Download Pharmacology of Antiasthmatic Drugs

P H A R M ACO LOGY O F A N T I AST H M AT I C D R UG S &
D R UG T R E AT M E NT O F AST H M A
Author: Professor Ken F, Ilett, Department of Pharmacology, University of Western Australia, Queen Elizabeth
Hospital, Subiaco, Perth, WA 6008, Western Australia. [email protected]
This exercise makes use of the software package 'Pharmacology of Asthma' (pharma-CAL-ogy; British
Pharmacological Society, www.bps.ac.uk) but could equally well be used independently of this software package by
providing the students with references to suitable paper of book from which to obtain the necessary information.
The students should be given the objectives of the exercise (Section 1) and then provided with appropriate
references to books and papers or direction to access the 'Pharmacology of Asthma' software package as detailed in
Section 2. Having assimilated this material there are two exercises which the students can carry out.
First, students should be provided with the questions (Section 3) and should provide the answers. These can then be
self-, peer- or demonstrator- marked using the answer sheet provided (Section 4).
Second, students should read through the poster (Section 5; provided as a PowerPoint file) and deal with each of the
discussion points as indicated on the poster. The answers to the points raised in the poster are provided in Section
6).
SECTION 1
PHARMACOLOGY OF ANTIASTHMATIC DRUGS EXERCISE
Objectives:
The objectives of this station are to gain familiarity with the different classes of antiasthmatic drugs:
1. 2-adrenoceptor agonists
1.1. Mode of action (salbutamol & salmeterol as examples)
1.2. Side-effects effects
2. Muscarinic antagonists
2.1. Mode of action (ipratropium as example)
2.2. Adverse effects
3. Glucocorticosteroids
3.1. Mode of action (beclomethadsone and prednisone as examples)
3.2. Adverse effects as related to route of administration
4. Xanthines
4.1. Mode of action (theophylline as example)
4.2. Therapeutic window, routes of administration and adverse effects
5. Understanding asthma management plans
SECTION 2
P H A R M ACO LOGY O F A N T I AST H M AT I C D R UG S E X E RC I SE
Getting Started
In the main menu of the pharma-CAL-ogy module: “The Pharmacology of Asthma”, choose row “6” to go to the
“Pharmacology ” submenu. Track through to the next window and choose the different drug groups below in turn:
2-adrenoceptor agonists
Select “ 2-adrenoceptor agonists”on (Page 1), then “Salbutamol” and then “Salmeterol” in turn. Note that
these agents are mostly aimed at “treatment”, rather than at “prevention”, although to some extent the
long-acting drugs to have a preventative role.
Select “Page 2”. Note the mechanism of action.
Select “Page 3”. Note that these two drugs have very different half-lives and therefore durations of action at
the 2-adrenoceptors
Press “Return to Previous Menu” to continue.
Muscarinic antagonists
Select “Ipratropium”, on Page 1.
Select “Page 2” Note how ipratropium causes bronchodilatation and what its actions are on mucus
secretion.
Select “Page 3”. Answer the question about Drug X..
Press “Return to Previous Menu” to continue.
Glucocorticosteroids
Select “Glucocorticosteroids”, on Page 1 and investigate only “Fluticasone” and “Prednisolone” as
examples.
Select “Page 2” which is all about the side—effect profile of these agents and drag the “Statements” to the
appropriate blackboard.
Select “Page 3 and 4 in turn”. Note how the glucocorticosteroids work in asthma. Their role is sometimes in
acute treatment of status asthmaticus (e.g. prednisolone) and sometimes in prevention (e.g. fluticasone).
Press “Return to Previous Menu” to continue.
Xanthines
Select “Xanthines”, on Page 1 and investigate “Theophylline / Aminophylline” which is ths only
representative in this class. Theophylline is an older drug that is not widely used now but it still finds
application in some situations.
Select “Pages 2 and then 3” to investigate the mechanism of action of theophylline.
Select “Page 4” to investigate the “Therapeutic Window” for theophylline.
Select “Page 5” and answer the questions to test your understanding of how and where this drug works.
Select “Page 6 and then 7” to investigate the anti-inflammatory actions of theopylline.
Select “Page 8” and answer the questions about allergen effects in asthma and the relation with
theophylline’s effects.
Select “Page 9” and answer the questions about theophylline and its actions.
Press “Return to Previous Menu” to continue.
Press “Return to Main Menu” and leave the program ready for the next group.
SECTION 3
PHARMACOLOGY OF ANTIASTHMATIC DRUGS EXERCISE
Q U E ST I O N S
Briefly describe the mechanism of action for the  2-adrenoceptor agonists and how half-life of the different drugs
may alter their use pattern and effects.
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
Briefly describe the mechanism of action for ipratropium. Why might it be advantageous to combine anti2-adrenoceptor drugs in the same patient? What adverse effects are commonly reported?(Hint –
see MIMS)
______________________________________________________________________________
______________________________________________________________________________
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List 4 different properties for ORAL and INHALED corticosteroids
ORAL:
1) ____________________________________ 2) ______________________________________
3) ____________________________________ 4)______________________________________
INHALED:
1) ____________________________________ 2) ______________________________________
3) ____________________________________ 4)______________________________________
List 2 adverse effects that can occur with chronic use of prednisolone or prednisone.
1) ____________________________________ 2) ______________________________________
What is the therapeutic window for theophylline and how would you describe its therapeutic index?
______________________________________________________________________________
What adverse effects might be seen with high dose theophylline therapy?
______________________________________________________________________________
SECTION 4
PHARMACOLOGY OF ANTIASTHMATIC DRUGS EXERCISE
Briefly describe the mechanism of action for the  2-adrenoceptor agonists and how half-life of the different drugs
may alter their use pattern and effects. What side-effect may occur with excessive salbutamol dosing?

agonists relax bronchial smooth muscle by activating adenylate cyclase and forming intracellular cAMP.
This in turn activales intracellular phosphokinase to cause the muscle cells to relax and the airways to dilate.
The end result is an improvement on an FEV1 that has been compromised by the asthma.

Some agonists such as salbutamol have short half-lives and asthmatics may need to use them frequently
(e.g. 4 hourly) to achieve an adequate degree of airways relaxation. This is a “treatment” mode. Newer
agonists such as salmeterol have long half-lives (e.g. 15 h) and may only need to be administered twice daily.
While this is still “treatment”, it does at least last longer and have the potential to improve control of
symptoms and improve compliance.

Hypokalemia can occur with excessives doses of salbutamol. Also tremor, palpitations etc.
Briefly describe the mechanism of action for the  2-adrenoceptor agonists. Why might it be advantageous to
combine anti-muscarinic and b2-adrenoceptor drugs in the same patient?

Bronchial smooth muscle also has parasympathetic receptors that mediate constriction. The antimuscarinics block M1, M2 and M3 receptors and hence prevent bronchoconstriction. Remember that M1 and
M3 are on the smooth muscle and mediate contstriction via acethycholine, while M2 are presynaptic and
feedback to decrease the release of acetylcholine. Ipratropium also decreases mucous secretion, which is a
feature of asthma and causes plugging of the airways.

2 agonists is logical in that the two classes act via different receptors and in addition
ipratropium also decreases mucous secretion.
List 4 different properties for ORAL and INHALED corticosteroids
ORAL:




Systemic side-effects likely
Subject to gastrointestinal absorption
Subject to first-pass metabolism
Severe side-effects possible
INHALED:




No systemic side-effects
Used prophylactically
Lower doses with no significant systemic absorption
Action is essentially local
List 2 adverse effects that can occur with chronic use of prednisolone or prednisone.





Suppression of the hypothalamic-pituitary axis
Stunted growth
Adrenocortical insufficiency
Gastrointestinal irritation, nausea, diarrhoea
Mood swing, psychiatric episodes
What is the therapeutic window for theophylline and how would you describe its therapeutic index?

10-20 mg/L – range over which there is therapeutic benefit with minimun chance of toxicity. Note that the
drug has a low therapeutic index.
What is usual route of administration for theophylline?

Usually orally as a slow release tablet because of its short half-life
What adverse effects might be seen with high dose theophylline therapy (hint – look at MIMS)?

Nausea, vomiting, GI upset, palpitations, insomnia, arrhythmias, convulsions
What is the difference between theophylline and aminophylline (hint – look at MIMS)?

Aminophylline is the soluble form of theophylline and can be given intravenously. Note that aminophylline
contains only 80% of active theophylline and doses will need to be adjusted when swapping from oral to i.v.
therapy.
What is an asthma management plan and how is it used?

An agreed (with medical practitioner) strategy for regular assessment of asthma in an individual patient.
Usually involves regular measurement of FEV1 at home, with pre-planned changes in drug treatment (e.g.
short term use of prednisolone during an intercurrent chest infection with worsening of asthma), and/or
guidelines for seeking emergency medical treatment when the usual alterations in drugs and dosage are not
working.
SECTION 5
PHARMACOLOGY OF ANTIASTHMATIC DRUGS EXERCISE
This is the poster - to be found in the associated PowerPoint file.
SECTION 6
PHARMACOLOGY OF ANTIASTHMATIC DRUGS EXERCISE
Answers to questions:
Question
Choose from the following possibilities:
(a)Mild allergic asthma
Answer
At this stage he looks like a mild allergic asthmatic
(b)Severe asthma precipitated by animal
dander
What signs, symptoms form the basis for
your diagnosis?
Classify each of the drug options according
to their pharmacological mode of action, as
to whether they are preventers or
relievers.
Which of the following symptoms would
indicate the severity of the attack”?
•The attack occurred during the day
•The beta2 agonist spray was not effective
•He was finding it difficult to speak
•Beta2 agonist bronchodilators such as salbutamol or terbutaline - Beta2 ag
•Inhaled corticosteroids such as fluticasone or beclomethasone – glucocortic
preventers
•Oral corticosteroids such as prednisone or prednisolone – glucocorticostero
•Sodium cromoglycate by inhalation – inhibitor of mediator release from ma
•Oral montelukast sodium – leukotriene receptor antagonist - preventer
•Oral theophylline – xanthine - reliever
A L L T H R E E O F T H ESE SY M P TO M S A R E I N D I C AT I V E O F A SE V E R E
If Fred had been cyanotic or had a
bradycardia, what would this indicate?
A very severe attack. Status asthmaticus most likely, with the need for imme
What is your diagnosis now?
If you had you fancy new portable pulse
oxymeter with you, would it be helfpul in
Fred’s assessment?
The options available to you are:
•High dose intravenous steroids
•Intravenous aminophylline
•High concentration oxygen via a face mask
•High dose inhaled beta2 agonists
Severe allergic asthma
Yes, may assist in determining the severity of the attack
The order of options is as follows:
First option -– Fred is in danger of dying from hypoxia. Oxygen via a face ma
oxygenation and minimize the risk of cardiac arrest.
Second option – Aerosol agonists like salbutamol or terbutaline are often dra
such cases. They should be given simultaneously with oxygen as if given on t
initially worsen hypoxia by their effect of relaxing blood vessels in unventilat
High dose i.v. or oral steroids is third. They are down the list because they tak
their inflammatory action is indirect.
Asthma Action Plans
The fourth option is probably i.v. salbutamol if the inhaled agonist was not e
aminophylline is rarely used and requires careful TDM because of its low the
Nevertheless, it is still are useful drug in some patients
Read up on asthma action plans – visit the National Asthma Campaign websi
http://www.NationalAsthma.org.au - Asthma Facts – Asthma Action Plans –