Pharmacotherapy of Asthma Flashcards
What 2 groups are asthma medications divided into?
- Controllers
2. Relievers
What are relievers?
Short acting bronchodilators for quick relief (e.g. Salbutamol)
What are controllers?
Drugs with sustained bronchodilatory and anti-inflammatory action
When are relievers used?
Used when necessary during an attack (PRN dosing)
When are controllers used?
Used to prevent asthma on a daily basis
What are the 3 types of relievers used in asthma?
- Rapid acting and short acting beta-2 agonists
- Inhaled Ipratropium Bromide
- Short acting xanthine derivatives (theophylline)
What are the 5 types of controllers used in asthma?
- Inhaled and systemic corticosteroids (usually dosed bd)
- Leukotriene receptor antagonists (Montelukost)
- Long acting beta-2 agonists (always given together with ICS)
- Sustained release theophyllines (longer acting)
- Anti-IgE
What are the two categories of anti-asthmatic agents?
- Bronchodilators
2. Anti-inflammatory agents
What classes of bronchodilators are used in asthma?
- Beta-2 receptor agonists (SABA, LABA)
- Xanthine drugs
- Muscarinic receptor antagonists
- Cysteinyl leukotriene receptor antagonists
What are the short acting beta-2 adrenoreceptor agonists used in asthma?
- Salbutamol
- Fenoterol
- Terbutaline
In what form are the short acting beta-2 adrenoreceptor agonists given?
Inhaled
What are the short acting beta-2 adrenoreceptor agonists used for?
Acute attack
What are the long acting beta-2 adrenoreceptor agonists used in the management of asthma?
- Salmeterol
- Formoterol
What are the long acting beta-2 adrenoreceptor agonists used for?
Chronic asthma
e.g. at night or exercise
In what form are the long acting beta-2 adrenoreceptor agonists given?
Inhaled or oral
What is the mechanism of action of the beta-2 adrenoreceptor agonists?
Agonist on beta2-adrenoreceptors
- dilate bronchi
(relaxes bronchial muscle = bronchodilation)
What are the 3 methods of administration of the beta-2 adrenoreceptor agonists?
- Inhalation
- IV
- Oral
How can the beta-2 adrenoreceptor agonists be administered via inhalation?
- Aerosol inhaler (MDI)
- Spacer devices (>500mls) improve delivery
- Dry powder inhaler (autohalers)
- Nebulizer solutions
When can the beta-2 adrenoreceptor agonists be given IV?
Only in acute severe asthma
How commonly are the beta-2 adrenoreceptor agonists given orally?
Rarely used
- onset of action is slower
- increased SE
- prolonged action
What does SABA stand for?
Short acting beta-2 adrenoreceptor agonist
What does LABA stand for?
Long acting beta-2 adrenoreceptor agonist
What are the SABA agents used as?
Relievers
- used on “as needed” basis
What SABA drugs are available for the management of asthma?
- Salbutamol
- Fenoterol
- Terbutaline
What is the onset and duration of action of the SABA agents?
Inhaled: effect within 5-15 minutes
Duration of effect: 3-5 hours
How are the SABA agents metabolized and excreted?
Metabolized in GIT and liver
Excreted in urine
What are the two LABA agents available?
- Salmeterol
2. Formoterol
What is the duration of action of the LABA agents?
Inhaled, duration of action is 8-12 hours
What is the difference between Salmeterol and Formoterol?
The onset of action!
- Salmeterol has a delayed onset of action, cannot be used “as needed” for an acute attack
- Formoterol has almost the same onset of action as Salbutamol: can be used to relieve
How are the LABA agents generally given?
Given regularly, 2 x daily with ICS
When are LABA agents associated with an increased risk of death?
Increased risk of death if given without an ICS agent
What are the adverse effects of the beta-2 adrenoreceptor agonists?
- CNS stimulation: tremor, tachycardia, cardiac dysrhythmia, nervousness, dizziness
- Tremor can be a problem in the elderly
- Hypokalemia
What is important to consider in the management of elderly asthmatic patients?
Don’t use beta-2 adrenoreceptor agonists as relievers in the elderly - can cause tremor, rather use muscarinic receptor antagonists
Which drug is a long-acting beta2 agonist?
Indacaterol Maleate
What is the mechanism of action of Indacaterol Maleate?
Increases cyclicAMP and causes bronchodilation
- long acting beta2 agonist
What is Indacaterol Maleate indicated for?
Indicated for use in COPD
BUT NOT ASTHMA
& cannot be used for an acute bronchospasm
When should Indacaterol Maleate be used with caution?
Used with caution in patients with CVD, CAD, cardiac arrhythmias, hypertension, acute MI’s
= can lead to hypokalemia
What are the adverse effects of Indacaterol Maleate?
Coughing, nasopharyngitis, URTIs, headaches, muscle spasms, worsening of COPD
&
Inhalation may result in PARADOXICAL BRONCHOSPASMS
- If this occurs, discontinue use of drug immediately
What are the two Xanthine drugs?
- Theophylline
2. Aminophylline
What is the mechanism of action of the Xanthine drugs
- relaxing of smooth muscle
- inhibition of phosphodiesterase = prevent breakdown of cAMP
- competitive antagonism of adenosine (A1 & A2) receptors
- mild anti-inflammatory effect: NOT CONSIDERED AN ANTI-INFLAMMATORY AGENT
How are the Xanthine drugs given?
- Orally (sustained release), tablets, syrups
- IV
- SR formulation is preferred (much more predictable kinetics - drugs have a very narrow therapeutic index)
What is the bioavailability of Theophylline?
Well absorbed
What is the half life of the Xanthine drugs?
Approximately 8-9 hours (varies)
- increased in premature infants, elderly, liver disease, cardiac failure and infections
- decreased in smokers
How are the Xanthine drugs metabolized and excreted?
Metabolized by the liver cytochrome P450 system
Excreted in the urine
Who is at greatest risk of toxicity with the Xanthine drugs?
Neonates, young infants and adults >55 years
= slowest clearance
- drug has a narrow therapeutic index
What drug interactions are seen with the Xanthine drugs?
- Decreased plasma concentration by drugs inducing CYP450 enzymes: alcohol, barbiturates, rifampicin, phenytoin etc. and smoking
- Increased plasma concentration by drugs inhibiting CYP450 enzymes: cimetidine, erythromycin, ciprofloxacin
- Sympathomimetic agents: increase cardiac effects (both increase cAMP = increase HR etc.)
What are the adverse effects of the Xanthine drugs?
- CNS, CVS, increase gastric secretions (PUD), GIT effects, vasodilation & diuretic
- Seizures (particularly at high doses)
What contraindications are there to Aminophylline use?
Aminophylline is contraindicated in pophyria
What are the muscarinic receptor antagonists?
- Ipratropium bromide
2. Tiotropium bromide
What is the mechanism of action of the muscarinic receptor antagonists?
- blocks muscarinic receptors
- causes bronchial smooth muscle relaxation and decreased mucous secretions
How is Ipratropium Bromide administered?
Aerosol inhalation
- highly polar, small amount absorbed
What is the onset and duration of action of Ipratropium Bromide?
Maximum effect after 30 minutes
Effect lasts for 3-5 hours
(short acting)
What is the o duration of action of Tiotropium Bromide?
24 hour duration of action
longer acting
What is important about the onset of action of Ipratropium Bromide?
NB for the bronchodilator reversibility test
- need to wait 30 minutes not the usual 15 before testing for reversibility
What are the adverse effects of the muscarinic receptor antagonists?
- dry mouth
- bitter taste
- paradoxical bronchoconstriction
- urinary retention and constipation (less likely as not absorbed in the GIT)
What are the Leukotriene Receptor Antagonists?
- Montelukast
2. Zafirlukast
What are the Leukotriene Receptor Antagonists also effective for?
- Exercise induced asthma
2. Reduce acute reaction to aspirin (aspirin sensitive asthma)
What is the mechanism of action
- blocks leukotriene receptor
- bronchodilation
- anti-inflammatory effect
How are the Leukotriene Receptor Antagonists administered?
Given orally
How is Montelukast taken?
Once daily at bedtime
- duration 24 hours
How is Zafirlukast given?
Twice daily, 1 hr before, 2 hrs after meals
- protein binding 99% = NB!
How are the Leukotriene Receptor Antagonists metabolized and excreted?
Extensively metabolized in the liver
Excreted in the bile
What are the adverse effects of the Leukotriene Receptor Antagonists?
- Emergence of Churg-Strauss Syndrome (rare) - idiosyncratic but extremely dangerous
- Hypersensitivity reactions (urticaria / angioedema)
- Neuropsychiatric adverse effects (nightmares / vivid dreams)
What is Churg-Strauss Syndrome?
Disorder marked by blood vessel inflammation - can restrict blood flow to vital organs and tissues.
Also known as eosinophilic granulomatosis with polyangiitis
- Asthma is the most common sign of this syndrome
What are important cautions with Zafirlukast?
- Causes inhibition of the cytochrome P450 enzymes (warfarin, erythromycin, terfenadine, theophylline)
- Causes elevated liver enzymes and hepatitis
What are the main inhaled corticosteroids?
- Beclomethasone
- Budesonide
- Fluticasone
- Ciclesonide
(last two are more potent)
What are the main oral corticosteroids?
- Prednisolone
- Prednisone
What is the main IV corticosteroid?
Hydrocortisone
What is significant about Ciclesonide?
It is a prodrug, metabolized to its active form inside the lung
- adverse effects profile therefore much less, especially local (candida)
What are the clinical uses of the glucocorticosteroids in asthma?
- Chronic asthma: IH beclomethasone
2. Clinical condition deteriorates: rescue course of oral prednisone
What is the mechanism of action of the corticosteroids?
- bind to intracellular receptors
- inhibition of transcription genes
- up-regulate beta-2 adrenoceptors
- decreased microvascular permeability
- reduce inflammation
What is significant about the fact that the corticosteroids up-regulate beta-2 adrenoceptors?
It makes the combination of long acting Beta2 agonists and glucocorticosteroids work well
What is significant about the fact that the corticosteroids decrease microvascular permeability?
Only drugs which do this
= prevents mucous plugging
How are glucocorticosteroids most commonly administered?
Inhalation via MD or DP inhaler
- use spacer devices to prevent adverse effects - wash regularly
What can be done to prevent the adverse effect of oral candida when using corticosteroids?
- Use a spacer
2. Wash mouth out afterwards
How much of the inhaled glucocorticosteroid is deposited in the lungs?
10-15%
- rest in oropharynx or GIT, highly metabolized by the liver therefore very little ends up in systemic circulation (in high enough doses possible that it can however)
How quickly is the effect of inhaled corticosteroids achieved?
Takes a long time to achieve full effect
What is significant about Fluticasone?
It has clinical efficacy at lower doses (½)
What are the adverse effects of the inhaled corticosteroids?
Oropharyngeal candidiasis
- sore throat, croaky voice (spacers will reduce this)
- regular high doses = adrenal suppression
Local adverse effects have a lower incidence with which inhaled corticosteroid and why?
Lower incidence with Ciclesonide because it is a prodrug
When are inhaled corticosteroids contraindicated?
CI: Fluticasone and HIV protease inhibitors = risk of systemic hypercortisolism
Which two combination asthma medications are used?
- Salmeterol + Fluticasone
2. Formoterol + Budesonide
What is the combination Salmeterol + Fluticasone used for?
Used only as a controller
- for chronic, persistent asthma
What is the combination Formoterol + Budesonide used for?
Used both as a controller and a reliever
- onset of action of Formeterol = Salbutamol
- for chronic persistent asthma
What is Omalizumab?
Humanized monoclonal anti-IgE antibody
How is Omalizumab administered?
SC injection 1-3 x every 2-4 weeks
What is the mechanism of action of Omalizumab?
- target IgE antibody
- prevent mast cell degranulation
What are the clinical uses of Omalizumab?
Effective for allergic asthma and allergic rhinitis
What is the major downside to Omalizumab use?
Very expensive
What are the adverse effects of Omalizumab?
- increased chances of malignancies (NB)
- possible induction of Churg-Strauss syndrome, nasal polyps and adrenal insufficiency
- viral infections, upper respiratory tract infections
- injection site reactions
