February 2017 – Page 2

Month: February 2017 (page 2 of 2)

Neuropsychiatric adverse events with leukotriene inhibitors

Neuropsychiatric adverse events are reported in some patients taking leukotriene inhibitors (e.g. montelukast and zileuton)

In 2009, the USA Food and Drug Administration (FDA) reported on an investigation of neuropsychiatric adverse events associated with the leukotriene pathway inhibitors, both the leukotriene receptor antagonists (e.g. montelukast) and the 5-lipoxygenase inhibitor (zileuton) (1). It was concluded that “reported neuropsychiatric events include postmarket cases of agitation, aggression, anxiousness, dream abnormalities and hallucinations, depression, insomnia, irritability, restlessness, suicidal thinking and behavior (including suicide), and tremor”. The FDA, therefore, issued the following advice to patients and healthcare professionals:

“Advice to patients and healthcare professionals

Patients and healthcare professionals should be aware of the potential for neuropsychiatric events with these medications.
Patients should talk with their healthcare providers if these events occur.
Healthcare professionals should consider discontinuing these medications if patients develop neuropsychiatric symptoms.”

Reference:
(1) Updated Information on Leukotriene Inhibitors: Montelukast (marketed as Singulair), Zafirlukast (marketed as Accolate), and Zileuton (marketed as Zyflo and Zyflo CR)

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.

Why is guaifenesin so difficult to spell?

February 6, 2017 / phcdgs / 2 Comments

Even among drugs names that are often difficult to pronounce or spell, guaifenesin stands out for tripping up more students on spelling in exams than other drug names. Why is “guaifenesin” spelt this way?

Breaking “guaifenesin” up into “guai” and “fenesin” may help us to remember how to spell the word. It is the “guai” that in particular seems unnatural in English and is difficult to spell. Perhaps understanding the origins of the “guai” in “guaifenesin” can help us to remember how to spell the word.

The “guai” in “guaifenesin” comes from the word “guaiac”. Guaiac has been an English word since at least 1558, some say 1533. It is the common name for trees of the genus Guaiacum. The word originates from the Maipurean language spoken by the native Taínos people of the Bahamas. “Guaiac” has the honour of being the first American language word adopted into the English language. The guaiac is famous for being the source of the hardest wood known. The resin and bark of the guaiac were also used in traditional medicine for coughs and various other conditions. Guaifenesin is the active compound in the treatment of coughs isolated from guaiac resin and bark.

Guaifenesin was also formerly spelt “guaiphenesin”. It is one of the few drugs for which the American contraction of “ph” to “f” is now adopted for the official international nonproprietary name of the drug. The chemical name for guaifenesin is glyceryl guaiacolate.

Interestingly, guaiac resin also made another significant contribution to medicine. A phenolic compound derived from guaiac tree resin has also been used in the faecal occult blood test (FOBT). The presence of haeme from blood causes this compound to form a coloured product when exposed to hydrogen peroxide.

Adverse effects of guaifenesin and acetylcysteine

February 6, 2017 / phcdgs / 0 Comments

When the expectorant, guaifenesin, and the mucolytic, acetylcysteine, are prescribed together patients are monitored for bronchospasm and anaphylactoid reactions. Which of these two drugs is responsible for these serious adverse effects?

Guaifenesin is an expectorant. It increases the production of respiratory tract fluids. This helps to liquefy and reduce the viscosity of mucus in the respiratory tract. Generally, guaifenesin is a relatively safe drug, but it has been associated with dizziness, headache, vomiting, nausea, rash and urticaria.

Acetylcysteine can be used as a mucolytic. It possesses a free sulfhydryl group that splits disulphide bonds between mucoproteins. This reduces the viscosity of pulmonary secretions. Acetylcysteine can also be used to treat paracetamol overdose as it restores liver glutathione levels. However, acetylcysteine can trigger bronchospasm and severe anaphylactoid reactions, including rash, hypotension, dyspnoea, and wheezing. If they occur, these responses are usually observed within 30 to 60 minutes of starting intravenous infusion for the treatment of paracetamol poisoning. Anaphylactoid reactions are less likely in use as a mucolytic. Nevertheless, caution must be exercised when using acetylcysteine. Due to the risk of bronchospasm, the acetylcysteine must also be used with caution in elderly or debilitated patients with severe respiratory insufficiency and in patients with 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).

Fluticasone and adrenal suppression

February 4, 2017 / phcdgs / 0 Comments

Why is fluticasone more frequently associated with adrenal suppression than other inhaled corticosteroids for the treatment of asthma?

Inhaled corticosteroids are highly effective in controlling asthma but have been associated with adrenal suppression. Adrenal insufficiency can occur chronically from systemic absorption of the corticosteroid resulting in feedback suppression of endogenous glucocorticoid production. Suppression can also occur acutely if the patient abruptly discontinues treatment rather than gradually stepping down the corticosteroid dose. The suppressed adrenal system is then unable to respond adequately to stressful stimuli such as trauma and infection. Signs and symptoms of adrenal suppression can include anorexia, abdominal pain, weight loss, fatigue, headache, nausea, vomiting, decreased level of consciousness, hypoglycaemia and seizures.

Although adrenal suppression can occur with any inhaled corticosteroid, fluticasone, in particular, has been most frequently associated with adrenal insufficiency. This is likely due to the greater potency of fluticasone, which results in a greater risk of prescription of higher-than-licensed doses of fluticasone (1). In particular, children, the elderly and other patients requiring dose adjustment may be at increased risk. It is also important for prescribers to remember that “beyond a certain limit, increasing the dose of inhaled corticosteroids offers minimal benefit but increases the risk of systemic adverse effects” (1).

Reference:
(1) WHO Drug Information Vol. 17, No. 4, 2003, Safety and Efficacy Issues, Fluticasone and adrenal suppression [accessed 4 Feb 2017]

Useful Resources on Asthma Medication

February 3, 2017 / phcdgs / 0 Comments

Links to useful resources on asthma medication from the National Asthma Council Australia:

Asthma & COPD Medications Chart

Inhaler Technique Checklists

Low-dose aspirin plus glycine for anti-platelet drug therapy

February 3, 2017 / phcdgs / 3 Comments

Why do some low-dose aspirin formulations intended for use as anti-platelet medications contain glycine?

Aspirin has a potent anti-platelet action because it is an irreversible inhibitor of cyclooxygenase (COX). COX-1 is required for synthesis of the prothrombotic factor, thromboxane A2 (TXA2), in platelets. Platelets, being fragments of megakaryocytes, do not have a nucleus and therefore cannot synthesise more COX when it is irreversibly inhibited by aspirin. Thus, to recover from irreversible inhibition of COX-1 in the platelets, your body has to make new platelets. The average lifespan of a platelet is 8 to 9 days, so the anti-platelet effect aspirin is potent and long-lasting. However, in the stomach, inhibition of COX-1 prevents the production of protective prostaglandins and results in increased risk of gastrointestinal disturbance and peptic ulcers.

The combination of aspirin with glycine is reported to improve gastrointestinal tolerance to aspirin for anti-platelet drug therapy (1). Glycine is also itself reported to have an anti-platelet effect (2). The evidence to date for the efficacy of glycine both in improving gastrointestinal tolerance of aspirin and in having anti-platelet actions is limited. However, as glycine is a common dietary amino acid, there is little concern over the risk-to-benefit ratio of including glycine in aspirin formulations for use in anti-platelet drug therapy.

References:
(1) Kusche W, Paxinos R, Haselmann J, Schwantes U, Breddin HK. Acetylsalicylic acid tablets with glycine improve long-term tolerability in antiplatelet drug therapy: results of a noninterventional trial. Adv Ther. 2003 Sep-Oct;20(5):237-45.

(2) Schemmer P, Zhong Z, Galli U, Wheeler MD, Xiangli L, Bradford BU, Conzelmann LO, Forman D, Boyer J, Thurman RG. Glycine reduces platelet aggregation. Amino Acids. 2013 Mar;44(3):925-31. doi: 10.1007/s00726-012-1422-8.

Abuse potential of dextromethorphan?

February 2, 2017 / phcdgs / 0 Comments

When comparing dextromethorphan to the opioid antitussive (cough suppressant), codeine, it is often said that, while codeine is the more potent antitussive, the advantage of dextromethorphan is that it has no opioid-associated abuse potential. This is true but, unfortunately, detromethorphan is not completely free from potential for abuse.

Codeine is a weak opioid agonist. Low doses of codeine are sufficient to achieve the antitussive effect. Therefore, there is relatively little risk of abuse of codeine when used as an antitussive. However, up 15% of codeine is metabolised to morphine, which is a much more potent opioid agonist (1). Codeine has a well-known potential for abuse and abuse of codeine cough mixtures is a peristent problem.

Dextromethorphan is not an opioid receptor agonist and so does not have opioid-associated abuse potential. However, dextromethorphan is abused as a recreational drug. At very high doses, well above the label-specified maximum dosages for use as an antitussive, dextromethorphan acts as a dissociative anaesthetic. Like other dissociative anaesthetics, such as ketamine and phencyclidine (PCP), dextromethorphan is abused. The mechanisms of the dissociative anaesthetic effects of dextromethorphan are thought to involve actions as a nonselective serotonin reuptake inhibitor and an NMDA receptor antagonist.

References:

(1) “Codeine and Morphine Pathway, Pharmacokinetic”
https://www.pharmgkb.org/pathway/PA146123006 [accessed 2nd Feb 2017]

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.