Pharmacology: PCOS - Treatment & Management

PHARMACOLOGY: PCOS Dr. Adam Gratton NMT250 MSc ND January 15, 2024 LECTURE COMPETENCIES 1. Compare and contrast the mechanisms of action, indications, and adverse effects of hormonal contraceptives a. Combined oral contraceptives b. Progestin-only contraceptives c....

PHARMACOLOGY: PCOS Dr. Adam Gratton NMT250 MSc ND January 15, 2024 LECTURE COMPETENCIES 1. Compare and contrast the mechanisms of action, indications, and adverse effects of hormonal contraceptives a. Combined oral contraceptives b. Progestin-only contraceptives c. Emergency postcoital contraception 2. Review absolute contraindications for combined oral contraceptives LECTURE COMPETENCIES 3. Discuss use of hormonal contraceptives during the postpartum period 4. Review drugs options for symptom management of PCOS a. Drugs used for menstrual irregularities b. Drugs used for hirsutisms and acne c. Drugs used for infertility d. Drugs used for weight loss and hyperglycemia INTRODUCTION Polycystic ovary syndrome is the most common endocrine abnormality in patients of childbearing age affecting 5 – 18% of this population Clinical presentation is quite variable but manifests with some degree of hyperandrogenism, ovulatory dysfunction, polycystic ovaries, and insulin resistance INTRODUCTION Results in adverse consequences with reproductive, metabolic, and cardiovascular health There is no “one picture” of PCOS, and many patients will present with concerns related to acne, hirsutism, fertility, menstrual irregularities, obesity and dysglycemia. INTRODUCTION Pathophysiology is complex but involves inappropriate gonadotropin secretion, insulin resistance with hyperinsulinemia, and excessive androgen production Treatment options are therefore going to involve those that target these pathways HORMONAL CONTRACEPTIVES MECHANISM OF ACTION High levels of estrogen and progesterone suppress GnRH release from the hypothalamus Reduced GnRH results in reduced FSH and LH release from the pituitary Inhibition of follicular development and ovulation Alteration in cervical mucus inhibiting sperm penetration MECHANISM OF ACTION Combined oral contraceptives are a combination of an estrogen (most commonly ethinyl estradiol) and a progestin Progestins have a wide range of action and they differ in their ability androgenic and progresterogenic activity MOA - PCOS The estrogen component suppresses LH resulting in a reduction of androgen production and increase production of SHBG in the liver (which reduces free testosterone) The progestin component inhibits the LH surge resulting in reduced ovarian androgen production PROGESTINS First (norethindrone) and second-generation (norgestrel and levonorgestrel) progestins have a higher risk of metabolic side effects and higher androgenic activity May be helpful for those seeking contraception, only, but not for those with PCOS PROGESTINS Third (norgestimate) and fourth-generation (drospirenone) progestins cause fewer metabolic adverse effects Fourth-generation progestins are anti-androgenic Cyproterone acetate has the greatest anti-androgenic activity among all progestins Drospirenone is also androgenic with 40% of the anti- androgenic activity of cyproterone acetate ABSOLUTE CONTRAINDICATIONS Breast cancer or hormone-dependent cancer Cerebrovascular disease, history of cerebrovascular accident Complicated valvular heart disease Current or past history of venous thromboembolism or pulmonary embolism, known thrombogenic mutations, e.g., factor V Leiden; prothrombin mutation; protein S, protein C and antithrombin deficiencies; or other known coagulation-factor deficiency Diabetes with microvascular complications ABSOLUTE CONTRAINDICATIONS History of or current myocardial infarction or ischemic heart disease, vascular disease Uncontrolled hypertension Current pregnancy 35 y of age (≥15 cigarettes/day) CHOOSING A COMBINATION ORAL CONTRACEPTIVE When choosing an oral contraceptive beyond simple contraception, the activity of the progestin will ultimately guide the selection Low or anti-androgenic progestins can be helpful in PCOS and acne When used solely for contraception, the lowest amount of estrogen that provides the best experience for the individual taking it Reasons to increase the amount of estrogen include breakthrough bleeding or spotting TYPES OF COMBINATIONS Monophasic pills are the most common and provide a steady dose of hormones throughout the entire pack Biphasic pills contain two sets of pills at different strengths. Usually, the dose of estrogen is the same throughout but the dose of the progestin changes Triphasic – steady estrogen and three progestin dosages NON-CONTRACEPTIVE BENEFITS Increased bone mineral density Decreased acne Decreased ovarian (30-50%), endometrial (30%), colorectal (15-20%) cancers Decreased peri-menopausal symptoms Decreased risk of fibroids Decreased benign breast disease ADVERSE EFFECTS Common adverse effects include breakthrough bleeding/spotting, amenorrhea, nausea/vomiting, bloating, chloasma, breast tenderness, mood changes such as depression, headache ADVERSE EFFECTS Major: thromboembolism (rare), stroke, retinal artery thrombosis, MI, benign liver tumor, cholelithiasis, hypertension. Watch for danger signals: ACHES—abdominal pain, chest pain, headaches, eye problems, severe leg pain ADVERSE EFFECTS Drospirenone containing contraceptives also include risk of hyperkalemia in patients prone to increase potassium (renal disease, concomitant use of ACEi, ARB, potassium sparing diuretics, NSAID) May have a higher risk of venous thromboembolism compared to other progestins Advisable to check potassium levels after the first cycle DO THEY CAUSE CANCER? There is no direct interventional data and all of the information comes from observational studies Overall, the risks of breast and cervical cancers are increased, and the risks of endometrial, ovarian, and colorectal cancers are reduced. DO THEY CAUSE CANCER? Risk of breast and cervical cancer decreases with elapsed time since last use and is no longer apparent after 10 years of past use Risk of endometrial and ovarian cancer remains reduced for at least 20 years after discontinuation PROGESTIN ONLY PILLS Sometimes referred to as the “mini pill” Progestins inhibit the LH surge preventing ovulation, thicken cervical mucus, and decrease motility of an ovum in the fallopian tubes PROGESTIN ONLY PILLS Regular and consistent use is necessary to maintain contraceptive efficacy If a dose is missed by more than 3 hours, a backup method of contraception is recommended as cervical mucus quickly returns to normal PROGESTIN ONLY PILLS Indicated for patients over 35 years of age who smoke, cannot tolerate estrogen, have unwanted side effects with COCs, experience migraine headache with neurologic symptoms or are breastfeeding ADVERSE EFFECTS Higher incidence of ectopic pregnancy compared to COC. Irregular bleeding (~12% of users in the first months, 1 cm in diameter respond poorly to danazol 6 months of use can effectively alleviate symptoms of endometriosis, particularly in the earlier stages of the disease ADVERSE EFFECTS Use is typically limited by its adverse effect profile Androgenic adverse effects include voice deepening (irreversible), decreased breast size, increased weight, hirsutism, increased LDL, decreased HDL May also cause menopausal symptoms like hot flashes and vaginal dryness Effective contraception necessary for the duration of treatment GONADOTROPIN-RELEASING HORMONE AGONISTS Inhibits the hypothalamic-pituitary-gonadal axis, reducing the secretion of LH and FSH required for follicular development The result is a significantly hypoestrogenic state, which induces atrophy and regression of endometriotic implants GONADOTROPIN-RELEASING HORMONE AGONISTS As effective as COCs​ and progestins​ in managing endometriosis-associated pain Because low-dose COC therapy can be unlimited in duration and is associated with fewer adverse effects, it is reasonable to consider GnRH agonist therapy only when low-dose COC therapy is ineffective or contraindicated GONADOTROPIN-RELEASING HORMONE AGONISTS Administered as intranasal sprays, subcutaneous injection, or intramuscular injection, depending on the drug Examples include leuprolide and goserelin ADVERSE EFFECTS Adverse effects are the same regardless of method of administration Reduced BMD (if used for 6 months, reversible upon cessation of treatment). Vasomotor symptoms: hot flashes, vaginal dryness, insomnia, loss of libido, emotional lability Temporary increase in pain upon initiation of therapy may occur GONADOTROPIN-RELEASING HORMONE ANTAGONISTS Competitively block GnRH receptors (which are present in endometrial cells) resulting in rather immediate suppression of LH and estrogen Ultimately leading to the same hypoestrogenic state seen with GnRH agonists, which induces atrophy and regression of endometriotic implants GONADOTROPIN-RELEASING HORMONE ANTAGONISTS Elagolix is the only option available in Canada Can be given as a once-a-day or twice-a-day option The higher twice-daily dose is associated with higher rates of adverse effects and should be reserved for more severe/refractory cases Orally administered ADVERSE EFFECTS Most common: headache, nausea, hot flashes, altered mood, depressive symptoms. Increased levels of serum lipids, reduced BMD (may be reversible upon cessation of therapy) “ADD-BACK” HORMONE THERAPY Used to mitigate the perimenopausal-type symptoms and bone density loss that occur with GnRH agonists (and sometimes GnRH antagonists) There is no standard approach, but it generally consists of estrogen or progesterone alone or in combination ENDOMETRIOSIS- ASSOCIATED INFERTILITY OVULATION INDUCTION Letrozole is the only option available in Canada Letrozole is an aromatase inhibitor that blocks the conversion of androgen to estrogen Reduced estrogen levels stimulate the pituitary gland to secrete FSH resulting in ovarian follicle recruitment OVULATION INDUCTION GnRH agonists for 3–6 months before IVF or intracytoplasmic sperm injection in women with endometriosis results in a 4-fold increase in the odds of clinical pregnancy Referred to as superovulation or controlled ovarian hyperstimulation ABNORMAL UTERINE BLEEDING INTRODUCTION Refers to any change in menses that includes an abnormal frequency, duration, amount of blood flow, or bleeding that occurs between cycles Can occur chronically or may be an acute situation warranting immediate intervention Also includes unpredictable bleeding in postmenopausal patients INTRODUCTION Heavy menstrual bleeding is characterized by excessive menstrual blood flow that interferes with quality of life and may result in iron deficiency anemia Recent definitions of heavy menstrual bleeding focus more on the patient’s perception of the impact of abnormal bleeding on the quality of life than volume of blood loss Thirty percent of patients consider their menstrual bleeding to be excessive GOALS OF THERAPY Reduce the deleterious effects of heavy menstrual bleeding on patient’s health, well-being, and quality of life Target and treat any specific underlying causes of heavy menstrual bleeding Identify and treat any associated iron deficiency anemia PREVIOUSLY DISCUSSED OPTIONS Combined hormonal contraceptives Progestin-only contraceptives GnRH agonists and antagonists NSAIDs ANTIFIBRINOLYTICS Medications that inhibit fibrinolytic activity in the endometrium are useful in the treatment of both acute and chronic HMB Tranexamic acid can be helpful for patients with heavy periods who do not wish to use hormonal treatments Mechanism of action appears to be related to reversible inhibition of lysine-binding sites on plasminogen SAMPLE QUESTION Which of the following drugs can be used to induce ovulation in people with endometriosis? A. Letrozole B. Levonorgestrel C. Elagolix D. Leuprolide PHARMACOLOGY: ASTHMA Dr. Adam Gratton NMT250 MSc ND February 12, 2024 LECTURE COMPETENCIES 1. Compare and contrast the mechanisms of action, indications, and adverse effects of drugs used to treat asthma in adults and children a. Beta-adrenergic receptor agonists b. Inhaled corticosteroids c. Muscarinic Antagonists d. Leukotriene receptor antagonists e. Biologics 2. Review correct inhaler technique for inhaled medications 3. Discuss Step-Up and Step-Down therapy within the context of asthma management 4. Review pharmacologic standards of asthma treatment during pregnancy INTRODUCTION Asthma is a chronic inflammatory disease of the airways Mast cell activation by allergens and physical stimuli release bronchoconstrictor mediators (histamine, leukotriene D4, prostaglandin D2) leading to smooth muscle contraction, vasodilation, microvascular leakage, plasma exudation, mucus hypersecretion, and activation of sensory nerves Chronic inflammation leads to irreversible fibrosis INTRODUCTION Like other atopic diseases, asthma is typically diagnosed in childhood Adults with asthma typically were diagnosed as children, but adult-onset asthma does exist INTRODUCTION The pharmaceutical standards for children and adults have been converging Many of the same drug classes are used in both population with evidence guiding the use of specific combination when it exists GOALS OF THERAPY FOR INFANTS AND CHILDREN Prevent cough, wheeze, or shortness of breath that interferes with daytime activities, exercise, school attendance, growth and development, or sleep Prevent exacerbations requiring emergency room visits, hospitalizations, or systemic corticosteroids Reduce the use of short-acting beta2-agonists (SABAs) for symptom relief to ≤2 doses/week​ Achieve normal measures of pulmonary function, e.g., forced expiratory volume in 1 second (FEV1) in those capable of performing the tests Avoid/minimize medication side effects, e.g., interference with normal growth GOALS OF THERAPY FOR ADULTS Prevent asthma-related mortality Prevent exacerbations Maintain asthma control - maintain normal activity levels, e.g., avoid absence from work or school, maintain the ability to exercise without limitations) - prevent daytime (e.g., cough, wheeze, dyspnea; goal: ≤twice/week) and nocturnal symptoms (e.g., night waking; goal: none) - prevent the need for reliever therapy (goal: ≤twice/week) Provide optimal pharmacotherapy and avoid adverse effects DRUG CLASS OPTIONS INHALED CORTICOSTEROIDS The mainstay for long-term asthma control Work by altering the transcription of many genes - Increase transcription of β2 adrenergic receptor and anti- inflammatory cytokines - Decrease transcription of proinflammatory cytokines Induce apoptosis in proinflammatory cells INHALED CORTICOSTEROIDS Do not directly affect mast cells as many mast cell mediators are preformed Indirectly inhibited over time due to overall muting of inflammatory response INHALED CORTICOSTEROIDS Do not directly affect smooth muscle function Indirectly over time as reduced inflammation results in less hyper-responsiveness Reduce vascular permeability which reduces airway edema INHALED CORTICOSTEROIDS Many have been modified to reduce systemic exposure either by increasing susceptibility to first-pass effect or by delivering a prodrug version that is activated in the lung For example, ciclesonide is biologically inert until activated by lung esterases. Another example is budesonide which is extensively metabolised by CYP3A4 resulting in bioavailability around 10% INHALED CORTICOSTEROIDS Are often used in combination with a bronchodilator The available combinations usually dictates which specific drugs are used as only certain combinations are sold together in the same device ADVERSE EFFECTS Sore mouth, sore throat, dysphonia, oral thrush Risk of oral thrush can be reduced by ringing the mouth after use or using a spacer Adverse effects related to systemic absorption are usually only seen with long-term use of high doses of inhaled corticosteroids ADVERSE EFFECTS In children, use is associated with an initial decrease in growth rate during the first year but minimally affects adult height (1 – 2.5 cm reduction) In adults, bone densitometry is suggested in those who require high doses or have risk factors for osteoporosis Patients with personal or family history of glaucoma (and need high-dose ICS) should have intraocular pressure checked soon after starting therapy and periodically thereafter INHALED BETA2- AGONISTS All selective β2 adrenergic receptor agonists activate the receptor resulting in an increase in cAMP through the activation of adenylyl cyclase cAMP activates protein kinase A which phosphorylates contractile proteins decreasing their affinity for calcium Results in MUSCLE RELAXATION INHALED BETA2- AGONISTS Short vs Long-acting Refers to how long they exhibit a bronchodilator effect Short-acting options, like salbutamol, should only be used as reliever therapy in combination with low-dose daily inhaled corticosteroid controller therapy Monotherapy is no longer recommended due to an increased risk of severe exacerbations and asthma- related death INHALED BETA2- AGONISTS Long-acting beta2-agonists should be used only in patients already using inhaled corticosteroids Adding Long-acting beta2-agonists to inhaled corticosteroids may permit decreasing the dose of the corticosteroid and has also been clearly shown to reduce the incidence of exacerbations to a greater extent in comparison to using an inhaled corticosteroid alone INHALED BETA2- AGONISTS Long-acting options differ in their onset of action Salmeterol has a slow onset and should not be used for immediate relief of bronchospasm Formoterol has a rapid onset and can be used when combined with an inhaled corticosteroid INHALED BETA2- AGONISTS Short-acting options are used on an as-needed basis to provide both rapid relief and valuable information on underlying asthma control Use of short-acting options more than 2 times per week indicates suboptimal long-term control INHALED BETA2- AGONISTS The evidence for the use of long-acting options is lacking in children although research is ongoing Adding a long-acting option can be considered if inhaled corticosteroid monotherapy is not sufficient for adequate control in children 6 – 11 years of age on moderate doses of inhaled corticosteroids and children 12 and up on low doses of inhaled corticosteroids The role of long-acting options in children under 6 years of age has yet to be determined EXERCISE-INDUCED ASTHMA Use of short-acting agents 5 – 10 minutes before exercise can help prevent exercise-induced bronchospasm for up to 2–4 hours Use of long-acting agents provides protection for 10 hours ADVERSE EFFECTS Tachycardia, palpitations, nervousness, tremor, hypokalemia, restlessness, dizziness, headache, nausea Use of more than 2 canisters per year of short-acting options is associated with increased risk of exacerbations and mortality Tolerance may develop to long-acting options with regular use Long-acting options are not to be used as monotherapy ANTICHOLINERGICS Bind to M3 receptors and block cholinergic stimulation from the vagus nerve. Blocks the rise in intracellular calcium and prevents bronchoconstriction ANTICHOLINERGICS Ipratropium is a short-acting muscarinic antagonist Can be used as an add-on therapy to beta2-agonists for management of acute asthma exacerbations A useful alternative for patients who are unusually susceptible to tremor or tachycardia from beta2-agonists Onset of action is delayed compared with beta2-agonists, but the bronchodilator effect lasts longer May also be useful in beta-blocker–induced bronchospasm ANTICHOLINERGICS Tiotropium is a long-acting (once-daily) muscarinic antagonist It has been shown to have value as an add-on therapy to improve lung function and decrease exacerbations ANTICHOLINERGICS Ipratropium is considered adjunctive therapy in the pediatric population with severe acute exacerbations Tiotropium is not approved for use in children in Canada but is sometimes used as add-on therapy in children over the age of 6 with a history of exacerbations despite appropriate, medium-dose inhaled corticosteroid/long-acting beta-agonist therapy. ADVERSE EFFECTS Dry mouth, metallic taste Mydriasis and glaucoma if released into the eye LEUKOTRIENE RECEPTOR ANTAGONISTS Asthma triggers (antigens, cold air, exercise, cytokines, etc.) result in the release of arachidonic acid from the phospholipid membrane via phospholipase A2 Arachidonic acid is converted to leukotriene A4 (LTA4) by the enzyme 5-lipoxygenase LEUKOTRIENE RECEPTOR ANTAGONISTS LTA4 is converted into other leukotrienes (LTB4 and LTC4) that are released from the leukocyte to act on target tissues LTC4 is converted into LTD4 and LTE4, all of which interact with a leukotriene receptor at target tissues (smooth muscle, endothelial cells, goblet cells, other leukocytes) to create a biologic effect LEUKOTRIENE RECEPTOR ANTAGONISTS Montelukast is the only option available in Canada It is considered second-line add-on therapy The inhaled corticosteroid/long-acting beta-agonist combination is more effective than combining an inhaled corticosteroid and a leukotriene receptor antagonist in both adults and children It might be more useful in those with concomitant rhinitis LEUKOTRIENE RECEPTOR ANTAGONISTS They may also be used in children when moderate to high doses of corticosteroids fail to adequately control symptoms or if inhaled corticosteroids cannot be used ADVERSE EFFECTS Headache, abdominal pain, flu-like symptoms, hepatotoxicity (rare). Boxed warning issued regarding neuropsychiatric effects (e.g., depression, agitation/aggression, hallucinations, suicidal ideation);​ monitor for symptoms BIOLOGICS Biologics are used as an adjunct in the treatment of patients with severe, uncontrolled asthma These agents may improve symptom control, FEV1, frequency of exacerbations, and/or reduce oral corticosteroid exposure Although pediatric patients can meet the criteria for use, most experts agree that more studies are needed to better indicate the benefit, especially in those