Clinical Pharmacology Study Guide (Ethinyl Estradiol)

Ethinyl Estradiol & Etonogestrel Ring (NuvaRing ) • • • • • • www.nuvaring.com Flexible, transparent, colorless vaginal polymer ring about 2.1 inches in diameter containing estrogen and progestin. A new ring is used each month for continuous contraception Instructions for use: A woman inserts the ring herself. It remains in the vagina for three weeks. The ring is removed for one week during which she will have her menstrual period Manufacturer provides a patient info brochure describing effectiveness, benefits, and risks of the product, information about proper use, insertion, and removal, as well as storage and disposal. Also includes information about reinserting the product if it is expelled. When used correctly, it has similar efficacy to the oral contraceptives. If ring has been out of vagina for > 3 hours, it is considered a “missed dose” and usual missed dose instructions are followed. Side effects: vaginal discharge, vaginitis, & irritation. Similar side effects to the COCs. Ethinyl estradiol & Norelgestromin transdermal patch (Ortho Evra ) Each patch contains 6mg norelgestromin & 0.75 mg ethinyl estradiol. Patch is applied weekly. Wear patch 3 weeks on, then 1 week off for menses. Package Insert: “Hormones from patches applied to the skin get into the bloodstream and are removed from the body differently than hormones from birth control pills taken by mouth. You will be exposed to about 60% more estrogen if you use Ortho Evra than if you use a typical birth control pill containing 35mcg of estrogen.” [Reasons: lack of first pass metabolism, lower estrogen peak with the patch, but larger area under the curve (AUC)] Caution: Increased failure rate in women weighing> 90kg. www.orthoevra.com Progestin only Oral Contraceptives Minipill norethindrone (Micronor , Nor-QD,) norgestrel (Ovrette ) Efficacy: As compared to COCs, the minipill is considered to have lower efficacy. The effects on cervical mucus decrease rapidly 22 hours after dosing; therefore, patients must take at the same time each day to maintain efficacy. Mechanism of Action: (1) Thickens cervical mucus, which inhibits sperm migration (2) Alters endometrium making it less favorable to implantation (3) Progestin inhibits LH surge thus inhibits ovulation in some women( about 40% of women will still ovulate regularly) Adverse Effects: The minipill is considered to have fewer side effects overall, but an increased incidence of menstrual irregularities such as breakthrough bleeding. Minipill has similar types of side effects, contraindications, & warnings to the COCs; however, thromboembolism risks are listed as warnings rather than contraindications. May be preferred in women who are breast-feeding due to a lower potential for breast milk reduction. These products are taken daily, continuously throughout the cycle. Patient Instructions for Missed Doses Progestin only products are “less forgiving” regarding maintaining efficacy with skipped doses than combination products. A dose > 3 hours late constitutes a “missed dose.” • One or more missed doses (even 3 hours late), take dose as soon as possible and use back-up contraceptive x next 48 hours. 97 Depot medroxyprogesterone (Depo-Provera ) (Depo-subQ Provera 104 ) Depo-Provera: IM injection of 150mg medroxyprogesterone once each 3 months (12-14 weeks). Depo-subQ Provera 104: SQ injection of 104mg medroxyprogesterone once each 3 months (1) Thickens cervical mucus, which inhibits sperm migration. (2) Alters endometrium, making it less favorable to implantation. (3) Progestin suppresses LH surge and thus inhibits ovulation. Adverse Effects • Similar side effects, contraindications, & warnings to the COCs, including thromboembolism • Most common SE is menstrual irregularities (25-30%) that can take months to resolve. • Infertility persists for a mean of 10 months after the last injection, in some cases to 1 – 2 years. • Bone Mineral Density: Possible increased risk of bone mineral density reductions. Women < 21yrs old are especially vulnerable. Recommend calcium & vitamin D, and annual bone mineral density checks. The product carries a black box warning to limit use to < 2 years; however, in 2008 the American College of Obstetrics and Gynecology stated this 2 year limitation is unnecessary because the bone loss appears to be at least partially reversible. Etonogestrel (Nexplanon ) • • Implantable (sub dermal) sustained release rods which contain progestin. Provides efficacy for up to 3 years. Hormonal Contraceptives in Breastfeeding Mothers Thrombosis issue: Estrogen contraceptives should not be used within 3-6 weeks post-partum due to increased risk of thrombosis. Progestin only contraceptives do not increase thrombosis risk, and thus may be initiated at any time. Breast-feeding issue: Estrogen contraceptives may reduce breast milk production, and therefore should not be used until breast milk flow is well established, especially in women not supplementing with formula. Estrogen contraceptives should also not be started until at least 6 weeks after delivery to avoid adverse effects on the liver of the baby. To avoid problems with breast milk production, the World Health Org (WHO) suggests waiting 6 weeks to 6 months after delivery before using estrogen contraceptives. Progestin contraceptives do not reduce breast milk production. Therefore, some experts feel comfortable initiating progestin only products immediately after delivery. The WHO suggests waiting at least 6 weeks in breast-feeding mothers to avoid any adverse effects on the liver of the baby. Emergency Contraception, post-coital contraception, “Morning-After Pill” Reserved for isolated incidents of contraceptive failure or non-use. Take as early as possible following intercourse & within 72 hrs of intercourse for best efficacy (89%). May still be somewhat effective up to 5 days after intercourse. Mechanism of Action (1) Inhibits ovulation and/or prevents implantation (post-fertilization). Extent of post-fertilization effect is controversial. (2) If implantation has already occurred, these regimens are not effective. Levonorgestrel 0.75mg (Plan B, Next Choice®) – take 1 dose now and 2nd dose 12 hrs later. Levonorgestrel 1.5mg (Plan B® One Step, NextChoice ® One Step) –take 1 tablet now. Side Effects: N/V (60 - 70%), headache (70%), breast tenderness (45%) 98 Osteoporosis • • • • • Characterized by low bone mass & increased bone fragility. Patients are susceptible to fractures from minor traumatic events such as coughing, rolling over in bed, walking, or falling. Fractures include (1.5 million/year): vertebrae, forearm, & hip fractures. Osteoporosis is most common in women. A majority of bone loss occurs within the first 5 years after menopause (2 – 3% per year) or stopping HRT. About 25% of hip fractures occur in men. Osteoporosis in men is often associated with oral corticosteroid use. There is a high mortality / morbidity rate associated with hip fractures. The leading cause of nursing home placements is hip fracture. Out of 100 hip fractures in persons > 65 years old, 30 will recover fully, 30 will die within 1 year, 20 will require lifelong help with activities of daily living (such as walker, cane, home health aid), and 20 will require nursing home placement. Calcium • >98% of all body calcium is present in bone. • Bone undergoes continuous remodeling. Old bone is resorbed, after which new bone is deposited. The cells that resorb (chew-up) old bone are called osteoclasts & cells that deposit (build) new bone are called osteoblasts. • Blood levels of calcium are tightly controlled. Preservation of serum calcium levels takes priority over the calcium requirements of the bones. (Blood will always win over the bones.) • Calcium levels are regulated by controlling (1) intestinal absorption (2) renal excretion and (3) resorption or deposition of calcium in bone. • Three factors control these processes (1) parathyroid hormone (2) vitamin D and (3) calcitonin. Primary Influences of Serum/Bone Calcium (1) Parathyroid Hormone (PTH) • Released from the parathyroid glands in response to low levels of plasma calcium. • Continuous endogenous PTH release promotes calcium resorption from bone. (moves Ca 2+ from bone to blood) • PTH inhibits renal excretion (loss) of calcium by promoting reabsorption of filtered calcium. • PTH activates vitamin D. (2) Vitamin D • Obtained through diet & exposure to sunlight. Vit D is converted into active form in response to low levels of plasma calcium. Vit D deficiency causes rickets & osteomalacia (soft, curved bones). • Vitamin D inhibits renal excretion (loss) of calcium. • Vitamin D increases calcium absorption from the intestine. • Vitamin D also promotes calcium resorption from bone. (Although it promotes the removal of Ca2+ from bone, overall there is no net loss of Ca2+ from bone. This is because Vit D increases serum Ca2+ which will stimulate osteoblast activity.) (3) Calcitonin • Hormone produced by the thyroid gland in response to high levels of plasma calcium. • Calcitonin inhibits the resorption of calcium from bone. (inhibits Ca2+ removal from bone) • Calcitonin increases renal excretion of calcium. (When used therapeutically, as long as adequate Ca2+ intake occurs, overall there is an increase in bone formation.) 99 Primary Prevention • Lifestyle: Regular weight-bearing exercise (walking, dancing, weight lifting, stair climbing). Avoid excessive alcohol, caffeine, soda, high-fat foods, & avoid smoking. • Ensure adequate amounts of calcium & vitamin D intake. Calcium (mg/day) 200 260 700 1000 1300 1000 1000 1200 1200 Age 0 – 6 months 6 – 12 months 1 -3 years 4 - 8 years 9 – 18 years 19 – 50 years 51—70 males 51—70 females Over 70 Calcium Supplementation Calcium carbonate (e.g. Tums, Viactiv chews) – usually the cheapest form Calcium citrate (e.g. Citracal) – perhaps the best absorbed form Vitamin D: Calcium products may be sold with or without vitamin D. Always consider vitamin D supplements in persons with low dietary intake of vitamin D or reduced exposure to sunlight, for example persons in nursing homes or home bound. Many Americans do not have enough vitamin D naturally; suggested supplementation: Vitamin D (IU/day) 400 600 800 Age Children < 1 1-70 years 71 years and older Patient Instructions • Choosing a supplement is a matter of personal preference. Supplements may also contain vitamin K (some evidence linking to osteoporosis) and/or magnesium (very little evidence supporting a link). • For best absorption, do not consume more than 500 – 650 mg of calcium in a single dose. Adverse Effects: constipation & flatulence. Use caution with history of Ca2+ based kidney stones. Medications Used in the Treatment & Prevention of Osteoporosis Bisphosphonates, calcitonin, and estrogen agonist/antag all prevent bone resorption. Increases in bone density are also seen; however, their main efficacy lies in preventing further bone loss. Success of all osteoporosis medications requires sufficient calcium & vitamin D intake! Bisphosphonates *Alendro NATE (Fosamax, Atelvia®) oral Ibandronate (Boniva) oral and IV Risedronate (Actonel) oral Zoledronate (Reclast) – IV (aLENdroenate) (eBANdroenate) (risEDroenate) (zoeLEDroenate) Dosing frequency varies from once daily to once annually. 100 Mechanism of Action – Bisphosphonates • Bisphosphonates are incorporated into the bone. Osteoclasts cannot resorb bisphosphonatebound bone. Osteoclast activity is, therefore, reduced. Therapeutic Use • Drugs of choice for treatment & prevention of osteoporosis. Adverse Effects • Poorly absorbed from the GI tract. Esophageal ulceration has occurred. Bone pain. Jaw necrosis following tooth extractions and other invasive dental procedures have rarely been reported. Administration • Take in the morning before breakfast, on an empty stomach. Take with a full glass of water (not juice, tea, coffee, or anything else). Remain upright for at least 30 minutes. Not recommended for patients who cannot remain upright for at least 30 min. Calcitonin (Miacalcin) nasal spray (kalsiTOEnin) Mechanism of Action • Same as the hormone. Decreases osteoclast activity & numbers. Increases osteoblast activity. Therapeutic Use • Treatment of osteoporosis. Treat pain associated with fractures. Adverse Effects • Nasal dryness & irritation. Periodic nasal exam recommended. • Allergic reactions have been reported. Alternate nostril daily. • Increased risk of malignancy has been reported. Estrogen agonist / antagonist *Raloxifene (Evista ) (ralOKSifeen) Mechanism of Action • It is an estrogen agonist in its effects on lipids & osteoclasts. • It is an estrogen antagonist on breast & uterine tissue. Similar to drugs like tamoxifen. No increased risk of endometrial or breast cancer. It does not reduce other symptoms of menopause such as hot flashes. Therapeutic Use • Treatment and prevention of osteoporosis in post-menopausal women AND also FDA approved to prevent breast cancer in women with estrogen sensitive breast cancer. Raloxifene will NOT treat menopausal symptoms – it is not a simple estrogen alternative – there are differences. Adverse Effects • Potential risk of thrombosis, just as with estrogen. Hot flashes, legs cramps, peripheral edema can occur. No problems with breakthrough bleeding or breast tenderness. Stopping therapy will trigger a period of accelerated bone loss similar to that seen after menopause. 101 Parathyroid Hormone *Teriparatide (Forteo ) SQ daily (terPARatide) Mechanism of Action • Recombinant human parathyroid hormone. Endogenous parathyroid hormone (PTH) is a chain of 84 amino acids. Teriparatide is a chain of the first 34 amino acids. Intermittent administration of exogenous 1-34 PTH results in preferential bone formation. Therapeutic Use • Due to administration problems (daily injections) and high cost ($500/month) and long-term safety concerns makes this drug appropriate only for treatment of severe disease. Adverse Reactions • Studies in mice showed an increase in osteosarcomas. No safety data > 2 years in humans. • Bone pain, weakness, leg cramps, orthostatic hypotension after injection. RANKL-inhibitor denosumab (Prolia) SQ every 6 months Mechanism of Action • RANKL is a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts. Denosumab binds to RANKL and prevents it from activating its receptor, RANK, on the surface of osteoclasts. This inhibits osteoclast formation, function, and survival, which in turn decreases bone resorption and increases bone mass and strength in bone cortical and trabecular bone. Therapeutic Use • Reserved for treatment of postmenopausal women with osteoporosis at high risk for fracture or who have failed or are intolerant to other osteoporosis therapy Adverse Effects • Back pain, pain in extremities, hypercholesterolemia, musculoskeletal pain • Increased risk of infection • Localized injection site reactions • Rarely: pancreatitis, osteonecrosis of the jaw Few head to head trials comparing one prescription drug to another. Ca2+ alone reduces risk of fractures and increases bone density better than placebo but not as well as prescription options. Ca2+ plus a prescription drug is more effective than Ca2+ alone and more effective than a prescription medication alone. 2012 guidelines regarding when to consider treatment: 1) Hip or vertebral fracture 2) Osteoporosis (Tscore of -2.5 or less at femoral neck or spine; T score is result of standard bone density scan) 3) Low Bone Mass (Osteopenia) (Tscore of -1 to -2.5 at femoral neck or spine) 102 Study Guide….this is not all inclusive Summary of Bacterial Coverage Specific infections and most likely antibiotic classes used to treat the infection Otitis Media *Amoxicillin *Amoxicillin/clavulanate Cephalosporins Macrolides (alternative treatment) Community Pneumonias Macrolides Fluoroquinolones Tetracycline (doxycycline) Cephalosporins Acne Tetracyclines Macrolides Clindamycin Atypical Pathogens Tetracyclines Macrolides Fluoroquinolones Urinary Tract Infections Treat C. diff diarrhea *Sulfamethoxazole/trimethoprim *Fluoroquinolones *Nitrofurantoin *Metronidazole *Oral Vancomycin (only used if metronidazole fails) Genital Herpes *Acyclovir Valacyclovir Famciclovir Systemic Fungal Infections *Amphoteracin B *Fluconazole General coverage information Gram Positive Coverage *1st gen cephalosporins *5th gen cephalosporins *Vancomycin *Clindamycin *Antistaphylococcal penicillins Gram Negative Coverage *3rd, 4th, 5th gen cephalosporins *Aminoglycosides Anaerobic Coverage *2nd gen cephalosporins *β-lactamase inhibitor combinations Carbapenems Clindamycin Metronidazole Pseudomonas Coverage Aminoglycosides *Antipseudomonal pcns Fluoroquinolones 4th gen cephalosporins Broad Spectrum Therapy Carbapenems β-lactamase inhibitor combinations Esp. ticarcillin/clav & pipericillin/tazobactam β-lactams or vanco with an aminoglycoside MRSA CA: Sulfamethoxazole/trimethoprim, CA: Minocycline, Doxycyline, Clindamycin CA: Alt tx: Vanco, Linezolid, Ceftaroline *HCA: Vancomycin HCA: Linezolid, Ceftaroline Atypical Coverage *Macrolides *Tetracyclines *Fluroquinolones 103 KNOW THIS!!!!! Study Guide….this is not all inclusive Summary of Side Effects & Drug Interactions Red-Man Syndrome Vancomycin Seizures Carbapenems Fluoroquinolones Nephrotoxicity Amphoteracin B Aminoglycosides Sulfamethoxazole/trimethoprim Causing Clostridium difficile Diarrhea Any antibiotic can, but especially Clindamycin Fever, Chills, Shaking Amphoteracin B Teeth & Bone Development Tetracyclines Fluoroquinolones Chelation Interactions Tetracyclines Fluoroquinolones P450 Metabolism Interactions Fluoroquinolones Macrolides Ketoconazole/Fluconazole/Itraconazole Rifampin Protein Binding Interactions Sulfamethoxazole/trimethoprim Changes in Urine Color Nitrofurantoin Rifampin Liver Failure TB Drugs Ketoconazole Fluconazole Itraconazole Tendon Rupture Fluoroquinolones Serotonin Syndrome Linezolid Anaphylactic PCN Allergy No penicillins No carbapenems No cephalosporins Everything else is OK to take. QT Prolongation Fluoquinolones Macrolides Ketoconazole Itraconazole Mild PCN Allergy No penicillins Everything else is OK to take. Ototoxicity Vancomycin Aminoglycosides 104 Common Pathogens by Disease Upper Respiratory Tract Streptococcus pneumoniae Haemophilus influenzae Streptococcus pyogenes Moraxella catarrhalis Urinary Tract (mostly gm-neg bacilli) Escherichia coli Proteus mirabilis Enterococcus Skin/Soft Tissue (mostly gm-pos) Staphylococcus aureus Staphylococcus epidermidis Streptococcus pyogenes Lower Respiratory Tract Streptococcus pneumoniae Haemophilus influenzae Mycoplasma pneumoniae Klebsiella pneumoniae Chlamydia pneumoniae Intra-abdominal (anaerobes, gm-neg bacilli) Escherichia coli Bacteroides Proteus mirabilis Peptostreptococci Klebsiella Enterobacter Enterococcus Bone/Joints (mostly gm-pos) Staphylococcus aureus Streptococcus pneumoniae Staphylococcus epidermidis Nosocomial Lung Infection Pseudomonas aeruginosa Klebsiella pneumoniae Staphylococcus aureus Suspect Anaerobes ….. Abscesses Diabetic foot infections Abdominal infections Aspiration pneumonias Infected animal bites Aspiration Bacteroides & other anaerobes Gram-Positive Cocci Staphylococcus aureus Staphylococcus epidermidis Streptococcus pneumoniae Streptococcus pyogenes Enterococcus Post trauma Pseudomonas aeruginosa STAFF-ah-la-KAH-kus Or-ee-us STAFF-ah-la-KAH-kus ep-ih-DER-mih-dus STREP-toh-KAH-kus new-MOW-nee-ay STREP-toh-KAH-kus pie-OH-jen-eez EN-ter-oh-KOH-kus Gram-Negative Enteric Bacilli (Enterobacteriaceae) Escherichia coli ESH-er-EE-she-ah KOH-lie Klebsiella pneumoniae KLEB-see-EL-ah new-MOW-nee-ay Proteus mirabilis PRO-tee-us mer-AH-bil-us Enterobacter EN-ter-oh-BACT-ter Other Gram-Negative Bacilli Pseudomonas aeruginosa Haemophilus influenzae soo-do-MOH-nus hih-MAH-fill-us a-ROO-jin-OH-sah in-flew-EN-zay Gram-Negative Cocci Moraxella catarrhalis Neisseria gonnorrhoeae Neisseria meningitidis MORE-ax-EL-lah kah-tar-AHL-us nigh-SEER-ee-ah gon-or-EE-ay nigh-SEER-ee-ah men-in-JIH-tih-dis Atypical Pathogens Mycoplasma pneumoniae Chlamydia pneumoniae Mycobacterium avium Chlamydia trachomatis Mycobacterium tuberculosis MY-koh-PLAZ-mah new-MOW-nee-ay kluh-MID-ee-ay new-MOW-nee-ay MY-koh-back-TEER-ee-um Ay-vee-um kluh-MID-ee-ay tra-KOH-mih-tus MY-koh-back-TEER-ee-um tuh-BUR-kyou-LOH-sis Anaerobic Pathogens Peptostreptococcus Clostridium difficile Bacteroides fragilis PEP-toh-STREP-tuh-KAH-kus klaw-STRIH-dee-um dif-fih-SEEL bact-ter-OY-dees FRA-jill-us 105 Basic Principles of Antimicrobial Therapy Pathogen: Organisms that are causing an active infection Normal Flora: Those organisms normally found on the host. Usually considered nonpathogenic. Microorganisms that cause disease in humans: • Bacteria: Single cell microbe • • • • • • • • Gram positive: Cell wall and cell membrane Gram negative: Cell wall, cell membrane, and outer envelope/membrane Anaerobic: Bacteria that do not require oxygen to live. May be gram (+) or gram (-) Atypical: No cell wall. Will not color with gram staining. Neither gram (+) or gram (-) Fungi: rigid cell wall and cell membrane containing ergosterol (sterol) Viruses: Intracellular parasites. Viruses have no cell wall, no membrane, and carry out no metabolic processes. They live and replicate within the host cell Protozoa: Single celled eukaryotes. Usually motile. Helminths: Parasitic worms Basic Principles of Antimicrobial Therapy • Antibiotic: Strictly speaking, a chemical produced by one microbe that can harm other microbes • Antimicrobial agent: Any agent that can kill or suppress microorganisms Selective Toxicity • • Toxic to microbes but harmless to host Differences in the cellular chemistry of mammals and microbes Classification of Antibiotics • Bacteriocidal: Drugs are directly lethal to bacteria at clinically achievable concentrations. Kills the organism. • Bacteriostatic: Drugs can slow bacterial growth but do not cause cell death • Narrow Spectrum: act on a single or limited group of pathogens • Broad Spectrum: Act on a wide variety of microbial organisms Selection of Antibiotics • Identify organism • Drug sensitivity of organism • Host factors • Drug may be ruled out owing to: • • • Allergy Inability to penetrate site of infection Patient variables Empiric Therapy • Antibiotic therapy for patients before causative organism is positively identified • Drug selection based on: • • Clinical evaluation Knowledge of microbes most likely to have caused infection 106 Identifying the Infectious Organism • Match the drug with the bug • Gram-stained preparation • Determining drug sensitivity • Minimum inhibitory Concentration (MIC) Host Factors • Host defenses • Site of infection • Previous allergic reactions • Genetic factors Drug Factors • Will the antibiotic penetrate target tissues? • Is it effective against the most likely pathogen(s)? • It is bactericidal or bacteriostatic? • What is the safety of the antimicrobial (its adverse effects)? • What is the cost of therapy? Monitoring of Antimicrobial Therapy • Monitor clinical responses and laboratory results • Frequency of monitoring should increase with severity of infection • Clinical indicators of success • Reduction of fever, resolution of signs/symptoms related to the affected organ • Serum drug levels for toxicity Prophylactic Use of Antimicrobials • Agents are given to prevent infection rather than to treat an established infection: • Surgery • Bacterial endocarditis • Neutropenia • Other indications Acquired Resistance to Antimicrobial Drugs • Over time, organisms develop resistance • May have been highly responsive and then became less susceptible to one or more drugs Microbial Mechanisms of Drug Resistance • Four basic actions • • Inactivate a drug (beta lactamases) Alter the structure of drug target molecules (changes in PBP’s, ribosomes, DNA gyrases) • • Decreased permeability Drug efflux 107 Mechanisms for Acquired Resistance • Spontaneous mutation • • • Random changes in a microbe’s DNA • • • Extrachromosomal DNA is transferred from one bacterium to another Resistance to one drug Conjugation Gram-negative bacteria Multiple drug resistance Antibiotic Use and Drug-Resistant Microbe Emergence • How antibiotic use promotes resistance • • Drugs make conditions favorable for overgrowth of microbes that have acquired mechanisms for resistance Antibiotics that promote resistance • • Broad-spectrum agents do the most to facilitate the emergence of resistance The extent of antibiotic use affects resistance • The more that antibiotics are used, the faster drug-resistant organisms emerge Antibiotic Use and Drug-Resistant Microbe Emergence • Nosocomial infections • • Health care–associated infections (HAI) Superinfection • • New infection that appears during the course of treatment for a primary infection Because superinfections are caused by drug-resistant microbes, they often are difficult to treat Delaying Emergence of Drug Resistance • Promote adherence to appropriate prescribing guidelines • Reduce demand for antibiotics among healthy adults and parents of young children • Emphasize adherence to prescribed antibiotic regimens • Public Health Action Plan to Combat Antimicrobial Resistance 108