A Textbook of Clinical Pharmacology and Therapeutics

use in asthma has declined considerably, with the efficacy of
the leukotriene receptor antagonists.

ANTI-IGE MONOCLONAL Ab

Omalizumabis 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 t1/2of 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 malignan-
cies. It can be used in children, but is a very expensive therapy.

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 con-

trolled ventilation, oxygenation and positive end expiratory

pressure (PEEP).

TREATMENT OF TYPE II RESPIRATORY FAILURE

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 tra-

cheobronchial 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

RESPIRATORYFAILURE 241

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.

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 t1/2of 6.5–10 hours and 8–10
hours, respectively. Cetirizineandloratidinedo 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