Endocrine Pharm II Exam

Posterior Pituitary Oxytocin ● Pitocin - IV infusion Production Location: Supraoptic Nucleus of the Hypothalamus Target location: Uterine muscle, Neuroendocrine reflex Mechanism of Action: ➢ Stimulates uterine contractions via oxytocin receptors ➢ Force and duration of contraction are dose dependent ➢ Milk Ejection ○ Neuroendocrine reflex Place in Therapy: ★ Induce/Speed labor - Contractions ★ Control postpartum bleeding ○ After delivery of the placenta to cause firm uterine contractions ★ Induce therapeutic abortions ADRs: ● Uterine rupture and Tetany ● Fetal distress ● Tachycardia ● N/V ● Vasoconstriction Antidiuretic Hormone ● 8-Arginine Vasopressin (SQ, IM, IV) ● Desmopressin (DDAVP) (INJ, Nasal spray, Tablet) Production Location: Supraoptic Nucleus of the Hypothalamus Target location: Kidneys Mechanism of Action: ➢ Increases blood pressure through fluid retention and vasoconstriction ➢ Regulates water balance by increasing water reabsorption in the kidneys Desmopressin ➢ Chemically related to vasopressin ➢ Lacking BP effects ➢ Stimulates release of Von Willebrand factor from endothelial cells 8-Argentine Vasopressin ➢ Contains ADH/Oxytocin 20:1 Place in Therapy: ★ Replacement therapy for Arginine Vasopressin Deficiency or Resistance 8 Arginine Vasopressin: ★ Hypotension associated with septic shock ★ Resuscitation of pulse less ventricular tachycardia and V Fib Desmopressin: ★ Central DI ★ Nocturnal diuresis - QD PO prior to bedtime ★ Von Willebrand disease ★ Mild Hemophilia (Factor VIII Deficiency) ★ Thrombocytopenia ADRs: ● N, GI cramping, Diarrhea ● SOB ● Nasal congestion, nasal Irritation ● Cation with CAD, HTN ● Beers drug ● FDA Warning: Children treated for PNE are susceptible to hyponatremia and seizures ● PNE treatment should be passed during acute illness due to electrolyte balance Prostaglandin E Analogs ● Misoprostol (oral or vaginal admin) ● Dinoprostone (vaginal gel) Mechanism of Action: ➢ Breakdown of collagen at the cervix ➢ Increase Submucosal water content Place in Therapy: ★ Labor induction ○ Beyond due date but cervix is not ready ★ Cervical ripening Methotrexate - (IM) Mechanism of Action: ➢ Folate reductase inhibitor –interferes with cell production Place in Therapy: ★ Ectopic Pregnancy Tocolytics ⇒ Inibit Uterine Contractions Tocolytic Mechanism of Action Place in Therapy ADRs Magnesium sulfate (IV infusion) ➢ Slows uterine contractions ★ IV infusion, titrate to desired effects. Good for acute onset ● May slow heart and respiratory rates Terbutaline (PO, INJ) ➢ Beta 2 agonist ➢ Inhibits uterine contractions ★ PO form shows little efficacy –should not be used ★ INJ form should be not be used for prolonged treatment ● May increase the heart rates of the mother and fetus Black Box Warning: Facilitating arrhythmias Beyond 48 to 72 hours of preterm labor – increased risk of SE ● ● Nifedipine (PO) ➢ Calcium channel blocker ★ Good for longer term therapy ★ If contractions persist, therapy can be continued with for 48-72 hours ★ After 72 hours, if maintenance is still required, long-acting nifedipine daily can be used. Hydroxyprogest erone (Makena INJ) ➢ Relaxes the uterus and suppresses contractions ★ Once a week by injection into the hip ★ Treatment should begin at 16 weeks and no later than 21 weeks of pregnancy Vaginal Progesterone ★ QD starting between 16 and 20 weeks of gestation Indomethacin ➢ Potent inhibitor of prostaglandin synthesis ➢ Prostaglandins have a role in initiation and maintenance of labor ● ● ● ● ● ● ● Limited to 48 hours to minimize SE Oligohydramnios (usually resolves w/ drug DC) Persistent fetal anuria Renal microcystic lesions Neonatal death premature closure or constriction of the ductus arteriosus Indomethacin therapy is not usually recommended after 32 weeks. Analgesia/Anesthesia During Delivery Systemic analgesia ● ● ● Fentanyl, morphine, nalbuphine/butorphanol Cross the placenta Higher degree of systemic side effects Regional anesthesia ● ● Neuraxial anesthesia –epidural (most common), spinal, combination of both Combination of local anesthetic and opioid –better pain relief; lower doses of each; less side effects General anesthesia ● Antenatal steroids ● Betamethasone IM ● Dexamethasone IM Mechanism of Action: ➢ Br Place in Therapy: ★ Recommended to improve neonatal outcomes when there is a risk of preterm birth ★ Decreases the incidence of neonatal respiratory distress, intracranial hemorrhage, necrotizing enterocolitis or death ★ Recommended for women 24 weeks to 33 weeks at risk of delivery within 7 days Reserved for emergent cesarean sections when neuraxial anesthesia is not an option Group B Streptococci Treatments ● ● ● ● PCN G or ampicillin ⇒ Standard Regimen** Cefazolin (low risk PCN allergy) Clindamycin (severe PCN allergy) Vancomycin (resistance) (Streptococcus agalactiae) Screening: ➢ Between 35-37 weeks gestation ○ If positive ⇒ Give ABX during delivery Neonatal Complicaiotns form Group B Strep: ● Sepsis ● Pneumonia ● Meningitis Prolactinoma Treatment Options Dopamine Agonists: ● Bromocriptine ● Cabergoline Method of Action ➢ dopamine inhibits prolactin release, reducing prolactin levels, shrinking tumors, and restoring pituitary and visual function in most cases. Dopamine Agonist Bromocriptine Advantages ● May be preferred when fertility is an issue ● Easier to administer ○ Longer t ½ = weekly dosing More effective ○ > 50% tumor shrinkage ○ Effective for bromocriptine resistant tumor Better dosing ⇒ DOC Cabergoline ● ● Disadvantages ● ● ● More ADRs NV, HA Orthostasis (same as cabergoline but more often seen with bromocriptine) Oral Contraceptives: ★ For use in microadenoma in a patient not desiring fertility and whose only indication for treatment is amenorrhea Surgery: ★ For patients unable to tolerate medical treatment, unresponsive to medical treatment, increased tumor size Hypothyroidism Treatments Hypothyroidism Treatment Guidelines ● ● ● ● ● T4 – Levothyroxine is preferred Evidence does not support use of LT3/LT4 combinations Do not use T3 in pregnancy T3 may suppress TSH Fluctuations of blood thyroid levels with T3 – short T1/2 TSH Value 4.5-6.9 Patients 65+ ● ● ● Patients <65 Measure TPO antibodies Follow TSH measurement in asymptomatic patients Consider Treatment: ○ Plan for pregnancy ○ Significant hypothyroid symptoms ○ Positive TPO antibodies ○ Goiter No Treatment 7.0-9.9 ● Treat with Levothyroxine ● Consider treatment with Levothyroxine >10 ● Treat with Levothyroxine ● Treat with Levothyroxine ➢ ➢ ➢ ➢ Replacement therapy is initiated with small doses and raised in small increments Life long therapy Orally as a single dose before breakfast IV admin for myxedema coma Clinical Indications for thyroid replacement: ● Approved for use in children & adults as replacement therapy ● Used in the treatment of thyroid nodules or thyroid carcinoma b/c they suppress TSH ● Levothyroxine for use in pregnancy (with hypothyroidism) ○ Increase dose by 25-30% once pregnancy is confirmed ADRs of thyroid hormone administration: ● Seen with overdose/excess administration ● Weight loss, diarrhea, fever ● Angina, increased BP and HR ● Menstrual irregularities, sweating, tremors ● HA, nervousness, insomnia, psychotic behavior Replacement Therapy Lotrix Composition ` ● Synthetic T3/T4 combination in a dose ratio of 4:1 Info ● ● Concern about higher levels of T3 and fluctuation of T3 levels Routine use is not recommended Liothyronine ● T3 – synthetic product; ● Short acting --- promoting hormone fluctuations Desiccated thyroid ● T3/T4 – natural product – porcine product; 8 available strengths ● Often in short supply Levothyroxine ● T4 - synthetic product; 12 available strengths ● ● ● Preferred therapy Thyroid hormone standardization Stable pharmacokinetics, a long half-life, well tolerated May take 3-6 months to see full benefit ● T3 vs. T4? ● Current recommendation is to start patients with levothyroxine (T4) ● If patient is still symptomatic on T4 a 2-month trial of add-on T3 ○ If no improvement after 2 months – d/c T3 (it isn’t working) ● T3 products may increase the risk of CV side effects Precautions and Special considerations for Replacement Therapy: ● Thyroid hormone should be used with caution in patients with underlying heart disease ● LT use has been associated with osteoporosis in postmenopausal women ○ Monitor bone density ● Some drugs may cause hypothyroidism ○ LT therapy with lithium, chlorpromazine, or imipramine ○ Amioderone ⇒ Hypo/Hyper ● Cholestyramine, vitamins and minerals will bind thyroid hormone in the GI tract ○ Seperate doses by 2 hours ● May require an increase in the dose of insulin or oral hypoglycemics ○ Thyroid hormone increases blood sugar levels ○ May exacerbate diabetes or adrenal insuffieiceny ● Estrogens may increase the requirement of thyroid hormone ○ Estrogens increase thyroid hormone binding proteins ● Do not abruptly D/C ● Carefully review of bioavailability before changing brands ○ Check TSH in 4-8 weeks if there are concerns about equivalence ● Pregnancy Category A Levothyroxine MOA/Composition: ➢ T4 - synthetic product; 12 available strengths Place in Therapy: ★ Preferred therapy ⇒ Long half life, well tolerated, stable pharmacokinetics ★ May take 3-6 months to see full benefit Special Considerations: ● The average daily levothyroxine replacement dose is 1.6 mcg/kg of total body weight ○ Monitor Q 6-8 weeks until stabilized ● Some seniors need only 0.5 mcg/kg/day ○ Lower dose for elderly patients ○ Risk of Afib ○ Risk of fracture ○ Recommend starting seniors at 25 mcg/d or less of levothyroxine Hyperthyroidism Hyperthyroidism Treatment Options: 1. Antithyroid drugs 2. Irradiation 3. Surgical removal of the overactive tissue Factors that may require alterations in doses of hyperthyroid or thyroid replacement doses: ● Compliance (does not require dose change but does require education) ● Weight changes ● Age ● Estrogens: pregnancy: OC, postmenopause • GI disease: reduced absorption, celiac, gastritis, bypass, achlorhydria ● Drug interactions Antithyroid Drugs - Radioactive Iodine Method of Action: ➢ Emits Beta and Gamma rays ➢ Gamma rays produce a picture of the thyroid that indicates abnormal activity ➢ Beta radiation remains in the cells and destroys overactive tissue Place in Therapy: ★ Most common treatment for hyperthyroidism ★ May also be used pre op in the treatment of thyroid cancer Special Considerations ● Should not be used during pregnancy or lactation ● Or in women wishing to be pregnant w/in 6 months Antithyroid Drugs - Thioamides ● Propylthiouracil ● Methimazole Method of Action ➢ Inhibit the incorporation of iodine in tyrosine Place in Therapy ★ Methimazole is the preferred agent in the class due to QD/TID dosing and lower ADR profile ★ Pregnancy Category D - Esophageal atresia, omphalocele, aplasia cutis ○ Use propylthiouracil for the first trimester ○ Use methimazole after the first trimester ADRs ● ● ● ● ● ● Rash, fever, myalgia, joint pain, jaundice, nausea, Leukopenia (12% of patients) Agranulocytosis (rare), Goiter formation (secondary to sustained TSH secretion) Propylthiouracil may compromise coagulation ○ Caution in surgical patients or those taking anticoagulation medications Propylthiouracil ○ Black box warning – liver toxicity – sudden/progressive onset 1:2000 children – 1:10,000 adults ○ Hepatotoxicity ○ Usually occurs in the first 180 days Iodides ● Potassium iodine - 50 mg iodine/drop ● Lugol’s solution - 8 mg iodine/drop Method of Action ● Wolff-Chaikoff Effect ⇒ The thyroid gland has a built-in regulatory mechanism to prevent excess thyroid hormone from being produced when presented with large amounts of iodine ○ An increase of iodine will decrease thyroid hormone production ○ Temporary effect Place in Therapy ● May be used short-term prior to thyroid surgery to reduce the size and vascularity of the thyroid gland ● 2-6 drops of Lugol’s solution TID 10 days prior to surgery Treatment of Palpations ★ Propranolol is the traditional choice (Q12-Q8) ★ Metoprolol and atenolol have better dosing schedules Thyroid Storm Burch-Wartofsky Score ● a score below 25 excludes thyroid storm ● 25–45 suggests impending storm ● above 45 suggests thyroid storm Treatment Options ● Thioamide drugs, iodine (ST), ● Beta blockers (dec. HR) ○ Propranolol Thyroid Eye Disease Treatment ● Teprotumumab-trbw (Tepezza) (IV admission Q3 weeks for 8 infusions) Method of Action ● Monoclonal antibody directed at IGF-1R (insulin-like growth factor receptor) ● Inhibits fibroblast activity – reducing inflammation and remodeling ADRs ● Worsening of IBD ● Hyperglycemia Calcium and Bone Disease Hypercalcemia Treatment Options: ● Intravenous fluids - rehydrate ● Loop diuretic (furosemide) ● IV Bisphosphonates ● Calcitonin hormone ● Hemodialysis or peritoneal dialysis Calcitonin ● Intranasal and INJ admin ● Extruded from salmon, greater potency than human calcitonin Method of Action ➢ Decreases plasma Calcium levels Place in Therapy ★ Paget’s disease ★ Hypercalcemia (along with furosemide and bisphosphonates) ADRs ● Allergic reactions ● Drug resistance (antibody formation), N/V/D ● Intranasal administration: rhinitis, insomnia, anxiety, HA Osteoporosis Treatment Guidelines ● Based on high risk of fracture or previous fracture ○ T-score < -2.5 at PA spine, total hip femoral neck, or distal radius ○ FRAX > 3% for hip fracture or > 20% for major osteoporotic fracture ○ Prior pelvis, humerus, or forearm fracture ● Agents recommended include: ○ SERM ⇒ Raloxifene ○ Bisphosphonates ⇒ Alendronate, risedronate zoledronate, ibandronate ○ RANK-L antibody inhibitor ⇒ Denosumab ○ Parathyroid hormone analogs ⇒ Teriparatide, abaloparatide ○ Sclerostin inhibitor ⇒ Romosozumab Bisphosphonates ● Alendronate (Fosamax) po ⇒ 1st Line * ● Risedronate (Actonel) po ⇒ 1st Line * ● Pamidronate inj (Aredia) ● Zoledronic acid inj (Reclast) ● Ibandronate po/inj (Boniva) Method of Action ➢ Inhibit normal and abnormal bone resorption (osteoclast breakdown of bone) in men and women ➢ By inhibiting the enzyme farnesyl diphosphate synthase (required for protein signaling) Place in Therapy ★ Drugs of choice in the management of osteoporosis for most patients with high risk and no prior fracture ○ Significant difference in bone mineral density w/in three months ★ W/in 24hrs - decrease in plasma calcium levels when used for treatment of hypercalcemia of malignancy ★ Alendronate or risedronate have demonstrated efficacy in decreasing hip and spine fracture ⇒ Therefore, considered first-line agents in the class ★ Effective in steroid-induced osteoporosis Special Considerations ● Poorly absorbed, not metabolized, excretion via kidneys and feces ⇒ Generally not recommended in patients with CrCl < 30 ml/min ● Use in combination with calcium and vitamin D for greatest efficacy ● Drug and food interactions ○ Calcium supplements and fortified foods may decrease absorption of bisphosphonates ○ Separate doses by at least one hour ● Current recommendations – bisphosphonates should be dc’d after 5 years of therapy ○ Bone density should be periodically monitored (Q 2years) ○ Agent may be restarted after a “drug holiday” of 3-5 years if the patient still has a high risk of fracture ● Agents appear to have long-lasting effects once dc’d ● All oral products must be taken with a full glass of water and 1 hour before meals ● Patients must remain upright for at least 30 minutes after administration to alleviate esophageal irritation ● Monitor compliance – 50% of patients stop therapy after 1 year ADRS: ● Long-term use complications: jaw osteonecrosis; atypical femur fractures ● Well tolerated - flatulence, gastritis, HA, dry mouth, musculoskeletal pain ● Osteonecrosis of the jaw, often preceded by dental procedures inducing trauma to the bone ○ Consider stopping bisphosphonate 3 months before elective procedure (extraction/implant) and restart 6-8 weeks after procedure ● No substantiated link to esophageal cancer, spontaneous vertebral fractures, atrial fibrillation Denosumab (Prolia) ● 60mg SQ every 6 months – by a healthcare provider Method of Action ➢ Monoclonal antibody – RANKL cytokine inhibitor ➢ Inhibiting RANKL decreases bone resorption and increases bone mass and strength in both cortical and trabecular bone Place in Therapy ★ indicated for high-risk patients or patients who have failed other treatments Special Considerations ● Denosumab discontinuation can lead to increased rebound vertebral fractures ○ Careful screening of patients is necessary ○ Transition to another agent if denosumab is d/c’d ● With calcium 1000 mg daily and at least 400 IU of vitamin D daily ● Delayed administration may result in rebound vertebral fractures due to rapid bone loss - compliance is important! ADRs ● Back pain, pain in extremities, hypercholesterolemia, musculoskeletal pain, cystitis, URI ● Pregnancy Category C ● New Black Box Warning ○ Severe hypocalcemia in patients with advanced CKD, CrCl < 30 ml/min Recombinant Parathyroid Hormone ● Teriparatide (Forteo) – INJ ● Abaloparatide (Tymlos) - INJ Method of Action ● intermittent exposure to PTH activates osteoblasts more than osteoclasts – t1/2 = 1 hour ● Stimulating new bone formation leading to increased bone mineral density Place in Therapy ● Used in the management of severe osteoporosis in men and women ● Second- or third-line therapy ○ Unless fracture risk is very high – then move to first line according to latest guidelines Special Considerations ● Use is limited to 2 years ○ Use > 2 years is associated with a significant increase in osteosarcoma (studies in rats) Romosozumab Administered SQ in an office setting Q month for one year Method of Action ● Monoclonal antibody that blocks the sclerostin protein (sclerostin inhibitor) ● Sclerostin is expressed in osteocytes and some chondrocytes and it inhibits bone formation by osteoblasts ● Inhibiting sclerostin will allow for increased osteoblast activity ● Additional anabolic activity Place in Therapy ★ Reserved for high-risk patients ADRs ● Black Box warning about CV risk ○ MI, stroke, sudden cardiac death ● Atypical fractures, jaw necrosis, arthralgia, HA, hypocalcemia, peripheral edema Estrogens ● Raloxifene (Evista) Method of Action ➢ Oral selective estrogen receptor modulator (SERM) ➢ Estrogenic action on bone; anti-estrogenic action on the uterus and breast ➢ Estrogen with calcium stimulates bone mineralization Place in Therapy ★ Bone mineralization ○ Even when started up to 10 years after menopause ★ Improve mood, reduce vasomotor symptoms, increase sexual satisfaction in postmenopausal women ○ Not used for osteoporosis, but can be used as prevention with other menopause symptoms Vitamin D ● Randomized trials showed that vitamin D supplements do NOT benefit heart disease, cancer or diabetes, depression ● Vitamin D alone has no benefit in preventing fractures ● Sustained intake of more than 50,000 IU/day can produce overt toxicity after several months ○ Hypercalcemia /symptoms of hypercalcemia ● Recommended serum vitamin D levels: ○ Optimal levels: 30-50 ng/mL for both children and adults ● The new RDA is 600 IU for people up to age 70...and 800 IU for those ● over 70 ○ RDA is set at the amount needed to prevent rickets and osteomalacia ○ Do NOT promote vitamin D if there is no reason ● Several vitamin D or vitamin D related agents are available for management of hypocalcemia or osteoporosis ● Selection of which agent to use depends on onset of action and presence of underlying liver or kidney disease ● Thiazide diuretics increase Ca++ reabsorption at the DCT and can be used for hypocalcemia Calcium supplementation ● ● ● ● ● Recommended daily intake ○ 1300 mg for adolescents ○ 1000 mg for women up to 50 and men up to 70 ○ 1200 mg for older adults (than above) Dietary sources are better absorbed than supplements Calcium loss via the kidneys each day = must replace daily Calcium intake of >2000 mg daily may increase the risk of hypercalcemia, kidney stones Link to CV disease has not been substantiated Glucocorticoid Osteoporosis Treatment Options ● Pharmacologic Intervention ○ Ideal body weight – weight loss?, weight-bearing exercise, smoking cessation ○ 1000mg + vitamin D 800 IU ○ Fall Prevention 1. 1st oral bisphosphonate (IV if poor compliance – oral intolerance) 2. 2nd teriparatide/abaloparatide; denosumab 3. 3rd raloxifene a. Low efficacy but use if above agents are not tolerated or not effective Top 200 Alendronate (Fosamax) 70mg po Q week (Post-menopausal osteoporosis) Ibandronate (Boniva) 150mg po Q month Levothyroxine (Synthroid) 12 doses – patient dependent • PO QD Risedronate (Actonel) 35 mg po Q week Denosumab (Prolia) 60 mg SQ Q 6 months Diabetes Mellitus Tx INSULINS Rapid Acting Insulins Method of Action: ➢ Provides quick glucose uptake by mimicking post-meal insulin surges. Place of therapy: ★ Mealtime (bolus) coverage ADRs: ● ● ● Lipodystrophy (rotate sites!) Weight gain (3–6 kg) Hypoglycemia (s/sx: hunger, naPlace in Therapya, HA, blurred vision, paresthesia, confusion) Special Considerations: ● ● ● Always have glucose (candy/juice) on hand Avoid combo with sulfonylureas (↑ hypoglycemia risk) Needs dose adjustment with stress, infection, surgery, or heavy exercise Regular Insulin Method of Action: ➢ Slower onset than rapid-acting but similar action Place in Therapy: ★ Mealtime coverage ★ Can be given IV during emergencies ADRs ● Lower hypoglycemia risk than rapid Intermediate-Acting (NPH) ● Isophane Method of Action: ➢ Addition of protamine to regular insulin increases the duration of action – Q12h ➢ Protamine binds to insulin to decrease absorption Place in Therapy: ★ Gestational DM ★ Newly Diagnosed Patients ★ Patients with Compliance issues ★ Teens unwilling to carb count Long-Acting Insulin ● Glargine (Basaglar, Semeglee) Method of Action: ➢ Deliver a consistent concentration of insulin over 24 hours ➢ Produce relatively “peakless” blood glucose levels Place in Therapy: ★ Administered once daily Ultra Long-Acting Insulin ● (Degludec) Method of Action: ➢ DOA - 42 hours Place Therapy: ★ Useful in patients who need additional dosing with long-acting insulins or high doses ★ The pen delivers 160u/dose Inhaled Insulin ● An alternative to mealtime (bolus) insulin ○ Does not eliminate the need for basal insulin injection ● Patients must be evaluated for pulmonary function before utilizing inhaled insulin ○ Not for patients with COPD, asthma, lung CA, or smokers ○ ○ REMS drug ■ Risk of serious sudden bronchospasms Maximum amount of drug dispensed per inhalation – 12 units INSULIN ADRs: ● Lipodystrophy ○ At the injection site ○ The skin eventually becomes pitted and concave ○ Rotating injection sites will decrease risk ● Weight Gain ○ 3-6kg gain is typical ● Hypoglycemia (with excess dosing) ○ s/s – hunger, nausea, HA, blurred vision, fatigue, anxiety, nervousness, confusion, paresthesia ■ Glucagon, candy bars, fruit juices, soda will supply an adequate amount of glucose to correct hypoglycemia ○ Avoid using insulin w/ sulfonylureas – highest risk of hypoglycemia ○ Short acting insulins are better at decreasing hypoglycemia risks ○ 100, 000 ER visits per year are due to insulin-related errors or hypoglycemia When should we consider insulin?? ➔ Reconsider routinely using insulin immediately if T2DM presents with BG 300-350+ ➔ Changing Insulin requirements ● Infection, illness, surgery, stress ⇒ increase blood glucose levels requiring higher doses of insulin ➔ Heavy exercise or not eating ● may require lower insulin doses Dosing ● Expressed as units – 25 units = 1 mg ● No standard dose ○ Weight-based; obese patients may need higher doses ● Initial daily doses are 20 – 60 units ○ Some patients may need 300-500 units daily to achieve control ● Blood glucose levels vary between diabetics and their dietary and exercise patterns ○ 1 unit of insulin covers 15 grams of carbohydrates ● Standard insulin preps are available in vials of 100 units per ml High dose preps available 500 units/ml ○ Caution --- overdose potential is high ○ Consider for patients who need > 200 units per day to minimize injection volume ○ Onset w/in 30 minutes – duration 12-24 hours Usually administered SQ in the arm, thigh, or abdomen Insulin Delivery Interactions ● Pens: Prime before Place in Therapy (except dulaglutide) The pen delivers 160u/dose ● Pumps: Lower A1C, ↓ hypoglycemia ○ Better control over basal insulin dosage ○ Bolus doses calculated to fractions of a unit ○ Calculators in the pump that may help with determining bolus infusion dosages ○ Less long-term complications secondary to tighter glucose control ● Inhaled insulin: CI in asthma, COPD, smokers. Must evaluate pulmonary function. REMS drug. Drug Interactions ● ● ● Salicylates, β-blockers, MAOIs may mask or potentiate hypoglycemia Risk of hypokalemia: insulin pushes K+ intracellularly—monitor when using diuretics, digoxin, ACEi Do not start insulin if K+ < 3.3 mEq/L ORAL HYPOGLYCEMICS Biguanides ● Metformin Method of Action: ➢ Activates AMPK → ↓ hepatic glucose production (no insulin effect) ➢ Suppresses hepatic gluconeogenesis Place in Therapy: ★ First-line for T2DM ★ Pediatric Place in Therapy approved (10+ yrs) ★ May be used as monotherapy or in combination with other agents ADRs: ● ● GI: N/V/D, flatulence ⇒ PROFOUND GI effects*** Black Box Warning: Lactic acidosis ○ (fatigue, myalgia, respiratory distress, GI distress) ● B12 deficiency with long term use ○ Consider periodic measurement of B12 levels and supplementation as needed Contraindications: ● ● ● Kidney insufficiency ⇒ Avoid in CrCl <30 mL/min, hold 48 hrs pre/post contrast imaging ⇒ Risk of Lactic acidosis Patients with h/o COPD or cardiac function impairment should NOT be prescribed metformin ○ Potential of lactate accumulation in hypoxic conditions The risk of lactic acidosis is increased in hepatic impairment Special Considerations: ● ● ● Caution in hepatic, heart failure, COPD Avoid alcohol Titrate over 4 weeks to reduce GI side effects Sulfonylureas ● ● ● Glipizide - preferred in class Glyburide Glimepiride Method of Action: ➢ Stimulates insulin secretion ➢ Long acting: duration 16-24 hours ➢ Slow onset: 1-4 hours Place in Therapy: ★ Best in early T2DM (pancreas must still function) ADRs: ● ● ● ● ● ● Hypoglycemia (profound, long-acting)** ○ sweating, tremors, weakness, anxiety Weight gain, rash, photosensitivity Increased BUN, SCr, LDL, AST, alkaline phosphatase Rare: hemolytic anemia, leukopenia, thrombocytopenia, aplastic anemia Beer's list (elderly) Contraindications: ● Liver/renal disease ● Pre-op: switch to insulin Thiazolidinediones (TZDs) ● Pioglitazone Method of Action: ➢ Increases insulin sensitivity; reduces resistance Place in Therapy: ★ 3rd/4th line for T2DM; niche for lipodystrophy (HIV) and MASH ★ Safe in renal impairment ADRs: ● ● ● Black Box Warning: Congestive Heart Failure Weight gain, edema, HF exacerbation Risk of fractures, macular edema Bladder cancer risk (long-term Place in Therapy) Contraindications: ● Class III/IV HF DPP-4 (“Gliptins”) ● ● ● ● Sitagliptin Saxagliptin Alogliptin Linagliptin Method of Action: ➢ Prevents incretin breakdown → ↑ GLP-1/GIP → ↑ insulin, ↓ glucagon ➢ PK: Saxagliptin – CYP450; Sitagliptin – renal dose adjust Place in Therapy: ★ T2DM; NOT with GLP-1 agonists ★ Weight neutral, low hypoglycemia risk ADRs: ● ● URI, HA, nasopharyngitis Joint pain, pancreatitis, ↑ HF risk Amylin Analog ● Pramlintide Method of Action: ➢ Slows gastric emptying, suppresses glucagon, ↑ satiety ➢ PK: DOA ~3 hours, refrigerate Place in Therapy: ★ T1DM or T2DM on mealtime insulin ADRs: ● N/V, HA, lethargy ● BBW: Severe hypoglycemia ● Gastroparesis GLP-1 Agonists (incretin mimetics) ● ● ● Exenatide Liraglutide Semaglutide Method of Action: ➢ ↑ satiety, ↓ gastric emptying, ↓ glucagon, ↑ insulin, ↓ hepatic glucose output Place in Therapy: ★ 1st/2nd line for T2DM ★ Weight loss ADRs: ● ● ● N/V (20–40%) Gallbladder disease, antibody formation BBW: Thyroid C-cell tumors (REMS drug) Contraindications ● ● ● ● CrCl <30 Pregnancy Gastroparesis PMH of thyroid CA or pancreatitis Special Considerations: ● Refrigerate, stop 1 week before elective surgery Dual GIP/GLP-1 Agonist ● Tirzepatide ("Twincretin") Method of Action: ➢ Slower Enhanced weight loss and glucose control Place in Therapy: ★ Alternative to adding or increasing insulin SGLT-2 Inhibitors “Flozins” ● ● ● ● ● Canagliflozin Dapagliflozin Empagliflozin Ertugliflozin Bexagliflozin Method of Action: ➢ Increase glucose excretion in urine by inhibiting sodium glucose co-transporter 2 in the kidney ➢ Resulting in less glucose being reabsorbed in the proximal tubule Place in Therapy ★ Glycemic control + Kidney protection ★ Decreases cardiovascular morbidity and mortality Considerations ● Considerations ○ Lowers HgA1c by 1%; Weight loss – 4-7lbs; Increased LDL – 4-8% ● Rarely causes hypoglycemia ● Take 30 minutes before first meal of the day – orally administered ADRs ● Increase glucose in urine ○ Increased diuresis, urinary tract infections, yeast infections** ○ Avoid in patients with CrCl < 45ml/min ○ Some evidence of renal protection by lowering intraglomerular pressure ● Small increased risk of bladder cancer seen with canagliflozin ● FDA Black Box Warning – 2018 - Fournier’s gangrene – men and women – rare finding ○ necrotizing fasciitis of the perineum and genital region ● Hypotension (secondary to dehydration, UTI) ● Ketoacidosis ○ Can occur with glucose levels near normal or only slightly elevated ■ Ketone strips are not very sensitive – may not detect early ketosis ○ Avoid in patients with renal impairment; dose adjust in patients with eGFR < 60ml/min/1.73m2 ○ Stop agent 3 days before surgery, colonoscopy to avoid ketoacidosis ● Bacteremia HYPOGLYCEMIA MANAGEMENT Patient Status Conscious with BG <70 Treatment 15–20g glucose ● Glucagon - IM ⇒ Fastest ● 3 sugar packets in water ● ¾ cup juice, soft drink ● Siz hard candies ● 1 TBL honey Recheck BG in 15 min Unconscious IV Dextrose 50% Complication Treatment Peripheral Neuropathy ● ● ● TCAs: Nortriptyline SNRIs: Duloxetine, Venlafaxine Gabapentinoids: Gabapentin, Pregabalin Diabetic Kidney Disease ● Finerenone (MRA): Add-on to ACEi/ARB PEDIATRIC T2DM ● First-line: Metformin ● Add-on: Insulin if needed TREATMENT GUIDELINES (ADA 2025 Position Statement) 1. Individualization: Base therapy on patient values, affordability, goals. 2. First-Line: GLP-1 or SGLT2 if CV/renal comorbidities; metformin remains cornerstone. 3. 3-Month Rule: Try monotherapy 3 months before intensifying (unless A1C >9%). 4. Lifestyle: Diet, education, weight loss (BMI <25 general; <23 Asians). 5. BP/Cholesterol: BP goal <130/80; statins first-line; ACEi/ARB for CKD or HTN. 6. Monitoring: ○ A1C: q3 months if uncontrolled ○ Yearly eye exam ○ Feet: inspect every visit DRUG INTERACTIONS ● ● ● ● ● ● ● ● ● Corticosteroids: ↑ glucose TZDs: Worsen HF Antipsychotics: ↑ diabetes risk, 10x DKA risk GLP-1 agonists + OCPs: ↓ absorption (backup needed 1st month) Sulfonylureas + insulin: Hypoglycemia DPP-4 + GLP-1: Duplicate Method of Action β-blockers: Mask hypoglycemia SGLT2 inhibitors: ↑ UTI risk Alcohol + Metformin: ↑ lactic acidosis ● Fluoroquinolones + Sulfonylureas: ↑ hypoglycemia risk Adrenal Hormones Suprarenal (Adrenal) Glands ● ● ● Divided into the cortex and medulla Yellow color of the cortex is due to stored lipids and cholesterol Three zones of the Adrenal Cortex (dehydroepiandrosterone) Zona glomerulosa (clustered cells) ● ● ● 15% of the volume of the cortex Secretes mineralocorticoids Ex. aldosterone ● Zona fasciculata (layered rows) ● Zona reticularis (reticular tissue) ● ● ● 78% of the volume of the cortex • Secretes glucocorticoids • Ex. Cortisol ● ● ● ● 7% of the volume of the cortex • Secretes sex steroids (androgens) • androstenedione and DHEA Glucocorticoids ● Stress, physical or mental, produces an increase in CRH and ACTH secretion leading to increased cortisol secretion ○ exercise, cold weather, infections, surgery, anxiety ○ to maintain glucose levels ● The glucocorticoids have some mineralocorticoid activity ○ Sodium and water retention ○ Edema and HTN ● Pharmacologic Effects ○ Replacement therapy for adrenal insufficiency (Addison’s Disease) ○ Treatment of inflammatory (acute or chronic) or allergic conditions ■ Cortisol reduces the production of cyclooxygenase and phospholipase A2, decreases leukocyte migration and cytokine production and inhibits antigen presentation ● Addison’s Disease Diagnosis ○ Following ACTH administration, plasma cortisol and 17-hydroxycorticosteroids (17-OHCS) are measured ○ If plasma steroid levels do not rise, primary adrenal failure (Addison’s Disease) is present ● Patients must receive chronic hormone replacement therapy ● Naturally occurring glucocorticoids are most often used ○ Cortisone, hydrocortisone ● Mineralocorticoids may be given additionally to patients who continue to lose sodium ● The most potent anti-inflammatory agents available ● Glucocorticoids interfere with all stages of inflammation ● Most cells have glucocorticoid receptors located in their cytoplasm ○ Activated receptors bind to DNA segments to activate transcription of anti-inflammatory proteins or prevents pro-inflammatory protein production ● ● ● ● Affects macrophages > B cells > T cells Also inhibit the secretion of vasoactive substances from macrophages ○ Limits capillary dilation and permeability Restrict accumulation of WBCs by decreasing cytokine secretion and capillary permeability ○ Inhibit the release of lysosome enzymes, decreasing destruction of healthy tissue Synthetic Steroids ○ Alterations in naturally occurring glucocorticoids • Increased anti-inflammatory potency and longer duration of action Clinical Indications ● Adrenal insufficiency ● Management of leukemias and lymphomas ● Acute and chronic inflammatory conditions ● Asthma ● Off-label uses ○ Acute mountain sickness (altitude sickness) ○ Bacterial meningitis ○ COPD- asthma ○ Grave’s ophthalmopathy ○ RDS ○ Septic shock ○ Spinal cord injury ○ Keloid treatment Administration ● Oral, IV, IM, topical, intra-nasal, inhalation ⇒ MANY formulations ● In general the lowest dose to treat the disease is used ● Intra-articular administration is used in the treatment of osteoarthritis, keloids ● Joint damage may occur with frequent use ● IM depot formulations of methylprednisolone are available for slow-release ● Topical use is indicated for the treatment of inflammatory and pruritic dermatoses Steroid Potency ● Agents ending in “isone” have relatively low potency at the GR receptor and have significant mineralocorticoid receptor activity ○ Hydrocortisone, cortisone, prednisone ● Agents ending in “solone” have increased potency at the GR receptor and less activity at the mineralocorticoid receptor ○ Prednisolone, methylprednisolone, triamcinolon ● Agents ending in “methasone” have very high potency at the GR receptor and very low potency at the mineralocorticoid receptor ○ Betamethasone, dexamethasone Medrol Dose Pal ● Methylprednisolone ● Used for 6 days tapering from 6 (4mg) tablets to 1 tablet OTC preps ○ ○ Hydrocortisone 0.5% to 1% ■ Ointment, cream, spray ■ Indicated for the temporary treatment of minor skin irritations; itching, rash, insect bites, contact dermatitis Fluticasone (Flonase) & Triamcinolone (Nasacort) ■ Allergic rhinitis ADRs ● Related to the dose and duration of therapy ● Usual ADRs: Increased appetite, weight gain, indigestion, restlessness, hirsutism ● Less Frequent ADRs ○ Changes in skin color, dizziness, increased sweating, flushing, rash, GI ulceration ● LT/high dose therapy ○ Iatrogenic Cushing’s Syndrome, steroid psychosis (mood changes, insomnia, euphoria, psychological dependency) ○ Psychiatric symptoms are seen in 1% of patients <40mg/day; 18% of patients > 80mg/day of prednisone ● Abrupt w/drawal may lead to symptoms of adrenal insufficiency ○ The adrenal glands atrophy with prolonged use secondary to inactivity ○ They are temporarily unable to produce sufficient endogenous glucocorticoids ○ LT or high dose therapies must be slowly tapered off to allow the adrenal glands to resume steroid production ○ Caution in patients using long-term corticosteroids who experience trauma or severe infection ■ Increased doses of corticosteroids may be necessary ■ INC dose in times of stress Tapering ● Tapering ○ For patients taking more than 20 mg/day of prednisone for longer than 2 weeks ○ Tapering by 5% to 20% every one to two weeks ● Alternate-Day Therapy (ADT) ○ Intended to reduce the ADRs seen with LT use ○ Prevent adrenal atrophy b/c the adrenal glands are “allowed” to secrete hormone QOD ○ May not provide enough anti-inflammatory effects for some patients Mineralocorticoids ● Hormones secreted by the zona glomerulosa layer of the adrenal cortex ○ Aldosterone ● Function – regulate body fluid balance ○ Aldosterone acts on the distal tubules to increase the reabsorption of sodium (water) and excretion of potassium ● Replacement therapy is necessary for Hypoaldosteronism if sodium/fluid balance is not controlled by glucocorticoid replacement ○ Fludrocortisone ■ Mineralocorticoid properties with some glucocorticoid properties • Used in conjunction with cortisone or hydrocortisone in the treatment of adrenal insufficiency - Addison’s disease ■ ADRs: Sodium & water retention, hypokalemia, edema, HTN, arrhythmias, muscle weakness, HF Hyperaldosteronism ● Conn’s Syndrome ● Spironolactone ■ Aldosterone inhibitor; potassium-sparing diuretic • ADRs Spironolactone: ■ Hyperkalemia, hyponatremia, hypotension ■ Gynecomastia, impotence (additional blockage of cortical androgens) ○ Also used in the management of HTN, HF, acne Special Considerations ● Patients should be monitored closely for ADRs ● Steroids should be used with caution in patients with ○ GI ulcers (ulcerogenic) ○ Renal disease ○ HF ○ Ocular herpes simplex ○ DM ○ Emotional instability/psychotic tendencies ● Live vaccinations should not be given to patients taking steroids for immunosuppression ○ not replacement doses ● Growth delay may be seen in children on LT steroid therapy ● Pregnancy C category ● Drug Interactions Drug Brand Name Dose Prednisone Sterapred Orapred 5-60mg po QD Methylprednisolone (Medrol Dose Pak) 24mg tapering to 4 mg over 6 days Mometasone (Nasonex)OTC – nasal spray 2 sprays/nostril QD (50mcg/spray) Budesonide/formoterol (Symbicort) 2 inhalations BID 80/4.5 160/4.5 Fluticasone/salmeterol (Advair ) 2 inhalations BID 100/50 250/50 500/50 Triamcinolone (Aristocort) 0.5% cream Fluticasone propionate (Flonase) – OTC – nasal spray 2 sprays/nostril QD (50mcg/spray) Estrogen + SERMs + Contraceptives Estrogen Places in Therapy ★ Contraception ★ HRT: Postmenopausal, Hypogonadism, Premature menopause, Surgical menopause ★ Estrogen for Bone Health ○ Estrogen therapy not indicated for the treatment of osteoporosis ○ Best used for prevention of osteoporosis when another menopause indication is present (to justify ADR risk) ★ Combination estrogen/progesterone therapy is indicated in patients with a uterus ○ Estrogen induces endometrial proliferation (potential for endometrial cancer) ⇒ progesterone decreases the risk ★ Combination therapy approved for hot flashes during menopause ○ Conjugated estrogens/medroxyprogesterone acetate (Prempro) ○ Estradiol/progesterone (Bijuva) ADRs ● ● ● ● ● ● ● Nausea Breast tenderness Thromboembolic events MI Endometrial cancer (unopposed estrogen) Metabolism (hepatic) ○ Patients with underlying liver damage may see increased estrogen concentrations secondary to reduced metabolism BLACK BOX WARNING - (including topicals) ○ Warning: Endometrial Cancer, Cardiovascular Disorders, Breast Cancer, and Probable Dementia Menopausal HRT ● ● Progesterone is included for patients who have an intact uterus ○ Decrease risk of endometrial cancer The amount of estrogen is less than contraception ⇒ Less SE Place In Therapy ★ Consider suggesting for menopausal symptoms in healthy women < 60 years old within 10 years of their last period ○ Higher risk of stroke, heart disease, and dementia when started in older patients ○ Most effective when isnitutitaured at early signs of menopause ★ Women who have only urogenital symptoms should be treated with topical products (first-line) ○ Vaginal atrophy ○ Estradiol tablets, cream, ring, softgel ★ For treatment of hot flashes – seen in up to 85% of women ★ NOT for the prevention of CV disease, osteoporosis, or dementia ★ Estrogen deficiency (age < 52) ★ Vasomotor symptoms, GU symptoms of menopause ★ Prevention of osteoporosis (not treatment) – usually not as stand alone therapy but in combination with another indication Contraindications ● Hx of breast cancer, CHD, previous VTE, TIA or stroke ● Active liver disease ● Unexplained vaginal bleeding ● High-risk endometrial cancer Ideal Candidates for menopausal HT ● Symptomatic, healthy woman ● Age 59 or less ● Less than 10 years post-menopause ● Low CVD risk ○ 10-year ASCVD risk < 5% ● Average risk of breast cancer ○ No h/o chest radiation ○ No history of breast biopsy ○ No family history or known genetic risk Treatment for Menopausal Symptoms Genitourinary Syndrome + Vaginal Atrophy ● ● Hot Flashes/Other Menopausal Symptoms ● ● ● ● Non Hormonal Vaginal moisturizers ○ Use on an ongoing basis ○ Hyaluronic acid (Revaree) Q2-3 days ○ Polycarbophil (Replens) Q3 days Vaginal lubricants ○ Use at the time of vaginal insertion ○ Water-based lubricants ○ Oils – cannot be used with condoms, dilators or vibrators ○ Silicone-based – cannot be used with dilators or vibrators ● Hormonal Urogenital symptoms should be treated with topical products (first-line) ○ Estradiol tablets, cream, ring, softgel SSRIs or SNRIs can be used to treat hot flashes in women who do not tolerate HRT ○ Lower doses than used for depression ○ Paroxetine, citalopram, venlafaxine have documented efficacy ○ Fluoxetine has not been shown to be effective in relie Gabapentinoids ○ Pregablin, gabapentin Fezolinetant (Veozah) – treatment of VMS ○ Centrally acting NK3 receptor antagonist ○ Check LFTs at 3 6, and 9 months ○ ADRs – liver toxicity, HA, GI disturbances Non-pharmacologic ○ Promising outcomes - weight loss Selective Estrogen Receptor Modulators (SERMs) ● Tamoxifen ● Raloxifene (Evista) ● Clomiphene Method of Action ➢ Bind to estrogen receptors to exert estrogenic or anti-estrogenic effects ➢ Different effects depending on receptor ➢ Blocks estrogen receptors in breast tissue ➢ Decreases bone resorption and bone turnover (Raloxifene) Clomiphene MOA: ➢ Interferes with the negative feedback of estrogens on the hypothalamus (promotes continued GnRH release) ○ Binds to both ER-alpha and ER-beta receptors and blocks estrogen activation ○ Subsequently increases FSH and LH release Place in Therapy Tamoxifen ★ Treatment of breast cancer ○ Can be used in pre/post menopausal women > 35 years old ★ Prophylaxis of breast cancer in high-risk patients ○ Patients with 1.67% risk or higher over 5 years ○ First degree relative with breast cancer ○ No contraindications ADRs ● ● ● ● ● ● Raloxifene Clomiphene ★ No effect on endometrial tissue ★ Decreases LDL ★ Prophylaxis of breast CA in high-risk patients ○ Postmenpausal women only ○ Not enough estrogen lowering effects to use with ovarian production of estrogen ★ Prevention and treatment of postmenopausal osteoporosis Hot flashes Nausea Vaginal bleeding Hyperplasia of endometrium, endometrial cancer DVT, PE Drug interactions, metabolized via CYP450 system Estrogen/SERM Combination ● Duavee (conjugated estrogens 0.45 mg plus bazedoxifene 20 mg) ★ Indicated for the treatment of infertility in women due to anovulation, irregular ovulation or luteal phase defects including women with PCOS ○ Clomiphene acts as an antiestrogen (SERM) in the uterus, cervix, and vagina ★ Not effective in women with ovulatory dysfunction due to pituitary or ovarian failure Clomiphene ADRs: ● HA, N, dizziness, vasomotor flushing, visual disturbances ● Ovarian enlargement, multiple births (several oocytes develop and are ovulated together – 5-10%) Method of Action ➢ Bazedoxifene is added to inhibit estrogen's endometrial effects as an alternative to a progestin ➢ Bazedoxifene is a selective estrogen receptor modulator Place in Therapy: ★ For treating moderate to severe hot flashes and preventing osteoporosis ★ Recommend saving Duavee for women who want to use estrogen for menopausal symptoms but need an alternative to a progestin Aromatase Inhibtors ● Letrozole (Femara) ● Anastrozole (Arimidex) ● Exemestane (Aromasin) Method of Action ➢ Estrogens are produced by the conversion of androgens by aromatase Place in Therapy Letrozole and Anatrazole ★ For the treatment of hormonally-responsive breast cancer after surgery in postmenopausal women after SERMs (tamoxifen) ★ Off-label for ovulation induction in females with PCOS ★ Better efficacy than clomiphene ● ADRs ● ● ● ● Exemestane ★ For the treatment and prevention of breast CA in postmenopausal women ★ Does not suppress ovarian estrogen production enough in premenopausal women ★ Avoid in osteoporosis – may decrease bone density Off-label use (both agents) The anti-estrogen action is preferred by athletes for use with anabolic steroids to reduce and prevent the formation of gynecomastia Joint or musculoskeletal pain Hot flashes Insomnia Weight gain Progesterone ● Produced in response to LH by males and females ● Also synthesized in the adrenal cortex by both sexes Places in Therapy: ★ Hormonal deficiencies – replacement therapy ★ Contraception ○ Norethindrone, norgestrel, levonorgestrel ○ Medroxyprogesterone acetate ★ Dysmenorrhea ★ Endometriosis ★ Infertility ADRs ● ● ● ● ● ● HA Depression Weight gain Decreased libido Increased LDL, decreased HDL Acne, hirsutism Antiprofestin ● Mifepristone Method of Action ➢ Acts as a competitive progesterone receptor antagonist (in the absence of progesterone, mifepristone acts as a partial agonist) Place in Therapy ● Administration early in pregnancy results in abortion of the embryo ● Often combined with misoprostol (prostaglandin analog) to induce uterine contraction – administered 2 days after mifepristone ADRs ● Significant uterine bleeding ● Incomplete abortion Contraceptives Mechanisms of Action ➢ Preventing ovulation (most common) ➢ Impairing gametogenesis ➢ Interfering with gestation Drug Interactions ● Antibiotics ⇒ rifampin, rifabutin, rifapentine ● Enzyme inducers - PIs, warfarin, carbamazepine, phenytoin, topiramate Places in Therapy: ● Polycystic ovarian syndrome ● Dysmenorrhea, menorrhagia ● Endometriosis ● Acne, hirsutism – estrogen component ○ Decrease androgen levels by inhibiting follicle activity and increasing hormone-binding globulin to bind more androgen ● Irregular periods Estrogen - ADRs ● Breast fullness, depression, fluid retention, melasma ● HA, N/V, breast cancer, ● CV: thromboembolic events, HTN, MI ○ Increased risk in pts >35 ○ Increases with age, smoking, history of clotting disorders Progesterone - ADRs ● Abnormal glucose tolerance, weight gain ● Progestins increase LDL and decrease HDL ● Edema, HTN, depression Contraindications ● CV disease, estrogen-dependent neoplasms, liver disease, pregnancy ● Discourage using hormonal therapy (especially estrogen) in women over 35 years old with thrombosis risk factors – smoking, CVD, previous history ● Hormonal contraceptives should be discontinued by age 50 ○ Safety is not established COCs ⇒ developed to mimic the menstrual cycle and provide predictable monthly bleeding Monophasic ● Constant dose of estrogen and progestin Triphasic ● Attempt to mimic the natural female cycle with Four phasic ● ● Natazia Estradiol valerate 3 mg x Extended Cycle - Seasonale ● 84 active pills followed by 7 days of placebo Extended Cycle - Quartette ● 3 months of 4-phase drug administration with ● ● given over 21 days Followed by 7 days of placebo Can be used continuously – skip the placebo pills – for continued contraception Example: Loestrin 21, Lo-ovral 28 ● ● a constant dose of estrogen with increasing doses of progestin given over three successive 7 day periods Followed by 7 days of placebo Example: Ortho Tricyclin; Ortho-Novum 7/7/7 ● 2 days, then 2 mg x 22 days, then 1 mg x 2 days, then 2-day pill-free interval Dienogest none x 2 days, then 2 mg x 5 days, then 3 mg x 17 days, then none x 4 days Instructions for Pateint ➔ Keep it simple ➔ Monophasic – no need to add iron or folic acid ➔ Start today – no need to wait until the Sunday after the next period ● Any contraceptive can be started any time you are reasonably certain a woman is not pregnant ● Per CDC – meet one of these criteria ○ < 7 days after the start of normal menses ○ Has not had sexual intercourse since the start of last normal menses ○ Has been correctly and consistently using a reliable method of contraception ○ Is < 7 days from spontaneously or induced abortion ○ Is w/in 4 weeks postpartum ○ Is fully or near fully breastfeeding (85% of feeds are breastfeeds) w/ amenorrhea Transdermal Patch ● Ethinyl estradiol and norelgestromin or levonorgestrel ● Applied each week for three weeks then off for one week ○ Can skip the off week for continuous contraception ADRs ● Less effective in patients > 90kg ● Total estrogen exposure is up to 60% more than oral contraceptives one week of placebo Useful in patients with dysmenorrhea ○ ○ ○ Increased risk of thromboembolic events Increased SE risk Contraindicated in patients with BMI >/= 30 Vaginal Ring ● Contains ethinyl estradiol & etonogestrel ○ Lower estrogen exposure then OCs ○ The ring is inserted into the vagina and left in place for 3 weeks with one week off ○ New ring inserted for next cycle ● Ethinyl estradiol/segesterone (Annovera) –“long-term” vaginal contraceptive that lasts for a year ○ Same ring inserted For next cycle ADRs/CIs/Disadvantages ● Rings may occasionally slip or be expelled accidentally ○ Rinse the ring off and place it back ASAP ○ If more than 2 hours, use backup contraception ○ Do not recommend for patients with BMI > 29 Progestin-Only Contraceptives ● ● ● Oral agents “mini-pill” ⇒ Norethindrone (Micronor) Opill (norgestrel) ⇒ OTC oral contraceptive Short t ½ ○ Remind patients that compliance is important ○ No “free” week – all pills contain active ingredients ○ Missing a dose by 3 hours may increase the chance of pregnancy ○ Backup contraception is recommended for 7 days after missing 2 or more pills Method of Action ➢ Partial suppression of ovulation and alteration of cervical mucus (increasing viscosity) ➢ w/o the addition of estrogen, women are more likely to ovulate ➢ Progestin-only pills – block ovulation in only 60-80% of cycles ⇒ More irregular bleeding Place in Therapy ★ May be used for patients who are breastfeeding or intolerant of estrogen Injectable progestin ● ● ● ● ● ● Medroxyprogesterone acetate (Depo-provera) Administered IM by a provider or SQ by the patient Q 3 months (t ½ - 45 days) Weight gain (5 lbs in 5 years), amenorrhea Fertility may be delayed for several months after d/c use FDA black box warning – potential bone loss with long-term use Limit use to 2 years unless other BC options are not available Progestin implants ● ● ● ● ● ● ● Etonogestrel (Nexplanon) One 4 cm capsule is placed subdermally in the upper arm Provides contraception for three years Nearly as reliable as sterilization Reversible contraception when surgically removed - with in one week ADRs: irregular menstrual bleeding, HA Less effective in patients > 130% of ideal body weight Post-Coital Contraception ● Levonorgestrel (Plan B - OTC) ● Preventeza – newest OTC agent – 1 dose (1.5mg levonorgestrel) Method of Action ➢ High doses of progestin ➢ Work to inhibit ovulation Progestin intrauterine device ● ● ● Levonorgestrel (Mirena) Highly effective LT contraception – 5 years Not associated with an increased risk of infertility Patient Instructions ● Administer within 72 hours and repeat dose 12 hours after first dose ● Efficacy decreases in patients > 154 lbs ● 95% pregnancy prevention when taken w/in 24 hours; 50% prevention when used w/in 72 hours Ulipristal acetate (Ella) 30mg tablet - Rx ● Selective progesterone receptor modulator (SPRM) ● Can delay follicle rupture which may provide an extra couple of days of coverage ● Approved for use up to 5 days after unprotected sex or birth control failure ● Efficacy decreases in patients > 187 lbs COC Prescription Pearls ★ Effective within one week ★ Extended interval – safe not to have a period ★ In clinical trials – no weight gain ★ Most ADRs resolve within 2 months ★ 4 months of spotting is normal ★ Too much estrogen ⇒ Nausea, breast tenderness, increased blood pressure, melasma, headache, bloating. ★ Too little estrogen ⇒ Early or mid-cycle breakthrough bleeding, increased spotting ◦ Too much progestin... Breast tenderness, headache, fatigue, changes in mood ★ Too little progestin ⇒ Late breakthrough bleeding. ★ Androgenic effects (more common with progestin) ⇒ Increased appetite, weight gain, acne, oily skin, hirsutism, increased LDL cholesterol, decreased HDL cholesterol. PCOS + Menstrual Disorders Polycystic Ovarian Syndrome Treatment ● ● ● ● ● ● Weight loss if above ideal body weight- #1** ○ 5-10% recommended Combined oral contraceptives – first-line for irregular menses, acne, and hirsutism Letrozole – first-line for infertility Clomiphene – second-line (less effective) Spironolactone ○ Can help with hirsutism or acne ○ Used as an add-on to hormonal contraceptives ○ Avoid in pregnancy Metformin ○ Beneficial if prediabetes is an issue ○ Not first-line for irregular periods, hirsutism or infertility ○ Currently not much evidence that it is better than lifestyle changes Polycystic Ovarian Syndrome Treatment ● ● ● ● ● ● ● ● Combo hormonal contraceptives ○ First line for most ○ Continued use is advantageous for women with dysmenorrhea Depot medroxyprogesterone or progestin-only pill (second line) ○ More evidence of efficacy than an IUD GnRH agonists ○ Trigger the GnRH receptor, eventually lowering estrogen levels (negative feedback) and leading to “medical menopause” ○ May see an initial flare of symptoms ○ Parenterally administered implant/nasal spray/IM ○ Goserelin (Zoladex), nafarelin (Synarel), triptorelin (Trelstar) GnRH antagonist ○ Directly blocks the GnRH receptors – estrogen levels are decreased ○ Elagolix (Orilissa) – newest agent ■ No initial flare; less severe menopause symptoms ■ Oral agent Aromatase inhibitors can be used to decrease estrogen formation if other therapies fail Danazol is no longer preferred therapy due to ADRs ○ Orally available synthetic steroid – antiestrogenic, androgenic Induces a low estrogen environment which leads to atrophy of endometrial tissue Teratogenic, androgenic ADRs (hair growth, acne, mood changes) Dysmenorrhea ● NSAIDs – pain management ● Hormonal contraceptives ○ OC, progestin IUD, etc. ● Surgery ● Antifibrinolytic - tranexamic acid (Lysteda) ○ Works to decrease excessive bleeding ■ Binds the 5 lysine binding sites on plasminogen to inhibit plasmin formation and displace plasminogen from the fibrin surface ■ It may also directly inhibit plasmin and partially inhibit fibrinolysis at higher concentrations ● Given for a maximum of 5 days during menses each month ● Can increase clot risk – do not combine with COC! Heavy Menstrual Bleeding Treatment ● R/O and treat underlying causes ● NSAIDs ○ 20-50% reduction in blood loss in 75% of patients + help with dysmenorrhea ■ High PG levels are often found in uterine tissue of women with heavy menstrual bleeding ○ Start on the day before or day of menses and continued until menses stops ● Oral combined contraceptives ○ Equal efficacy compared to NSAIDs ● Antifibrinolytics ○ Modest efficacy – ADRs, contraindications, cost limit use ○ Elevated levels of plasminogen activators have been found in women with heavy menstrual bleeding ○ Tranexamic acid – dosed TID x 5 days during menses Qmonth ○ Increases clot risk – do not combine with COC ● Levonorgestrel-releasing IUD ○ Significantly reduce heavy menstrual bleeding ○ Up to 86% reduction in blood loss at 3 months More effective than oral treatments Androgens Androgens Overview of Androgens ● Steroids that have masculinizing effects in males and females ● Testosterone: The most important androgen in humans ● Synthesized by Leydig cells in the testes and Thecal cells in the ovary ● DHT (dihydrotestosterone), androstenedione, dehydroepiandrosterone (DHEA) are also secreted by the testes in small amounts ● Adrenal glands are responsible for producing additional androgens Functions and Therapeutic Uses ● Required for: Normal maturation in males, Sperm production, Increased synthesis of muscle proteins and hemoglobin, Decreased bone resorption ● Therapeutic uses: Replacement therapy for testicular dysfunction, hypothalamus or pituitary failure ● Not recommended for erectile dysfunction ● Discontinue therapy if no improvement in 3–6 months Low Testosterone Effects ● Associated with: Sexual & reproductive dysfunction, Mood and concentration impairment, Sleep disturbances, Exacerbation/development of diabetes, dyslipidemia, metabolic syndrome, CV disease, osteoporosis ● Interference with muscle mass, hemoglobin production, immune cell function Replacement Therapy Guidelines ● American Urological Society 2012: Recommend weight loss before prescribing testosterone ● Correlation between BMI and testosterone levels ● Testosterone decline begins at ~30 years old Criteria for Replacement Therapy ● Total testosterone < 300ng/dL plus one sexual or one physical symptom ● Symptoms: Erectile dysfunction, decreased libido, decreased muscle mass, increased body fat, decreased bone mineral density ● Outcomes: Small improvement in libido or erectile dysfunction, No benefit for low energy or cognitive impairment Endocrine Society Guidelines ● Trial of testosterone for 3–6 months ● Testosterone therapy discontinued if Hct >50% ● Monitor Hct, PSA, digital rectal exam at baseline, 3–6 months, annually ● Risks: gynecomastia, sleep apnea, edema, CV disease ● Stop therapy if no improvement in 3–6 months ● PDE-5 inhibitors more effective for sexual dysfunction Testosterone Replacement Forms ● Schedule III agents: Intramuscular (propionate, enanthate, cypionate), Buccal (Striant®), Patches (Androderm®), Gels (AndroGel®, Testim®, Fortesta®, Axiron®), Pellets (Testopel®) ● Formulations not interchangeable between application sites and doses New Oral Testosterone ● Jatenzo – 2019: Oral, used for Klinefelter syndrome, pituitary tumors, genetic conditions ● Not for age-related low testosterone ● Black Box Warning: HTN, MI, stroke ● ADRs: HA, increased Hct, decrease HDL, HTN, nausea, increase PSA Black Box Warnings ● Androgel, Testim: Exposure to children can cause genital enlargement, pubic hair, bone age advancement, increased libido, aggressive behavior ● Application site-specific guidance: drying and washing requirements Other Therapeutic Uses ● Anabolic effects: Osteoporosis, HIV/cancer-related wasting, Severe burns ● Danazol (for Endometriosis & Fibrocystic breast disease): Anti-estrogenic, inhibits FSH/LH, ADRs include weight gain, acne, deepening voice Unapproved Uses ● Improved strength and endurance in athletes ● DHEA touted as anti-aging/performance enhancer – no evidence ● Testosterone must be given parenterally due to liver metabolism ● Oral synthetic forms: Fluoxymesterone, oxandrolone (associated with liver toxicity) Adverse Drug Reactions ● Females: Masculinization, acne, hirsutism, deep voice, baldness, muscle development, menstrual irregularities ● Males: Priapism, impotence, decreased spermatogenesis, gynecomastia, acne, hirsutism, prostatic hypertrophy ● Children: Abnormal sexual maturation, premature epiphyseal closure ● General: Increased LDL, decreased HDL, fluid retention (edema), CAD ● Athletes: Testicular shrinkage, hepatic abnormalities, aggression, mood disorders Anti-Androgens ● Mechanisms: Inhibit synthesis or block receptors ● Ketoconazole: Inhibits steroid synthesis ● Finasteride & Dutasteride: 5-alpha reductase inhibitors – treat BPH and alopecia ● Flutamide, Bicalutamide, Nilutamide: Receptor blockers – treat prostate cancer ● Side effects: Sexual dysfunction, weight gain, breast enlargement, muscle loss; finasteride – rare depression/self-harm Prostate Hypertrophy ● Alpha-blockers (Tamsulosin, Doxazosin, Terazosin): Relax prostate muscle, fast onset, ADR: orthostatic hypotension ● 5-alpha-reductase inhibitors (Finasteride, Dutasteride): Add-on therapy, slow onset ● PDE-5 inhibitors (Tadalafil): Vasodilation, not PRN, avoid combo with alpha-blockers; Entadfi combo product Erectile Dysfunction ● PDE-5 inhibitors: Sildenafil, Tadalafil, Vardenafil, Avanafil ● Mechanism: Increase cGMP → vasodilation ● Avoid with nitrates, alpha-blockers, high-fat meals ● ADRs: NAION, retinal detachment, hearing loss, priapism, hypotension, CYP3A4 interactions ● Drugs that cause dysfunction: Tobacco, marijuana, alcohol, antipsychotics, beta-blockers, SSRIs, finasteride Urinary Incontinence ● Lifestyle: Reduce fluid, caffeine, constipation; weight loss, pelvic exercises ● AUA 2019: Antimuscarinics (Oxybutynin, Tolterodine, etc.), ADRs: dry mouth, constipation ● Beta-3 agonist (Mirabegron): ADRs – HTN, UTI, nasopharyngitis ● Low-dose estrogen for postmenopausal women ● Duloxetine under FDA review for stress incontinence Precocious Puberty ● Definition: Girls <8 yrs, Boys <9 yrs ● Idiopathic Central (GnRH-dependent) treated with GnRH analogs ● GnRH analogs prevent FSH/LH release via negative feedback Top 200 Drug List Drug Name Dosage Premarin (conjugated estrogen) 0.3–1.25mg QD Dutasteride (Avodart) 0.5mg QD Ethinyl estradiol/drospirenone (Yaz) 1 tab QD Raloxifene (Evista) 60mg QD Sildenafil (Viagra) 50mg 1hr before sex Tadalafil (Cialis) 10mg 1hr before sex Vardenafil (Levitra) 10mg 1hr before sex Finasteride (Proscar) 5mg QD