How Genes Influence The Breakdown Of Amitriptyline?

What Is Amitriptyline

Amitriptyline is a tricyclic antidepressant (TCA) that is used to treat signs of depression.

It is also used to treat migraines, chronic headaches, and chronic neuropathic pain (pain due to nerve damage).

TCAs are a class of psychotic medications used to treat mood and depressive disorders.

They are named after their chemical structure which contains three atom rings.

Image: Structure of TCAs

Amitriptyline is sold under the brand names Elavil, Vanatrip, and Endep.

How Does Amitriptyline Work?

Amitriptyline works by inhibiting the actions of the Norepinephrine Transporter (NET) and the Serotonin Transporter (SERT).

These transporters reuptake (reabsorb) the neurotransmitters once they have performed their activities.

Reuptake is a necessary process to recycle neurotransmitters and control their levels available to the brain. Reuptake also decides how long a neurotransmitter’s signal lasts.

**Neurotransmitters like serotonin, norepinephrine, and dopamine are signaling molecules that alter the mood.

Inhibiting these transporters ensures delayed reuptake of the neurotransmitters. As a result, the brain experiences increased norepinephrine and serotonin activities.

Studies show that low levels of norepinephrine result in depression. Similarly, serotonin deficiency can play a role in worsening a person’s depressive state.

By ensuring the brain has access to increased levels of norepinephrine and serotonin, amitriptyline helps treat the signs of depression.

Side Effects Of Amitriptyline

Some common side effects of amitriptyline are:

Dry mouth
Drowsiness
Constipation
Dizziness
Increased appetite
Weight gain
Increased heart rate
Fatigue
Swelling of breasts

Some of the severe side effects of amitriptyline are:

Vision problems
Erectile dysfunction and low libido (lowered sexual interest)
Liver toxicity

Interactions With Other Drugs

Amitriptyline may interact with other medications and lead to severe side effects or changes in drug efficacy.

Notify your doctor if you take the below medications along with amitriptyline.

Other antidepressants, including Duloxetine, Sertraline, and Escitalopram
Monoamine Oxidase Inhibitors (used to treat depression and panic disorders)
Cyclobenzaprine (used to treat musculoskeletal conditions like muscle spasms)
Topiramate (used to treat epilepsy)
Cold and allergy medications
CYP2D6 inhibitor drugs like Paroxetine and Terbinafine
Anticholinergic medications (used to treat overactive bladder, gastrointestinal diseases, Chronic Obstructive Pulmonary Disease, and motion sickness)

CYP2D6 And CYP2C19 Genes And Amitriptyline

The CYP2D6 gene contains instructions for the production of the Cytochrome P450 2D6 enzyme that plays a vital role in eliminating xenobiotics (chemicals not found naturally in the body).

Likewise, the CYP2C19 gene contains instructions for the production of the Cytochrome P450 2C19 enzyme that helps eliminate xenobiotics from the body.

The CYP2D6 and CYP2C19 enzymes eliminate 25% and 10% of all clinical drugs, respectively.

Amitriptyline is also eliminated from the body using these enzymes.

People carry different versions of the CYP2D6 and CYP2C19 – according to the version they carry, they’re classified as follows.

Type of metabolizers	Implications	Suggestions
Ultrarapid metabolizers	Amitriptyline is rapidly eliminated from the body, leading to lowered drug efficacy.	The drug may not work effectively. Using an alternative drug that is not eliminated by CYP2D6 and CYP2C19 will help.
Normal metabolizers	Amitriptyline is normally eliminated from the body	Amitriptyline can be used effectively for treatment.
Intermediate metabolizers	Amitriptyline is eliminated from the body at a slightly lower rate when compared to normal metabolizers.	A 25% reduction in recommended dose is suggested to prevent the risk of an overdose.
Poor metabolizers	Amitriptyline is very slowly eliminated from the body, leading to a risk of a drug overdose.	Consider using an alternative drug that is not eliminated by CYP2D6 and CYP2C19. Else, a 50% reduction in the drug dose is recommended.

CYP2D6 Gene Haplotypes

A haplotype is a group of gene changes that are inherited together. Star alleles are used to name different haplotypes.

There are more than 100 changes noted in the CYP2D6 gene.

Out of these, the *1, *2, *33, and *35 alleles of the gene are normal functioning alleles associated with normal metabolism.

The *3, *4, *5,*6, *7, *8, *10, *12, *17, *29, and *41 alleles have no function or decreased activity alleles and are associated with poor metabolism.

Individuals who have multiple copies of the normal function alleles experience ultrarapid metabolism.

CYP2C19 Gene Haplotypes

The CYP2C19 gene also has multiple versions.

The *1 allele is the normal functioning allele associated with normal metabolism, while the *17 allele is associated with ultrarapid metabolism.

The *2 and *3 alleles are no-function alleles and are associated with poor metabolism.

ABCB1 Gene And Amitriptyline

The ABCB1 gene helps produce the ATP Binding Cassette Subfamily B Member 1 protein that transports substances between cells.

It also plays a role in multidrug resistance (a process by which cells develop resistance to clinical drugs).

rs4148740 is a Single Nucleotide Polymorphism (SNP) in the ABCB1 gene.

When treated with amitriptyline, people with the G allele have an improved chance of depression remission (disappearance or reduction in symptoms) compared to those with the A allele.

Allele	Implications
G	Improved chance of depression remission when treated with amitriptyline
A	Regular chance of depression remission when treated with amitriptyline

Recommendations To Safely Use Amitriptyline

Usage In People With Recent Heart Attacks

Amitriptyline can alter the heart rhythm and lead to irregular and fast heartbeats. This can be dangerous in people who have had recent heart attacks.

If you have had a heart attack or any heart ailment, make sure you talk to your doctor about it.

Usage In People With Diabetes

Studies show that amitriptyline may increase or decrease blood sugar levels and make it challenging to handle diabetes.

If you have diabetes and are on amitriptyline, then make sure you monitor the sugar levels regularly.

Usage in Pregnancy

Studies show that using TCAs like amitriptyline, when taken during pregnancy, can increase the risk of organ-specific defects in the fetus.

Monitor Symptoms

In rare cases, the use of antidepressants may worsen the initial symptoms of depression and mood swings and lead to the development of new symptoms.

Therefore, monitor how you feel while on amitriptyline and notify your doctor right away if you notice mood swings, behavioral issues, or other mental and physical changes.

Risk Of Overdose

Amitriptyline overdose may be very dangerous and lead to the below conditions.

Slow or difficult breathing
Abnormally low blood pressure
Rapid heartbeat
Hallucinations
Serotonin syndrome (excess serotonin in the body causes agitation, restlessness, loss of muscle control, seizures, and dizziness)
Coma

If you or someone you know has overdosed on amitriptyline, contact the nearest Emergency Room right away.

Discontinuing The Medicine

Discontinuing antidepressants abruptly can lead to worsening of the initial symptoms and withdrawal symptoms too.

Instead, your doctor will bring down the dosage levels gradually to make the weaning process easier.

Genetic Testing

Genetic testing can help identify the metabolizer phenotype (ultrarapid, normal, intermediate, or poor).

Planning drug doses based on the phenotype will ensure the drug works better without the risk of overdosing.

Genetic testing can also help understand if a person will respond better to amitriptyline or another alternate medication.

Analyze Your Genetic Response to Amitriptyline

Summary

Amitriptyline is an antidepressant that treats depression, chronic neuropathic pain, and headaches and migraines.
Amitriptyline belongs to a class of drugs called tricyclic antidepressants (TCA) that work by exposing the brain to increased levels of norepinephrine and serotonin.
Some common side effects of amitriptyline are dry mouth, drowsiness, dizziness, increased appetite, constipation, and swelling of breasts.
Some of the more severe side effects of amitriptyline are vision problems, erectile dysfunction, and liver toxicity.
Amitriptyline may interact with other antidepressants, Monoamine Oxidase Inhibitors (MAOs), and CYP2D6 inhibitors, leading to changes in drug efficacy or severe side effects.
CYP2D6 and CYP2C19 gene changes lead to ultrarapid, normal, intermediate, and poor metabolism of amitriptyline, affecting how quickly amitriptyline is eliminated from the body.
ABCB1 gene changes may increase or decrease the chances of depression remission when treated with amitriptyline.
People with existing heart conditions and diabetes need to be monitored carefully while on amitriptyline.
Amitriptyline overdose may lead to breathing difficulties, hallucinations, rapid heart rate, serotonin syndrome, and coma.
Discontinuing the medication abruptly may lead to worsening of the initial symptoms. Gradual weaning is recommended.
Genetic testing can help identify how a person is likely to respond to certain medications, including amitriptyline. This can help doctors administer the correct dosages.