asthma – PharmaNUS

Tag: asthma

Why is monotherapy with LABAs contraindicated in asthma?

Why is the chronic use of long-acting beta agonists (LABAs) alone without the concomitant use of an inhaled corticosteroid contraindicated in asthma? What about short-acting beta agonists (SABAs), can they be used without taking an inhaled corticosteroid at the same time?

Activation of β₂-adrenoceptor promotes bronchodilation. β₂-adrenoceptor agonists are the most potent bronchodilators in current clinical use. Inhaled short-acting beta agonists (SABAs), for example salbutamol (known as albuterol in the USA) have a bronchodilator effect that lasts for 4 to 6 hours, while long-acting beta agonists (LABAs), for example salmeterol, have a bronchodilator effect that lasts for 12 to 24 hours (depending upon the drug). SABAs are used to relieve acute bronchoconstriction. Use of a SABA can be a life-saving intervention during an asthma attack. In contrast, LABAs are used chronically to mainain bronchodilation improving airway function and controlling occurance of symptoms.

Chronic use of LABAs causes tolerance due to downregulation of β₂-adrenoceptors. This is associated with an increased risk of mortality in patients with asthma. Therefore the use of LABAs alone is contraindicated. The downregulation of β₂-adrenoceptors by chronic use of LABAs can impair the response to SABAs when they are need for acutre relief of symptoms during an asthma attack.

Clonidine as an analgesic?

April 3, 2018 / phcdgs / 0 Comments

Administration of clonidine can reduce the doses of opioid analgesics required for pain control. Clonidine is also used to counteract symptoms of opioid withdrawal. How does this work?

Clonidine is an alpha-2-adrenoceptor agonist. Clonidine activates presynaptic alpha-2-adrenoceptors serving as autoreceptors on both central and peripheral nervous system noradrenergic nerve terminals. Activation of these autoreceptors reduces release of nordrenaline. Clonidine also activates alpha-2-adrenoceptors on the neurones of the locus coeruleus, the major source of noradrenergic innervation in the brain, to inhibit locus coeruleus neurone firing and further reduce central nervous system noradrenergic neurotransmission. By these mechanisms, clonidine is an indirect sympatholytic agent and has been used as an antihypertensive drug.

Clonidine is also a direct adrenoceptor agonist at presynaptic alpha-2-adrenoceptors serving as heteroreceptors on the primary afferent neurone nerve terminals bringing nociceptive signals into the spinal cord and at postsynaptic alpha-2-adrenoceptors on secondary spinal cord neurones relaying pain information up to the brain. The descending systems gating pain transmission through the spinal cord include noradrenergic neurones releasing noradrenaline to activate the presynaptic alpha-2-adrenoceptor heteroreceptors on the primary afferent neurone nerve terminals preventing them from releasing their neurotransmitters and transmitting their nociceptive signals. Meanwhile, the noradrenergic descending projections also active postsynaptic alpha-2-adrenoceptors on secondary spinal cord neurones, inhibiting these neurones, and preventing them from relaying the nociceptive signals up to the brain. Therefore, clonidine, which activates these alpha-2-adrenoceptors, has analgesic properties.

The descending pain gating systems also activate local engodenous opioid peptide releasing interneurones within the spinal cord. These interneurones inhibit the secondary spinal cord neurones relaying the nociceptive information up to the brain and so further block transmission of nociceptive signals through the spine. There is therefore a good additive effect between clonidine and the opioid analgesics, which produce spinal analgesia by mimicking the action of the endogenous opioid peptides. Administering clonidine can reduce the doses of opioid analgesics required to control pain.

Another use for clonidine is in controlling symptoms of opioid withdrawal. Part of the reason why clonidine helps is that by its non-opioid analgesic mechanisms it controls the pain associated with opioid withdrawal. Opioid receptors also normally inhibit the neurones of the locus coeruleus and opioid withdrawal is also associated with over activation of the locus coeruleus and the brain noradrenergic system. This results in symptoms such as anxiety, agitation, irritability, and mood swings. Clonidine activates alpha-2-adrenoceptors inhibiting the cells of the locus coeruleus and presynaptic alpha-2-adrenoceptor autoreceptors reducing noradrenaline release.

Why does overdose of salbutamol cause tachycardia?

March 14, 2018 / phcdgs / 0 Comments

Salbutamol is beta-2 adrenoceptor agonist used to treat the respiratory symptoms of asthma. We learned that it is beta-2 adrenoceptors in the lungs and beta-1 adrenoceptors in the heart. So why does overdose of salbutamol cause a rapid heart rate?

Activation of beta-2 adrenoceptors in the airways promotes bronchodilation, reduction of airway secretions, and stimulation of mucociliary clearance. Thus beta-2 adrenoceptor agonists are used in treating the symptoms of asthma. Meanwhile, in the heart, beta-1 adrenoceptor activation has inotropic and chronotropic effects, increasing contractile force and heart rate, respectively.

For the treatment of the symptoms of asthma without causing cardiovascular adverse effects, selective beta-2 adrenoceptor agonists would be the preferred. Salbutamol is an example of a selective beta-2 adrenoceptor agonist. However, the beta-2 and beta-1 adrenoceptors are very similar, so salbutamol is not entirely selective. Salbutamol shows dose-dependent selectivity for beta-2 adrenoceptors but does still act as a weak beta-1 agonist. Thus, on overdose, the beta-1 agonist activity of salbutamol can start to cause cardiovascular adverse effects by activating beta-1 adrenoceptors in the heart to increase the force and rate of heart contractions.

Why is zileuton not a bronchodilator?

February 7, 2017 / phcdgs / 0 Comments

If cysteinyl-leukotriene receptor antagonists such as montelukast can relax the airways, why is it that the 5-lipoxygenase inhibitor, zileuton, does not produce any clinically significant bronchodilation?

Montelukast and other cysteinyl leukotriene (CysLT) receptor antagonists are unique among the anti-asthma drugs in that they are used clinically both for their anti-inflammatory and their bronchodilator effects. They are weak bronchodilators compared to the beta-2 agonists. They can not be used for relief of acute asthma attack because their effect is too weak and their onset of action is too slow. Nevertheless, they do have some bronchodilator effect because they block CysLT receptor-mediated bronchoconstriction. But CysLT receptor antagonists are weak bronchodilators because the CysLTs are just one of many signals triggering bronchoconstriction.

Zileuton is an inhibitor of the 5-lipoxygenase (5-LOX) enzyme necessary for the synthesis of the leukotrienes, including the CysLTs. So, if zileuton prevents the production of CysLTs, why does it not produce clinically significant bronchodilation? In fact, zileuton does produce some bronchodilation but not enough for it to be clinically useful as a bronchodilator. In theory, if zileuton was given at a sufficiently high dose to block all production of the CysLTs, one would expect that zileuton could achieve the same degree of bronchodilation as the CysLT receptor antagonists. In practice, however, this is not possible as side effects become the limiting factor in giving high doses of zileuton since it inhibits 5-LOX, and so blocks production of all the leukotrienes. Thus, within the clinical dose range, zileuton has anti-inflammatory effects but does not have a sufficient bronchodilator effect to be considered as a bronchodilator clinically. Zileuton does not inhibit either the early reaction acute bronchoconstrictor response or the late reaction to inhaled antigen and irritants. It is therefore not useful clinically as a bronchodilator.

What about the bronchodilators that have anti-inflammatory effects? Why are they not also considered to be dual-use bronchodilator and anti-inflammatory drugs?

Some of the bronchodilators do produce some beneficial anti-inflammatory effects. But these anti-inflammatory effects are nowhere near strong enough for these drugs to be used alone as preventers in the treatment of asthma. For example, both beta-2 agonists and theophylline stabilise mast cells, reducing mast cell degranulation, and reduce microvascular leakiness, thus reducing airway oedema. These are anti-inflammatory effects, but they are not sufficiently strong anti-inflammatory effects for these bronchodilators alone to prevent the ongoing inflammatory disease and airway remodelling. Hence, these bronchodilators are not considered to be anti-inflammatory drugs in the treatment of asthma.

Cromoglycate and Amiodarone

February 4, 2017 / phcdgs / 0 Comments

The surprising connection between cromoglycate and amiodarone

Cromoglycate is a mast cell stabiliser administered by inhalation as a preventer in the prophylactic control of asthma. It is also used for prophylactic control of allergic rhinitis and allergic conjunctivitis. Amiodarone is a class III antiarrhythmic agent, which prolongs repolarization of the cardiac action potential thus increasing the cardiac action potential duration.

Pharmacologically there is no obvious connection between cromoglycate and amiodarone. However, both drugs were first synthesised as derivatives of khellin the active ingredient obtained from plant extracts of khella (Ammi visnaga).

Controllers versus preventers for asthma

February 2, 2017 / phcdgs / 0 Comments

Sometimes there is confusion over the usage of the term “controllers” in the treatment of asthma.

The term “controllers” can refer to the long-acting beta agonists (LABAs). But sometimes it is used to refer to both the LABAs and the anti-inflammatory drugs such as corticosteroids. As the LABAs and anti-inflammatory drug have different roles in asthma treatment, the term “preventers” can be used to refer specifically to the anti-inflammatory drugs.

The situation can be further confused by the fact that LABAs are no longer used alone as controllers. They are now always prescribed together with corticosteroids, often in combination inhalers. This is because the use of beta-2 agonists alone leads to beta-2 adrenoceptor tolerance and increased risk of asthma-related death. Concomitant use of a corticosteroid helps to reduce beta-2 adrenoceptor tolerance and treats the underlying inflammatory disease.

In our lectures, we will use the terminology as follows:

Preventers reduce swelling and inflammation in the airways, stopping them from being so sensitive and reducing the risk of severe attacks. Thus they prevent the risk of recurrent attacks.

Controllers are long-acting beta-adrenoceptor agonists (LABAs) taken regularly at the same time daily to provide long-acting bronchodilation.

Relievers are short-acting beta-2 adrenoceptor agonists (SABAs) used “as needed” to relieve asthma attacks.