Pharmacology of Respiratory MedicinesToby CapstickToby.Capstick@leedsth.nhs.ukLead 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