Adverse drug reactions (ADRs) occur when medications produce unintended, harmful effects. These reactions range from mild discomfort to severe complications like organ damage or life-threatening conditions. Many ADRs result from improper dosing, drug interactions, or individual variations in drug metabolism. An adverse drug reaction is preventable (significant number of reactions) through personalized medicine, pharmacogenomic testing, and careful monitoring.

Drugs Metabolism

Drugs undergo metabolism primarily in the liver, where enzymes break them down for elimination. Although various enzymes contribute to drug metabolism, the cytochrome P450 (CYP) enzyme family plays a crucial role in metabolizing numerous drugs. Variants in these enzymes affect how quickly or slowly a person processes medications, influencing drug efficacy and safety.

Genetic variations in metabolism create four patient types:

• Poor metabolizers (PMs) – Process drugs slowly, leading to toxicity.
• Intermediate metabolizers (IMs) – Have a reduced ability to metabolize drugs, increasing side effect risks.
• Normal metabolizers (NMs) – Process drugs as expected.
• Rapid/ultrarapid metabolizers (RMs/UMs) – Break down drugs too quickly, reducing effectiveness.

Pharmacogenomic (PGx) testing helps predict these responses, allowing for tailored drug selection and dosing to minimize ADRs. An easy-to-read PGx test by RPh labs does not only show how you may respond to certain medications, but also provides alternatives to some drugs.

Drug Classes with High ADR Risks

Certain drug classes are more prone to causing ADRs due to their mechanisms and genetic variability in metabolism. Some of the most problematic ones reported by PubMed according to their percentage of occurrences include:

1. Antipsychotics (Highest ADR Probability)

Clozapine, Olanzapine, Haloperidol, Risperidone, Aripiprazole, Amisulpride, Quetiapine, Lurasidone, Chlorpromazine, Levosulpiride, Ziprasidone, and Fluphenazine fall under the class of anti-psychotic drugs. CYP1A2 enzyme is primarily involved in metabolizing Clozapine, and Olanzapine. Apparently CYP3A4 is the main isoform responsible for metabolizing Haloperidol. Risperidone is primarily metabolized by P450 2D6 (CYP2D6) in humans. Metabolism and elimination of Aripiprazole is primarily facilitated by CYP2D6 and CYP3A4. Quetiapine and Lurasidone are primarily metabolized by CYP3A4. Similarly there are specific enzymes and isoforms in our body which are responsible for metabolizing and clearing out the drugs from our body.

2. Antidepressants

Antidepressants are primarily metabolized by cytochrome P450 (CYP) enzymes, with specific isoforms responsible for different drugs:

• Tricyclic Antidepressants (TCAs): These are extensively metabolized by CYP2D6 and CYP2C19. Genetic polymorphisms in these enzymes can significantly impact TCA metabolism, leading to varied drug responses and potential interactions.
• Selective Serotonin Reuptake Inhibitors (SSRIs): Many SSRIs are substrates of CYP2D6 and CYP2C19. For instance, escitalopram is metabolized by CYP2C19, and genetic variations in this enzyme can affect drug response and tolerability.
• Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Drugs like venlafaxine are primarily metabolized by CYP2D6. Variations in this enzyme’s activity can influence the drug’s efficacy and risk of adverse effects.
• Atypical Antidepressants: Mirtazapine is metabolized by multiple CYP enzymes, including CYP1A2, CYP2D6, and CYP3A4. Genetic differences in these enzymes may alter mirtazapine’s pharmacokinetics.

3. Anti-Addiction Medications

Medications used to treat substance use disorders are metabolized by various CYP enzymes:

• Methadone: This opioid replacement therapy is primarily metabolized by CYP3A4, with contributions from CYP2B6 and CYP2D6. Genetic polymorphisms, especially in CYP2B6, can affect methadone plasma levels and treatment outcomes.
• Naltrexone: Used for opioid and alcohol dependence, naltrexone is metabolized by the liver, but specific CYP enzymes involved are not well-defined.
• Disulfiram: Employed in alcohol dependence treatment, disulfiram inhibits aldehyde dehydrogenase rather than CYP enzymes, leading to unpleasant effects when alcohol is consumed.

4. Miscellaneous Psychotropic Medications

Other psychotropic drugs and their metabolic pathways include:

• Benzodiazepines: Many, such as diazepam and alprazolam, are metabolized by CYP3A4. Variations in this enzyme can influence drug clearance and patient response.
• Mood Stabilizers: Carbamazepine is primarily metabolized by CYP3A4 and can induce its own metabolism, leading to variable blood levels.
• Stimulants: Drugs like amphetamines are metabolized by CYP2D6. Genetic differences in this enzyme can affect drug levels and therapeutic outcomes.

Understanding the metabolism of these medications is crucial for predicting drug interactions, individualizing dosages, and minimizing adverse effects.

How an Adverse Drug Reaction is Preventable?

A pharmacogenetic test, commonly known as a PGx test, gives insights into how your body may respond to certain medications. Humans can be divided into 4 types of metabolizers, i.e., poor, intermediate, normal, and rapid metabolizers. You may be a rapid metabolizer of one drug, while poor of another, etc. If we have 4 patients of the same age, sex and other health conditions, but having different genetic makeups, here is how a doctor may tailor their medications:

One FDA-labeled drug that affects individuals differently based on genetic makeup and requires careful dosing is Warfarin. Warfarin is primarily metabolized by the CYP2C9 enzyme, and its effect is influenced by variations in CYP2C9 and VKORC1 genes.

Here’s a hypothetical case of four patients with the same age, sex, and health conditions but differing in their CYP2C9 metabolism:

 

Patient Type	Genotype (CYP2C9 Variant)	Metabolism Type	Expected Warfarin Response	Dosing Considerations
Patient A	CYP2C9 *3/*3	Poor Metabolizer (PM)	Warfarin is metabolized very slowly, increasing bleeding risk.	Requires significantly lower dose; close INR monitoring.
Patient B	CYP2C9 *1/*3	Intermediate Metabolizer (IM)	Reduced warfarin clearance, higher sensitivity.	Lower-than-standard dose; more frequent INR checks.
Patient C	CYP2C9 *1/*1	Normal Metabolizer (NM)	Warfarin clearance is as expected; standard response.	Standard dosing with routine INR monitoring.
Patient D	CYP2C9 *1/*17	Rapid Metabolizer (RM)	Warfarin is broken down quickly, leading to reduced effect.	May require a higher dose to maintain anticoagulation.

 

Key Takeaways:

• Poor metabolizers (PMs) have a significantly higher bleeding risk due to slow drug clearance.
• Intermediate metabolizers (IMs) also have increased sensitivity but to a lesser extent.
• Normal metabolizers (NMs) generally respond as per standard guidelines.
• Rapid metabolizers (RMs) may require higher doses since warfarin is broken down faster.

If administered the same dosage of Warfarin (an anti-coagulant) to all 4 different metabolizers in the above case, the chances of adverse drug reaction could have increased. An adverse drug reaction is preventable with the help of Vigilant dosing or tailored dosing which involves a careful sight on all such factors. Still have ambiguities? Here you can see how it works.

References:

https://pmc.ncbi.nlm.nih.gov/articles/PMC8664397/
https://www.ncbi.nlm.nih.gov/books/NBK532903/
https://pubmed.ncbi.nlm.nih.gov/10628896/