RESPIRATORY PHARMACOLOGY - ASTHMA

Primary Exam Teaching - Westmead ED

Sympathomimetic agents

• MOA: relax airway smooth muscle and inhibit broncho constricting mediators from mast cells

• May also inhibit microvascular leakage and increase mucocilliary transport by increasing ciliary activity

• The beta agonists stimulate andeylyl cyclase and increase formation of intracellular cAMP

• Beta 2 effect causes

• Relaxation of airway smooth muscle

• Inhibits mediator release

• Causes tachycardia and skeletal muscle tremor as side effects

• Best mode of delivery is via inhalation - results in the greatest local effect on airway smooth muscle with the least systemic toxicity

• Aerosol deposition depends on particle size, pattern of breathing and geometry of airways - deposition can be increased by holding breath during inspiration

ADRENALINE

• Effective, rapidly acting bronchodilator

• Maximal bronchodilation 15 min after inhalation

• Stimulates alpha and beta one as well as beta two

• Causes tachycardia, arrythmias and worsening of angina pectoris

• These CV effects are of value for treating the acute vasodilation and shock as well as the bronchospasm of anaphylaxis

Beta 2 selective agents

• Salbutamol

• Use - asthma, hyperkalemia

• Pharmacokinetics

• A - 10 - 30% act directly on smooth muscle when inhaled,

• D - minimal entry into systemic circulation when inhaled, otherwise low Vd

• M - signifiant first pass metabolism

• E - excreted really

• Pharmacodynamics - selective beta two receptor agonist and causes bronchodilation

• Maximal effect within 15 - 30 minutes and persists for 3 - 4 hours

• Nebulisers are no more effective than MDI - should only be given when patients cannot coordinate their own breathing

• Longer acting agents such as salmeterol have a 12 hour duration as a result of HIGH LIPID SOLUBILITY - and appear to interact with corticosteroids to improve asthma control

• Adverse effects:

• Cardiac arrythmia and hypoxemia - ma increase the perfusion of poorly ventilated lung and thus transiently decrease arterial oxygenation - this is overcome by the administration of supplemental oxygen

• Fine tremor + palpitations + cramps

Methylxanthine drugs

• Three important agents

• Theophylline

• Theobromine

• Caffeine

• Importance as a therapeutic agent in asthma has weaned over time

• Aminophylline is a commonly used theophylline preparation

• Mechanism of action

• At high concentrations —> inhibits phosphodiesterase enzyme family

• This results in higher concentrations of intracellular cAMP

• Another proposed mechanism in inhibition of cell surface adenosine receptors - which has been shown to provoke contraction of isolated airway smooth muscle and histamine release

Methylxanthine drugs

• Pharmacokinetics :

• A - 100% bioavailibilty, serum levels in 30 - 120 minutes

• D - low Vd 0.5L/kg, 60% protein bound

• M - hepatic

• E - 85 - 90% hepatic elimination, remainder renal, half life 4 - 8 hours

• Pharmacodynamics

• CNS effects - low and moderate doses, especially caffeine, can cause mild cortical arousal with increase alertness

• Larger doses are required for bronchodilation effects and in very high doses can cause convulsions and death

• CV effects - positive chronotropic and inotropic effects - at low doses these effects are thought to be mediated by inhibition of adenosine receptors in sympathetic nerves.

• Higher concentrations are associated with inhibition of phosphodiesterase and increased influx of calcium

• Results in slight tachycardia, increased CO, increased TPR, HTN

• GI - stimulates secretions

Methylxanthines

• Clinical use

• Theophylline is the most important bronchodilator

• Relieves airway obstruction in acute asthma and reduces severity of symptoms in chronic asthma

• Should only be used when methods to measure blood levels are available because it has a narrow therapeutic window

• Toxicity includes: Anorexia, Nausea, Vomiting, Higher levels cause seizures and arrhythmia

• Levels over 20mcg/mL

• Plasma clearance of theophylline varies wildly

• It is metabolised in the liver and should be used in caution in patients with liver disease

Antimuscarinic agents

• Mechanism of action - competitively inhibit the effect of acetylcholine at muscarinic receptors

• In the airways Ach is released from the parasympathetic nerve endings (muscarinic) and block airway smooth muscle relaxation and increase airway secretions

• Ipratropium Bromide

• Pharmacokinetics

• A: oral route - can be given in high doses because of its poor systemic absorption and lack of CNS penetration, onset of action 15 min

• D: low Vd and low systemic absorption

• M: hepatically

• E: Renal (46%) - half life 2 hours

Cromolyn and Nedocromil

• Mechanism of action: Mast cell stabiliser - inhibits release of histamine, leukotrienes and slow reacting substances of anaphylaxis by inhibiting mast cell degranulation

• Pharmacokinetics:

• A: PO bioavailibility 0.5 - 2%

• D: Peak plasma time 15 min

• M:

• E: 98% in feaces unabsorbed, half life 90 min

• Clinical use: Blocks bronchoconstriction caused by

• Allergen inhalation

• Exercise

• Sulfure dioxide

• Both agents reduce symptom severity and need for bronchodilator medications

Leukotrine pathway inhibitors

• Leukotirnes results from the activation of 5 - lipoxygenase on arachadonic acid and are synthesised by a variety of inflammatory mediators

• LTB 4 is a potent chemoattractant

• LTC4 and LTD4 are responsible for many of the effects associated with asthma

• Two pharmacological approaches exist to the inhibition of this pathway

• Inhibition of 5 - Lipoxygenase - preventing leukotrine synthesis

• Inhibition of binding of LTD4 to receptor of target tissues

• Have been shown to improve asthma control and reduce the frequency of exacerbations

Corticosteroids

• Presumed to act by broad anti-inflammatory mechanisms

• Reduce bronchial reactivity and reduce the frequency of asthma exacerbations if taken regularly

• Also induce contraction of engorged vessels in the bronchial mucosa and potentiate effects of beta receptor agonists

• Most important mechanism of action is the inhibition of lymphocytic, eosinophilic mucosal inflammation of asthmatic airways

Corticosteroids

• Effective in improving all indicies of asthma control

• Severity of symptoms

• Tests of airway calibre

• Bronchial reactivity

• Frequency of exacerbation

• QOL

• Oral and parenteral treatments reserved for those people who require urgent treatment - aerosolised treatment is the most effective mode of delivery to avoid systemic side effects

• Budesonide

• Fluticasone

• Main side effect it oral candidiasis which can be avoided by mouth gargling post treatment