Asthma agents week 5 Flashcards
Name the short acting and long acting B2 agonists and their effects.
How are they administered?
What are the side effects?
Metaproterenol (alupent), albuterol (proventil, ventolin, airet), terbutaline (brethair)
– Inhaled bronchodilator of choice for acute asthma
- For episodic relief of bronchospasm
- Effects are rapid, short acting -few side effects
- Can protect against exercise, cold air, allergen challenges
Salmeterol (servent)-Can be given orally for longer duration of benefit
– longer acting, caution: delayed onset (2hrs)
• Useful for suppressing night time asthma
Side effects
- Muscle tremor due to skeletal muscle B receptors
- Tachycardia and palpitations due to reflex cardiac stimulation
– 2° to peripheral vasodilation (hypotension)
– Direct stimulation of cardiac B1 receptors
- Residual action of less than 10% for metaproterenol, albuterol, and terbutaline but not salmeterol
- Tolerance to side effects after prolonged use
- Metabolic effects: increase FFA, glucose, lactate after large systemic doses
What is the new FDA warning about long acting beta agonists (LABAs)?
What is the reason for this?
New FDA Warning:
Long-Acting Beta-Agonists (LABAs) are medications used for the treatment of asthma and chronic obstructive pulmonary disease (COPD).
- These drugs act on the beta2-adrenergic receptor, thereby causing smooth muscle relaxation, resulting in dilation of bronchial passages, vasodilation in muscle and liver, relaxation of uterine muscle and release of insulin
- FDA’s analyses indicate there is an increase in the risk of severe exacerbation of asthma symptoms leading to hospitalization in pediatric and adult patients as well as death in some patients using LABAs for the treatment of asthma.
- In order to ensure the safe use of these medicines, FDA is requiring the manufacturers of LABAs to include a warning in the product labels of these drugs that the “drugs in the class of LABAs should never be used alone in the treatment of asthma in children or adults.”
- The FDA requires that the product labels reflect the following:
- The use of LABAs is contraindicated without the use of an asthma controller medication such as inhaled corticosteroid. Single-agent LABAs should only be used in combination with an asthma controller medication; they should not be used alone;
- LABAs should only be used long-term in patients whose asthma cannot be adequately controlled on asthma controller medications
- LABAs should be used for the shortest duration of time required to achieve control of asthma symptoms and discontinued, if possible, once asthma control is achieved. Patients should then be maintained on an asthma controller medication.
- Pediatric and adolescent patients who require a LABA in addition to an inhaled corticosteroid should use a combination product containing both an inhaled corticosteroid and a LABA to ensure compliance with both medications.
- Pathophys session: Dr. Ahmad said effects are thought to be due to down regulation and desensitization of B2 receptors with use of LABAs
Mast cell stabilizers
drugs in this class
MOA
effects
therapeutic use
pharmacokinetics
toxicities
What are they often administered with? Why?
Why are these drugs not used as much?
MOA
• Cromolyn Sodium and Nedocromil Sodium
– Have same MOA
• Mast cell stabilization
– Inhibition of degranulation by a variety of stimuli including cell bound IgE
– Appears to alter the function of the delayed chloride channel in the cell membranes inhibiting cell activation.
• Other Cells
– Suppresses activation effects of chemoattractant peptides on PMN, eosinophils and monocytes
– Reverses elevated receptor expression on leukocytes of asthmatic patients undergoing allergic challenge
– No bronchodilator or antihistaminic activity
Therapeutic Use
• Primarily prophylactic
– Mild to moderate (especially allergic asthma)
- Often administered with B2 agonist (albuterol) to assure better access of cromolyn to the airways
- Also used for allergic rhinitis
– When administered before challenge (exercise, allergens, cold air, etc.)
• Inhibits or modifies response to challenge
– Long term treatment
- Prevents early and late response to allergens
- Decreases level of bronchial responsiveness
Pharmacokinetics
– Less than 1% is absorbed, best effects through direct local administration to the bronchioles through inhalation
• Side effects
– Very few, likely due to the low rate of absorption- virtually no systemic bioavailability. The lack of side effects made this drug attractive for use with childhood asthma. However this use has diminished with the greater efficacy of Leukotriene inhibitors and low dose inhaled corticosteroids.
Corticosteroids
drugs in this class, administration
MOA
clinical use, compare and contrast use of systemic vs inhaled corticosteroids
side effects of inhaled vs systemic
Prototype: hydrocortisone
Analogs:
Beclomethasone, inhal.
Triamcinolone, inhal.
Prednisone, po (dosage varies)
Methylprednisolone, iv, q.i.d
Fluticasone (Flovent). Inhaled
Corticosteroids:
• The most potent anti-inflammatory agent
– Systemic administration (Prednisone-po, Methylprednisolone, injectable )
• Side effects have limited injectable use to severe cases
– Advent of low dose aerosols (Beclomethasone, triamcinolone)
- Re-evaluate use in less severe cases
- Long term usage is now more common
Corticosteroids MOA
- Reduce number and activity of inflammatory cells in the airway
- Inhibit release of arachidonic acid metabolites in the airway
- Prevent increase in vascular permeability
- Suppress IgE binding
- Decrease the severity of the disease and increase bronchodilator efficacy
- Are not bronchodilators
Therapeutic use
- Indicated for patients who require B2 -adrenergic agonists more than 4 x per week
- Suppresses the late response
– Little effect on early response
Systemic:
Used for short term “burst”
- To gain control of persistent asthma
- Use should be limited and tapered off
Inhaled:
- Used for long-term prevention of symptoms suppression, control and reversal of inflammation.
- reduces the need for oral corticosteroid
- Used with LABA (the combination of salmeterol + fluticasone = Advir)
Remember LABAs are no longer prescribed alone for Asthma
Side effects
• Inhaled preparations
– Dysphonia
– Oropharyngeal candidiasis
- Inhaled drugs are not well absorbed-less side effects
- Both can be reduced by rinsing with water after administration and using inhalation spacers to avoid oral deposition
- Bone resorption modest but significant with doses as low as 500μg/day
Systemic Administration
• Short term:
– Reversible abnormalities in glucose metabolism, increased appetite, fluid retention, weight gain, mood alteration, hypertension, peptic ulcer, and rarely aseptic necrosis of the femur
• Long Term:
– Adrenal axis suppression, growth suppression, hypertension, diabetes, osteoporosis, infection
Theophylline, Aminophylline
Drug class
MOA
Therapeutic use
Administration
Pharmacokinetics
Drug interactions
Toxicities
Theophylline MOA
• Inhibition of phosphodiesterases
– Increases intracellular cAMP
- A minor effect at drug concentrations reached in vivo
- Adenosine receptor antagonism
- Blocks the adenosine receptor which mediates bronchoconstriction
• Bronchodilation may be independent of adenosine receptors
Therapeutic use
- Reverses bronchoconstriction in asthmatics
- Less potent than B2 agonists
- Theophylline and B2 agonists have additive effects on bronchodilation
- If B2 agonists do not provide relief, theophylline can be added to the regimen
- Administration: IV (Aminophylline) or Oral
- wide fluctuation in plasma levels with tablets or elixer
- Sustained release preps are good for nocturnal asthma
Single dose of 8mg/kg slow release prep is often effective
Theophylline Pharmacokinetics
• Effective blood level should be 10-20 mg/L –very narrow therapeutic index
– Dose may vary because of clearance factors
• Dosage should be individualized
– Plasma levels measured 4 hrs after dosing or after reaching steady state for slow release preps
Drug interactions: see attached
Side effects
- Significant when plasma levels reach 20mg/L or higher
- Low therapeutic index
• TI=TD/ED 20mg/L / 15/mg/L TI=1.3
- Initial dose should be low, rising slowly until therapeutic plasma level is reached
- Low concentrations: headache, N&V, restlessness, increased acid secretion, diuresis
- High concentrations: convulsions, cardiac arrhythmias
Ipratropium, Tiotropium
MOA
Therapeutic use
Pharmacokinetics
Toxicities
Ipratropium bromide: Inhaled 5 hrs
- MOA- Muscarinic antagonist
- Parasympathetic pathway may initiate bronchospasms in some patients
- Utility must be assessed in individual patients
- Therapeutic Use
- When useful, combinations with B2 agonists are more effective than either alone
- Patients with worst initial lung function benefited from combined therapy
Pharmacokinetics
– Is a quaternary amine-poorly absorbed and avoids systemic distribution and side effects
– Aerosol delivery lasting up to 6 hrs
Side effects
– Few side effects due to poor absorption from the airways or GI tract (swallowing following inhalation).
Leukotriene modifiers
drugs in this class
administration
MOA
Therapeutic use
Side effects
- MOA
- Zafirlukast is a selective leukotriene receptor (LKT4) antagonist
- Zileuton is a 5 lipoxygenase inhibitor, decrease leukotriene synthesis
- Therapeutic use
- Used as an alternative to a low dose of inhaled corticosteroids, cromolyn or nedocromil
- Beneficial in aspirin sensitive asthma
- Theory: Aspirin blocks cyclooxygenase and arachidonate is diverted to the alternative lipoxygenase pathway producing more leukotrienes that are potent bronchoconstrictiors.
Side effects
Common: diarrhea, dizziness, cough headache, nausea, vomiting and difficulty sleeping. These are generally mild and the patient should report if they persist.
Uncommon: Patient should report fever, earache persistent sore throat, muscle weakness, allergic reactions, changes in mood, hallucinations, suicidal ideation or activity.
Anti IgE Abs
Drug(s) in this class
MOA
Administration
Therapeutic use
Side effects
Omalizumab is an antibody that binds to the IgE antibody in the circulation and prevents it binding to its cell receptors. It also can bind to IgE on the cells but this does not activate IgE already on the cells.
Administration 2X week (subcutaneous injection) reduces circulating IgE to undetectable levels and specifically reduces the magnitude of early and late bronchospastic responses to allergens.
This monoclonal antibody was developed in mice and then “humanized’ by replacing all the mouse proteins except for the binding domain. This greatly reduces the chance of rejection of the antibody.
In general the patients who respond the best to this treatment are the ones with chronic severe asthma, who are poorly controlled by existing medications and have a history of repeated exacerbations, a high requirement for corticosteroid treatment and poor pulmonary function.
- Most effective in patients who have a specific precipitating allergen or a seasonal allergen response
- Reduces Frequency and severity of Asthma exacerbations
- Can enable a reduction of corticosteroid requirements
THIS IS A VERY EXPENSIVE TRATMENT. It is reserved for patients with chronic severe asthma inadequately controlled by high dose inhaled corticosteroid plus long acting B2 agonist. Patients must also show IgE mediated sensitivity (skin test) to a particular allergen and high levels of circulating IgE.
- Reduced exacerbations requiring hospitalization by 88% in clinical trials
Side effects: Injection site reactions, possible anaphylaxis-extremely rare.
