Individual Drug Classes

β₂ ADRENOCEPTOR AGONISTS

Examples: Salbutamol (Ventolin^®) short-acting & Salmeterol (Serevent^®) long-acting*

Mechanism: Stimulation of airway β₂ adrenoceptors causes relaxation of bronchial smooth muscle and stabilises mast cells. Administration Can be given by inhalation, nebulisation, orally (tab and liquid) and iv. Note high-first pass metabolism of oral β₂ agonists (eg 4mg salbutamol tab vs. single MDI puff of 100 mg) reflecting extensive sulphation in the gut wall.

Side effects:

• tremor (effect on muscle spindles)
• tachycardia (and hence palpitations)
• hypokalaemia (K pumped into skeletal muscle)

Comments:

1. Side effects seen with increasing dose and especially with parenteral administration.
2. Parenteral administration may require KCl supplements to prevent the risk of cardiac arrhythmia from the substantial hypokalaemia (fall plasma K typically 1-1.5 mmol/L).
3. Can be used safely in pregnancy by inhalation/nebulisation although β₂ agonism causes relaxation of uterine smooth muscle.
4. * Long-acting β₂ agonists have effects for 12-24h versus 4-6h with short-acting agents like salbutamol. BD they can give continuous 24h bronchodilatation and symptom relief but should only be used to even out variations in airflow resistance (morning and evening dips) when patients are already taking a glucocorticoid – otherwise they may seriously mask underlying deterioration of airway inflammation.

ANTIMUSCARINICS

Example: ipratropium bromide (atrovent^®)

Mechanism: Vagolytic action by competitive inhibition of muscarinic receptors on airway smooth muscle (M3-type) leading to bronchodilatation. Administration Can be given by nebulisation or inhalation.

Side-effects: Because IPB contains a permanently charged quaternary N, its absorption is restricted c.f. 3ary N in atropine. High doses occasionally cause typical atropine-like effects ….

• dry mouth
• mydriasis (usually a topical action of the aerosol!)
• urinary retention
• constipation

Comments: Generally less effective than β₂  agonists since high vagal tone is usually only a feature of acute/unstable asthma. Blockade of presynaptic M2 receptors may even stimulate ACh release from X nerve terminals (defective M2 function may underlie asthmatic sensitivity to b adrenoceptor blockade).

METHYLXANTHINES
Should be seen as 3rd line agents (step 4) in chronic management scheme. Role in acute asthma still debated with unequivocal benefit lacking – trials are often small and flawed.

Examples: theophylline (nuellin^®) &  aminophylline* (phyllocontin^®)

Mechanism: They cause relaxation of bronchial smooth muscle and have an effect on late-phase responses (eosinophil recruitment especially). Still unclear to what extent these reflect phoshodiesterase inhibition but competitive adenosine receptor blockade know seems unlikely. They also have effects on diaphragmatic contractility and cardiac output. In chronic use they are disease-modifying i.e. immunomodulatory like glucocorticoids. They can be administered orally or intravenously (suppositories withdrawn due to proctitis).
NB If the IV route is used always establish if the patient is already taking them orally – bolus IV loading doses, even a maintenance IV infusion in a patient with plasma levels near the upper end of the therapeutic range, is hazardous and potentially lethal!

Side-effects:

• tachycardia (hence palpitations)
• nausea and abdominal disturbances
• cardiac arrhythmias and convulsions

Comments:

1. Side effects are concentration dependent and begin within the usual therapeutic range of plasma theophylline (55-110 m M). Levels above this are associated with risk of fatal arrhythmias and convulsions. The latter are frequently resistant to anticonvulsant therapy.
2. Aminophylline is a 1:1 mixture of theophylline and EDTA to enhance solubility.
3. Proconvulsant effect precludes use in epileptics
4. May also cause hypokalaemia especially when combined with β₂ agonists.

 

CHROMOGLYCATE AND RELATED THERAPY

Examples: sodium chromoglycate (intal^®)/children and adults & nedocromil (tilade^®)/adults only

Mechanism: Suppression of early and late inflammatory responses (mast cell stabilisers). Administration Can be given by inhalation or nebulisation.

Side-effects: Cough, transient bronchospasm and throat irritation. May cause drowsiness in high dose.

Comments:

1. Most useful in children since adults less responsive.
2. Only used prophylactically and not to terminate an acute attack e.g. extrinsic allergic asthma and exercise induced asthma.
3. Probably has a small but useful steroid sparing effect in children (only).
4. Ketotifen is an antihistamine with a sodium chromoglycate like action. It causes drowsiness and has no advantage over SCG.

 

GLUCOCORTICOIDS

Examples of the colours of various delivery devices

prednisolone	oral
beclomethasone (Becotide/Becloforte)	inhaled/neb	Beige to red-brown (BF)
budesonide (Pulmicort)	inhaled/neb	Beige to chocolate
fluticasone (Flixotide)	inhaled/neb	Orange
hydrocortisone (cortisol	i.v.

Mechanism Is not fully understood but is dependent on the typical steroid scheme of binding to cytosolic receptors that translocate to the nucleus to affect gene transcription/translation i.e. effects have a typical lag-time of at least 6-8h. Glucocorticoid anti-inflammatory effects include:  

• reduced inflammatory cells influx
• reduced release of mast cell mediators (and reduced mast cell numbers)
• reduced microvascular leakage and hence airway oedema

Side Effects: Even low-dose inhaled glucocorticoid can cause:

• cough
• oral candidiasis
• dysphonia

These can be largely abolished by rinsing the mouth after use and/or use of a spacer device. Systemic exposure with inhaled therapy is not negligible and increases with dose, especially above 1-1.5mg/d (e.g. 3 puffs BD of Becloforte) but again can be reduced by a spacer. Documented systemic effects include:

• Growth retardation (children)
• Increased bone catabolism (osteoporosis risk)
• Adrenal suppression
• Bruising

Oral glucocorticoids can cause additional Cushingoid features, e.g.

• Hypertension
• Diabetes
• Proximal myopathy
• Frank osteopenia/osteonecrosis
• Central adiposity/purple striae/buffalo hump

Comment With inhaled drugs, up to 90% of the drug deposits in the mouth/pharynx and is swallowed. In principle all glucocorticoids would be highly effective if administered by inhalation but 90% would be swallowed and absorbed. Hence only those agents that also show high first-pass metabolism (and hence low bioavailability) give restricted systemic exposure. For BDP and budesonide, bioavailability is around 10% compared to essentially 0% for fluticasone (100% first-pass metabolism).

LEUKOTRIENE ANTAGONISTS

Example: montelukast Mechanism Competitive antagonists of CysLT1 receptors. The first drug to work on this system was Zileuton which actually inhibited 5-lipoxygenase the proximal most enzyme in the synthetic pathway for cysteinyl-leukotriene generation. It has been withdrawn. Administration Only available for oral use but this may be an advantage for patients who cannot manage inhaler devices. Side Effects (all are CSM designated black triangle)

Side Effects: No specific side effects have yet been demonstrated although elevated transaminases are common at higher doses - a number of cases of Churg-Strauss have been seen but this probably represents initial masking of the disease by GCC therapy.

Note:

•  Their role in chronic management of asthma is currently uncertain.
•  They are claimed to have a steroid sparing effect but this is small and inconstant.
•  Effective in aspirin-induced and exercise-induced asthma.