DRUGS FOR BRONCHIAL ASTHMA

DRUGS AFFECTING BRONCHIAL TONE

SITES OF ACTION OF ANTI-INFLAMMATORY DRUGS IN ASTHMA

CLASSIFICATION OF DRUGS FOR ASTHMA A) Bronchodilators

1. Selective β2 receptor agonists: Salbutamol, Torbutaline, Salmeterol, Formoterol, Bambuterol

2. Non-selective sympathomimetics: Epinephrine, Ephedrine, Isoprenaline

3. Anti-cholinergics: Ipratropium, Tiotropium, Oxitropium

4. Methylxanthines: Teophylline, Aminophylline

B) Anti-Inflammatory Drugs

1. Corticosteroids i. Oral: Prednisone, Prednisolone, Methylprednisolone

ii. Parenteral: Methylprednisolone, Hydrocortisone iii. Inhalational: Beclomethasone, Fluticasone, Budesonide, Triamcinolone, Flunisolide

2. Mast cell stabilisers: Sodium cromoglycate, Nedocromil 3. Leukotriene modulators

i. 5-lipoxygenase inhibitor: Zileuton ii. Cysteinyl leukotriene receptor antagonists: Montelukast

4. Monoclonal anti-IgE antibody: Omalizumab 5. Miscellaneous: Nitric oxide donors

SELECTIVE β2 RECEPTOR AGONISTS

Short acting (short term relievers): Salbutamol, Terbutaline

Long acting (long term prevention): Salmeterol, Formoterol, Bambuterol MOLECULAR MECHANISM OF AIRWAY SMOOTH MUSCLE RELAXATION Adrenergic drugs β2 receptors

Bronchial smooth Mast cells muscle cells ↑ CAMP production Bronchial relaxation ↓ mediators release ↓ inflammation

Adenylyl cyclase

stimulate

BENEFICIAL EFFECTS

Mainstay – reversible airway obstruction (asthma)

Caution – Blood pressure instability, ischaemic heart disease patients

Additional anti-inflammatory property (drawback desensitization due to down-regulation of β2 receptors)

Selectivity to β2 receptors minimal cardiac stimulation and minimal side effects

Inhaled medication targeted, more β2 selective and lessens systemic side effects

Improve mucociliary transport

Effective and fastest bronchodilator property SABA VS. LABA

SABA (Short acting β2 receptor agonists) LABA (Long acting β2 receptor agonists)

They bind to active site of β2 adrenoreceptor

Less lipid soluble

Early onset of action (<5 minutes), persists for 4-6 hours

Orally, inhalational (metered dose/dry powder/nebuliser), I.V. and I.M. route

Drug of choicefor acute attacks of asthma

Terbutaline is safe bronchodilator in pregnancy

They bind to active site and exo-site of β2 adrenoreceptor

Highly lipid soluble

Delayed onset

Inhalational and oral route

Indicated in nocturnal asthma and long-term prevention of asthma

ADVERSE EFFECTS

Minimal if inhaled (preferred)

Oral route Muscle tremors (direct + β2 in skeletal muscle) Tachycardia (chronotropic β2 and in high doses, β1 receptor is activated) Hyperglycaemia (↑ gluconeogenesis and ↑ glycogenolysis) Hypotension (peripheral vasodilatation)

Continued use Desensitization/down-regulation of receptors Diminished responsiveness to the previous dose Prevented by concurrent use of glucocorticoids (there is risk of ↓ K+)

Aerosol preparations – myocardial toxicity (fluorocarbons)

NON-SELECTIVE SYMPATHOMIMETICS

Epinephrine & Ephedrine (α & β)

Isoprenaline (β1 & β2)

Non-selective action cardiac side effects (↑ blood pressure, tachycardia, arrhythmia)

Epinephrine Can cause effective and rapid bronchodilatation Drug of choice for acute asthma till β1 agonists were available Rarely used due to cardiac side effects (tachycardia, hypertension, worsening of

angina, myocardial infarction and arrhythmias)

ANTI-CHOLINERGICS

Act as pharmacological antagonists of acetylcholine released from parasympathetic fibres

Ipratropium, Tiotropium & Oxitropium (aerosol) MOLECULAR MECHANISMS OF AIRWAY SMOOTH MUSCLE CONTRACTION

Acetylcholine acts on M3 receptor of airway smooth muscle cells and mucous glands ↓

Cause ↑in cGMP ↓

CGMP activates phospholipase C, PIP2 is converted into IP3 ↓

Release of Ca2+ from sarcoplasmic reticulum ↓

Bronchodilation ROLE IN ASTHMA

Less effective than selective β2 agonists

Also blocks M2 presynaptic autoreceptors (↑ acetylcholine release) ↓ Rx efficacy

Relieved by inhalational route (MDI, rotacaps, nebulizer)

Delayed onset of action (>30 minutes)

Poor absorption into systemic circulation (quartenary compounds)

Lacks classic anti-cholinergic side effects)

Additional to brochodilatory action, they also decrease mucous secretion (unlike atropine, lesser drying effect on mucous no mucous plugs)

No effect on late asthmatic response (inflammatory stage)

Second line drugs in moderate to severe asthma used as an adjuvant to β2 agonists/glucocorticoids (longer duration)

Action of acetylcholine is blocked by anti-

cholinergics, hence cause

bronchoconstriction

METHYLXANTHINES

Natural alkaloids: Caffeine, Theophylline, Theobromine

Beverages: coffee, tea, chocolate

Drugs: Theophylline, Aminophylline, Diprophylline

Mechanism of action: Inhibition of PDE-IV (eosinophils & mast cells) Inhibition of PDE-III (airway smooth muscle) Adenosine receptor inhibitor (bronchodilation)

Exhibits bronchodilatory + anti-inflammatory + immunomodulatory

Increase mucous clearance

Used in combination with β2 agonists – asthma and chronic obstructive pulmonary disease PHARMACOKINETICS OF THEOPHYLLINE

Absorption Well absorbed orally (sustained release preparation – SR)

Rectal absorption – suppositories (erratic)

Distribution

Distributed to all tissues

Crosses placenta

Secreted in milk

50% PPB (plasma protein binding)

Metabolism

Metabolized extensively in liver by CYP1A2 (>85%)

Metabolizing enzymes are saturable

At higher doses, first order kinetics (t1/2: 4-6 hours) zero order kinetics disproportionate ↑ plasma concentration

Prolongation of t1/2: 60 hours

Excretion Unchanged in urine (10%)

Elimination rate is variable

Varies according to age, comorbidities and concurrent medications

FACTORS AFFECTING ELIMINATION RATE (CLEARANCE) OF THEOPHYLLINE

Faster elimination Slower elimination

Children (t1/2: 3-5 hours)

Smoking

Cystic fibrosis

Hyperthyroidism

Adults (t1/2: 7-12 hours)

Elderly >60 years

Premature infants

Hypothyroidism

Cirrhosis

Congestive heart failure

Febrile viral illness, pneumonia

↓ breakdown of CAM ↑ cAMP

ADVERSE EFFECTS OF METHYLXANTHINES

Has a narrow safety margin (therapeutic window)

Therapeutic plasma range: 10-20 µg/ml

Dose dependent toxicity: >20 µg/ml

Systems affected: GIT, CNS and CVS Relationship between plasma concentration of

theophylline to its effects

Toxic effect

Therapeutic effect

Sub-therapeutic effect

>60 µg/ml: death

>40 µg/ml: seizures, diuresis, fever, arrhythmias

>30 µg/ml: tachypnoea, flush, hypotension

>20 µg/ml: nausea, vomiting

DRUG INTERACTIONS WITH THEOPHYLLINE 1) Agents which ↑ CYP1A2 (enzyme inducers) decrease theophylline concentration

Drugs: Phenytoin, Rifampicin, Phenobarbitone, Carbamazepine

Charcoal broiled meat

Smoking 2) Agents that inhibit theophylline metabolism

Drugs: Erythromycin, Ciprofloxacin, Cimetidine, Oral contraceptives, Allopurinol 3) Theophylline enhances the effects of sympathomimetics, digitalis, furosemide, hypoglycaemic

agents, oral anticoagulants THERAPEUTIC USES OF METHYLXANTHINES

Management of bronchial asthma

Treat chronic obstructive pulmonary disease (COPD)

Dyspnoea associated with pulmonary oedema that develops from congestive heart failure DRUGS FOR MANAGING “LATE ASTHMATIC RESPONSE” WITH ANTI-INFLAMMATORY PROPERTY Mainly a prophylactic role – “controllers of symptoms”

Corticosteroids: Systemic & Inhalational

Mast cell stabilizers : Inhalational

Leukotriene (LT) modulators : Oral

Anti-IgE antibody: S.C. / I.V.

20

10

0

Plasma conc.

(µg/ml)

CORTICOSTEROIDS

Inhaled/Systemic corticosteroids mainstay for Rx of moderate to severe asthma – “preventers” of attack

Anti-inflammatory and immunosuppressant

↓ mucosal oedema & bronchial hyper reactivity to allergens

Symptomatic reliefs, improve airflow, retard disease progression, reduce asthma exacerbations

Long term – adverse effects with oral CS are worse than asthma itself, tapering dose essential

Prophylaxis and treatment of seasonal and perennial allergy DRUGS

Oral: Prednisone, Prednisolone, Methylprednisolone

Parenteral: Methylprednisolone, Hydrocortisone

Inhalational: Beclomethasone, Fluticasone, Budesonide, Triamcinolone, Flunisolide, Ciclesonide

ROUTES OF ADMINISTRATION

Inhalation: ↑ topical action, ↓airway remodeling, ↓inflammation, long term treatment of asthma & COPD (combination with SABA/LABA)

Systemic: Severe chronic asthma when not controlled by other drugs – shift to inhaled steroid Following severe acute asthma (7-10 days) – oral corticosteroids Status asthmaticus – start with I.V., then switch to oral

Intranasal spray: Allergic rhinitis, nasal polyposis ADVERSE EFFECTS

Inhalational: dryness of mouth, voice changes & oral candidiasis

Ciclesonide: higher topical:systemic ratio

Oral: short courses (<2 weeks) – no HPA (hypothalamic-pituitary-adrenal) axis

Parenteral: used during status asthmaticus only for a brief period oral route (Hydrocortisone hemisuccinate)

MAST CELL STABILIZERS

Sodium cromoglycate & Nedocromil sodium (inhalation)

Inhibit degranulation of mast cells (all inflammatory cells)

Inhibit release of histamine, leukotrienes, platelet activating factor, interleukins

Prevent bronchospasm/asthma by allergens

Decrease frequency and severity of attacks

Effect over 4 weeks and lasts 2 weeks after discontinuation MECHANISM OF ACTION

THERAPEUTIC USES

Prophylaxis of chronic & seasonal asthma: long term in mild to moderate cases (not in acute)

Prophylaxis allergic rhinitis (nasal spray)

Allergic conjunctivitis (eye drops)

Preferred in patient having multiple allergic disorders ADVERSE EFFECTS

Inhalational: least systemic side effects

Cromoglycate inhalation: throat irritation, cough, arthralgia, headache

Mast cell degranulation

LEUKOTRIENE ANTAGONIST

Zileuton – blocks leukotriene receptor & leukotriene synthesis

Montelukast, Zafirlukast – leukotriene receptor blocker

Antagonise – leukotriene receptor mediated actions like bronchospasm, eosinophil accumulation in lung, bronchus inflammation, hyper reactivity

THERAPEUTIC USES

Prophylactic treatment of mild to moderate asthma as adjuvants with inhaled corticosteroids or selective β2 agonists

Prophylaxis in severe asthma: permit reduction in steroid dose, rescue β2 inhalation

Effective in aspirin induced asthma ADVERSE EFFECTS

Gastrointestinal distress, headache, rashes, eosinophilia

Churg-Strauss syndrome (vasculitis with eosinophilia)

Zileuton: hepatotoxic

MONOCLONAL ANTI-IGE ANTIBODY

The allergic cascade is interrupted by omalizumab

Omalizumab is a monoclonal antibody

It neutralizes free IgE in circulation

Little IgE available to bind mast cell to release mediators

Reserved for resistant asthma cases

Not useful for acute attacks or status asthmaticus

High cost limits its use as first line drug

DRUGS & DEVICES USED FOR ADMINISTRATION

INHALATIONAL DRUGS

β2 agonists: Salbutamol, Terbutaline, Salmeterol, Formoterol

Anti-cholinergics: Ipratropium, Tiotropium

Mast cell stabilizer: Cromoglycate

Glucocorticoids DRUG PARTICLE SIZE

Large particles – settle on oropharynx

1-5µm diameter – deposits on bronchioles

Very fine particles are exhaled out

Slow and deep inbreathing & hold the breath after inhalation * Inhalation devices: 10% drug reaches lung AEROSOLS

Drug in solution Metered dose inhaler (MDI) Nebulizer

Dry powder inhalers Rotahaler Spinhaler/Twisthaler

METERED DOSE INHALER (MDI)

Actuation – coordination with deep inspiration

Device – carried along, convenient

Improve drug delivery: spacer, face mask

Don’t require synchronized coordination with inspiration

Advantages of using a spacer

Improves drug delivery

Does not require synchronized coordination with inspiration

Increases inhaled to swallowed drug ratio

Decreases deposition of larger particles in the mouth (candidiasis) NEBULIZER

Produces mist of drug solution by pressurized air or O2

Inhaled through mouthpiece or face mask

Used at bed side

Severe episodes of asthma – kids and elderly

More drugs can be mixed simultaneously

ROTAHALER

Rotacap – capsule containing drug

Punctured while rotating the cap

Drug is aerosolized by inspiratory air flow

Requires high velocity of airflow (kids, elderly and sick patients)

Powder – irritate, cough, spasm SPINHALER/TWISTHALER

Keep drug

Use it

Reset to use again

STATUS ASTHMATICUS

Hydrocortisone hemisuccinate 100 mg I.V., followed by 100 mg 4th hourly infusion

Nebulized salbutamol (5 mg) + ipratropium (0.5 mg)

Salbutamol 4 mg I.M. (inhaled drug don’t reach smaller bronchi – severe narrowing/plugging)

High flow humidified oxygen inhalation

Intubation & mechanical ventilation

Sodium bicarbonate + saline – correct dehydration

Antibiotics – treat infection

ASTHMA SEVERITY CLASSIFICATION

Clinical course, severity

Daytime asthma symptoms

Night time awakenings

FEV1, PEF

Intermittent <1/week 2 and <2/month >80% predicted. Daily

variability <20%

Mild persistent ≥1/week but not daily >2/month >80% predicted. Daily variability is 20-30%

Moderate persistent Daily >1/week >60% but <80% predicted.

Variability >30%

Severe persistent Persistent, which limit

normal activity Daily

<60% predicted. Variability >30%

CHOICE OF DRUG FOR MANAGEMENT OF VARIOUS TYPES OF ASTHMA

Step-wise guidelines are recommended

After asthma control for 3-6 months, reduction of medication stepwise

Types Steps Drug therapy

Seasonal asthma – Regular inhaled: cromoglycates or low dose

steroids

Episodes: inhaled SABA

Mild episodic asthma Step 1

Inhaled SABA

Mild chronic asthma with occasional exacerbation

Step 2

Regular inhaled: cromoglycates or low dose steroids

Moderate asthma with frequent

Step 3

↑ dose inhaled corticosteroids + LABA

Additional: theophylline

Severe asthma Step 4 High doses inhalational corticosteroids + LABA

Additional: Leukotriene antagonist/oral theophylline/oral β2 agonist/inhaled ipratropium

Not controlled severe asthma

Step 5

High inhaled steroid + LABA

Add oral steroid