Pharmacology of obstructive airway diseases Flashcards
bronchospasm
reversible airflow obstruction due to constriction of bronchi
bronchial hyperresponsiveness
non-specific • histamine • metacholine/ carbachol • cold air • sulphur dioxide
specific
• adenosine (as AMP)
bronchial changes in mild asthma
- remodelling of bronchial tissues
goals of asthma therapy
Relief • Reverse bronchoconstriction • In severe attacks: • reduce mucus secretion • suppress airway oedema
Prevention • Inhibit bronchoconstriction • Suppress chronic inflammation • Inhibit airway remodelling
COPD
Disease of smokers
• Impairment of normal lung defences against infection-> recurrent infections of airways (bronchitis) and alveoli (pneumonia)
• Inflammatory reaction -> tissue destruction (emphysema)
goals of COPD
Relief
• Increase airway patency
• Control recurrent infections
Prophylaxis
• Suppress chronic inflammation
• Control mucus secretion
drug treatment of asthma
Relievers
• Bronchodilators
– B2-adrenoceptor agonists
– Muscarinic receptor antagonists
Preventers • Long-acting bronchodilators • Methylxanthines • Cromones • Glucocorticoids (inhaled/oral) • Leukotriene receptor antagonists
Extremely potent class of drugs
• Glucocorticoids
Bronchodilators
• b2-adrenoceptor agonists
– Salbutamol, terbutaline
• Mechanism of action
– Relaxation of bronchial smooth muscle
– Predominantly cyclic AMP mediated
– Some cAMP-independent actions on ion channels (KCa channels)
– Stimulus-independent
Treatment of COPD
• Smoking cessation • Vaccination – Streptococcus pneumoniae – Influenza virus • Anti-bacterial drugs • Oxygen • Ventilatory support • Pulmonary rehabilitation
Drugs
• Bronchodilators
– Less effective than in asthma
– Anti-muscarinic often preferred
– Long-acting anti-muscarinics (e.g.tiotropium) often used
– Theophylline frequent second-line choice
• Glucocorticoids
– Can have some benefit in acute exacerbations
Drug treatment of chronic asthma
Mild intermittent
• Inhaled B2-agonist prn
• Inhaled ipratropium + oral theophylline if necessary
Mild persistent • As above plus: • Adults: inhaled steroid • Children: inhaled cromone • May try CysLT1 antagonist
Moderate persistent
• Bronchodilator + inhaled steroid plus:
• Long-acting B2-agonist and/or increased dose of steroid
• If necessary, add CysLT1 antagonist or theophylline or oral B2-agonist
Severe
• Add oral prednisolone
Bronchodilators
• b2-adrenoceptor agonists
– Salbutamol, terbutaline
• Pharmacokinetics
– Active p.o., i.v. or by inhalation
– Inhalation allows rapid action and minimizes adverse effects
– Onset within 5 min
– Duration up to 6 h (not taken up or metabolized at synapse)
– Metabolized in liver (sulphate conjugation)
– t½ = 4 h (oral)
– Excreted in urine unchanged or as sulphate conjugate
Bronchodilators
• b2-adrenoceptor agonists
– Salbutamol, terbutaline
•interactions
– B-adrenoceptor antagonists inhibit actions
– Methylxanthines enhance actions
Bronchodilators
• b2-adrenoceptor agonists
– Salbutamol, terbutaline
•Adverse actions
– Tremor
– Tachycardia/dysrhythmia (systemic B1 and B2)
– Tolerance may occur to therapeutic actions and tremor
-Salbutamol has ‘off-target’ effects at B1 receptors in the heart. Also, B2 receptors mediate dilation of blood vessels supplying heart & skeletal muscle
Drop in systemic blood pressure leads to reflex tachycardia
Drug treatment of asthma-
Bronchodilators
• LABA – Salmeterol, formoterol
- Mechanism of action
- Pharmacokinetics
• Mechanism of action – Same as salbutamol • Pharmacokinetics – Duration of action 8-12 h – Administered twice daily – Avoid “morning dip”
Drug treatment of asthma Bronchodilators • Muscarinic antagonists – Ipratropium • Mechanism of action
– Relaxation of bronchial smooth muscle
– Inhibition of bronchial mucus secretion
– Antagonism of bronchial muscarinic receptors
– Specific to parasympathetic bronchoconstriction
Drug treatment of asthma Bronchodilators • Muscarinic antagonists – Ipratropium • Pharmacokinetics
– Active by inhalation – 10-30% deposited in airways; remainder swallowed – High pulmonary bioavailability – Very low oral bioavailability – Onset within 30-60 min – t½ = 1.6 h (ipratropium) but not related to duration of action – Duration = 3-5 h (ipratropium), >_24 h (tiotropium) – Excreted unchanged in urine
Drug treatment of asthma Bronchodilators • Muscarinic antagonists – Ipratropium • Interactions
– Ocular effects enhanced by B2 agonists
Drug treatment of asthma Bronchodilators • Muscarinic antagonists – Ipratropium • Adverse actions
– GI effects (constipation) – Mouth dryness – Rarely: • Tachycardia • Ocular accommodation disturbances • Urinary retention (especially in prostatic hypertrophy/ hyperplasia
Drug treatment of asthma Bronchodilators • Muscarinic antagonists – Ipratropium • Contraindication
– Closed-angle glaucoma
– Urinary tract obstruction
Drug treatment of asthma Bronchodilators • Methylxanthines – Theophylline, aminophylline • Mechanism of action
• Mechanism of action
– Relaxation of bronchial smooth muscle
– Inhibition of cyclic nucleotide phosphodiesterase (PDE)
– Possible anti-inflammatory actions
– Stimulus-independent
– Non-selective PDE inhibition
– Isoenzyme family-selective inhibitors under investigation for asthma (and COPD)
Bronchodilators
• Methylxanthines
– Theophylline, aminophylline
• Pharmacokinetics
– Active orally but absorption unpredictable
– May be administered i.v. as aminophylline (theophylline ethylenediamine)
– Metabolized by CYP1A2 and CYP3A4
Bronchodilators
• Methylxanthines
– Theophylline, aminophylline
• Adverse actions
– Narrow therapeutic window – Blood concentrations should be monitored – Vomiting (PDE4 inhibition) – CNS stimulation – Hypotension (PDE3 inhibition) – Cardiac arrhythmias
Bronchodilators
• Methylxanthines
– Theophylline, aminophylline
• Interactions
– Hepatic enzyme inducers (ciprofloxacin, erythromycin,
fluconazole, etc.)
Drug treatment of asthma Asthma preventers • Glucocorticoids – Beclometasone, fluticasone, prednisolone • Mechanism of action
– Reduce inflammatory cell activation
– Decrease IgE synthesis
– Up-regulate B2-adrenoceptor expression
Drug treatment of asthma Asthma preventers • Glucocorticoids – Beclometasone, fluticasone, prednisolone • Pharmacokinetics
– Active by inhalation (beclometasone/fluticasone)
– Low pulmonary/oral bioavailability (beclometasone)
– Rapid first-pass metabolism (fluticasone)
– Active orally (prednisolone)
– Potent forms i.v. (methylprednisolone)
Drug treatment of asthma Asthma preventers • Glucocorticoids – Beclometasone, fluticasone, prednisolone • Adverse actions
– By inhalation, encourage oral candidiasis (thrush) and dysphonia (hoarseness)
Drug treatment of asthma Asthma preventers • Cromones – Sodium cromoglycate, nedocromil • Mechanism of action
– Mast cell stabilization (questionable importance)
– Inhibition of sensory nerves (blockade of Cl- channel)
– Small effect against mild paediatric asthma (especially exercise-induced)
Drug treatment of asthma Asthma preventers • Cromones – Sodium cromoglycate, nedocromil • Pharmacokinetics
– Active by inhalation
– Extremely low pulmonary/oral bioavailability
– No systemic drug - eliminated by coughing or in faeces
Drug treatment of asthma Asthma preventers • Cromones – Sodium cromoglycate, nedocromil • Adverse actions
– Transient cough and wheeze
Asthma preventers
• Anti-leukotriene drugs
– 5-lipoxygenase inhibitors (zileuton)
– CysLT1 antagonists (zafirlukast, montelukast)
– Affect early, late and chronic reactions
– Orally active
– Few adverse actions
Drug treatment of asthma
Anti-IgE therapies
• Omalizumab – Humanized monoclonal antihuman IgE – Neutralizes circulating IgE – Suppresses allergic reactions, including chronic allergy underlying asthma
Drug treatment of acute severe asthma
Severe • Unable to speak freely • Pulse = 110 beats min-1 • PEFR = 50% predicted • Severe hypoxaemia (PaO2 < 8 kPa) with normo- or hypercapnia (PaCO2 > 5 kPa)
Life-threatening
• No breath sounds
• Cardiovascular depression (bradycardia or hypotension)
• PEFR
Drug treatment of asthma may ..
Drug treatment of asthma may address symptoms (bronchodilators) or underlying causes (preventers)
What changes are seen in a airway with asthma
Increased glands Thicker smooth muscle Increased mucous Increased macrophages, neutophils and mast cells in the lamina propria Increased eosinophils in mucous Decrease in goblet cells Thicker basement membrane
Pathophysiological features of asthma
Bronchospasm and bronchial hyper responsiveness
IgE
The cascade begins with a helper t-cell at the top stimulating a b-cell by the secretion of interleukin 13 and interleukin 4 and via cell-cell interactions. That allows the b-cell to reach its activation threshold and start to secrete antibody in this case IgE.
IgE is released into circulation where it binds to its receptors on mast cells, once bound it will then cross link with antigen leading to activation of the mass cells, degranulation and the release of variety and inflammatory mediators such as histamine leukotrienes and various cytokines.
These have the physiological effects both in early and late responses. In the early responses they’re responsible for the bronchospasm, the oedema and airway obstruction and in the late response they’re involved with airway inflammation, airway obstruction and the airway hyper responsiveness.
Inhibitory auto receptor dysfunction in asthma
under normal circumstances airway tone is maintained by a balance between dilation through stimulation of
airway smooth muscle by the B-adrenergic receptors and constriction by stimulation through the muscarinic receptors.
The two neurotransmitters involved here are adrenaline for b2 and acetylcholine for b3.
In humans there’s no direct sympathetic innervation of the smooth muscle however the B2 adrenergic receptors shown here just as b2 are available to circulating adrenaline by the sympathetic nervous system shown here in SNS. we believe that both the B2 receptors and the M2 muscarinic receptors are inhibitory to acetylcholine release and we believe that there’s a crosstalk between these two receptors in the pre junctional membrane which is shown here as the dotted line the M2 receptor itself is stimulated by free acetylcholine that is an inhibitory feedback so that further inhibits further acetylcholine release.
We believe in reset that in asthma it’s possible that this Auto receptor the M2 receptor is somehow defective therefore in response to viruses for example we might see this negative feedback being lost and therefore we see an increased airway hyperactivity.
Postsynaptically we have the muscarinic M3 receptor and that’s the main bronco constrictors receptor if you like for the smooth muscle here although the post synaptic M2 receptors are also present their role here is actually to prolong M3 initiated bronchoconstriction by opposing the actions of the stimulated B2 adrenergic receptor therefore the same receptors will have different pre and postsynaptic effects and will exert independent effects on airway hyper activity and airway tone.
drug targets in asthma
the immediate phase first of all we have our eliciting agents these can either be allergens or nonspecific stimuli. these recruit and activate the mast cells and
mononuclear cells and these will produce spasmogens such as the leukotrienes, protaglandins d2 and the chemo toxins and chemokines.
Spasmogens versions cause bronchospasm first of all this can be reversed by b2 Adrenoceptor agonists, cysts leukotriene receptor antagonists and theophylline.
The chemo toxins and chemokines have an effect in the late phase causing infiltration of cytokine releasing th2 cells, monocytes and activation of the inflammatory cells specifically the eosinophils.
Eosinophils start to secrete various mediators such as cysts leukotrienes possibly neuropeptides nitric oxide and adenosine these together cause airway inflammation, airway hyperactivity and bronchospasm together with wheezing and coughing.
In addition they can produce a EMBP or ECP which directly causes epithelial damage. Epithelial damage itself contributes to airway hyperreactivity.
All of this late phase section including the new chemo toxins and chemokines can be inhibited by the glucocorticoids
beyond that acute inflammation
So what if we want to look beyond that acute inflammation so first of all we have the:
- acute phase where we have the symptoms such as bronchoconstriction that crosses over into
- chronic inflammation so we have exacerbations and nonspecific hyperactivity so this is where the condition is causing problems even in between acute attacks.
- the third phase of that is airway remodelling so we end up with a persistent airway obstruction and that causes significant problems for patients than that acute inflammation phase.
Airway changes in chronic sever asthma
This remodelling in chronic severe asthma is shown in several ways.
So if we start from the inside and moving outwards from this diagram first of all in lumen of the bronchial you see a mucous plug, this mucus plug consents a significant number of inflammatory cells such as eosinophils and desquamated epithelial cells that have come off that layer of epithelial lining. We don’t have a thickened basement membrane in addition to the damage being seen on the epithelium itself and we go then into the mucosal layer which you can see is significant number of inflammatory cell infiltrates these can be eosinophils monocytes mononuclear cells etc. We also see oedema in this level moving outwards again you get into the muscular layer, the smooth muscle layer is showing significant increase in mass here this is hypertrophied it’s increased. The final layer is a submucosa again we see infiltration of lots of inflammatory cell types, we see oedema both in here as well as in the mucosal layer and we also see dilation of the blood vessels
the most commonly associated antibodies with asthma is
IgE
