Category: cough medicines

Is dextromethorphan an opioid or not?

The Monthly Index of Medical Specialities (MIMS) states under Anatomical Therapeutic Chemical (ATC) Classification: “R05DA09 – dextromethorphan; Belongs to the class of opium alkaloids and derivatives. Used as cough suppressant”. But your lecture and the textbooks say that dextromethorphan is a non-opioid antitussive. Why is there this discrepancy?

An opium alkaloid is an alkaloid found in opium. An opioid is a drug which acts at opioid receptors. The major active alkaloids in opium, such as morphine and codeine, act at opioid receptors.  They are both opium alkaloids and opioids. But not all opium alkaloids act at opioid receptors. Dextromethorphan is chemically an opium alkaloid derivative but it does not act at opioid receptors so pharmacologically it is not an opioid. It is a non-opioid opium alkaloid derivative.

Just as codeine is metabolised to morphine, dextromethorphan is converted to the more potent active metabolite dextrorphan. Dextrorphan is a dextro- (right-handed) enantiomer (dextrorotatory-stereoisomer) of which the corresponding levo- (left-handed) enantiomer is levorphanol, a potent opioid analgesic. Dextromethorphan and dextrorphan are right-handed enantiomers that do not act at the opioid receptor. They are therefore not opioids despite being opium alkaloid derivatives closely related to the potent opioid levorphanol.

The importance of dextromethorphan being a non-opioid is that does not share the same mechanisms of opioid dependence and addiction as codeine and so has a lower potential for abuse than codeine.  However, dextromethorphan is not utterly devoid of risk of abuse. Dextromethorphan is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist and at high doses has dissociative anaesthetic-like effects similar to ketamine and phencyclidine (PCP).

Why is guaifenesin so difficult to spell?

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

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.

Abuse potential of dextromethorphan?

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]

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