Question 10

 Describe the pharmacology of salbutamol (70% of Marks), including the principles
and efficacy of methods of delivery (30% of Marks).

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College Answer

Good candidates answered this question in 4 parts; pharmaceutics, pharmacokinetics, pharmacodynamics and delivery devices. The most common reason for not passing this question was providing vague statements without explanation or the specific information required. Candidates were expected to comment on importance of particle size and drug delivery, patient compliance, the effect of a spacer and systemic effects of different routes of administration. Whilst some candidates did make reference to this it lacked the detail required to demonstrate that they understood the concepts. 

Discussion

Class Bronchodilator
Chemistry Synthetic sympathomimetic amine, structurally analogous to catecholamines
Routes of administration IV, nebulised
Absorption Poor oral bioavailability; but it is still somehow available as a syrup. When given as a nebuliser, approximately 10% of an inhaled salbutamol dose is deposited in the lungs.
Solubility Alkaline drug with two ionisable groups, phenolic hydroxyl group (pKa = 9.3) and
the secondary amine group (pKa 10.3). Freely soluble in acidic solutions.
Distribution VOD is 1.3L/kg; minimally protein bound
Target receptor Beta-2 receptor; less selective for beta-1
Metabolism Metabolised in the liver (extensive first-pass metabolism); The main metablite is the biologically inective salbutamol-o-sulphate. It can also be de-aminated by oxidative
deamination or conjugated with glucuronide.
Elimination The elimination half-life of salbutamol is 118 minutes (range 69 to 162 minutes); unchanged drug and metabolite are 72% excreted in the urine within the first 24 hours.
Time course of action Airway resistance decreases within 5 to 15 minutes after inhalation of salbutamol; maximum effect is seen at 60 to 90 minutes, and some level of activity persists for 3 to 6 hours.
Mechanism of action Beta-adrenoceptors are coupled to Gs-proteins, which activate adenylyl cyclase to form cAMP from ATP. This results in increased protein kinase A activity, which results in the inhibition of phosphoinositol hydrolysis, which in turn results in decreased intracellular Ca2+ levels. With less intracellular calcium, the bronchial smooth muscle tone decreases.
Clinical effects Bronchodilation, tachycardia, hypokalemia, hyperlactataemia, insomina, muscle cramps
Single best reference for further information Sandoz product monograph

Methods of delivery:

  • Inhaled as aerosol
    • Dispensed as metered dose dispersed by gas available from a pressurised canister
    • Particle size of less than 5 μm (1-5 μm is required to reach the lower respiratory tract)
    • Requires patient compliance or careful timing with respiratory cycle (for sedated intubated patients), unless using a spacer. 
    • Only 10%–20% of the expelled dose reaches the lung
  • Inhaled as nebulised particles
    • Dispersed by continuous pressurised gas, eg. from a wall source
    • Particle size often larger than 5 μm
    • Up to 10 times the amount of drug is required in a nebuliser to produce the same degree of bronchodilation achieved by a metered-dose inhaler
  • Inhaled as dried powder
    • A suitable alternative to an MDI/neb
    • Requires patient spontaneous respiratory effort
  • Infused intravenously
    • ​​​​​​​Requires no patient effort or breath syncrony
    • Maximal systemic toxicity
  • Ingested orally
    • Excellent patient compliance
    • Slower response of a lower magnitude
    • Gastrointestinal absorption is erratic and unreliable

References

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