NMT250 - pharm

Lecture Competencies

• Compare and contrast the mechanisms of action, indications, and adverse effects of drugs used to treat asthma in adults and children. Focus on Beta-adrenergic receptor agonists, Inhaled corticosteroids, Muscarinic Antagonists, Leukotriene receptor antagonists, and Biologics.
• Review correct inhaler technique for inhaled medications.
• Discuss Step-Up and Step-Down therapy within the context of asthma management.
• Review pharmacologic standards of asthma treatment during pregnancy.

Introduction to Asthma

• Asthma is a chronic inflammatory disease of the airways.
• Allergens and physical stimuli activate mast cells, releasing bronchoconstrictor mediators like histamine, leukotriene D4, and prostaglandin D2, which lead to smooth muscle contraction, vasodilation, microvascular leakage, plasma exudation, mucus hypersecretion, and activation of sensory nerves.
• Chronic inflammation can lead to irreversible fibrosis.
• Like other atopic diseases, asthma is typically diagnosed in childhood.
• Some adults experience adult-onset asthma, but typically, adults were diagnosed as children.
• Pharmaceutical standards for children and adults have been converging.
• The same drug classes are often used in both populations, with evidence guiding the use of specific combinations.

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 from requiring emergency room visits, hospitalizations, or systemic corticosteroids.
• Reduce short-acting beta2-agonist (SABA) use for symptom relief to ≤2 doses/week.
• Achieve normal measures of pulmonary function, such as forced expiratory volume in 1 second (FEV1), when capable of performing the tests.
• Avoid or minimize medication side effects, such as interference with normal growth.

Goals of Therapy for Adults

• Prevent asthma-related mortality and exacerbations.
• Maintain asthma control by:
  • Maintaining normal activity levels (avoiding absence from work or school, and enabling exercise without limitations).
  • Preventing daytime symptoms (cough, wheeze, dyspnea; goal: ≤twice/week) and nocturnal symptoms (night waking; goal: none).
  • Preventing the need for reliever therapy (goal: ≤twice/week).
• Provide optimal pharmacotherapy while avoiding adverse effects.

Inhaled Corticosteroids

• Mainstay for long-term asthma control.
• They alter gene transcription by:
  • Increasing transcription of β2 adrenergic receptors and anti-inflammatory cytokines.
  • Decreasing transcription of proinflammatory cytokines.
• They induce apoptosis in proinflammatory cells.
• They do not directly affect mast cells, as many mast cell mediators are preformed.
• They indirectly inhibit inflammation over time by muting the inflammatory response
• They do not directly affect smooth muscle function.
• They reduce vascular permeability, which reduces airway edema indirectly, and reduces inflammation
• Many inhaled corticosteroids are modified to reduce systemic exposure either by increasing susceptibility to first-pass effect or by delivering a prodrug version activated in the lung.
• Ciclesonide must be activated by lung esterases to be biologically active.
• Budesonide gets extensively metabolized by CYP3A4, resulting in about 10% bioavailability.
• Often used with a bronchodilator.
• Available combinations dictate which specific drugs are sold together in the same device.

Adverse Effects of Inhaled Corticosteroids

• Sore mouth, sore throat, dysphonia, and oral thrush.
• The risk of oral thrush can be reduced by rinsing 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.
• In children, they're associated with an initial decrease in growth rate during the first year but minimally affect adult height (1 – 2.5 cm reduction).
• Adults requiring high doses or with risk factors for osteoporosis may benefit from bone densitometry.
• Monitor intraocular pressure soon after starting therapy and periodically thereafter in patients with a history of glaucoma (and needing high-dose ICS).

Inhaled Beta2-Agonists

• All selective β2 adrenergic receptor agonists activate the receptor, increasing cAMP through the activation of adenylyl cyclase.
• cAMP activates protein kinase A, which phosphorylates contractile proteins, decreasing their affinity for calcium resulting in muscle relaxation.
• There are short- and long-acting options, referring to how long they exhibit a bronchodilator effect.
• Short-acting options, like salbutamol, should only be used as reliever therapy combined 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.
• Long-acting beta2-agonists should only be used in patients already using inhaled corticosteroids.
• Adding long-acting beta2-agonists to inhaled corticosteroids may allow for decreasing the corticosteroid dose and reduce exacerbations compared to using an inhaled corticosteroid alone.
• 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.
• Short-acting options are used on an as-needed basis for 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.
• Evidence for the use of long-acting options is lacking in children, research is ongoing
• Adding a long-acting option can be considered if monotherapy is not sufficient for adequate control in children ages 6 – 11 years of age on moderate doses of inhaled corticosteroids, and ages 12 and up on low doses of inhaled corticosteroids.
• The determination of effects long-acting options in children under the age of 6 has yet to be determined

Exercise-Induced Asthma

• Use of short-acting agents 5 – 10 minutes before exercise can prevent exercise-induced bronchospasm for up to 2-4 hours.
• Long-acting agents provide protection for 10 hours.

Adverse Effects of Beta2-Agonists

• Tachycardia, palpitations, nervousness, tremor, hypokalemia, restlessness, dizziness, headache, and 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 should not 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.
• Ipratropium is a short-acting muscarinic antagonist.
• Ipratropium can be used as an add-on therapy for beta2-agonists for acute asthma exacerbations management.
• Ipratropium serves as an alternative for patients who are unusually susceptible to tremor or tachycardia from beta2-agonists.
• The delayed onset of action, compared with beta2-agonists, has a longer lasting bronchodilator effect.
• May also be useful in beta-blocker-induced bronchospasm
• Tiotropium is a long-acting (once-daily) muscarinic antagonist.
• Tiotropium has shown value as an add-on therapy to improve lung function and decrease exacerbations.
• 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 moderate-dose corticosteroid/long-acting beta-agonist therapy history of exacerbations.
• Adverse effects include dry mouth, metallic taste, mydriasis, and glaucoma (if released into the eye).

Leukotriene Receptor Antagonists

• Asthma triggers (antigens, cold air, exercise, cytokines) result in the release of arachidonic acid from the phospholipid membrane via phospholipase
• Arachidonic acid is converted to leukotriene A4 (LTA4) by the enzyme 5-lipoxygenase.
• LTA4 is converted into other leukotrienes (LTB4 and LTC4) released from the leukocyte to act on target tissues.
• LTC4 is transferred into LTD4 and LTE4, all of which interact with a leukotriene receptor at target tissues (smooth muscle, endothelial cells, goblet cells, leukocytes) to create a biologic effect.
• Montelukast is the only option available in Canada.
• It is considered second-line add-on therapy.
• A combination inhaler like Long-acting beta-agonist with corticosteroid is more effective than combining an inhaled corticosteroid with a leukotriene receptor antagonist in both adults and children.
• There is an increase in usefulness in people with concomitant rhinitis.
• 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.
• Headache, abdominal pain, flu-like symptoms, and hepatotoxicity are adverse effects (rare).
• Boxed-warning regarding effects on neuropsychiatric effects (e.g., depression, agitation/aggression, hallucinations, and suicidal ideation), monitor for symptoms

Biologics

• Used as an adjunct in the treatment of patients with severe and uncontrolled asthma.
• The agents may improve symptom control; FEV1, frequency of exacerbations, and/or reduce oral corticosteroid exposure.
• Although pediatric patients can meet the criteria for use, many experts agree that more studies should benefit the pediatric population; especially those lower than 12 years of age.

IgE-Neutralizing Antibodies

• Omalizumab is considered to fall under this category
• It's indicated for children greater than or equal to 6 years of age, and for adults with moderate to severe asthma inadequately controlled with inhaled corticosteroids.
• To use, you must have evidence of allergic IgE-mediated asthma (positive skin prick test or other objective determination).
• Common adverse effects include injection site reactions (45%), viral infections (24%), upper respiratory tract infections (19%), headache (15%), sinusitis (16%), and pharyngitis (10%).

Interleukin-5 Inhibitors

• Mepolizumab
• IL5 plays a key role in the generation and survival of eosinophils in allergic disease.
• It is indicated as add-on maintenance treatment for patients greater than or equal to 6 years of age with severe eosinophilic asthma who are inadequately controlled. This is for use with medium-to-high-dose inhaled corticosteroids with additional asthma controller(s).
• This is for patients needing greater than or equal 300 cells/µL in the past 12 months for children and adolescents OR greater than or equal 150 cell/µL in adults
• Headache, nasal congestion, pharyngitis, injection site reactions (pain, erythema, swelling, itching), and malignancy are adverse effects (rare).
• Hypersensitivity reactions (rare) may occur within hours or days of treatment. Symptoms: swelling of face, mouth, and tongue; fainting; dizziness; hives; breathing and rash.

IL4R Neutralizing Antibody

• Dupilumab is a common option
• IL4 and IL 13 are cytokines involved in multiple pathways of allergic inflammation and share a common receptor subunit.
• It can be used for patients greater than or equal to 6 years of age with severe asthma OR atopic dermatitis.
• Common adverse reactions include injection site reactions (14-18%), oropharyngeal pain (2%), eosinophilia (2%), arthralgia, and hypersensitivity.

Step-Up/Step-Down Therapy

• Personalized asthma management should be followed, considering patient needs.
• It involves assessing, adjusting, and reviewing.
• In confirmation, look to find the diagnosis, control the symptoms, modifiable risks factors, comorbidities, adherence to inhaler instructions and patient goals.
• Assess for severity and adjust accordingly by helping the patients treat risk factors and comorbidities via pharmacological and non-pharmacological treatments.
• Medication adjustments and skill education of the patient should be given with constant reviews.

Assessment of Asthma Control

• Symptoms and controls are observed and evaluated.
• If there is more then twice per day use of daytime medication or night time waking due to asthma, a need for a reliever more then twice per day and any activity limitations should be evaluated on scales.
• High SABA use, not perscribed ICS, poor adherance, incorrect inhaler techniche, obesity, chronic, allergies, exposures, Socioeconomics problems and low lung function are all risk factors that increase ashtma.

Step Down Therapy

• Based off of track 1 and track 2
• Track 1 is a preferred reliever and controller
• Track 2 is a controller and alternative reliever

How To Use a Metered-Dose Inhaler

• Shake the inhaler for 10 seconds
• Make sure the inhaler cap is taken off
• Breathe out away from the device and put the mouthpiece in mouth while pressing inhaler
• Breathe in deep and steady as you press the inhaler and hold for 10 seconds then breathe out slowly
• Wait one minute and repeat steps one through 6 for another puff of medicine.
• Spit it out

Management of Asthma During Pregnancy

• Pregnancy typically does not affect asthma, some worsen, some see changes and only those who notice an improvement or not.
• Good control to asthma is associated with normal outcomes, while inadequate control has worse outcomes such as a low birth weight.
• Follow regular stepwise approach with those pregnant, and beta-adrenergic agonists and inhaled corticosteroids are safe to pursue during pregnancy.
• The use of LABAs hasn't shown adverse defects but the use of biologics during pregnancy have few published data to address effectiveness and safety during pregnancy.

Asthma and Breastfeeding

• Does not have know effect on asthma severity whether using breastfeeding or not
• Consider bronchodialtors (short- an long acting beta2-agonist)
• Inhaled and oral corticosteroids are safe for breastfeeding, but there is a lack of evidence of efficacy and saftey of biologics.

Explore hormonal contraceptives: mechanisms, uses, adverse effects, and contraindications. Discuss managing PCOS symptoms such as menstrual irregularities, hirsutism, acne, infertility, weight, and hyperglycemia. Review drug options for PCOS and contraceptives during postpartum.