Personalised medicine deserves a crown

Pharmacogenomics really has expanded to all areas of medicine, even dentistry. So there’s no need to lose your nerve when you have to get your teeth checked. 

 
 Illustration by Sarah Nagorcka

Illustration by Sarah Nagorcka

 

Gene Dosage is a monthly column by Janan Arslan that finds out what genome science is uncovering about each individual's unique response to drugs and pharmaceuticals. Janan is a graduate student and pharmacogenomics researcher with a keen interest in personalised medicine.

Most people seem frightened by a visit to the dentist. I must be the odd one out; I really don’t mind it. It's something we all should do, after all. Whilst I thankfully have never had the need for any dentistry-related medication, I’ve known others who weren’t so lucky. So I think it always pays to be a little informed about the drugs you might be administered ‒ it’s better to be safe than sorry.

It’s probably best to start with the most obvious concerns many have when they visit the dentist: pain and anxiety. Anxiolytics are drugs administered to minimise anxiety and provide a light level of sedation. Benzodiazepine drugs such as midazolam, diazepam, alprazolam, and triazolam have a wide therapeutic range, and can be used as both oral and injectable anxiolytic medications. All of these benzodiazepines are metabolised by our very own CYP3A4 and CYP3A5 enzymes, with diazepam also being metabolised by CYP2C19. 

  There’s no need to be scared of the dentist.   Kate Mereand-Sinha/Flickr  (CC BY 2.0)

There’s no need to be scared of the dentist. Kate Mereand-Sinha/Flickr (CC BY 2.0)

Benzodiazepines can be harmful if a patient has a variant for one of these genes, or is co-administered another medication that inhibits CYP3A4, CYP3A5 or CYP2C19’s functions. In both cases, the patient may experience prolonged and excessive sedation. For instance, the antibiotic drug erythromycin strongly inhibits CYP3A4, and is widely used in dentistry. So even if the patient had no genetic variants to begin with, prescribing this antibiotic could cause the patient harm.   

I have previously discussed the drug-gene interactions of codeine and briefly touched on tramadol, which can both be used to alleviate post-operative dental pain and are primarily metabolised by the CYP2D6 gene. Both of these are pro-drugs: in their original form they are pretty much useless, and to have any effect on the patient they must be converted to their active metabolites (morphine and O-desmethyltramadol, respectively). CYP2D6 facilitates this metabolism. If there is a defect in the CYP2D6 gene, you’ll either have excessive amounts of the metabolite (which causes toxicity and side effects) or minute amounts (which results in the patient not receiving any benefits from taking that medication). 

Just like with the benzodiazepines, co-administering a medication that affects the function of CYP2D6 can lead to side effects or no effect. For example, if the patient was on the antidepressant fluoxetine, which is known to inhibit the function of CYP2D6, it may limit the conversion rate of codeine to morphine, or tramadol to O-desmethyltramadol. As these drugs are pro-drugs, this would result in the patient taking the medication, but not really feeling any benefits from it. 

  Don’t buy cheap teeth…or cheap anaesthetics.   rosefirerising/Flickr  (CC BY-NC-ND 2.0)

Don’t buy cheap teeth…or cheap anaesthetics. rosefirerising/Flickr (CC BY-NC-ND 2.0)

Some of the local anaesthetics used in dentistry include lidocaine, prilocaine, mepivacaine, articaine and bupivacaine. These anaesthetics function by inhibiting the cells of the nervous system. Adverse drug reactions for these medications can lead to lethargy, loss of consciousness, respiratory depression, convulsions or cardiac arrest. 

There are multiple genes that have been thought to contribute to lidocaine (lignocaine) metabolism. Some of these include CYP2D6, CYP3A4 and even CYP1A2. I mentioned earlier the inhibitory effect of the drug erythromycin on the function of the CYP3A4 gene. While some consider co-administering such drugs with lidocaine to be clinically significant, others believe that any inhibitory effects of these drugs are minimal, as lidocaine is metabolised by multiple genes. 

Unfortunately, there isn’t much drug-gene interaction information for prilocaine, mepivacaine or articaine. However, we do know that bupivacaine is primarily metabolised by the CYP3A4 gene, although other genes, such as CYP2D6 and CYP2C19, have been suggested to play a part, as well. I’m starting to see a pattern here. 

Actually, it is unsurprising that so many of the drugs we have reviewed in this column are metabolised by the CYP3A4 gene. The CYP3A family accounts for the metabolism of 45-60% of drugs currently on the market. Since CYP3A4 has been the common theme in this column, it is worth discussing how many people have a variant for this gene. 

In terms of its prevalence, that really depends on your ethnicity. For example, one study found genetic variants ‒ such as the CYP3A4*1B ‒ in 4% of Europeans and 82% in Africans. However, the variant CYP3A4*3 is found in 2% of Europeans and 0% in Africans. While I was working in the US, I found approximately 80% of patients had some variant for the CYP3A4 gene; it would be fair to say the same for many of the people reading this column. But don’t fret ‒ really, it's normal to have at least one genetic variant. Throughout my career, I’ve found only a handful of people who are completely normal for all currently testable genes.

  Stay away from these, and you won’t even need this month’s column.   Richard Stebbing/Flickr  (CC BY-SA 2.0)

Stay away from these, and you won’t even need this month’s column. Richard Stebbing/Flickr (CC BY-SA 2.0)

According to the US Food and Drug Administration (FDA), the one dentistry-related medication that has any pharmacogenomics information is cevimeline. This drug is used to treat dry mouth in patients with Sjogren’s syndrome, an autoimmune disease characterised by the breakdown of salivary glands. Both CYP2D6 and CYP3A3/4 (again) are responsible for the metabolism of cevimeline. The FDA guidelines recommend caution for patients who either have a known genetic variant for these genes, or are concurrently taking medications that could inhibit their function. Some of the more commonly reported side effects from cevimeline usage include nausea, headache, diarrhoea and abdominal pain.   

Among all that pharmacogenomics, here’s some additional advice: just stay away from the sweets. Really. Take care of your chompers, and get regular dental check-ups. If you take good care of your teeth, then you really won’t need this month’s column, will you? As my mother has always said, “Prevention is better than cure.”

Edited by Andrew Katsis and Ellie Michaelides.