Clinical Pharmacology and Therapeutics

RESPIRATORY FAILURE 241
use in asthma has declined considerably, with the efficacy of
the leukotriene receptor antagonists.
ANTI-IGE MONOCLONAL Ab
Omalizumab is a recombinant humanized IgG1 monoclonal
anti-IgE antibody. It is used as additional therapy in patients
with severe persistent allergic asthma due to IgE-mediated
sensitivity to inhaled allergens and inadequately controlled by
glucocorticosteroids plus long-acting β 2 -agonists. It binds to
IgE at the same epitope on the Fc region that binds FcεRI, this
means it cannot react with IgE already bound to the mast cell
or basophils and is not anaphylactogenic. It is administered
subcutaneously every two to four weeks. It causes a 80–90%
reduction in free IgE and it reduces FcεRI expression on
inflammatory cells. It has a t 1/2 of 20–30 days and is cleared via
the reticuloendothelial system. Side effects include rashes,
urticaria, pruritus, sinusitis, gastro-intestinal upsets, injection
site reactions and possibly secondary haematologic malignancies.
It can be used in children, but is a very expensive therapy.
Key points
Leukotriene modulation in asthma
• Leukotriene B 4 is a powerful chemo-attractant
(eosinophils and neutrophils) and increases vascular
permeability producing mucosal oedema.
• Leukotrienes C 4 , D 4 and E 4 (cysteinyl leukotrienes) are
potent spasmogens and pro-inflammatory substances
(‘SRS-A’).
• Clinically used agents that modulate leukotrienes are
leukotriene antagonists (which antagonize cysteinyl
leukotrienes – LTD 4 , LTC 4 at the Cys-LT 1 receptor)
• Leukotriene antagonists (e.g. montelukast) are
effective as oral maintenance therapy in chronic
persistent asthma. Montelukast has anti-inflammatory
properties and is a mild, slow-onset bronchodilator.
chronic asthmatics, but because of their long-term toxicities
(Chapters 26 and 50), they are not used routinely.
RESPIRATORY FAILURE
Respiratory failure is the result of impaired gas exchange. It is
defined as a normal or low PaCO 2 . Causes include:
1. Type I (ventilation/perfusion inequality) is characterized
by a low PaO 2 and a normal or low PaO 2 . Causes include:
• acute asthma;
• pneumonia;
• left ventricular failure;
• pulmonary fibrosis;
• shock lung.
2. Type II (ventilatory failure) is characterized by a low PaO 2
and a raised PaCO 2 (6.3 kPa). This occurs in:
• severe acute asthma as the patient tires;
• some patients with chronic bronchitis or emphysema;
• reduced activity of the respiratory centre (e.g. from
drug overdose or in association with morbid obesity
and somnolence – Pickwickian syndrome);
• peripheral neuromuscular disorders (e.g.
Guillain–Barré syndrome or myasthenia gravis).
TREATMENT OF TYPE I RESPIRATORY FAILURE
The treatment of ventilation/perfusion inequality is that of
the underlying lesion. Oxygen at high flow rate is given by
nasal cannulae or face mask. Shock lung is treated by controlled
ventilation, oxygenation and positive end expiratory
pressure (PEEP).
TREATMENT OF TYPE II RESPIRATORY FAILURE
ANTIHISTAMINES
H 1 -BLOCKERS
See Chapter 50 for further information.
Antihistamines are not widely used in the treatment of
asthma, but have an adjunctive role in asthmatics with severe
hay fever. Cetirizine and loratadine are non-sedating
H 1 -antagonists with a plasma t 1/2 of 6.5–10 hours and 8–10
hours, respectively. Cetirizine and loratidine do not cause the
potentially fatal drug–drug interaction (polymorphic VT)
with macrolide antibiotics, as was the case with astemizole (or
terfenadine).
ALTERNATIVE ANTI-INFLAMMATORY AGENTS
Other anti-inflammatory drugs, such as methotrexate or
ciclosporin, reduce glucocorticosteroid requirements in
Sedatives (e.g. benzodiazepines) or respiratory depressants
(e.g. opiates) must never be used unless the patient is being
artifically ventilated.
SUPPORTIVE MEASURES
Physiotherapy
Physiotherapy is used to encourage coughing to remove tracheobronchial
secretions and to encourage deep breathing to
preserve airway patency.
Oxygen
Oxygen improves tissue oxygenation, but high concentrations
may further depress respiration by removing the hypoxic
respiratory drive. A small increase in the concentration of
inspired oxygen to 24% using a Venturi-type mask should be
tried. If the PaCO 2 does not increase, or increases by 0.66 kPa
and the level of consciousness is unimpaired, the inspired
oxygen concentration should be increased to 28% and after