazines** - **Clinical uses:** prevent and treat N/V - **Actions:** - Antagonist at dopamine receptors in the chemoreceptor trigger zone (CTZ) (bind at multiple other receptors as well) decreased nausea and vomiting - **Adverse effects** - EPS -- highest risk in the pediatric population - Sedation and other anticholinergic effects - Respiratory depression in the pediatric population (Black Box Warning) - Agranulocytosis with long term use (four months or more) - **Important to remember** - Contraindicated in Parkinson disease - Contraindicated in narrow-angle glaucoma, bone marrow depression, cardiovascular disease - Cough reflex is decreased -- might cause problems in those with lung disease such as chronic bronchitis-caused COPD or those prone to aspiration (cannot protect airway as well) - Most adverse effects are not as likely with only short-term use - Avoid use in pregnancy - Alert patients that their urine may change color -- pink to reddish-brown - **Antiemetics (cont.)** - **Cannabinoids** - **Clinical uses:** treat N/V due to chemotherapy when other agents have failed; appetite stimulation - **Actions:** - Action at cannabinoid receptors centrally - **Adverse effects** - THC-like adverse effects - Euphoria, but depression can also occur - Increase in sensory experience/level - Unusual thoughts and problems with concentration - Memory alterations - Loss of time - Seizures can be precipitated due to lowering of the seizure threshold - Cardiovascular: palpitations, tachycardia, and hypotension - **Important to remember** - Avoid in patients with a history of hypersensitivity to any of the ingredients, including sesame oil - Avoid in patients with a history of seizures - Avoid in patients with cardiovascular disease - Patients may abuse the drug due to its effects - **Antiemetics (cont.)** - **5-HT3 receptor antagonists** - **Clinical uses:** pretreatment to prevent chemotherapy-induced N/V - **Actions:** - Serotonin receptor blockade peripherally and centrally so that the enhanced release of serotonin due to chemotherapy is blocked - **Adverse effects** - Constipation or diarrhea - Headache - Fatigue and dizziness - Rare potential cardiovascular adverse effects: tachy- or bradycardias; hypotension, QTc prolongation; hypotension - **Important to remember** - May make ileus asymptomatic so that it becomes more serious and life-threatening - Aspartame is in the orally disintegrating tablets so avoid in patients with phenylketonuria (PKU) - Can be used in pregnancy - **Antiemetics (cont.)** - **Anticholinergics** - **Clinical uses:** prevention of N/V due to motion sickness - **Actions:** - Scopolamine - Bella donna alkaloid anticholinergic acts in the parasympathetic nervous system as an antagonist at muscarinic receptors - May also block transmission of signals from the cholinergic nerves in the reticular center to the vomiting center (CNS) - Decreased salivation - Decreased GI motility - **Adverse effects** - Anticholinergic effects - Cautious use or avoid in older patients due to the anticholinergic effects, especially sedation and risk of falls with serious injury - **Important to remember** - Avoid use in pregnancy - Contraindicated in narrow-angle glaucoma due to its anticholinergic effects; cautious use in open-angle glaucoma - Cautious use or avoid in patients with conditions that might turn into urinary obstruction (BPH, urinary bladder neck obstruction) and those who have risk factors for bowel obstruction - Mydriasis may affect vision significantly and cause light sensitivity avoid activities where clear vision is imperative such as driving and wear sunglasses, respectively caution patients - **Antiemetics (cont.)** - **Substance P/neurokinin 1 (NK1) receptor antagonist** - **Clinical uses:** prevention of N/V due to chemotherapy - **Actions:** - Blockade of the substance P/neurokinin 1 receptor used as adjunctive therapy with the 5-HT3 receptor antagonists and dexamethasone - **Adverse effects** - Fatigue, dizziness, and hiccups - Elevation of AST, ALT, and BUN - **Important to remember** - Contraindicated with a history of hypersensitivity to any part of the formulation (same for all pharmacologic agents) - Inhibitor of CYP3A4: many drug-drug interactions are possible - Avoid use in pregnancy - Use not approved in the pediatric population - **Antiemetics (cont.)** - **Miscellaneous** - trimethobenzamide - **Clinical uses:** therapy to treat N/V - **Actions:** - The CTZ is inhibited from inducing N/V from the central vomiting center due to its antagonist action on dopamine-2 receptors - **Adverse effects** - CNS -- depression and EPS; headache - IV administration -- hypotension - Diarrhea - **Important to remember** - Not as efficacious as other drug classes - Gastrointestinal Drug Pharmacology - First review the normal biology and physiology of the gastrointestinal system, the pathophysiology of diseases and conditions of the system, and then study the therapy for these diseases and conditions. - Goals of GERD Therapy - Prevent or decrease symptoms - Heal esophagitis or any erosive esophageal lesions - Prevent complications, including those that might be life-threatening such as esophageal carcinoma - Prevent recurrent symptoms - **Nonpharmacologic Therapy for GERD** - Avoid all foods or drinks that cause symptoms - Do not overeat and avoid bending over and strenuous exercise for three hours after ingesting anything - Avoid lying supine for three hours after ingesting anything (food or drink) - Elevate the head of the bed at night or if lying down otherwise - Weight loss to ideal body weight - Smoking cessation - **Drugs used to treat GERD** - **Antacids** -- can be used as adjunctive therapy for frequent symptoms, as needed, and for non frequent symptoms as needed - **Proton pump inhibitors** (PPIs) are considered first line therapy for most patients with frequent GERD symptoms or other serious complications (e.g., esophagitis) - **Histamine-2 receptor antagonists** (H2RAs) are used to treat GERD as well but not first line in most cases - **Drugs that improve lower esophageal sphincter (LES) tone** -- used adjunctively with a drug that is suppressing the production of hydrochloric acid (HCl) - **Prokinetic agents** -- serious potential adverse effects so reserved for use in those who still experience symptoms after maximal acid suppression therapy and maximal lifestyle modifications - **Cytoprotective agents** -- usually, only used in PUD since they affect the gastric mucosa see the PUD material - **Drugs used to treat GERD (cont.)** - **Antacids** - **Clinical uses:** GERD, PUD, hypersecretory states, hyperphosphatemia, calcium deficiency - **Actions:** - Weak bases that form salt and water when they interact with hydrochloric acid (HCl), thus neutralizing HCl and elevating gastric and duodenal bulb pH; they include a metallic cation plus basic anion - Inhibit pepsin's proteolytic activity - Improve lower esophageal sphincter (LES) tone - Slow gastric motility via inhibition of smooth muscle contraction locally in the stomach -- just the aluminum-based antacids - Used in renal failure to bind phosphates and lower blood phosphate levels -- calcium-and aluminum-based antacids - **Adverse effects:** - Constipation with aluminum- and calcium-based antacids - Diarrhea with magnesium-based antacids - Alkalosis -- usually, only in patients with renal failure - **Drugs used to treat GERD (cont.)** - **Antacids (cont.)** - **Important to remember:** - Not used as monotherapy for significant disease (e.g., esophagitis) or frequent symptoms - Can be used as needed in concert with an acid suppressive drug - Do not use if a patient's gastrointestinal symptoms' cause has not been elucidated -- e.g., in the setting of severe abdominal pain of undetermined cause - Do not use calcium-based antacids in the setting of hypercalcemia or with a patient history of renal stones - Do not use magnesium- or aluminum-based antacids in the setting of renal failure hypermagnesemia and worsened osteomalacia can be the results, respectively - Do not use high sodium-containing antacids in settings where fluid overload will exacerbate a condition -- e.g., HFrEF, HTN, and RF - Many drug interactions re absorption -- check the drug information if prescribing with an antacid - Caution patient to call if symptoms continue or worsen within two weeks and if new symptoms arise - **Drugs used to treat GERD (cont.)** - **Proton pump inhibitors (cont.)** - **Clinical uses:** GERD, PUD, hypersecretory states such as Zollinger-Ellison syndrome - **Actions:** - Suppression of gastric acid secretion by parietal cells by preventing the H+/K+-ATPase enzyme system from secreting hydrogen ion needed to form hydrochloric acid (HCl) very effective and can result in achlorhydria (no gastric acid) - Less gastric acid results in: - Decrease of blood flow to the gastric antrum, pylorus, and duodenal bulb - Increase in pepsinogen levels - Decrease in pepsin activity - Increase in gastrin levels (compensatory) no clinically significant effects known - **Drugs used to treat GERD (cont.)** - **Proton pump inhibitors (cont.)** - **Adverse effects -- usually, well-tolerated in the short term:** - GI symptoms: nausea, abdominal pain, flatulence, constipation or diarrhea - Dizziness and drowsiness - Acute interstitial nephritis - Long term use: - Nutrient deficiencies: iron, magnesium, vitamin B12, and calcium - Potential risk for hip fracture - Chronic and acute kidney disease -- chronic kidney disease (CKD) and acute kidney injury (AKI) - Increased risk of infections such as *Clostridioides difficile* and even short-term use increases the risk of pneumonia - Concern that they are a risk for gastric cancer (chronic atrophic gastritis association) - Potential association between PPIs and the development of dementia more data is needed - Potential increased risk of overall mortality more study is needed - **Drugs used to treat GERD (cont.)** - **Proton pump inhibitors (cont.)** - **Important to remember:** - Contraindicated with a history of hypersensitivity - Cautious use in the setting of hepatic dysfunction - Cautious use in older patients - Avoid in pregnancy unless needed (must have a favorable benefit to risk ratio) - Cautious use only in lactating patients - Some drugs within the class have shown efficacy and safety in the pediatric population - Any drug therapy must be combined with ongoing lifestyle modifications - If response to therapy is not adequate, check for compliance with medication and with lifestyle modifications - **Drugs used to treat GERD (cont.)** - **Histamine-2 Receptor Antagonists (H2RAs)** - **Clinical uses** (PPIs preferred in almost all instances)**:** GERD, with or without erosive esophagitis; PUD; hypersecretory states - **Note:** ranitidine is no longer available in the U.S. due to nitrosodimethylamine (NDMA) being found within the formulations (NDMA a likely human carcinogen) - **Actions:** - Blockade of the histamine-2 receptor on gastric parietal cells less HCl is produced, and the pH of the gastric juices increases toward a more alkaline state - Drugs within the class have varying effects on: - The volume of gastric secretions and hydrogen ion concentration (famotidine most potent at lowering gastric acid secretion but, unclear if any clinical benefit) - Speed of gastric emptying - LES pressure - Level of postprandial and fasting serum gastrin levels - **Drugs used to treat GERD (cont.)** - **Histamine-2 Receptor Antagonists (H2RAs) (cont.)** - **Adverse effects:** - Antiandrogenic: gynecomastia and erectile dysfunction (usually seen with cimetidine) - Cardiac: potential rhythm and conduction abnormalities with both oral and IV forms - CNS: alterations of cognitive function, agitation, psychosis, depression, headache, seizures -- avoid use in the older population re cognition effects, and these CNS adverse effects tend to occur in those with renal and/or hepatic dysfunction - Hematologic: individual cell line deficiencies to pancytopenia -- rare but monitor with CBC - GI: constipation or diarrhea, nausea, hepatic cell injury with nizatidine (avoid in those with a history of liver disease or those at risk for it) monitor LFTs - Vitamin B12 deficiency with long term use monitor vitamin B12 levels and CBC, and the patient's course (deficiency can cause anemia and neurologic deficits) - Immune-related: polymyositis, nephritis, immune-related rashes - Fever - **Drugs used to treat GERD (cont.)** - **Histamine-2 Receptor Antagonists (cont.)** - **Important to remember:** - They do not block the histamine-1 receptors so are not anticholinergic - Not well-studied in pregnancy so avoid use always weigh the benefit to risk ratio when prescribing in pregnancy - Avoid use in lactation, evaluating the benefit to risk ratio in this clinical situation as well - Pediatrics: can be used - **Drugs used to treat GERD (cont.)** - **Drugs that improve lower esophageal sphincter (LES) tone and some that have prokinetic activity** - **Metoclopramide** -- used for lower tiers of therapy due to serious adverse effects (EPS -- younger age a higher risk factor for this) possible and not used as monotherapy; mostly used for gastroparesis therapy re GI disorders -- prokinetic properties; no healing of esophageal lesions - **Bethanechol** -- used for lower tiers of therapy and not as monotherapy; mostly used for gastroparesis therapy re GI disorders -- prokinetic properties; no healing of esophageal lesions - **Antacids** -- improve LES tone in addition to increasing gastric pH - **Drugs used to treat PUD** - **Goals of therapy** - Elimination of *Helicobacter pylori* (main cause of PUD) - Reduction or elimination of any symptoms - Healing of ulcer lesions - Avoidance of complications such as bleeding and perforation; carcinoma - Prevention of recurrent disease - **Drugs used to treat PUD** - **Antisecretory medications: PPIs** (H2RAs rarely used because the PPIs are much more effective at gastric acid suppression) -- see the GERD material re PPI information - **Anti-*H. pylori* antimicrobials: clarithromycin, amoxicillin, metronidazole, tetracycline, doxycycline, nitazoxanide, levofloxacin, bismuth subsalicylate** in various three- and four-drug combinations with PPIs microbial resistance to antibiotics may cause treatment failure - **Cytoprotective agents:** - **Sucralfate** - Binds to the ulcer site to shield the area from HCl, pepsin, and bile salts; safety not established in children - **Misoprostol** - Inhibits formation of cAMP that occurs due to histamine stimulation inhibition of gastric acid secretion; promotes gastric mucus formation and production of bicarbonate - Mucosal protection from HCl, etc. - Induction of uterine contractions *absolutely contraindicated in pregnancy if pregnancy termination is not desired* - Cautious use in renal dysfunction - Safety not established in patients less than 18 years of age - Primarily used for prevention of NSAID-induced PUD