Pharmacology of Respiratory

Medicines
Toby Capstick
Toby.Capstick@leedsth.nhs.uk
Lead Respiratory Pharmacist
St James’s University Hospital
February 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 • Anti-inflammatory
asthma and COPD agents
• Bronchodilators ▫ Corticosteroids
▫ β2 adrenoceptor ▫ Leukotriene receptor
antagonists
agonists
▫ Mast cell stabilisers
▫ Anticholinergics
▫ Anti-IgE
▫ Methylxanthines
• Mucolytics
Pathophysiology of Asthma and
Chronic Obstructive Pulmonary
Disease (COPD)
Asthma
Immediate Phase Late Phase
Infiltration
Infiltration of
of cytokine-releasing
cytokine-releasing TT
Eliciting
Eliciting agent:
agent: allergen
allergen or
or non-
non- cells
cells &
& activation
activation of
of inflammatory
inflammatory cells
cells
specific
specific stimulus
stimulus activates…
activates… esp.
esp. eosinophils,
eosinophils, with
with release
release of…
of…

Mast
Mast cells,
cells, mononuclear
mononuclear cells,
cells, Mediators
Mediators e.g.e.g.
causing
causing release
release of…
of… LTC
LTC44,, LTD
LTD44,, PAF
PAF EMBP,
EMBP, ECP
ECP

Axon
Axon reflex
reflex release
release
Spasmogens
Spasmogens Chemotaxins
Chemotaxins of
of excitatory
excitatory Epithelial
Epithelial
H,
H, PAF,
PAF, PGDPGD22,,
e.g.
e.g. LTN
LTN44,, PAF
PAF neuropeptides
neuropeptides damage
damage
LTB
LTB44,, LTDand
and TT cell-
LTD44 cell-
derived
derived
Inflammation:
Inflammation:
chemokines,
chemokines, Bronchial
BRONCHOSPASM
BRONCHOSPASM which vasodilation,
vasodilation, oedema,
oedema, Bronchial hyper-
hyper-
which cause…
cause… responsiveness
responsiveness
mucus
mucus secretion
secretion
BRONCHOSPASM
BRONCHOSPASM
 Asthma pathology
Asthma is a chronic inflammatory disease associated with
airway hyperresponsiveness (AHR), short-term
consequences… …and long-term consequences

Airway obstruction
and symptoms by:
 Bronchoconstriction Remodelling:
 Mucus plugs Increased vascularity
 Mucosal oedema
Epithelial cell disruption

Increased airway smooth

muscle mass (hyperplasia)

Reticular basement
Inflammatory cell
membrane thickening
infiltration/activation
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
COPD is a Disease Characterised
by Inflammation
Cigarette Smoke

Epithelial
Cells

Macrophage/Dendritic Cell
Neutrophil
Monocyte

Fibroblast CD8+ Tc Cell Proteases

Fibrosis

Obstructive Bronchiolitis Emphysema Mucus Hypersecretion

Reproduced from The Lancet, Vol 364, Barnes PJ & Hansel TT, "Prospects for new drugs for chronic obstructive pulmonary disease",
7
pp985-96. Copyright © 2004, with permission from Elsevier.
Treatment of Respiratory
Diseases
Bronchodilators
Homeostasis
• Sympathetic • Parasympathetic
Innervation Innervation
• Bronchial smooth muscle • Bronchial smooth muscle
▫ Relaxation ▫ Constriction of airways
▫ Increased mucociliary • Glands
clearance ▫ Increased secretion
β2-Agonists
• Short Acting • Long Acting
• Salbutamol + Terbutaline • Salmeterol
▫ Onset 5 mins ▫ Onset 10-20 mins
▫ Duration 4-6 hrs ▫ Duration 12 hrs
• Formoterol
▫ Onset 1-3 mins
▫ Duration 12 hrs

Salbutamol Terbutaline Salmeterol

(Ventolin) (Bricanyl) (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 • Long Acting
• Ipratropium • Tiotropium
• (M1, M2 and M3 • (M1and M3 antagonist)
antagonists) ▫ Onset 3-7 days
▫ Onset 15-30 mins ▫ Duration 24 hrs
▫ Duration 6-8 hrs

Ipratropium Tiotropium
(Atrovent) (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
Diseases
Anti-Inflammatory Agents
Corticosteroids
Inhaled Oral
• Beclometasone • Prednisolone (preferred
• Budesonide agent in UK)
• Fluticasone • methylprednisolone
• ciclesonide Intravenous
Nebulised • Hydrocortisone
• Budesonide • methylprednisolone
• fluticasone
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
Treatment steps

Step 1 Step 2 Step 3 Step 4 Step 5

Asthma education
Environmental control

As-needed rapid-
As-needed rapid-acting 2-agonist
acting 2-agonist

Select one Select one Add one or more Add one or both

Low-dose ICS plus Medium-or high- Oral

Low-dose inhaled long-acting dose ICS plus long- glucocorticosteroid
ICS
2-agonist acting 2-agonist (lowest dose)

Leukotriene Medium-or high- Leukotriene

Anti-IgE treatment
modifier dose ICS modifier
Controller options
Low-dose ICS plus
Sustained release
leukotriene
theophylline
modifier

Low-dose ICS plus

sustained release
theophylline

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
•FEV1/FVC < 0.70 or FEV1 < 50%
•30% ≤ FEV1 < 50% predicted plus chronic
•FEV1/FVC < 0.70 predicted
•50% ≤ FEV1 < 80% respiratory failure
•FEV1/FVC < 0.70 predicted
•FEV1 ≥ 80% predicted
Active reduction of risk factor(s); influenza vaccination
Add 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