Pharmacology of Respiratory MedicinesToby [email protected] Respiratory PharmacistSt James’s University HospitalFebruary 2011
Objectives
•By the end of this session, you should:▫Be able to list the different classes of
medicines used in the management of conditions affecting the respiratory tract.
▫Be able to describe how these drugs work and their clinical use.
Outline• Pathophysiology of
asthma and COPD• Bronchodilators
▫β2 adrenoceptor agonists
▫Anticholinergics▫Methylxanthines
• Anti-inflammatory agents▫Corticosteroids▫Leukotriene
receptor antagonists
▫Mast cell stabilisers▫Anti-IgE
• Mucolytics
Pathophysiology of Asthma and Chronic Obstructive
Pulmonary Disease (COPD)
Asthma
Eliciting agent: allergen or non-specific stimulus
activates…
Eliciting agent: allergen or non-specific stimulus
activates…
Mast cells, mononuclear cells, causing release of…Mast cells, mononuclear
cells, causing release of…
Spasmogens H, PAF,
PGD2, LTB4, LTD4
Spasmogens H, PAF,
PGD2, LTB4, LTD4
Chemotaxins e.g. LTN4,
PAF and T cell-derived chemokines,
which cause…
Chemotaxins e.g. LTN4,
PAF and T cell-derived chemokines,
which cause…
BRONCHOSPASM
BRONCHOSPASM
Infiltration of cytokine-releasing T cells & activation of inflammatory
cells esp. eosinophils, with release of…
Infiltration of cytokine-releasing T cells & activation of inflammatory
cells esp. eosinophils, with release of…
Mediators e.g. LTC4, LTD4, PAFMediators e.g. LTC4, LTD4, PAF EMBP, ECPEMBP, ECP
Axon reflex release of excitatory
neuropeptides
Axon reflex release of excitatory
neuropeptides
Epithelial damage
Epithelial damage
Inflammation: vasodilation,
oedema, mucus secretion
BRONCHOSPASM
Inflammation: vasodilation,
oedema, mucus secretion
BRONCHOSPASM
Bronchial hyper-
responsiveness
Bronchial hyper-
responsiveness
Immediate Phase Late Phase
Asthma pathologyAsthma is a chronic inflammatory disease associated with airway hyperresponsiveness (AHR), short-term consequences…
Airway obstruction and symptoms by:Bronchoconstricti
onMucus plugsMucosal oedema
Inflammatory cell infiltration/activation
Remodelling:Increased vascularity
Epithelial cell disruption
Increased airway smooth muscle mass (hyperplasia)
Reticular basement membrane thickening
…and long-term consequences
Bousquet J et al. Am J Respir Crit Care Med 2000;161:1720–1745; GINA Report 2007 (www.ginasthma.org); Beckett PA et al. Thorax 2003;58:163–174
7
COPD is a Disease Characterised by Inflammation
Reproduced from The Lancet, Vol 364, Barnes PJ & Hansel TT, "Prospects for new drugs for chronic obstructive pulmonary disease", pp985-96. Copyright © 2004, with permission from Elsevier.
Cigarette Smoke
Epithelial Cells
CD8+ Tc Cell
Emphysema
Proteases
Mucus Hypersecretion
Macrophage/Dendritic Cell
NeutrophilMonocyte
Fibroblast
Obstructive Bronchiolitis
Fibrosis
Treatment of Respiratory Diseases
Bronchodilators
Homeostasis• Sympathetic
Innervation• Bronchial smooth
muscle▫Relaxation▫Increased
mucociliary clearance
• Parasympathetic Innervation
• Bronchial smooth muscle▫Constriction of
airways• Glands
▫Increased secretion
β2-Agonists• Short Acting• Salbutamol +
Terbutaline▫Onset 5 mins▫Duration 4-6 hrs
• Long Acting• Salmeterol
▫Onset 10-20 mins▫Duration 12 hrs
• Formoterol▫Onset 1-3 mins▫Duration 12 hrs
Salbutamol(Ventolin)
Terbutaline(Bricanyl)
Salmeterol(Serevent)
Mechanism of Action of β2 Agonists
Adverse Effects of β2-Agonists•Skeletal muscle: tremor, hypokalaemia•Blood vessels: vasodilation•Heart: reflex tachycardia secondary to
peripheral vasodilation. Tachycardia and positive inotropic effect by direct stimulation of β1-adrenoceptors at high doses
Use in Practice - Asthma•Short Acting (Salbutamol, Terbutaline)
▫Chronic Management - Step 1 British Thoracic Society Guidelines (prn use)
▫Acute Management - first Line•Long Acting (Salmeterol, formoterol)
▫Chronic Management - Step 3 British Thoracic Society Guidelines (Add to inhaled corticosteroid)
▫Acute Management - No role
Use in Practice - COPD•Short Acting (Salbutamol, Terbutaline)
▫Chronic - prn or regular (Symptom control)
▫Acute - 1st line, Increase dose/Frequency•Long Acting (Salmeterol, formoterol)
▫Chronic Moderate disease - Regular long acting + prn short acting
▫Acute - No role
Anticholinergics• Short Acting• Ipratropium • (M1, M2 and M3
antagonists)▫Onset 15-30 mins▫Duration 6-8 hrs
• Long Acting• Tiotropium• (M1and M3 antagonist)
▫Onset 3-7 days▫Duration 24 hrs
Ipratropium(Atrovent)
Tiotropium(Spiriva)
Effects of Acetylcholine•M1 receptors:
▫Medium & large airways - bronchoconstriction
▫Neural - facilitate neurotransmission through parasympathetic ganglia.
•M2 receptors:▫Cardiac (atria) – inhibition▫Neural presynaptic terminals – inhibition
•M3 receptors:▫Medium & large airways –
bronchoconstriction▫Exocrine glands - secretions
Adverse Effects of Anticholinergics•Bitter taste•Paradoxical bronchoconstriction (rare)•Inhibition of secretions: dry mouth•Cardiac: tachycardia•Eye: blurred vision, ↑IOP•GI: constipation•Urinary Tract: urinary retention
Use in Practice - Asthma•Short Acting (Ipratropium)
▫Chronic Management - No longer recommended
▫Acute Management (Nebulised ipratropium Add on) Faster recovery/decreased duration
admission Only if poor initial response to β2 agonists, O2,
steroids or acute severe/life threatening asthma.
•Long Acting (Tiotropium)▫Not licensed for asthma, no clinical trial
data
Use in Practice - COPD•Short Acting (Ipratropium)
▫Chronic - Add on as regular therapy or substituted for β2
▫Acute - Add on if insufficient response to short acting β2 therapy.
•Long Acting (Tiotropium)▫Chronic use only - Regular maintenance
therapy in place of Ipratropium.▫With short acting β2
▫+/- Long acting β2
Mechanism of Action of Methylxanthines (Theophylline / Aminophylline / Caffeine)
•Bronchodilation▫Phosphodiesterase inhibition▫Blockade of adenosine receptors
•Immunomodulatory▫Inhibition of eosinophil degranulation▫Reduced cytokine production▫Reduction in inflammatory cell numbers
•Increased diaphragm muscle contractility
Adverse Effects of Methylxanthines•N & V•Restlessness•Headache•Gastro-oesophageal reflux•Diuresis•Hypokalemia•Cardiac arrhythmias•Seizures•Coma => death
Theophylline & Aminophylline•Narrow therapeutic range 10-20mg/L -
need to monitor blood levels.▫Minor transient toxicity (5-20 mg/L)
Nausea, vomiting, headache▫Moderate toxicity (20-30 mg/L)
Irritability, nervousness, sinus tachycardia▫Severe toxicity (>35 mg/L)
Seizures, arrhythmias, arrest and death▫Check peak level at steady state.
IV – anytime, PO 6-8 hrs post dose (MR preparations)
Methylxanthines - TDM•Significant number of drug interactions
▫Level ed by macrolides, ciprofloxacin, verapamil, cimetidine, OCP
▫Level ed by rifampicin, phenytoin, phenobarbitone
•Clearance affected by patient factors:▫Level ed in CCF, Hepatic disease, infection,
obstructive airway disease▫Level ed by smoking
Use in Practice - Asthma•Chronic
▫Failure to respond long acting β2
(Step 3)▫Add on step 4
•Acute▫IV in severe or life threatening asthma already on maximal therapy.
Use in Practice - COPD•Chronic
▫Add on to long acting bronchodilators.
▫Review PEFR, FEV1, QOL – stop if no benefit
•Acute ▫IV – last resort as no evidence (?central effect)
Treatment of Respiratory DiseasesAnti-Inflammatory Agents
CorticosteroidsInhaled• Beclometasone• Budesonide• Fluticasone• ciclesonideNebulised• Budesonide• fluticasone
Oral• Prednisolone
(preferred agent in UK)
• methylprednisoloneIntravenous• Hydrocortisone• methylprednisolone
Mechanism of Action of Corticosteroids•Bind to intracellular receptor leading to
increased transcription of anti-inflammatory genes and decreased transcription of pro-inflammatory genes▫Reduction in number and activity of mast cells,
macrophages, T cells & eosinophils▫No effect on neutrophils (ed levels in COPD,
but macrophages, T cells & eosinophils also implicated)
▫↓ed generation of prostaglandin’s and leukotrienes
▫↓ airway hyper-responsiveness▫Aids healing of damaged epithelium▫Decreased mucosal oedema
Inflammatory Pathway
Adverse Effects of Corticosteroids• Cushing Syndrome
• Adrenal suppression
• Hyperglycaemia
• Growth retardation
• Osteoporosis
• susceptibility
infection
• Euphoria/Psychosis
• Hypokalaemia
• Fluid retention
• Skin thinning/muscle
wasting
• Poor wound healing
• Cataracts/exac. of glaucoma
• Peptic ulceration
• Local dysphonia & oral
candida
Use in Practice - Asthma•Lessen airway hyper-responsiveness•Chronic (BTS guidelines 2005)
▫Step 2: if using inhaled β2 agonist at least 3 times per week (200-800mcg/day*)
▫Step 5: daily low dose oral steroid plus high dose inhaled steroid (2000mcg/day*)
•Acute▫↓ mortality, relapses, hospital admissions▫Prednisolone 40-50mg/day for 5 days or until
recovery (or IV hydrocortisone 100mg qds)* = beclometasone doses
Use in Practice - COPD•Chronic
▫High doses do not reduce the number of inflammatory cells or levels of cytokines
▫No change in lung function, exacerbation rate (from 1.32 to 0.99/year)
▫Use inhaled corticosteroids if FEV1 <50%, and 2+ exacerbations per year (NICE)
•Acute▫Improvement in FEV1, shorter hospital stay▫Use in all patients admitted with exacerbation
(NICE)▫Oral Prednisolone 30mg daily for 7-14 days
Mechanism of Action of Leukotriene Receptor Antagonists (Montelukast / Zafirlukast)
Mechanism of Action of Leukotriene Receptor Antagonists (Montelukast / Zafirlukast)
Adverse Effects of Leukotriene Receptor Antagonists
•Most common – headache and gastro-intestinal disturbance.
•Zafirlukast associated with liver toxicity•Churg-Struass Syndrome – often followed
by a reduction or withdrawal of oral Corticosteroids. Prescriber should be alerted to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications and peripheral neuropathy.
Use in Practice – Asthma only•Reduce severity of bronchial hyper-
responsiveness•Improvement in lung function &
symptoms, reduction in exacerbations.•Recommended in chronic asthma (BTS)
▫Step 3: if no response to long acting β2 agonist or moderate dose inhaled corticosteroid
▫Step 4: as a fourth drug▫Exercise induced asthma
Mast Cell Stabilisers (Sodium Cromoglicate / Nedcromil Sodium)
•Stabilise Mast cell membrane (low potency)
•Inhibit activation of & mediator release from mast cells, eosinophils, macrophages
•Lack of evidence of efficacy•Administration – inhaled QDS•Adverse effects (rare: Bitter taste, sore
throat, pulmonary eosinophilia)•Use in Practice:
▫Asthma – exercise induced asthma?▫COPD – no role
Anti-IgE (Omalizumab)•Monoclonal antibody, given by SC injection•Mechanism of Action
▫IgE binds to Mast cell and basophil receptors to allergens to release pro-inflammatory mediators.
▫Antibody therefore prevents this•ADRs: injection site reaction, headache,
anaphylaxis?•Use in Practice
▫Reduction in frequency of severe asthma exacerbations
▫Chronic asthma – Severe persistent allergic asthma
Mucolytics Acetylcysteine (Parvolex®), Carbocisteine (Mucodyne®), Mecysteine (Visclair®)•Alter structure of mucus•Decreased viscosity = easier expectoration•Acetylcysteine increases glutathione levels
in lung (?antioxidant)•ADRs: mild to moderate nausea and
gastritis•Use in practice:
▫Reduction in exacerbation rate and total days of disability. No effect on lung function.
▫COPD: in patients with chronic productive cough
Use of Inhalers
•Inhalers should be prescribed only after patients have been trained and have demonstrated satisfactory technique.▫Reassess inhaler technique as part of
structured clinical review.▫The choice of device may be determined
by choice of drug.▫If patient unable to use a device
satisfactorily, find alternative.▫Titrate medication needs against clinical
response to ensure optimum efficacy.
REDUCE INCREASE
Asthma educationEnvironmental control
As-needed rapid-acting 2-agonist
As-needed rapid-acting 2-agonist
Controller options
Select one Select one Add one or more Add one or both
Low-dose inhaled ICS
Low-dose ICS plus long-acting 2-agonist
Medium-or high-dose ICS plus long-
acting 2-agonist
Oral glucocorticosteroid
(lowest dose)
Leukotriene modifier
Medium-or high-dose ICS
Leukotriene modifier
Anti-IgE treatment
Low-dose ICS plus leukotriene modifier
Sustained release theophylline
Low-dose ICS plus sustained release
theophylline
Treatment steps
Step 1 Step 2 Step 3 Step 4 Step 5
GINA Report 2007 (www.ginasthma.org)
Therapy at Each Stage of COPD (GOLD 2007)
I: Mild II: Moderate III: Severe IV: Very Severe
•FEV1/FVC < 0.70•FEV1 < 30% predicted or FEV1 < 50% predicted plus chronic respiratory failure
•FEV1/FVC < 0.70•30% ≤ FEV1 < 50% predicted
•FEV1/FVC < 0.70•50% ≤ FEV1 < 80% predicted
•FEV1/FVC < 0.70•FEV1 ≥ 80% predicted
Active reduction of risk factor(s); influenza vaccinationAdd short-acting bronchodilator (when needed)
Add regular treatment with one or more long-acting bronchodilators (when needed); Add rehabilitation
Add inhaled glucocorticosteroids if repeated exacerbations
Add long term oxygen if chronic respiratory failure.Consider surgical treatments