Respiratory Pharmacology

Lecture 30: Bronchodilators

• Bronchodilators: inhaled drugs used to treat narrowed airways due to smooth muscle contraction. Relieves daily symptoms such as wheezing
- Inhaled beta-adrenergic agonists
- Inhaled cholinergic agents
- Theophylline
• Adrenaline: β2 receptors respond to circulating adrenaline which stimulates cAMP and smooth muscle relaxation. However adrenaline is non-selective as it activates both α and β receptors (also constrict blood vessels).
- Isoprenaline: β1 and β2 agonists (β2 is important while β1 will increase heart rate)
• Fast acting β2 agonists: salbutamol and terbutaline. These are resistant to COMT (cathechol-o-methyl transferase) which breaks down catecholamines so effects last 5-6 hours.
- Administrated through inhalers to allow fewer side effects and faster rate of acting (if taken orally, only a proportion will go to lung)
- Adverse effects: at high doses, palpitations and tremors occur. Heart beat becomes rapid and may suffer sinus tachycardia while β2 in skeletal muscles causes tremor.
• Problems with inhalers:
- Tachyphlaxis: developing resistance. However usually even with down-regulation of repeated doses, there is still sufficient receptor to cause smooth muscle dilation.
- Mucus plugging: loss of response does not indicate tolerance but mucus plugging can block drug from going to distal lung to site of action.
• Types of inhalers:
- Metered dose inhalers: aerosol spray
- Dry powder device: breath activated (inspiration to spread with powder)
• Usage of inhalers: inhalers should be used as required when short of breath or wheezing
- Exercise induced asthma, cooling and drying of airways
• Long acting β agonists (LABAS): salmeterol and eformoterol. These bronchodilators acts for 12 hours or mores as the drug stays in the cell membrane so binds to β2 for longer. Long time required for action hence works as a preventor
- Feature: added a long hydrocarbon tail to the sabutamol to make it more lipid soluble and in addition a functional group at the end of the tail will bind to an exosite and keep the drug close to the receptor.
• Anticholinergic agents: M1 – M5. M5 causes smooth muscles to contraction and mucus gland to secrete mucus. This type of drug is much less effect as majority of constriction is due to inflammation response but nevertheless, slight dilation works. Agents are histamine and prostaglandins that bind to sensory nerve endings
- Ipratropium (atropine): block Ach and cause smooth muscle dilation for 6 -8 hours. Slower and lower peak effect compared to beta-agonists but used when beta agonist can not be tolerated.
- Problems: reduced mucocillary clearance. Even though mucus is reduced slightly, it is possible to cause blockage and be stuck.
- Tiotropium: action over 24 hours and used as treatment for COPD. Problems with dry mouth in 10-15% (systemic absorption of the drug is low but sufficient to cause this). Once per day is sufficient as effect is sustained.
• Theophylline: phosphodiesterase inhibitor (block degradation of cAMP and GAMP) that non-selectively block all 4 types of phosphodiesterases (type IV is the most relevant to asthma). This allows increase in cAMP that cause bronchodilation.
- Have anti-inflammatory problems
- Narrow therapeutic index
- Minor effect: nausea, vomiting, headache, tremor and insomnia
- Major effect: ventricular tachycardia, atrial fibrillation, seizures
- Blocks adenosine also
• Clearance of theophylline:
- Decrease clearance with heart failure, erythromysin block, CYP1A2 and G profluxacin.
- Increase clearance with smoking and phenytoin

Lecture 31: Anti-inflammatory drugs

• Cortisone: steroid substance. Hydrocortisone is the oral cortisone with very effective anti-inflammatory effect
• Gluccocorticoid: over 100 genes present. These bind to receptors located in the cell cytoplasms after crossing the cell membrane. Once bound, the receptor dimerizes and goes into the nucleus where it binds to the GRE (glucocorticoid response element) of the DNA to alter expression
- Example: increased expression of beta-2 adrenergic receptors.
- Other effects: decrease IL-4 IgG, IL-5 (eosinophil) and IL-3 synthesis
• Other effect of steroids: able to target a wider range of mediator and cytokines instead of one making it more effective
- Lipoportin (inhibit phospholipase-A2)
- Reduce prostaglandin
- Increase synthesis of surfactant (for babies near birth)
• Histone deacetylases: DNA wound around histone and acetylation of histone as the DNA unwound allows transcription. Steroid promotes histone de-acetylation and rewind of DNA. Transcription is prevented.
• Prednisone: corticosteroid drug that act as an immunosuppressant for autoimmune and inflammatory disease.
- Prednisone is the inactive prodrug but it is metabolized in liver to form prednisolone which is the active form.
- The drug has less glucocorticoid effect so reduced swelling of ankle, retaining of water and salt.
• Dexamethasone: synthetic glucocorticoid class of steroid hormone for anti-inflammatory and immunosuppressant effect. It has no mineralocorticoid effects and have 25 times the potency of hydrocortisone.
• Adverse effect of glucocorticoid drugs:
- Cushing syndrome: hypercortisolism promote distribution of body to trunk, back of neck (buffalo hump) and also face (moon-face), i.e. central obesity with thin arms and legs
- Increased gluconeogenesis with increased glucose levels causing diabetes and protein/muscle breakdown causing proximal weakness.
- Osteoporosis with loss of collagens and increased risk of fracture
- Increase blood pressure
- Affect central nervous system which decrease depression but become euphoric (happy)
- Maybe verbally psychotic
- Increase risk of cataract
- Increased susceptibility to reactions of tuberculosis
- Salt water retention
• Rhemmatoid arthritis: disease last for months and is treated with prednisone (intra-articular injection)
• Inhaled steroids: around 20% of the drug is inhaled while 80% is deposited in the month and swallowed, reaching the systemic circuit and metabolized by liver
- Bypass metabolism: beclomethasone (80%), budesonide (90%) and fluticasone (99%).
- Fluticasone is twice as potent as beclomethasone so dosage is halved, i.e. 100mg per day as opposed to 200mg.
- As 80% of drug pass to systemic circuit, high doses can cause problems
• Allosteroid: preventer with long period of acting but slow onset
- Adverse effects: thrush infection (oral candidiasis) in the mouth due to immunosuppressant effect and myopathy of the vocal cords producing hoarse voice
• Reliever: salbutimol – fast acting
• Spacer: easier administration of drug to the lung and does not cause thrush. Drug is dispensed into an container from the inhaler for greater dispersion and the mouth simply breath it all in.
- Improvement in co-ordination
- Rinse your mouth to prevent thrush (can be taken just before brushing your teeth)

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