36. Drugs Used to Treat Asthma Flashcards
Asthma is a common disease
Asthma is a common disease characterised by reversible airway obstruction secondary to bronchoconstriction.
It is a potentially life-threatening condition
causing approximately three deaths per day in the UK.
Anaesthetists will regularly anaesthetise patients with asthma and also be involved in the management of the patient with severe or life-threatening asthma.
Thus, a thorough understanding of the pathophysiology of asthma and its treatment is expected.
Describe the pathophysiology of severe and life-threatening asthma.
> Bronchospasm from a combination
of bronchial smooth muscle constriction,
inflammation and mucus production.
> Common triggers include allergens
(e.g. house dust mite),
tobacco smoke, cold air, exercise,
viral infection and, in some patients, drugs such
as non-steroidal anti-inflammatory drugs or β-blockers.
> Bronchoconstriction is mediated by the parasympathetic nervous system –
acetylcholine released from vagal afferent nerve endings leads to a rise in
cyclic cellular calcium levels,
causing bronchial smooth muscle contraction.
> Bronchoconstriction results in increased
airways resistance and reduced
expiratory gas flow,
leading to dynamic hyperinflation of the lungs
and the generation of intrinsic positive airway pressure.
> Type 1 respiratory failure ensues in the
early stages of an acute episode
primarily due to ventilation–perfusion
mismatching;
however, type 2 respiratory failure may
develop as the patient becomes exhausted from
the increased work of breathing.
This is a very ominous sign.
Outline the pharmacological management of asthma.
The aim of pharmacological management of asthma
is disease control as defined by absence of symptoms,
no limitations on activities
and normal lung function.
A step-wise approach is adopted,
with therapy titrated to severity:
> Step 1: Mild intermittent asthma –
inhaled short-acting B2 agonist
(e.g. salbutamol) as required.
> Step 2: Regular preventative therapy –
add inhaled steroid
200–800 μg/day.
> Step 3: Initial add-on therapy –
add inhaled long-acting B2 agonist
(e.g. salmeterol).
Assess response and if good then continue.
If improvement seen but
control still inadequate,
increase inhaled steroid dose.
If no improvement seen,
discontinue long acting B2 agonist
and increase inhaled steroid
and
consider other therapies
such as leukotriene receptor antagonist
(e.g. montelukast) or slow-release theophylline.
Leukotriene receptor antagonists
block the bronchoconstricting effects of
leukotrienes on the airways and
act synergistically with inhaled steroids.
This class of drug is especially of benefit in exercise-induced asthma.
Churg–Strauss syndrome
(eosinophilia, vasculitic rash, pulmonary
infiltrates) is a rare association with the use of leukotriene receptor antagonists.
> Step 4:
Persistent poor control –
consider trial of increasing inhaled
steroid, addition of a fourth drug, e.g. leukotriene receptor antagonist, slow release theophylline or β2 agonist tablet.
> Step 5: Continuous or frequent use of oral steroid – refer to specialist care.
Discuss the drug treatment
of severe and life-threatening
asthma.
Treatment of severe and
life-threatening asthma involves correcting the
hypoxaemia and
reduction of airways resistance through bronchodilation.
1 Oxygen –
initially commence high-concentration
oxygen and then titrate
to maintain SaO2 > 92%.
Hypoxia is the most common cause of death in
life-threatening asthma.
2 a2 receptor agonists (nebulised) – oxygen-driven nebulisation of salbutamol 2.5–5.0 mg back-to-back initially. Drug delivered to the bronchioles is only a small percentage of the total administered dose, due to bronchoconstriction.
3 Muscarinic antagonist (nebulised) –
oxygen-driven nebulisation of
ipratropium bromide 500 μg 6 hourly.
4 Steroids – depending on the clinical situation administer either 40 mg prednisolone orally or 200 mg hydrocortisone intravenously followed by
50–100 mg hydrocortisone 6 hourly.
5 Magnesium sulphate –
administer 2 g over 20 min intravenously.
Side effects can include hypotension and muscle weakness however, being an excellent smooth muscle dilator it has an important role in the
management of asthma.
6 Intravenous a2 agonist –
salbutamol may be administered as an
infusion at a rate of 5–20 μg/min,
but this is not without potential serious
systemic effects such as severe tachycardia
and lactic acidosis.
7 Intravenous phosphodiesterase inhibitor – aminophylline loading dose of 5 mg/kg
followed by an infusion at 0.5 mg/kg/min.
Omit the loading dose in those patients
already taking oral theophylline
(narrow therapeutic index).
Aminophylline acts by blocking the enzyme phosphodiesterase thereby increasing intracellular levels of cyclic AMP, which reduces intracellular calcium within the bronchial smooth muscle leading to bronchodilation. Plasma aminophylline levels should be monitored during its use.
8 Adrenaline –
an excellent bronchodilator through its β agonist
action.
It should be considered in resistant bronchospasm. It may be administered via nebulisation (1:1000 adrenaline) or in extremis via the
intravenous route (titrated 100 μg intravenous boluses).
9 Heliox –
a mixture of helium and oxygen (commonly 30% oxygen/70% helium).
The low density of this gas mixture theoretically improves gas flow within the airways by converting turbulent flow to laminar flow,
thereby reducing work of breathing.
There is no evidence that it improves
outcomes and its use in asthma is no longer recommended by the British
Thoracic Society.
10 Ketamine –
an NMDA receptor antagonist with excellent bronchodilating properties.
It may be used to induce anaesthesia
in patients with lifethreatening
asthma and may be used for sedation and
treatment of
bronchoconstriction in ventilated patients.
11 Inhalational volatile anaesthetics – sevoflurane is a good
bronchodilator and may be used in resistant bronchospasm.
Delivery usually requires an anaesthetic machine although it may be administered
through in-line devices in certain critical care ventilators.
Gas analysis and
scavenging are essential requirements when using volatile agents.
Which drugs should be avoided in acute severe/life-threatening asthma?
> β-Blockers.
> NSAIDs.
> Caution with thiopentone,
which may cause histamine release.
> Avoid atracurium, which causes histamine release.
> Caution with morphine, which causes histamine release.
SALBUTAMOL
b2 agonist some small
b1 activity
• Clear colourless solution:
50–500 μg/mL
- Metered dose inhaler: 100 μg, 2 puffs prn
- Powder for inhalation: 200–400 μg, 2 puffs prn
• Liquid 2.5/5 mg/mL for
nebulising, prn, titrate to
symptoms
- Tablets: 2/4/8 mg, 2–4 mg t.d.s.
- Syrup: 0.4 mg/mL, 2–4 mg t.d.s.
DOSE
• Run infusion at 5–20 ug/min.
Titrate to effect
MOA • Direct stimulation of b2 receptors • Less pronounced action at b1 receptors
USES • Asthma • COPD • Hyperkalaemia • Uncomplicated pre-term labour
METABOLISM AND EXCRETION • Hepatic metabolism • Metabolites and unchanged drug excreted in urine
ABSORPTION/
DISTRIBUTION
• Extensive firstpasa metabolism
- Protein binding 8–64%
- VD 156 L/kg
EFFECTS
CVS
• ↓ BP (b2)
• At high dose b1 effects
cause ↑ HR and
contractility
RS
• Bronchodilation (b2)
• Reduces hypoxic pulmonary
vasoconstriction so can worsen shunt.
Always give nebs with O2
OTHER
• ↓ Uterine tone
• Hypokalaemia – Na+/K+ ATPase
stimulated transporting K+ into cells
- ↑ Blood glucose and fatty acids
- Anxiety
- Sweating
• Potentiates nondepolarising
muscle relaxants
AMINOPHYLLINE
AMINOPHYLLINE
Methlyxanthine derivative
- Tablets: 100/225/350 mg
- Suppositories: 180/360 mg
- Clear colourless solution: 25 mg/mL
DOSE
- Oral: 900 mg in 2–3 divided doses
- Rectal: 360 mg od
• IV Loading: 5 mg/kg over 10 min
(do not load if already on oral drug)
• Maintenance: 0.5 mg/kg/hr
MOA
• Direct stimulation of b2 receptors
• Less pronounced action
at b1 receptors
TOXICITY
• Subject to zero order kinetics at > 35 μg/kg
• Causes tachyarrhythmias, tremor, seizures,
nausea and vomiting, rhabdomyolisis
• Must monitor plasma levels
METABOLISM AND EXCRETION • Hepatic metabolism • Affected by drugs which induce/inhibit P450 enzyme system
• Subject to zero order kinetics at high doses
ABSORPTION/
DISTRIBUTION
• Oral bioavailability up to 96%
- Rectal absorption unpredictable
- Protein binding 50–60%
- VD 0.4–0.5 L/kg
USES • Asthma • COPD • Hyperkalaemia • Uncomplicated pre-term labour
EFFECTS
CVS • ↑ HR • ↑ CO • ↓ SVR • Arrhythmogenic in higher doses
RS
- Bronchodilation
- ↑ Diaphragmatic contractility
- ↑ Central sensitivity to pCO2
- Synergistic with b2 stimulants
CNS • ↓ Seizure threshold ↓ Cerebral blood flow • Syndrome of inappropriate antidiuretic hormone (SIADH)
RENAL
• Weakly diuretic – inhibits tubular Na+ reabsorption
