Salbutamol Resistance

Topics: Pharmacology, Signal transduction, Asthma Pages: 12 (2924 words) Published: August 24, 2011

The scope of this paper focuses on Salbutamol as a drug and the mechanisms behind;

1) The drug function.

2) Development of drug resistance.

3) The clinical features of drug resistant individuals.

4) How to diagnose them.

5) Management of these patients.

Salbutamol resistance

Salbutamol is a beta 2 adrenergic receptor agonist that is short acting and used in the management of conditions that cause bronchospasms/bronchoconstriction. These conditions mainly include asthma and chronic obstructive pulmonary disease. Its systemic name is (RS)-4-[2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl) phenol. It has a half life of 1.6 hours, metabolized in the liver and exclusively excreted by the kidneys (1). It was one the first selective β2-receptor agonist drug to be developed (1968). Salbutamol has different trade names depending on the pharmaceutical company marketing it.

It has different routes of administration, and the physician determines which to use depending on the type of medical condition. The most popular and effective route is via inhalation. This is mainly achieved by using a metered dose inhaler (MDI), nebulizer or other trademarked devices (2). This route is the most effective owing to the direct action of the drug on the respiratory tract. The maximum effect can take place within five to fifteen minutes. The other routes are orally (via tablets) and intravenously.

Salbutamol has a number of medical uses, but it is mainly used to treat asthma and exercise induced bronchospasms. Treatment of chronic obstructive pulmonary disease is another key use of this drug (diseases in this category include chronic bronchitis and emphysema). Other less widely applied uses is in treatment of premature labor in obstetrics since the drug can also relax uterine smooth muscles (intravenous administration) and in the treatment of cystic fibrosis in combination with other drugs (3).

Despite the fact that this drug has been invaluable in the treatment of serious medical conditions like asthma, there is still a serious pitfall in the long-term use of the drug since most people who have been on it for a long duration tend to the develop some form of drug resistance/tolerance to the drug. This results in a slower and less dynamic effect of the drug on patients who have been using it chronically. Therefore, directly translating to the need to adjust dose and frequency of the drug administration, this can become quite a burden to everyone involved. Down regulation of the β2-receptors and a reduction of their sensitivity (desensitization) causes this resistance (4).

The drug has an intricate mode of action that involves a number of pathways at microscopic cell level. Initially, it acts by binding on beta2 adrenergic receptors (4). The receptor is coupled to a stimulatory guanine nucleotide–binding protein (Gs – protein) and usually fluctuates between different conformations in the inactive state (5). Once the agonist (Salbutamol) binds to the receptor, it stabilizes one of the conformations leading to the activation of the G-protein. The G-protein is a transmembrane signal transducer that has alpha and beta-gamma subunits (6). After activation of the protein the alpha subunit dissociates, resulting in a form that stimulates activity of the enzyme adenylyl cyclase (7). This enzyme now increases the production of cyclic adenosine monophosphate (cAMP) in the cell. It does this by transforming adenosine triphosphate (ATP) into cAMP through dephosphorylation and structure shifting (8). Increased levels of cAMP results in activation of cAMP-dependant protein kinase A. Protein kinases are enzymes that modify proteins by adding to them a phosphate group(usually derived from ATP). This phosphorylation leads to a functional change in the targeted protein either by altering the enzyme activity, its intracellular location or its interaction with other proteins (9). Protein...

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