Bronchodilators

Question 1

Bronchodilators

Answer 1

Bronchodilators act to reduce bronchomotor tone to bring about bronchodilation.

These are symptom relieving treatments that are regularly used in chronic conditions such as asthma and COPD.

Question 2

Beta-2 agonists

Answer 2

Used in both asthma and COPD this is an important class of bronchodilator. It is utilised in both chronic and acute management of these conditions.

Question 3

Beta-2 adrenoceptors

Answer 3

Beta-2 adrenoceptors are G-protein coupled receptors found primarily in the lungs. These are key receptors of the sympathetic nervous system that are stimulated by catecholamines such as adrenaline.

Beta-2 adrenoceptors are found throughout the lungs with a particularly high density in the bronchial smooth muscle. Activation of these receptors by the sympathetic nervous system cause bronchodilation through smooth muscle relaxation.

Question 4

Beta-2 adrenergic agonists are sympathomimetics that activate beta-receptors. These drugs act to relax the airways smooth muscle.

Additional actions include:

Answer 4

Reduced release of inflammatory mediators from mast cells.

Increased mucociliary clearance.

Question 5

Can be short-acting (e.g Salbutamol) or long-acting (e.g Salmeterol):

Answer 5

Short-acting beta-2 agonists (SABA): The short-acting forms are hydrophilic and as such are quickly metabolised. They have a rapid onset (< 5 minutes) and effects last around 6 hours. They are used as required (PRN). High use indicates inadequately controlled disease.
Long-acting beta-2 agonists (LABA): The long-acting forms are more lipophilic and effects last for around 12 hours. Used in a regular manner, concordance is often poorer than with SABAs.

Question 6

Many of beta-2 agonists unwanted effects result from its systemic actions: (3)

Answer 6

Tachycardia: Results from activation of beta-1 (dominant receptor in the heart) and beta-2 adrenoreceptors in the heart. May also cause arrhythmias.
Tremor: Results from activation of beta-2 adrenoreceptors in skeletal muscle.
Hypokalaemia: Results from activation of beta-2 adrenoreceptors linked Na/K-ATPase channels leading to increased cellular uptake of potassium. Salbutamol may be used to help treat hyperkalaemia.

Question 7

Muscarinic antagonists

Answer 7

Used primarily in chronic management of COPD, muscarinic antagonists also play a role in treatment of an acute asthma attack and acute exacerbation of COPD.

Question 8

Inhaled antagonists

Answer 8

Inhaled muscarinic antagonists block the action of muscarinic acetylcholine receptors, they are non-selective. When administered these agents act to relax the airways smooth muscle.

They are primarily of use in the chronic management of COPD but may be used in the treatment of an acute asthma attack.

Can be short-acting (e.g Ipratropium) or long-acting (e.g Tiotropium).

Question 9

Typical ‘anti-cholinergic’ effects:

Answer 9

Dry mouth (xerostomia)
Urinary retention
Headache
Exacerbation of glaucoma (pilocarpine - an agonist of M3 - is used in the treatment of angle-closure glaucoma).

Question 10

Inhaled muscarinic antagonists block the action of muscarinic acetylcholine receptors, they are non-selective. When administered these agents act to relax the airways smooth muscle.

They are primarily of use in the chronic management of COPD but may be used in the treatment of an acute asthma attack.

Can be short-acting (e.g …) or long-acting (e.g …).

Answer 10

Can be short-acting (e.g Ipratropium) or long-acting (e.g Tiotropium).

Question 11

.. are a nonselective phosphodiesterase (PDE) inhibitor that may be used in the management of COPD and asthma.

Answer 11

Methylxanthines are a nonselective phosphodiesterase (PDE) inhibitor that may be used in the management of COPD and asthma.

Question 12

Methylxanthines

Answer 12

They occur naturally and are found in coffee, tea and chocolate. Bronchodilation is one of a number of effects of methylxanthines that contribute to its therapeutic effect. However with the advent of newer bronchodilators, methylxanthines have somewhat fallen from favour.

Theophylline may also be used to treat apnea and bradycardia of prematurity.

Question 13

… may also be used to treat apnea and bradycardia of prematurity.

Answer 13

Theophylline may also be used to treat apnea and bradycardia of prematurity.

Question 14

Mechanism of action

Two forms are used in clinical practice:

Answer 14

Theophylline is a naturally occurring methylxanthine.
Aminophylline is a 2:1 combination of theophylline and ethylenediamine that is more water-soluble. It can also be administered intravenously.

Question 15

Their action is a result of adenosine receptor antagonism and indirect adrenergic activity.

Methylxanthines have a similar structure to caffeine, they have a wide range of effects including: (4)

Answer 15

Immunomodulation
Anti-inflammatory
Vasodilation
Bronchodilation

Question 16

Toxicity - theophylline and aminophylline

Answer 16

Theophylline and aminophylline have a narrow therapeutic window - with a clinical therapeutic index of 1 to 1.5. The majority of the adverse effects are dose related and are seen more frequently in overdose.

Question 17

Manifestations of toxicity include (Theophylline and aminophylline)

Answer 17

Metabolic:
Hypokalaemia
Hyperglycaemia
Cardiovascular:
Hypotension - PDE3 inhibition of smooth muscle in blood vessels
Sinus tachycardia
Tachyarrhythmias
Gastrointestinal:
Nausea and vomiting - due to PDE4 inhibition in the vomiting centre
Diarrhoea
Neurological:
Insomnia
Mood changes
Seizures
Muscular:
Coarse tremor
Rhabdomyolysis

Question 18

Inhaled devices more accurately target the intended site of action (compared to oral options) allowing for lower therapeutic doses, reduced systemic concentrations and unwanted effects.

Answer 18

There are disadvantages, effective administration via handheld inhalers may require a great deal of patient education. Compliance may be poor and effectiveness in severe disease is reduced.

Question 19

Metered-dose inhalers

Answer 19

Metered-dose inhalers (MDIs) are aerosol based inhalers, which are the most common delivery device for bronchodilators.

Effective use requires significant patient education to ensure adequate delivery of medication.

Question 20

Breath-actuated inhalers

Answer 20

Breath-actuated inhalers can deliver a dry powder or aerosol.

Activation is triggered by the patient inhaling. The patient must be able to generate a strong inspiratory flow and as such they are less effective in severe disease.

Question 21

Volume spacer

Answer 21

Spacer devices are used in conjunction with MDIs. They remove the need for coordination between activation of the inhaler and inhalation.

They are useful for young children and during an acute attack. Increasingly they are being used in the wider population due to poor inhaler technique.

Question 22

Nebuliser

Answer 22

Nebulisers are typically reserved for acute attacks but may be used at home in those unable to effectively use other devices.

Nebules of liquid are vaporised by either an air jet (jet nebuliser) or vibrations of a piezoelectric crystal (ultrasonic nebuliser).

The vapour is then inhaled via a face mask or mouthpiece. A greater dose is typically required for equivalent effect when compared with a normal inhaler.

Question 23

Which of the following is not part of the recommended technique when using a metered-dose inhaler (MDI)?

A The canister should be well shaken before use
B The patient should breath out gently but fully before inhaling
C Whilst depressing the canister inhale as fast as possible
D Once inhaled, breath should be held for 5-10 seconds
E Replace cap after use

Answer 23

Whilst depressing the canister inhale as fast as possible

Remove cap 
Shake inhaler well 
Breathe out gently but fully 
Place mouth around mouthpiece 
Depress canister and breathe in slowly and deeply 
Hold breath for 5-10 seconds 
Repeat as necessary 
Replace cap

Question 24

Technique is dependent on inhaler type, for MDIs:

Answer 24

Remove cap 
Shake inhaler well 
Breathe out gently but fully 
Place mouth around mouthpiece 
Depress canister and breathe in slowly and deeply 
Hold breath for 5-10 seconds 
Repeat as necessary 
Replace cap

Question 25

Which of the following medications should be used with caution in asthma? ``` A Paracetamol B Aspirin C Salbutamol D Prednisolone E Levothyroxine ```

Answer 25

It is suggested that NSAIDs (e.g. aspirin and diclofenac) should be used with caution in patients with asthma. This is because of the risk of bronchospasm with these agents. If there is any worsening of respiratory function or hypersensitivity to NSAIDs they are contraindicated. NSAIDs should also be used with caution in patients with renal impairment, cardiovascular disease or GI bleeding.

Question 26

Which of the following statements is not a recognised effect of corticosteroids in asthma? ``` A Suppression of goblet cells B Decreased IgE synthesis C Reduced synthesis of inflammatory mediators D Beta-2 adrenoreceptor downregulation E Reduced mucosal oedema ```

Answer 26

Corticosteroids lead to the upregulation of beta-2 adrenoreceptors, a synergistic activity that leads to increased bronchodilation in response to beta-2 agonists. Other effects of corticosteroids include reduced T-cell production, reduced eosinophil production, reduced mast cell deposition and suppression of goblet cell hyperplasia.

Question 27

Which of the following is not an effect of methylxanthines? ``` A Immunomodulation B Anti-emetic C Anti-inflammatory D Vasodilation E Bronchodilation ```

Answer 27

In addition to bronchodilation methylxanthines have immunomodulatory, anti-inflammatory and vasodilatory effects. They also have numerous side-effects including being emetogenic.

Question 28

Which of the following is best described as a muscarinic agonist? ``` A Atropine B Pilocarpine C Tiotropium D Salbutamol E Fluticasone ```

Answer 28

Pilocarpine is a M3 agonist used in the treatment of angle-closure glaucoma and xerostomia. Atropine is an anticholinergic sometimes utilised in bradycardia. Tiotropium is a muscarinic antagonist whilst salbutamol is a beta-2 agonist. Fluticasone is an inhaled corticosteroid.

Question 29

Which of the following is not true regarding G-protein coupled receptors? A They are metabotropic receptors B Its action is mediated by secondary messenger molecules C They have a seven transmembrane domain D They are ionotropic receptors E Beta-2 adrenoceptors are an example of this class of receptor

Answer 29

G-protein coupled receptors are the largest group of receptors in eukaryotes. They have a seven transmembrane domain i.e. they pass through the cell membrane seven times. They are metabotropic receptors whose actions are mediated by a secondary messenger. Beta-2 adrenoceptors and muscarinic receptors are both G-protein coupled receptors. Nicotinic receptors are an example of ionotropic receptors, these are ligand-gated ion channels.

Question 30

Nicotinic receptors are an example of … receptors, these are ligand-gated ion channels.

Answer 30

Nicotinic receptors are an example of ionotropic receptors, these are ligand-gated ion channels.

Question 31

Which of the following is not an adverse effect of muscarinic antagonists? ``` A Dry mouth B Blurred vision C Xanthopsia D Headache E Urinary retention ```

Answer 31

All of the above are typical side-effects of anti-muscarinic agents except xanthopsia (this may be caused by digoxin). Anti-muscarinic side-effects include xerostomia (dry mouth, most common), headaches, nausea, constipation, urinary retention and exacerbation of angle-closure glaucoma.

Question 32

A 32 year old female presents to the acute medical unit with an acute asthma attack. She is given several doses of salbutamol nebulisers to help improve her breathing. Which electrolyte abnormality would you expect with the use of high doses of salbutamol? ``` A Hypernatraemia B Hypokalaemia C Hyperkalaemia D Hyponatraemia E Hyperphosphataemia ```

Answer 32

High doses of salbutamol can lead to hypokalaemia. This results from activation of beta-2 adrenoreceptors linked Na/K-ATPase channels leading to increased cellular uptake of potassium. Salbutamol may be used to help treat hyperkalaemia. At high doses salbutamol may also lead to tachycardia, hypomagnesaemia and hyperglycaemia.

Question 33

Which of the following management options is the only effective way to halt the natural history of chronic obstructive pulmonary disease (COPD)? ``` A Inhaled beta-2 agonists B Smoking cessation C Inhaled muscarinic antagonists D Exercise E Pulmonary rehabilitation ```

Answer 33

Smoking cessation is the most effective way to halt the natural history of the COPD. Long-term oxygen therapy at home also improves mortality in a subgroup of patients with COPD. Bronchodilators provide symptomatic relief but do not significantly affect mortality.

Question 34

Which muscarinic receptor subtype is thought to be most important in the treatment of chronic airway disease? ``` A M1 B M2 C M3 D M4 E M5 ```

Answer 34

Blockade of M3 receptors are thought to be the most important effect of muscarinic antagonists. Of the five subtypes M1, M2 and M3 are best characterised. M3 (and to a lesser extent M1) is thought to be the most important in the aetiology and treatment of chronic airway diseases. Activation of M3 receptors by the parasympathetic nervous system leads to bronchoconstriction and its blockade results in bronchodilation.

Question 35

Which of the following is not typically associated with verapamil therapy? ``` A Gingival hyperplasia B Constipation C Hypotension D Headaches E Xanthopsia ```

Answer 35

Xanthopsia refers to yellowing of vision, which can be a side-effect of digoxin therapy.