RXRS-302 Study Guide 3 PDF

Week 9: Understanding the different types of anemia and roles of treatments for anemia Background: Most common blood disorder is anemia and it affects over 3 million Americans Anemia is a decrease in hemoglobin (Hgb) and hematocrit (Hct) concentrations below the normal range for age and gender Eryth...

Week 9: Understanding the different types of anemia and roles of treatments for anemia Background: Most common blood disorder is anemia and it affects over 3 million Americans Anemia is a decrease in hemoglobin (Hgb) and hematocrit (Hct) concentrations below the normal range for age and gender Erythropoiesis: Hgb is an iron-rich protein found in red blood cells (RBCs) ○ Carries oxygen from lungs to tissues RBCs are formed from bone marrow ○ Take up Hgb and iron from bone marrow ○ Released into circulation as immature RBCs (Reticulocytes) After 1 to 2 days, reticulocytes mature into erythrocytes ○ Lifespan of 120 days Erythrocytes are removed from circulation by macrophages, mainly in the spleen Anemia: Impaired RBC production ○ increased RBC destruction (hemolysis) or blood loss Decreased Hgb or RBC volume ○ decreased oxygen carrying capacity of the blood Caused by: ○ Nutritional deficiencies Such as iron, folate, vitamin B12 ○ Chronic kidney disease ○ Malignancy Symptoms of Anemia: Fatigue Weakness Shortness of breath Exercise intolerance Headache Dizziness Anorexia Pallor Pica Types of Anemia: Low Hgb/Hct Signs and Symptoms of Anemia – > Check mean corpus volume: 1. MCV < 80 fL Microcytic caused by iron deficiency 2. MCV 80-100 fL Normocytic caused by acute blood loss, malignancy, CKD, bone marrow failure (aplastic anemia), hemolysis 3. MCV > 100 fL Macrocytic caused by Vitamin B12 or folate deficiency Mean Corpuscular Volume: Mean Corpuscular Volume (MCV) reflects size or average volume of RBCs ○ Low MCV means RBCs are smaller than normal (microcytic) ○ High MCV means RBCs are larger than normal (macrocytic) Common Laboratory Tests in Anemia: Iron Studies ○ Serum iron (bound to transferrin) - LOW ○ Serum ferritin (iron stores) - LOW ○ Transferrin saturation (amount of transferrin binding sites occupied by iron) - LOW ○ Total iron binding capacity (amount of transferrin binding sites available to bind iron or unbound sites) - HIGH Vitamin B12 and folate levels ○ Vitamin B12 is required for enzyme reactions involving methylmalonic acid (MMA) and homocysteine ○ High MMA levels indicate vitamin B12 deficiency, excessive MMA production due to vitamin B12 deficiency ○ High homocysteine indicate vitamin B12 deficiency in breaking down homocysteine to create other essential chemicals for the body 1. Iron Deficiency Anemia: Sources of Iron: Dietary Iron ○ Heme Iron found in meat and Seafood ○ Non-heme iron found in nuts, beans, vegetables, fortified grains (i.e. cereal) ○ Heme iron is more readily absorbed compared to non-heme iron Thus those with a vegetarian diet may need iron supplementation Causes of Iron Deficiency: Inadequate dietary intake: ○ Iron-poor diets (e.g., vegetarian, vegan), malnutrition, disease related (e.g., dementia, psychosis) Blood loss ○ Acute (e.g., GI hemorrhage) ○ Chronic (e.g., heavy menses, blood donations) ○ Drug-induced (e.g., NSAIDS, steroids, anticoagulants) Decreased iron absorption ○ High gastric pH (e.g., PPIs), GI diseases Increased iron requirements Pregnancy, lactation, infants, rapid growth (e.g, adolescence) Symptoms of Iron Deficiency Anemia: Inflamed sore tongue Thin, concave spoon-shaped nails Soreness and cracking of corners of the mouth Craving and eating non-foods such as chalk or clay Treatments for iron deficiency anemia: Oral Iron Therapy ○ Ferrous gluconate (12% elemental iron) ○ Ferrous Sulfate (20% elemental iron) ○ Ferrous sulfate, dried (30% elemental iron) ○ Ferrous fumarate (33% elemental iron) ○ Carbonyl iron, polysaccharide iron complex, ferric maltol (100% elemental iron) Recommended dose: 150-180 mg elemental iron per day Divided in two to three doses per day Mechanisms of Action for Iron Therapy: Replaces iron found in hemoglobin, myoglobin, and other enzymes Which then allows transportation of oxygen via hemoglobin Alternative Treatments for Iron deficiency anemia: Intravenous (Parental) Iron ○ Increases Hgb faster than oral iron and reduces gastrointestinal issues seen with oral administration ○ Due to risk of more severe adverse reactions and cost, IV iron administration is limited to CKD on hemodialysis CKD receiving erythropoiesis-stimulating agents (ESAs) Unable to tolerate oral iron Losing iron too fast for oral replacement Alternative when blood transfusions not accepted ○ i.e. religious reasons IV (Parental) Iron Treatments: Iron Sucrose (Venofer) Ferumoxytol (Feraheme) Iron dextran complex (INFeD) Sodium ferric gluconate (Ferrlecit) Ferric carboxymaltose (Injectafer) Ferric derisomaltose (Monoferric) Ferric pyrophosphate citrate (Triferic) Notes: Antidote: Deferoxamine (Desferal) is antidote to iron overdose Drug Interactions ○ Deferoxamine and Dimercaprol which chelates iron (binds iron) Pharmacokinetics of Oral Iron Therapy: Onset of action: Hematologic response: Oral: ~3 to 10 days Peak effect: Reticulocytosis: 5 to 10 days; hemoglobin increases within 2 to 4 weeks Absorption: ○ In the duodenum and upper jejunum. ○ Acidic conditions in the stomach keep iron in the reduced ferrous form (more soluble) ○ Percentage of iron absorbed decreases with increasing doses. ○ In persons with normal serum iron stores lower oral dose is absorbed and vice versa. ○ Food and achlorhydria will decrease absorption Protein binding: To transferrin Excretion: Urine, sweat, sloughing of the intestinal mucosa, and menses Side effects of iron therapy Gastrointestinal (GI) disturbances caused by local irritation (abdominal pain, constipation, nausea, diarrhea) Dark stools are the most common adverse effects of oral iron supplements. Fatal hypersensitivity and anaphylactoid reactions can occur in patients receiving parenteral iron (mainly iron dextran formulations). ○ A test dose should be administered prior to iron dextran. In addition, intravenous iron should be used cautiously in the presence of active infections. [Note: Iron is essential for bacterial growth.] Monitoring Parameters: Hemoglobin/Hematocrit (H/H) Serum iron TIBC Transferrin level Reticulocyte count 2. Macrocytic Anemia: Vitamin B12: Vitamin B12 is an coenzyme for various metabolic functions Deficiencies of vitamin B12 can result from ○ Low dietary levels ○ Due to the failure of gastric parietal cells to produce intrinsic factor (as in pernicious anemia) ○ A loss of activity of the receptor needed for intestinal uptake of the vitamin ○ Nonspecific malabsorption syndromes or gastric resection can also cause vitamin B12 deficiency Folate: Primarily used in treating deficiency states that arise from inadequate levels of the vitamin. Folate deficiency may be caused by ○ Increased demand (i.e., pregnancy and lactation) ○ Poor absorption caused by pathology of the small intestine ○ Alcoholism ○ Treatment with dihydrofolate reductase inhibitors (i.e., methotrexate and trimethoprim), drugs that directly inhibit DNA synthesis (i.e., azathioprine and zidovudine), or drugs that reduce folate absorption (i.e., phenytoin and phenobarbital). A primary result of folic acid deficiency is megaloblastic anemia (large-sized red blood cells), which is caused by diminished synthesis of purines and pyrimidines. ○ This leads to an inability of erythropoietic tissue to make DNA and, thereby, proliferate. Pathophysiology of macrocytic anemia: Caused by vitamin B12 deficiency or folate deficiency or both Pernicious anemia is a common cause of vitamin B12 deficiency due to lack of intrinsic factor (IF) Required for vitamin B12 absorption ○ Diagnosed by positive test for autoantibodies to IF Will require lifelong parental vitamin B12 replacement Other Causes of Macrocytic Anemia: Poor nutrition Gastrointestinal disorders (e.g Crohn’s disease, celiac disease) and pregnancy Symptoms of Macrocytic Anemia: Vitamin B12 deficiency ○ Serious neurologic dysfunction Cognitive impairment: Visual disturbances, psychiatric symptoms Peripheral neuropathy 3 months = irreversible Folate deficiency ○ Ulcerations of tongue and oral mucosa ○ Changes to skin, hair, and fingernail pigmentation Treatments for macrocytic anemia: Cyanocobalamin, Vitamin B12 ○ Formulations: Injection, lozenge, tablets (including ER and SL), SL liquid, nasal solution (Nascobal) Folic acid, folate, Vitamin B9 ○ Formulations: tablet, capsule, injection Megaloblastic anemia ○ Folic acid + Vitamin B12 Drug Interactions: Vitamin B12 ○ Proton pump inhibitors May decrease oral absorption of vitamin B12 Folate ○ Cholestyramine May interfere with folate absorption Mechanism of Action: Vitamin B12 ○ Coenzyme for various metabolic functions i.e., Fat and carbohydrate metabolism and protein synthesis Folate ○ Coenzyme in metabolic systems Specifically: Purine and Pyrimidine synthesis Vitamin B12 Pharmacokinetics: Onset of action: 8 hours, up to 10 days Absorption: terminal ileum; requires the presence of calcium and gastric "intrinsic factor" to transfer the compound across the intestinal mucosa. Distribution: Stored in the liver and bone marrow, also stored in the kidneys and adrenals. Protein binding: Transcobalamin. Metabolism: Converted in tissues to active coenzymes, methylcobalamin and deoxyadenosylcobalamin; undergoes some enterohepatic recycling. Bioavailability: Intranasal (Nascobal): 6.1% (relative to IM); Oral: Pernicious anemia: 1.2%. Time to peak, serum: IM, SUBQ: 30 minutes to 2 hours; Intranasal: 1.25 ± 1.9 hours. Excretion: Urine (50% to 98%, unchanged drug). Folate Pharmacokinetics: Absorption: Proximal part of small intestine Metabolism: Hepatic Bioavailability: Oral: Folic acid supplement: ~100%; In presence of food: 85%; Dietary folate: 50% (IOM 1998) Time to peak: Oral: 1 hour Excretion: Urine Side effects: Vitamin B12 ○ pain with injection ○ Rare: rash, polycythemia vera, pulmonary edema Folate ○ Rare: bronchospasm, flushing, rash, pruritus, malaise Monitoring Parameters: Vitamin B12 ○ Vitamin B12 levels ○ Folate levels ○ Iron levels Folate ○ CBCs ○ Serum folate level 3. Normocytic Anemia: Erythropoietin (EPO): Peritubular cells in the kidneys respond to hypoxia and synthesize and release erythropoietin, a glycoprotein. EPO stimulates stem cells to differentiate into proerythroblasts and promotes the release of reticulocytes from the marrow and initiation of hemoglobin formation. Thus, EPO regulates red blood cell proliferation and differentiation in bone marrow. Anemia of Chronic Kidney Disease Deficiency of EPO ○ Causes anemia of chronic kidney disease ○ Caused by decreased kidney function EPO production decreases Reduced hemoglobin Exacerbates CKD, inflammatory state Symptoms: Fatigue Pale skin Weakness Dizziness Fainting Treatments: Iron Therapy Erythropoiesis-stimulating agents (ESAs) ○ Epoetin alfa (Epogen, Procrit) IV, SC 3x weekly injections ○ Darbepoetin (Aranesp) IV, SC Weekly injections ESAs help maintain Hgb levels but are ineffective if iron stores are low Drug Interactions: Duplication of Darbepoetin alfa or Epoetin alfa therapy can lead to increased adverse events ESA Warnings: If Hgb > 11 g/dL, serious cardiovascular events (such as thrombosis and severe hypertension), increased risk of death, shortened time to tumor progression, and decreased survival have been observed. Minimum effective dose that does not exceed Hgb of 12 g/dL, and a hemoglobin level that does not rise by more than 1 g/dL over a 2-week period. If the Hgb > 10 g/dL, doses of epoetin alfa or darbepoetin should be reduced or treatment should be discontinued. Neither agent has any value in the acute treatment of anemia due to their delayed onset of action. ESA Mechanism of action: Stimulating the division and differentiation of committed erythroid progenitor cells ○ Induces the release of reticulocytes from the bone marrow into the bloodstream, where they mature to erythrocytes. Results in an increase in reticulocyte counts followed by a rise in hematocrit and hemoglobin levels. ESA Pharmacokinetics: Onset of action: Reticulocyte count increase: Within 10 days. Peak effect: Hemoglobin level: 2 to 6 weeks Absorption: SubQ: Slow (McMahon 1990; Salmonson 1990) Distribution: Vd: 9 L; rapid in the plasma compartment; concentrated in liver, kidneys, and bone Marrow Metabolism: Some degradation does occur Bioavailability: SubQ: Premature neonates: 42% (Brown 1993); Adults: 36% (Salmonson 1990) Half-life elimination: Infants, Children, Adolescents, and Adults: CKD: IV: 4 to 13 hours ESA Side effects: Arthralgia/bone pain Fever Headache Pruritus/rash Nausea/vomiting Cough Dyspnea Injection site pain Dizziness ESA Monitoring Parameters: Hemoglobin/Hematocrit (H/H) Serum ferritin Blood pressure Week 9 - Clinical Management of GERD and PUD and Pharmacology of GI Agents Gastrointestinal Physiology: GI Tract: ○ Mouth, Esophagus, Stomach, Small Intestine, Large Intestine, Rectum Small Intestine: ○ Duodenum, jejunum, ileum Large Intestine: ○ Appendix, cecum, colon\ Pathway of Food: Peristalsis: ○ Involuntary contraction and relaxation of muscles throughout the digestive tract, allowing for the movement of contents from pharynx to anus Lower Esophageal Sphincter (LES): ○ High pressure zone located where the esophagus meets the stomach, protects esophagus from reflux Pyloric Sphincter: ○ Controls the flow of content between the stomach and duodenum Stomach: Function: ○ Mechanically breaks down food and partially digests protein Four main parts: ○ Cardia, Fundus, Body, Pylorus Stomach wall: ○ Mucosa, Submucosa, Muscularis, Serosa Mucosa: Mucous Cells: ○ Secrete alkaline mucus to protect epithelium from gastric acid Parietal Cells: ○ Secrete HCl and Intrinsic Factor (IF) ○ HCl: Breaks up food, denatures proteins ○ HCl: Activates pepsinogen ○ IF: Vit B12 absorption in small intestine Chief Cells: ○ Produce pepsinogen Enteroendocrine Cells: ○ G cells: secretes gastrin Promotes gastric secretion and emptying ○ D cells: secretes somatostatin inhibits release of gastrin and reduces gastrin secretion & motility ○ ECL-like cells: secretes histamine Increases gastric acid production by parietal cells Gastroesophageal Reflux Disease (GERD) Epidemiology: One of the most common GI disorders Prevalent in about 20% of adults in the western culture United States: prevalence is 18.1% - 27.8% Aging associated with an increased risk of GERD symptoms Prevalence of GERD more likely in men compared to women Pathophysiology of GERD Impaired lower esophageal sphincter function and transient esophageal sphincter relaxation (LES and TLESRs) Hiatal Hernia ○ Hinders the function of the LES ○ Size of hernia may have other contributory effects Impaired esophageal mucosal defense ○ Breached by prolonged exposure to the refluxate: acidic and alkaline Defective esophageal peristalsis ○ Decreased clearance of gastric reflux leading to increased mucosal damage Risk Factors of GERD: Medications: ○ NSAID (Ibuprofen), bisphosphonates, steroids Other: ○ Obesity, high-fat diet, smoking, alcohol, pregnancy, H. Pylori infection Symptoms of GERD: Two cardinal esophageal symptoms: ○ Heartburn (reflux) ○ Regurgitation Extra-esophageal symptoms: ○ Gastric pain, bloating, non-cardiac chest pain, dental erosion, cough Alarming symptoms: ○ Dark stool (internal bleeding), crushing chest pain, anemia, frequent vomiting, vomiting blood, unintentional weight loss >5%, severe abdominal pain, feeling full after eating a small amount of food. ○ Dysphagia (trouble swallowing), odynophagia (painful swallowing) Diagnosis of GERD: Endoscopy: erosive vs non-erosive Mainly based on symptoms and risk factors: ○ Heartburn, regurgitation for >2 times per weed Improvement in symptoms with medication therapy Complications of GERD: Barett’s esophagus: ○ Tissue that is similar to the lining of the intestine replace tissues in the esophagus (erosion changes cell type) ○ Can lead to esophageal adenocarcinoma (cancer) ○ 5% of patients with GERD develop Barrett’s Esophagitis: ○ Erosion and inflammation of esophageal mucosa ○ Extensive erosions, ulceration, GI bleeding and narrowing of the esophagus (esophageal stricture). Goals of treatment: Reduce or eliminate GERD symptoms Promote healing of any mucosal injury Decrease and prevent the development of esophageal damage and complications Improve quality of life Minimize long-term adverse effects from therapy Lifestyle modifications: Adjust with pharmacotherapy Avoid triggers (spicy food, caffeine, carbonated beverages) Avoiding smoking and alcohol Weight loss Avoiding medication known to increase symptoms (NSAIDs) Pharmacological treatment of GERD: Antacids or H2RA (histamine 2 receptor antagonists) or PPI (proton pump inhibitors) plus lifestyle modifications OTC treatment should not last >2 weeks Scheduled pharmacologic therapy ○ H2RAs or PPIs for 8-12 weeks ○ PPI preferred for documented erosive esophagitis Maintenance therapy ○ Symptomatic relapse or complicated disease Surgery ○ Disease complications, severe symptoms Antacids: MOA - neutralizes acid leading to increased pH of gastric contents Forms water and salt as a byproduct Some are absorbable and some aren’t Sodium bicarbonate: ○ Not commonly used by itself due to potential for sodium overload ○ Sodium Bicarbonate + Aspirin + citric acid (Alka Seltzer®) for heartburn Calcium carbonate: ○ Tums®, used in patients who have bone deficiency (osteoporosis or osteopenia) Magnesium hydroxide: ○ Causes diarrhea ○ Aluminum hydroxide + magnesium hydroxide (Maalox®) Aluminum hydroxide: ○ Causes constipation ○ Usually avoided due to Aluminum toxicity ○ Aluminum + Simethicone (Mylanta Pharmacokinetics of Antacids: Onset of 30-60 minutes Duration of action: up to 3 hours when taken with meals and can be dosed 4-6 times a day Taken after meals for maxim efficacy, fasted state duration is 1 hour Excretion: Feces and urine Significant drug interactions with antibiotics leading to decreased absorption Caution: rena;/heart failure, low sodium diets, edema Histamine 2 receptor antagonist: MOA: Gastrin secretin after a meal leads to histamine release Stimulated histamine receptor release HCL via H+/k+ ATPase proton pump H2RAs are selective antagonists of histamine production and release histamine. Treatment of GERD: Famotidine (pepcid) ○ Well tolerated ○ Caution with cardiovascular conditions ○ Decreased doses required in patients with kidney issues Nizatidine (Axid) ○ Most common side effect is headache ○ Decreased doses require Ranitidine (Zantac) ○ Pulled off market due to cancer ○ Zantac products contain Famotidine ○ Decreased doses required in patients with kidney problems Cimetidine (Tagamet) ○ Rarely used ○ Drug interaction ○ Decreased doses required in patients with kidney problems. Pharmacokinetics of H2RA’s: Onset of action: ○ Oral: 45-60 minutes, IV: 30 minutes Duration of action: IV/Oral: 10-12 hours Caution in patients with altered kidney function Excretion: mainly through urine Taken twice daily ○ Prevention (before meals) ○ Symptom relief (after meals) Proton Pump Inhibitors: MOA: Bind to the H+/K+ ○ ATPase proton pump and suppresses the secretion of hydrogen ions in to the gastric lumen PPI allow for irreversible inhibition of the enzyme Treatment of GERD with PPI: Esomeprazole (Nexium), Dexlansoprazole (Dexilant), Lansoprazole (Prevacid), Omeprazole (Prilosec), Pantoprazole (Protonix), Rabeprazole (Aciphex) Preferred treatment for GERD Superior to H2RA’s in suppressing acid and healing ulcers Reduces risk of bleeding from medications such NSAID Side effects: ○ Headache, nausea, diarrhea Warnings with prolonged therapy: Low magnesium, risk of fractures, Vitamin B12 deficiency, C. Difficile infection ○ Pantoprazole and Esomeprazole have IV formulations Pharmacokinetics of PPI: Onset of action: ○ Oral: 2.5 hours ○ IV: 15-30 mins Duration of action: ~24 hours ○ Taken once daily ○ Ideally taken 30-60 minutes before breakfast or the largest meal of the day Excretion: Primarily urine; feces DDI with medications such as Clopidogrel (CYP2C19 substrate) ○ Decreases ability of Clopidogrel to form active metabolites PPI & CYP2C19 Genetics: PPIs are cleared in the liver primarily by the Cytochrome P450 2C19 Enzyme ○ Cleared to a lesser extent by CYP3A4 (drug interactions) CYP2C19 is responsible for >80% of the metabolism of: Omeprazole,Lansoprazole, and Pantoprazole ○ Esomeprazole, Dexlansoprazole, and Rabeprazole metabolized through CYP2C19 CYP2C19 metabolizing activity is classified into: ○ Ultra-rapid, rapid, normal, intermediate or poor May affect efficacy of PPI Peptic Ulcer disease (PUD) Epidemiology: Global problem with a lifetime risk of development ranging from 5% to 10% United States: ~4 million people have active ulcer disease 10% of the population has had duodenal ulcer at some point in their,life Incidence of 0.1%-0.3% in the general population in Western countries H. Pylori infection: ○ 20% of those aged 60 years old are infected ○ Accounts for 90% of duodenal ulcers and 70%-90% of gastric ulcers Pathophysiology of PUD: Ulcer = open sore ○ Characterized by discontinuation in the inner lining of the GI tract because of gastric acid secretion or pepsin Extends into the muscularis propria layer of the gastric epithelium Most common are gastric and duodenal ulcers ○ Occurs less commonly in the lower esophagus, distal duodenum or jejunum Types of Peptic Ulcer Disease: Gastric ulcer: ○ Pain is worse during meals within 15-30 mins ○ Food worsens the pain ○ Weight loss Duodenal ulcer: ○ Pain is worse 2-3 hours after eating ○ Food lessens the pain ○ Weight gain ○ 4x more common than gastric ulcers ○ More common in men versus women Causes of Peptic Ulcer disease: Common: ○ Helicobacter Pylori Infection ○ NSAIDs Uncommon: ○ Stress, cancers, Zollinger-Ellison syndrome Symptoms of PUD: Common symptoms: ○ Epigastric abdominal pain, Bloating, Abdominal fullness, Nausea/vomiting, Weight loss/weight gain, Dark stools, Vomiting blood Alarming symptoms requiring urgent referral: ○ Unintentional weight loss, Progressing dysphagia, Excessive GI bleeding, Iron deficiency anemia, Early satiety, Family history of upper GI malignancy Diagnosis - PUD: Examining patient history, physical examination and invasive/non-invasive medical tests Esophagogastroduodenoscopy (EGD) ○ Gold standard and most accurate ○ Preferred in patients >50 years old with new onset symptoms ○ Patients presenting with alarm symptoms Barium swallow ○ When EGD is contraindicated Goals of Treatment: Relieve symptoms Prevent recurrences Heal lesions and prevent further progressive damage Prevent complications of PUD NSAID Induced PUD: NSAIDs inhibit COX-1 and COX-2 ○ COX-1 and COX-2 catalyze the synthesis of prostaglandins ○ COX-1: GI specific prostaglandins ○ Inhibiting GI prostaglandins → decreased mucus production and increased acid production Non-selective NSAIDs (high GI risk) ○ Ibuprofen ○ Naproxen ○ Ketorolac ○ Indomethacin COX-2 selective NSAIDs (lower GI risk) ○ Celecoxib ○ Diclofenac ○ Meloxicam ○ Nabumetone ○ Etodolac NSAID Induced PUD - Treatment: Discontinue offending agent ○ Switch to Tylenol if possible PPI, H2RA or Sucralfate for 4-8 weeks ○ PPI is preferred therapy (rapid healing and symptom relief) Prostaglandin analogs such as Misoprostol are also used NSAID Induced PUD Treatment: H. Pylori Infection: Gram negative bacteria Transmission: Fecal-oral ○ Gastric-oral Ability to survive harsh conditions of the stomach ○ Neutralizes acid through Urease (urea → ammonia) Movement mediated through flagella and use of adhesins for colonization Release of cytokines → tissue damage and inflammation ○ Leakage of gastric HCl into mucosa Diagnosis (H. Pylori testing): Serologic testing ○ Urea breath test (UBT) ○ May be used to confirm eradication after stopping treatment Antibodies to H. Pylori Stool antigen test or urine based ELISA Endoscopic biopsy: ○ Indicated if eradication fails ○ Biopsies from 4-6 sites needed H. Pylori Infection Treatment: Complications of PUD: Upper GI bleeding ○ Occurs in 15-20% of patients ○ Medical emergency Perforation ○ Occurs in 2-10% of patients ○ Sudden severe abdominal pain with shock ○ Surgery is treatment of choice Gastric outlet obstruction ○ Inflamed stomach ulcer prevents food from entering digestive tract → weight loss Gastric cancer ○ Infection with H. Pylori can increase risk of gastric cancer Week 11 - Estrogen and Progesterone Pharmacology Examples of Hormone-Related Therapy: Hormonal Contraceptives ○ Pregnancy prevention ○ Menstrual cycle regulation (heavy or painful periods) ○ Acne Hormone Replacement Therapy (HRT) ○ Postmenopausal symptoms Hormone Therapy ○ Gender transition ○ Endometrial cancer ○ Breast cancer Selective Estrogen Receptor Modulator (SERM) ○ Osteoporosis ○ Postmenopausal symptoms ○ Breast cancer Selective Progesterone Receptor Modulator (SPRM) ○ Emergency contraception Assisted Reproductive Technology (ART) ○ Infertility Steroid hormones: Messengers released into the blood & travel EVERYWHERE Produced by gonads or adrenal glands Gonads produce sex hormones that are important for conception, embryonic maturation, development of sexual characteristics at puberty Pharmacologically, sex hormones can be used for contraception, manage menstrual cycles, acne, and replacement therapy in hormone deficiency Antagonists are effective in treatment or prevention of certain cancers Estrogen = 18 carbons ○ More chemically stable than testosterone (emotional maturity) ○ Estrogens are generated mainly by the action of aromatase, which converts testosterone to estradiol and androstenedione to estrone in excess. Androgen = 19 carbons Pregnanes = 21 carbons Biosynthesis of steroid hormones: Cholesterol is the main precursor for all steroid hormones Cholesterol is synthesized by joining short carbon chains Aromatization occurs where androgens are converted further to estrogens The Hypothalamic-Pituitary Gonadal Axis: Hypothalamus: ○ Gonadotropin releasing hormone (GnRH) synthesized in the arcuate nucleus in hypothalamus. ○ GnRH is released into the GnRH receptors in pituitary ○ Pulsatile release of GnRH → FSH, LH release ○ Chronic release of GnRH → desensitization of GnRH receptors → down regulates and decreases FSH, LH secretion Pituitary: ○ Site of synthesis, release of Luteinizing ○ Hormone (LH), Follicle Stimulating Hormone (FSH) Ovary: Follicle Stimulating Hormone: Structure – α and β subunits; β confers specificity Receptor – GPCR on granulosa cells ○ Follicle maturation ○ Increases aromatase activity and estrogen production ○ Induces LH receptor expression Males – stimulates Sertoli cells to promote sperm maturation Luteinizing Hormone: Structure – α and β subunits; β confers specificity Receptor – GPCR on theca cells ○ Androstenedione production and secretion to granulosa cells ○ Promotes rupture of follicle, release of ovum ○ Progesterone synthesis in corpus luteum Males – stimulates androgen production (testosterone) Estrogen Types: Estradiol: Most potent estrogen produced and secreted by ovary, main estrogen in premenopausal women Estrone: A metabolite of estradiol that has 33% potency of estradiol and is the main form of estrogen after menopause Dehydroepiandrosterone (DHEA) → estrone in adipose tissues Estriol: another metabolite of estradiol, less potent, synthesized by placenta (high amounts during pregnancy) Ethinyl estradiol (EE): a synthetic estrogens are effective when given at a lower dose due to their potency. Estrogen Physiologic Effects: Normal sexual maturation and growth of the female Development of the endometrial lining Metabolic and Cardiovascular Effect ○ Maintenance of the normal structure and function of the skin and blood vessels, bone ○ Increases triglycerides, HDL; decreases cholesterol synthesis, LDL ○ Increases cholesterol secretion (gallstones), decreases bile acid, Blood Coagulation ○ Enhance the coagulability of blood Induce the synthesis of progesterone receptors Sodium retention → Edema Structures of Estrogen: Ethinyl Estradiol (EE) is Very similar in structure to natural estradiol Addition of a triple bond makes it significantly more stable (i.e., steric hindrance resists metabolic degradation) than estradiol ↑ Bioavailability as compared with estradiol when taken orally EE is the only estrogen used in hormonal contraceptives (though dosage varies). Estrogen and Blood Clots: Estrogen receptors in the liver are involved in the production of blood clotting factors Ethinyl estradiol is much more potent than natural estradiol, and it remains in the body far longer, so it hyperactivates the liver pathway, creating conditions that promote blood clotting Contraceptive use in the United States: More than 99% of women aged 15-44 who have ever had sexual intercourse have used at least one contraceptive method Hormonal Contraceptives: Progestin (Synthetic) Progestin = derived from testosterone or spironolactone ○ Mechanism of action: Inhibit the LH Surge in the pituitary Atrophies the endometrium Thickens the cervical mucus Delays fallopian tube peristalsis, decreases secretion ○ Physiological effect: Decreases serotonin → Depression Androgenic effect: Weight gain/ Acne Decreases HDL/ Increases LDL Does not interfere with lactation ○ Available formulations: First generation: Norethindrone, norethindrone acetate, and ethynodiol Second generation: Desogestrel and norgestrel Third generation: Norgestrel and norgestimate Fourth generation: Drospirenone Estrogen (Synthetic) ○ Mechanism of action: Suppresses FSH Secretion – no dominant follicle Stabilizes the endometrium – no breakthrough bleeding Potentiates action of progestin agents ○ Physiological effect: Increases fluid retention Increase hepatic protein in liver (coagulation factors) → Increases risk for DVT (deep vein thrombosis) Increases HDL / Decreases LDL ○ Available formulations: Ethinyl Estradiol Estradiol Valerate Estrogen Signaling: Classic signaling: ○ Estrogen binding ○ Estrogen receptor dimerization ○ Translocation to nucleus ○ Elicits estrogen response elements (ERE) binding ○ Slow transcriptional response Nonclassical Signaling: ○ Estrogen binding ○ Estrogen receptor dimerization ○ Protein-kinase cascade activation ○ Fast non genomic response Overview of Progesterone Signaling: Contraindication: Clot or clot history Liver Disease (estrogen) Breast cancer (BRCA)/ Estrogen dependent malignancies Migraine with aura Smokers age greater than 35 CVA = Stroke, HTN, DM ○ Diabetes with vascular disease ○ Severe hypercholesterolemia or hypertriglycemia Systemic lupus erythematosus (SLE) Benefits: Decreased risk for endometrial and ovarian cancer Fewer ectopic pregnancies Regular, lighter period – less anemia Increased bone density (estrogen) Likely improvement: endometriosis, benign breast disease, fibroids, ovarian cysts Acne: Estradiol increases SHBG in liver, decreases free testosterone level. Premenstrual dysphoric disorder (Yaz) Side effects of hormonal contraceptives: Progestin associated: ○ Bloating, anxiety irritability, depression, breakthrough bleeding late cycle (progestin deficit) Estrogen associated: ○ Breast tenderness, cyclic fluid retention, headache, nausea, breakthrough bleeding early to mid cycle (spotting) due to insufficient estrogen. Oral Pills (COC): Administration 1 tablet po daily Monophasic (in each of the active pills, the same amount of hormones are delivered in the entire pill pack), biphasic, triphasic (these two mimic normal menstrual cycle with hormones in the active pills), extended cycle Starting hormonal contraceptives: Sunday start: ○ Protection after 7 days of active pills/patch/ring ○ Cycle begins on sunday always First day of bleeding start ○ Protection immediate (no back-up required) ○ Cycle begins on the same day each month Starts pills today (or tomorrow if EC used today) ○ Anytime start or quick start ○ Protection requires 7 days of active pills/patch/ring Who should not take CHC: 35 or older and smoke cigarettes (as this puts you at high risk for cardiovascular complications such as blood clots or heart attack) Pregnancy History of blood clot or stroke ○ This increases your risk of blood clots while taking the pill History of an "estrogen-dependent" tumor eg, breast or uterine cancer Abnormal or unexplained menstrual bleeding ○ Cause of the bleeding should be investigated before starting the pill Have active liver disease Have migraine headaches associated with certain visual or other neurologic symptoms (eg, aura), which increases risk of stroke Week 12 - Initiation of Hormonal and Emergency Contraceptives Role of a pharmacist: Scope of practice: the boundaries within with a health professional may practice Collaborative practice agreement: voluntary agreements that create a formal practice relationship between a pharmacist and a prescriber Furnish: supplying patients with medications,therapeutic devices, or appliances, following established protocols. Furnishing emergency contraception: Emergency contraception is used when: ○ Failure of hormonal contraception Missed oral contraceptive pills, UID or vaginal ring falling out Patch falls off for extended period of time Barrier displaces itself Condom breaks Not using contraception in the first place Exposure to teratogen: valproic acid, warfarin. Hormonal Contraception vs. Emergency Contraception: Morning after pill not intended, usually not intended as a method of regular birth control due to its higher cost/decreased convenience, side effects: bleeding between periods, nausea, decreased effectiveness: not as effective as IUD, implant, pill. Furnishing self administered hormonal contraceptives (SAHC): Purpose: to provide timely access to self-administered hormonal contraception medication and to ensure that the patient receives adequate information to successfully comply with therapy Self administered hormonal contraceptive include: ○ Oral: Yaz, Tri-lo-sprintec ○ Transdermal: Xulane patch ○ Vaginal: NuvaRing ○ Depot injection: Depo-Provera Not self-administered: ○ Sterilization, IUD intrauterine device or system), implantable rod SAHC Procedure: Pharmacist training: ○ Complete 1 hour of a board-approved continuing education program or equivalent training program on or after 2014 at an accredited california school of pharmacy Self screening tool and blood pressure screening ○ Patient risk factors: identifies patient risk factors before pharmacist initiates SAHC ○ USMEC: answers are screened for all category 3 and 4 conditions and characteristics from the united states medical eligibility criteria for contraceptive use (USMEC) Criteria include: condition, sub-condition, type of contraception, initiation or continuation of contraception, key ○ Key for USMEC: No restriction (method can be used) Advantages generally outweigh theoretical or proven risks Theoretical or proven risks usually outweigh the advantages Unacceptable health risk (method not to be used) ○ Provided in multiple languages ○ Blood pressure screening: Cu-UID, LNG-IUD, DMPA (depot medroxyprogesterone acetate), POP (progestin-only pill), CHC (combined hormonal contraception: pill, patch, ring), I (initiation of contraceptive method), C (continuation of contraceptive method). ○ Contraindications: Severe liver disease Smokers aged 35 or above/greater than 15 cigs a day Breastfeeding less than 21 days postpartum migraine headaches with aura Uncontrolled hypertension Breast cancer ○ Product selection: any hormonal contraceptive listed in USMEC as category 1 or 2, generic equivalent products may be furnished Appropriate counseling ○ Information about dosage, effectiveness, potential side effects, safety, importance of receiving recommended preventative health screenings, SAHC doesn’t protect against STIs Fact sheet provided by pharmacist ○ FDA required patient product info leaflet and answers to questions the patient may have regarding SAHC ○ A copy of current, consumer-friendly BC guide ○ A copy of an administration specific fact sheet ○ Ex. how to take med, drug-drug interactions, missed doses, when to start the first pack, common/serious side effects, switching between different HC. ○ Notifications after furnishing SAHC: Patients w/ PCP: Notify patient’s PCP of drug furnished to patient Patients without PCP/unable to provide contact information of PCP: Provide written record of furnished drugs and advice patient to consult health care provider of choice Follow up and referrals ○ Follow up: Use of SAHC not recommended → refer PCP or nearby clinic if patient doesn’t have a PCP ○ Referral: SAHC services not immediately available/pharmacist declines to furnish → refer another appropriate healthcare provider Other considerations: ○ No age limit, parental consent not required to minors, may prescribe up to 1 year’s supply, patient confidentiality and privacy must be maintained 72 Hour Rule: Sperm lives up to 6 days after sexual intercourse ○ If ovulating while a sperm is in your body, may cause pregnancy. Emergency contraception works by temporarily inhibiting the ovary from releasing an egg (aka delays ovulation). Emergency contraception will not work if you’re already ovulating (or if you’re already pregnant). Use EX ASAP as you may be ovulating and might not know it so the sooner you take it the more effective it will be ○ May use it up to 5 days after unprotected sex ○ If creator than 72 hours the ulipristal is a safer option than levonorgestrel Purpose: To provide timely access to emergency contraceptive medication and ensure that the patient receives adequate information to successfully complete therapy. Pharmacist training: Complete a minimum of 1 hour of continuing education specific to EC Procedure: When a patient requests emergency contraception (EC) Allergies to medications Timing: sooner it’s taken, the more effective it will be, initiate up to 5 days after unprotected sex If >3 days after unprotected sex, ella may be more effective than levonorgestrel, follow up with your healthcare provider after the use of EC Referrals and supplies: EC servers not immediately available/pharmacist declines to furnish → refer another emergency contraception provider Other pharmacist abilities: Provide up to 12 non-spermicidal condoms to each medi-cal and family PACT client who obtains EC. Advanced provision: pharmacist may dispense EC for a patient in advance of the need of EC Emergency contraception products: Levonorgestrel (Plan B, next choice), Ulipristal (ella), high dose of regular oral contraceptive pills Levonorgestrel: Mechanism of action: progestin only pill that prevents or delays ovulation Common side effects; nausea, vomiting, heavy menstrual bleeding, menstrual irregularities, abdominal pain Clinical pearls: can become pregnant if the patient has unprotected intercourse in the same menstrual cycle after taking levonorgestrel. Long-term birth control can be initiated right away (abstinence or protection required in the first 7 days). Considerations: ○ Over the counter–may be purchased by male or female ○ No age limit/ID required ○ No quantity limit ○ Will not affect an established pregnancy (not a clinical abortion) ○ Will not protect against STIs Ulipristal: MOA: selective progesterone receptor modulator that delays or prevents ovulation Side effects: nausea, headache, dizziness, menstrual irregularities, abdominal pain Clinical pearls: wait 5 days after ulipristal prior to initiating long-term hormonal BC. use barrier protection for 14 days or until menstrual cycle (whichever comes first) Other considerations: Drug (brand name) Levonorgestrel (Plan B One-Step) Ulipristal (ella) OTC/Rx OT Rx Number of tablets One tablet One tablet Timing after unprotected sex Asap, up to 3 days after unprotected sex Asap, up to 5 days after unprotected sex Effectiveness 89% effective 95% e Weight considerations No FDA approved weight, but some studies indicate decreased effectiveness >165 lbs No FDA approved weight, recommended if the patient is >165 lbs. Decreased effectiveness if patient is >196 lbs Drug interactions? Yes yes Vomiting If vomited within 2 hours after first dose, consider repeat dose If vomited within 3 hours of first dose, consider repeat dose Menstrual cycle No regard to menstrual cycle Repeated use in same menstrual cycle isn’t recommended Emergency contraception - Oral contraceptive pills (Yuzpe method): Least effective form of EC, used only when unable to access other formed of EC as readily Load up active progestin to reach an effective dose to delay ovulation Dose 1 and dose 2 are given 12 hours apart (100 ug ethinyl estradiol/dose and ~0.5 mg progestin/dose) Anti nausea treatment options (Non prescription drugs): Meclizine hydrochloride (Dramamine 2, Bonine): one or two 25 mg tablets, 1 hour before first EC dose and repeat if needed in 24 hours Diphenhydramine hydrochloride (Benadryl): one or two 25 mg tablets or capsules, 1 hour before first EC dose, repeat as needed every 4-6 hours Dimenhydrinate (dramamine): one or two 50 mg tablets or 4-8 teaspoons of liquid, 30 minutes to 1 hour before first EC dose, repeat as needed for every 4-6 hours. Summary: Foundation: self screening tool, blood pressure screen, USMEC Product selection should be guided by screening, consider patient preference Counsel appropriately, provide fact sheets, and notify provider Know when to refer Week 12 - Pharmacotherapy considerations for Gender Affirmation Transgender Statistics: 1.4 transgender adults in the U.S. 150,000 youth 15,000 transgender people in the U.S. military, 134,000 veterans identify as transgender Health Disparities in LGBTQ+ community: LGBTQ+ – smoking, alcohol use, other drug use, depression and anxiety, less likely to get preventive services for cancer General lack of data for the community MSM, higher risk of HIV and STD, especially among communities of color Overall higher rates of substance use Lesbians are less likely to receive preventative cancer screenings, are more likely to use tobacco/alcohol, and LB women are more likely to be obese. GB men make up 83% of new HIV cases among male. Isolation, diminished family support, reduced availability of social services, discrimination from peers when living in communal housing. Youth: ○ LGBT youth are 2 to 3 times more likely to attempt suicide ○ Estimated that between 20% -40% of all homeless youth are LGBT ○ More likely to suffer from mental illness and to be physically or sexually abused Elderly: ○ Elderly LGBTQ+ individuals face social isolation, and lack social services as well as culturally competent medical care. ○ Dual identity: Age + Sexual Minority Health disparities of transgender individuals: High prevalence of HIV and STDs Victimization and suicide 2015 U.S. Transgender Survey: ○ ○ ○ 23% of respondents didn’t see a doctor, fearing being mistreated as a transgender person 33% did not see a doctor because they could not afford it. 33% of those who saw a provider had at least one negative experience related to being transgender, with higher rates for people of color and people with disabilities. ○ 40% have attempted suicide in their lifetime (this is 9x the U.S. population rate) ○ Transgender men are less likely to be up to date on cervical cancer screenings Intersectionality within the LGBTQ+ community: Transwomen of color: ○ Make up 4 out of 5 homicides against transgender individuals, with an arrest rate of 50%) Moderate risk of adverse outcomes Liver function test (LFTs) measuring Alanine transaminase (ALT) and Aspartate transaminase (AST) is >3x the the upper limit of normal (ULN) CAD (coronary artery disease), HTN (hypertension), Cerebrovascular disease (strokes), breast or uterine cancer, Absolute contraindications: pregnancy, unstable coronary artery disease, hormonally sensitive cancer, untreated polycythemia with hematocrit >55%. Transdender broken arm syndrome: Providers should ask about family/life support if the patient’s complaint is relevant (depression, anxiety) They shouldn’t assume that a transgender person’s every complaint is due to being on HRT. They can have conditions outside of treatment-related effects. Role of healthcare providers: Take a cultural humility perspective ○ Acknowledge their authority over their own experience Make efforts to educate yourself ○ Do not rely on your patient to educate you Introduce yourself with your pronouns ○ Creates a welcoming environment for conversation Provide a corrective experience within healthcare ○ Providers who champion the LGBTQ+ community can change the entire care trajectory in the future Be a patient advocate and educate student/staff/care teams regarding unique barriers Week 13 - Principles of Antimicrobials Types of Pathogens: Bacteria: single celled organisms that can live inside or outside a host ○ Tuberculosis, e. Coli, staphylococcal, salmonella, streptococcus, pneumococcus, meningococcus Virus: multi-celled but can only reproduce in a host ○ Hepatitis, herpes, SARS, influenza, HIV, chicken pox, ebola, measles Fungus: multi-celled that extracts nutrition from a host ○ Ringworm, candidiasis, histoplasmosis, cryptococcosis, aspergillosis, coccidiomycosis, blastomyces Parasite: complex living organisms that lives on/in a host and gets its food from or at the expense of its hosts: trichinosis, tapeworm, roundworm, nematode Microbiology: The Human Microbiota and Microbiome: Microbiota: live in particular ecosystem ○ Skin, oral cavity, vagina, intestine ○ Bacteria, fungi, archaea, viruses, protozoans ○ Human GI tract: 100 trillion (1014) bacteria (=2 kg of body st) ○ Increased richness and diversity of bacteria species Better nutritional status Fewer comorbidities Greater overall health Microbiome: collective genomes and gene products of resident microbes ○ Gut microbiome: at least 100 times as many genes as the human genome 2008: Human microbiome project (HMP) ○ NIH initiative to ‘map’ the human microbiome ○ Lead to the first reference database of human bacteria from 242 healthy adults Microbiome variability: Number and types of organisms vary between body sites in the same individual between same body sites in different individuals Humans are inoculated at birth, and microbiome remains relatively stable over time Bacterial Infections: The human immune systems have mechanisms to respond to non-self antigens ○ Innate immune systems ○ Adaptive immune system Sometimes, bacteria multiply too fast or release toxins do damage host tissues Sometimes, the host is immunocompromised Immune manifestations may cause fatalities in some populations (children, elderly, immuno-compromised) Treat with antibiotics and supportive therapies. Antibiotic usage: Antimicrobial strength is due to their selectivity. Antibacterial agents, antiviral agents, antiparasitic agents, antifungal agents Sterilizing needed ○ Transplants ○ Dialysis ○ Suppressed immune systems ○ Joint replacement Overuse: overprescribing, continuous use in livestock feed What are antibacterials: Chemical substance produced by certain molds and bacteria that kills or inhibits the growth of another microorganism Although initially isolated as natural products of microorganisms, cna now also be synthesized in the lab Due to structural and biochemical differences between humans and bacteria, antimicrobials exploit the differences for targets of their activity ○ Bacterial cell wall ○ Bacterial ribosomes Tools to identify the bacterial: Bacterial structure - cell wall: Multilayered, located external to the cytoplasmic membrane ○ inner layer of peptidoglycan surrounded by an outer membrane ○ Peptidoglycan layer: single covalently linked Maintains the shape of the cell Provides the rigid support of the cell wall Bacterial staining: ○ Cram positive: Remains purple/blue Bacteria have a thicker peptidoglycan layer ○ Gram negative: Remains red More complex outer layer of lipopolysaccharides, lipoproteins and phospholipids ○ Non-staining bacteria Mycobacteria: “Acid fast” inability to be stained due to high concentration of mycolic acids Types of B-lactams: Add a side-chain to the penicillin structure Alters: chemical characteristics, spectrum activity, development of bacterial resistance. Penicillin class: Clinical indication ○ Penicillin: DOC for syphilis ○ Amoxicillin: respiratory tract infection (otitis media/pharyngitis, or pneumonia ○ Piperacillin: broad spectrum, paired with beta lactamase inhibitor Side effects: ○ Nausea, committing, diarrhea ○ Allergic reaction (5% in adults) ○ Bacterial resistance Cephalosporin: Produced by fungi, Cephalosporium with ring similar to penicillins Actions similar to penicillins Penicillin allergic persons can also be sensitive (5-10%) Generations: ○ First generation: cephalexin, cefazolin ○ Second generation: cefaclor, cefuroxime, cefotetan ○ Third generation: cefixime, cefdinir, ceftriaxone, cefotaxime, ceftazidime ○ Fourth generation: cefepime ○ Fifth generation: ceftaroline, ceftolozane Carbapenems: Most stable to hydrolysis by B-lactamases compared to other beta lactams Spectrum of activity: ○ Very broad (gram + and gram -. Aerobes, and anaerobes ○ De-escalate ASAP is possible PNC allergy ○ Cross sensitivity ~10% Precautions: ○ Seizures (class effect)