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The Prospect of Pharmacogenetics in Pediatrics

By | Opioids, Other, Pharmacogenetic Testing, Provider | No Comments

Pharmacogenetics of Opioids as a Potential Alternative in Pediatric Pain Management

 
Opioid and codeine treatment in pain management for children has been a primary concern in clinical settings, specifically for surgical pain management. The concerns are the adverse reactions caused by the opioids, such as respiratory depression. Current Opinion in Anesthesiology, “Codeine and Opioid Metabolism: Implications and Alternatives for Pediatric Pain Management” (2017), reviews how important clinical factors and genetic polymorphisms affect the metabolism of opioids after surgical operations.

 

Adverse Side Effects of Codeine

 
Codeine’s efficacy has been questioned in the pain management of children. Current Opinion in Anesthesiology identifies the adverse reactions of it. The prominent ones are respiratory depression, anoxic brain injuries, and even death occurring in children. With reported doses of codeine, significant respiratory depression was found in newborns in a report by Canadian Pharmacists Journal “Pain Management in Children: A Transition from Codeine to Morphine for Moderate to Severe Pain in Children” (2012).

 
Opioids in Pain Management

 
Opioids are the cornerstone of pain and chronic pain management. “Successful pain management provides adequate analgesia without excessive adverse reactions affirms Clinical Biochemistry “Pharmacogenetics of Chronic Pain Management” (2014). Drug metabolism and responses are influenced by numerous factors, including pharmacogenetics. Genetic variations contribute to the distinct inter individual responses to pain medications.

 
Involvement of CYP2D6 in Codeine

 
Those with two nonfunctional alleles of CYP2D6 are considered poor metabolizers. Extensive metabolizers have one or two effective CYP2D6 alleles and those with duplicated CYP2D6 alleles are ultra rapid metabolizers. Canadian Pharmacists Journal indicates the functions of CYP2D6 are similar in both children and adults.

 
The review also acknowledges the safety concerns of CYP2D6 ultra rapid metabolizers from several studies. One study demonstrated how a breastfed newborn infant died after his mother consumed Tylenol #3 for postpartum pain. Toxicology testing found the mother had abnormally high concentration levels of morphine in her breast milk. Genotype testing found the mother was an ultra rapid metabolizer of codeine. The study concluded since the mother was an ultra rapid metabolizer, higher than normal morphine levels crossed into the breast milk and resulted in the infant dying from morphine intoxication.

 
Another study found a two-year-old child who also died of morphine intoxication. The child was prescribed codeine in recommended dosages after having his tonsils removed. Genotype testing revealed the child was an ultra rapid metabolizer of codeine. However, there were also other contributing factors; the child had bronchopneumonia and sleep apnea. The study concluded these factors “may have increased his risk of hypoxemia, leading to alterations in opioid receptors and increased sensitivity to morphine.”

 
Canadian Pharmacists Journal concludes these studies show ultra rapid metabolizers of codeine are correlated with a higher risk of morphine intoxication among children.

 

Alternatives to Prevent Adverse Drug Reactions

 
Canadian Pharmacists Journal argues morphine as a safer alternative compared to codeine. They argue morphine has “demonstrated efficacy and relative safety when used appropriately in pain management in both adults and children.” A study they analyzed found morphine treatment more effective than a placebo for children in postoperative pain.

 
Current Opinion in Anesthesiology also outlines the possible alternatives to prevent the risks of opioids, such as pharmacogenetics. They indicate personalized opioid therapy for pain management is “distant from reality”, but current CYP2D6 pharmacogenetic research on codeine is hopeful. The review summarizes, “pharmacogenetics has the potential to guide anesthesia providers on perioperative opioid selection and dosing to maximize efficacy and safety.”

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Pharmacogenetics Emerging as a Method to Guide Medication Therapy

By | Gene Panel, Opioids, Other, Pharmacogenetic Testing, Provider | No Comments

According to a recent article published in American Family Physician “Pharmacogenetics: Using Genetic Data to Guide Drug Therapy (2015), pharmacogenetics is being more widely used by family physicians and the number of patients who are interested in acquiring genetic information is growing.

 

The Components of Pharmacogenetics Testing

 
Pharmacogenetics involves genetic variations that code for drug metabolizing enzymes. It also involves how a medication breaks down in the body and how the body responds to the medication. The most common forms of genetic variations are single nucleotide polymorphisms.

 
The differences in single nucleotide polymorphisms or other polymorphisms result in diverse types of genes or alleles, the American Family Physician explains. Individuals inherit these alleles that “govern expression of the gene and the cor¬responding enzyme or protein.” As a result, these genetic differences influence how the drug reacts in the body and how the body metabolizes the drug.

 

Genetic Variability Can Alter the Effects of Drugs

 
Studies have demonstrated there is a connection between genetic variations and changes in drug levels and effects.

 
CYP2D6 and Opioids

 
The enzyme activity of CYP2D6 is volatile because of single nucleotide polymorphisms and other variations of CYP2D6. American Family Physician indicates codeine metabolism occurs in 90% of patients and results in normal morphine formation. However, 1% to 2% of people are ultra rapid metabolizers of codeine signifying they have an increased risk of morphine toxicity.

 
American Family Physician analyzed a study involving the death of a breastfed infant and a mother who was an ultra rapid metabolizer of codeine. The study demonstrated the infant died of morphine intoxication. There was opioid toxicity in the breast milk, which passed onto the infant.

 
They recommend pharmacogenetic testing for patients who are possible poor or ultra rapid metabolizers of opioids.

 

CYP2C19 and Clopidrogrel

 
Clopidogrel is primarily metabolized in the enzyme CYP2C19. CYP2C19 is highly polymorphic and 80% of individuals metabolize clopidogrel normally. However, 18% to 45% of people have intermediate enzyme activity and 2% to 15% have poor enzyme activity.

 
American Family Physician presents meta-analyses of CYP2C19 poor metabolizers. Poor CYP2C19 metabolizers taking clopidogrel treatment and undergoing percutaneous coronary intervention have a higher risk of cardiovascular death, myocardial infraction, stroke, and stent thrombosis.

 
These results lead to the recommendation that clinicians should consider alternative treatments, such as pharmacogenetic testing of CYP2C19 to guide antiplatelet therapy.

 

The Benefits of Pharmacogenetics

 
American Family Physician examined the clinical implications of pharmacogenetic testing and the various resources available and developing to support the usage of pharmacogenetics in clinical settings. They conclude “pharmacogenetic testing can be a practical tool to optimize drug therapy and avoid medication adverse effects.”

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The Pharmacogenetics of Antiplatelet Agents: Meta-Analyses of Aspirin and Clopidogrel Loss-of-Function Alleles

By | Gene Panel, Other, Pharmacogenetic Testing | No Comments

 
Antiplatelet agents combined with aspirin have been shown to play a significant role in mitigating the effects of coronary disease, and ample research has found that distinct genetics determine patients’ response to clinically significant antiplatelet agents.

 

Platelets play a decisive role during the formation of an initial hemostatic plug through their intricate response to injury. When inappropriately activated, platelets contribute to pathological thrombus formation. Arterial thrombus formation can then lead to tissue ischemia causing potentially fatal coronary and cerebrovascular events.

 

Interindividual Genetic Variation Impacts Aspirin Antiplatelet Efficacy

 

Aspirin is regarded as “the cornerstone for secondary cardiovascular prevention,” the efficacy of it, which has long been established, as noted in Current Pharmaceutical Design, “Pharmacogenetics of the Antiplatelet Effect of Aspirin” (2012).

 

The researchers avert that there is considerable interindividual variation in response to aspirin, thus reducing its efficacy in treating heart disease in some patients.

 

P1A2 and P2Y1 Association with Decreased Aspirin Antiplatelet Efficacy

 

Specifically, the review conducted by Current Pharmaceutical Design examined polymorphisms of genes that contributed highly to antiplatelet responses. These were P1A2 from glycoprotein GP IIb/IIIa, and the P2Y1 polymorphism from AD receptor (ADP) genes.

 

P1A2 was characterized as having an association with coronary thrombus formation. One study showed P1A2 allele was related with a shorter baseline bleeding time in comparison to a wild type allele. After measuring bleeding after aspirin ingestion, there was a reduced antiplatelet effect.

 

Another study supported this finding by discovering an enhanced thrombin formation in P1A2 carriers compared to P1A1/A1 homozygotes before and after aspirin ingestion. The review concluded that P1/A2 polymorphism is a prothrombotic platelet phenotype responding inadequately to aspirin.

 

Polymorphism P2Y1 was utilized in an arachidonic acid-induced optical platelet aggregometry to assess its antiplatelet effect of aspirin. The results showed that the T allele of the C893T P2Y1 polymorphism was substantially linked with a decreased antiplatelet effect of aspirin.

 

CYP2C19 Mediates Clopidogrel Non-Response

 

Evidence for association of CYP2C19 with clopidogrel response was investigated in the Journal of Human Genetics “Pharmacogenomics of Anti-Platelet Therapy: How Much Evidence is Enough for Clinical Implementation?” (June 2013).

 

The study established CYP2C19 as a genetic factor contributing to the creation of the active metabolite of clopidogrel. A corresponding analysis detailing the associations of CYP2C19 alleles and increasing residual on-treatment platelet reactivity corroborated this finding. The study concluded that patients with even one reduced function of CYP2C19 and taking clopidogrel as treatment for percutaneous coronary intervention may be “associated with increased risk of major adverse cardiovascular events as a consequence of aspirin antiplatelet inefficacy.”

 

The International Journal of Environmental Research and Public Health “Pharmacokinetic and Pharmacodynamics Responses to Clopidogrel” (February 2017) also reviewed the connection between CYP2C19 and clopidogrel. The review was based on the authors’ argument that genetic polymorphisms impact the absorbtion and metabolism of clopidogrel and that the P2Y12 receptor may interfere with its antiplatelet activity.

 

In one meta-analysis, it was found there was a critical relation between CYPC219 loss-of-function in diverse patients with frequent cardiovascular events. In another meta-analysis, CYPC219 was identified as having a having a crucial part in reducing the active metabolite of clopidogrel.

 

CYP3A4/5 Mediates Clopidogrel Non-Response

 

In addition to analyzing clopidogrel, the review also analyzed CYP3A4/5. The authors found that the CYP3A5*3 allele has an influence on clopidogrel metabolism because of its possible dependence on CYP2C19 and CYP3A4 inhibitors. In the study, the patients with a CYP3A5*3/3 genotype displayed enhanced platelet reactivity compared to those with a CYP3A5*1 allele in CYP2C19 poor metabolizers. An additional study reported CYP3A5*3 on clopidogrel response is prominently in patients with the CYP2C19 loss-of-function.

 

 

Benefits of Individualizing Antiplatelet Therapy with Pharmacogenetic Testing

 

Research has been conclusive in identifying potential antiplatelet pharmacogenetic applications pointing to effective individualized treatments, according to the studies.

 
The review by the International Journal of Environmental Research and Public Health asserted there is an “inter-individual variability” in clopidogrel’s antiplatelet effects. They concluded inadequate platelet responsiveness to clopidogrel has a role in accumulating the risk of cardiovascular events, and therefore increasing drug dosage or switching to alternative drug medications may be more beneficial for patients.

 
Similarly, the review published in Current Pharmaceutical Design concludes by recommending utilization of antiplatelet pharmacogenetics in clinical practice. “The promise of pharmacogenetics lies in the prospect of improving treatment efficacy and safety.”

 

 

 

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Overview of Alprazolam (Xanax) Uses and Side Effects

By | Adverse Drug Reactions, Antianxiety Medications, Other | No Comments

Alprazolam, commonly referred to by its brand name Xanax, is the one of the most common benzodiazepine used. Benzodiazepines like alprazolam are anxiolytics (antianxiety drugs) used in the treatment of a number of diseases including panic disorder, generalized anxiety disorder and social anxiety disorders. Occasionally the drug is used for nausea and vomiting symptoms associated with chemotherapy. (PubMed Health “Alprazolam” May 2017).

 

Alprazolam Mechanism of Action

Alprazolam, like all benzodiazepines, binds nonspecifically to benzodiazepine receptors at the BDZ site. This bind tightens the connection of GABA with the receptor and results in increasing hyperpolarization of neurons. This mechanism is the base for the drug’s antianxiety effects.

 

Alprazolam Side Effects

 
Alprazolam has a significant effect on a major neurotransmitter which results into psychiatric and nervous system side effects. According to the FDA label on Xanax, the most common adverse effects include (occur in more than 1% of patients):

 

  • Irritability
  • Anxiety
  •  Depression
  •  Confusion
  •  Derealization or alteration of perception
  •  Dream abnormalities
  •  Fear
  •  Disinhibition
  •  Drowsiness (77% of patients)
  • Impaired coordination (40% of patients)
  •  Memory impairment
  • Lightheadedness
  • Insomnia
  • Headache
  •  Cognitive disorder
  •  Dysarthria
  •  Ataxia
  •  Balance disorders
  •  Nasal congestion
  •  Hyperventilation
  •  Upper respiratory tract infections
  • Fatigue/tiredness (49%)
  •  Weakness
  •  Edema (swelling)
  •  Decreased libido (14%) and increased libido
  •  Micturition difficulties (inability to urinate etc)
  •  Menstrual disorders (in females)
  •  Sexual dysfunction
  •  Sweating
  •  Rash
  •  Allergies
  •  Tachycardia (increased heart rate)
  •  Chest pain
  •  Palpitations
  •  Hypotension
  •  Increased appetite (33%)/ decreased appetite (28%)
  •  Weight gain (27%)/ loss (23%)

The Xanax label from the FDA reports Alprazolam has rare side effects, which are anger, self-harm and irregular menstruation. These occur in less than 1% of patients

 
Risk of Suicide

 
Research has shown that the use of benzodiazepines can influence suicide risk.  A literature review evaluated studies that involved the relationship between benzodiazepines and concluded there was a significant relationship between increased suicide risk and benzodiazepines (The Primary Companion for CNS Disorders “Prescribed Benzodiazepines and Suicide Risk” March 2017). The results were consistent in different populations and methods used.  The review also found that possible suicidal warnings may include “increases in impulsivity or aggression, rebound or withdrawal symptoms, and toxicity in overdose.”

 
Alprazolam and Pharmacogenetic Testing

 
Some patients do not develop any side effects when taking Alprazolam and some do.  This interpatient variability may be due to differences in patients’ genetics. Polymorphisms in the genes that code for enzymes and receptors that interact with Alprazolam have been shown to account for a significant proportion of this inter patient variability.

 
Alprazolam is metabolized by the cytochrome P450 superfamily of enzymes, namely isoenzymes CYP3A4 and CYP2C9. Polymorphisms in these enzymes have been shown to alter the blood plasma concentrations of the drugs they metabolize. Alleles may alter the probability of individual developing side effects when taking Alprazolam.

 

Understand Your Genetic Risks for Side Effects with the Rxight Test

Identifying these polymorphisms can aid in clinical decision-making. Knowing a patient has a given polymorphism can result in a clinician altering the starting dose of a medication like Alprazolam, potentially reducing their probability of developing side effects.

 
MD Labs provides a genetic testing service, Rxight®.  Accurate, reliable, and easy to understand, Rxight® sequences 18 genes to establish how a patient is likely to respond to hundreds of clinically relevant medications (including Alprazolam).

 
As a key component of precision medicine, Rxight® allows your healthcare provider and pharmacist to see if Alprazolam is right for you and create the best possible treatment for you.  With a simple cheek swab done at your pharmacy, Rxight® will provide you with a DNA Blueprint that minimizes drug’s side effects and proper course for present and future treatments.

 
Contact us for more information about how Rxight® can benefit you through phone at 1-(888) 888-1932 or email at support@Rxight.com.

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Pharmacogenomic Data May Help Guide Opioid Pharmacotherapy in Patients with Cancer-related Pain

By | Cancer Treatments, Other, Pain Medications, Pharmacogenomics, Provider | No Comments

Opioids are the most potent analgesics and are used to treat severe pain, specifically pain associated with cancer – a significant factor in reducing quality of life and clinical outcomes in such patients as detailed in Cancer Control “Clinical Implications of Opioid Pharmacogenomics in Patients with Cancer” (October 2015).

 

Inter-individual Differences in Genetically Modulated Opioid Response

 
The study reviewed clinical studies involving the pharmacodynamics and pharmacokinetics of opioids. It examined the opioid agents morphine, codeine, tramadol, oxycodone, fentanyl, and hydrocodone and the relationship to single nucleotide polymorphisms (SNPs): OPRM1, COMT (specifically COMT Val Met), CYP2D6, CYP3A4/5, and ABCB1, which the study claimed are responsible for the inter-individual differences in opioid response.

 
The authors specifically found that OPRM1, COMT Val Met, and ABCB1 are most strongly correlated with morphine response. One study combined OPRM1 and ABCB1 and found that patients with both of these genetic variants were the best responders as indicated in patients’ measures of pain intensity. In another study, patients with OPRM1 and COMT Val Met needed the lowest morphine dose compared to other genotypes. All three together demonstrated no difference in morphine dose requirements.

 

CYP2D6 Variants Correlate with Drug Efficacy

 
Similarly, the presence of CYP2D6 variants correlated positively with variations in codeine and tramadol efficacy. CYP2D6 is responsible in converting the analgesic properties of codeine and tramadol. In studies investigating codeine pharmacotherapy in cancer patients, analgesic differences and adverse effects were found for CYP2D6 poor, intermediate, and extensive metabolizers.

 
The authors concluded CYP2D6 testing helps in finding which patients respond positively to codeine. Studies with tramadol focusing on non-cancer pain populations identified CYP2D6 poor metabolizers as having a decreased analgesic response compared to extensive metabolizers. However, the authors noted there has been no specific study relating to tramadol’s analgesic efficacy in cancer populations, arguing tramadol will likely have decreased clinical benefit in patients who are poor CYP2D6 metabolizers.

 

Call for Preemptive Genotyping in Clinical Practice

 
The authors assert that these findings “suggest genotyping patients for some of these genetic variants may help predict responses to pain treatments with good rates of sensitivity and specificity and with greater benefits for patients and decreased health care utilization.” Furthermore, the authors assert that utilizing pharmacogenomics data combined with a preemptive genotyping be a “key element” in guiding treatment decisions for cancer patients.

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Researchers at Vanderbilt University Call for Pre-emptive Genetic Testing in CVD Patients

By | Other, Pharmacogenetic Testing, Pharmacogenomics, Precision Medicine, Provider, Statins | No Comments

Cancer and cardiac patients are typically prescribed multiple medications due to the severity and clinical complexity of their illness. It has been proposed in numerous studies citing relevant data on statistically significant adverse medication reactions in this population that pharmacogenetic testing should be conducted pre-emptively on such groups to prevent adverse clinical outcomes.
 
Researchers at Vanderbilt University Medical Center’s Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment (PREDICT) investigated gene variants that were deemed clinically actionable based on institutionally approved clinical decision support advisors for five common DGIs (drug-gene interactions) in a clinical group of 10,044 cardiovascular disease (CVD) patients, as detailed in a January 2017 article in Pharmacogenomics and Personalized Medicine “Prevalence of clinically actionable genotypes and medication exposure of older adults in the community.”
 
The study analyzed clinically actionable pharmacogenotypes for clopidogrel, warfarin, statins, thiopurines, and tacrolimus. The researchers reported that 91% of patients had at least one actionable gene and more than 5% of patients were at high risk of suffering strong adverse reactions. Similar studies corroborate the PREDICT researchers’ findings, according to the article.
 
Pre-emptive genetic testing should therefore be integrated into standard care models, the researchers concluded. Given the preponderance of data on DGIs such as these, the investigators called for prescribers to give greater consideration to the possibility of clinically relevant drug-gene interactions in the older adult group. “Our findings affirm that pre-emptive genotyping is likely to have strong potential to improve medication safety, efficacy, and health outcomes,” the article stated. “Further investigations correlating genotypes and medication exposures to adverse reactions and other outcomes in older people appear justified.”

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Dopamine Agonists: Parkinson’s Disease and Beyond

By | Other | No Comments

A dopamine agonist is a drug that stimulates dopamine receptors. Under normal circumstances, neuron A releases dopamine, which stimulates dopamine receptors on neuron B. Physicians, however, can use a dopamine agonist to directly stimulate dopamine receptors to achieve certain beneficial effects.

 

Am I Taking a Dopamine Agonist?

 

Most people who take dopamine agonists have Parkinson’s disease, restless legs syndrome (RLS), or both. The most commonly prescribed dopamine agonists include:

 

  • Bromocriptine
  • Pramipexole
  • Ropinirole
  • Rotigotine

Apomorphine and lisuride (available in Europe) are available by injection for Parkinson’s patients who suddenly lose the ability to move (i.e. akinesis).

 

What about Carbidopa-Levodopa or L-Dopa?

 

Levodopa is not technically a dopamine agonist. Levodopa is converted into (actual) dopamine within cells. The newly created dopamine, made from levodopa, is released from neurons just like the body’s own dopamine. While this dopamine does stimulate dopamine receptors, it is not a dopamine agonist, because it needs to be converted by cells and released. A true dopamine agonist can bind to and stimulate dopamine receptors directly.

 

Why Dopamine Agonists are Important in Parkinson’s Disease

 

In Parkinson’s disease, neurons in a particular brain region die. This region is called the substantia nigra, which contains most of the dopamine neurons in the brain. Early in the disease, levodopa can make up for the loss of these dopamine neurons by increasing the amount of dopamine they contain. Later in the disease, however, cell death gets progressively worse and levodopa is less effective. A dopamine agonist does not require living cells in the substantia nigra to exert a positive effect for the patient.

 

Dopamine agonists exert many beneficial effects in people with Parkinson’s disease. These drugs decrease the motor symptoms of the disease including resting tremor, limb (cogwheel) rigidity, motor “freezing,” dyskinesia, and dystonia.

 

Acute akinesia is the sudden and severe worsening of freezing, in which a person with Parkinson’s disease can be rendered motionless by the disease. This state is often brought on by influenza or physical stress, such as stress. An injectable dopamine agonist may be able to overcome acute akinesia where other Parkinson’s treatments, like levodopa, may fail.

 

Dopamine Agonists in Other Conditions

 

A dopamine agonist may be prescribed for other conditions besides Parkinson’s disease and restless legs syndrome (Willis-Ekbom disease). Examples include periodic limb movement disorder, hyperprolactinemia, and peripartum cardiomyopathy. Dopamine agonists such as bromocriptine and cabergoline may be used to stimulate ovulation in women who are infertile due to hyperprolactinemia or excessive prolactin release.

 

Researchers and public health officials are attempting to use dopamine agonists to treat cocaine use disorder and methamphetamine use disorder. In these conditions, dopamine agonists are used to help people curb their addiction, much like methadone is used to treat heroin and opioid addiction. Research trials have been mildly successful to date.

 

Dopamine Agonist Side Effects

The most common adverse drug reactions associated with dopamine agonists are:

 

  • Constipation
  • Dizziness
  • Fatigue
  • Headache
  • Nausea
  • Runny nose
  • Weakness

 
More serious but less common side effects include:

 

  • Hypoglycemia (low blood sugar)
  • Hypotension (low blood pressure, especially just after standing up)
  • Visual problems

 
When doses of dopamine agonists are too high, they may cause cardiac arrhythmia, increased blood pressure, insomnia, euphoria, and hallucinations.

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