Drug to Drug Interactions in Patient with Physical and Physiological Conditions

Abstract

This paper examines a fictional case conceptualization and explores possible drug to drug interactions with a patient who suffers from a physical bodily condition while also suffering from a physiological condition, both requiring treatment in the form of medications. This particular case conceptualization will focus on familial atrial fibrillation and depression with regards to the patient being a newly pregnant, 27-year old, African American women who has been treated for Depression before through counseling. This client will have only been previously treated for atrial fibrillation. Aside from this, no prior history is present with medication usage. The specific medications mentioned in this paper will be Warfarin and Cymbalta.

Keywords: Warfarin, Cymbalta, pregnancy

Case Conceptualization Paper

Client X is a 27-year old female who is working on her graduate degree to become a school counselor. She also works part-time as an assistant secretary in the local high school. Client X reports always being passionate about children and has enjoyed being around them since she started babysitting at 15 years old. Client X is currently dating her boyfriend of five years whom she lives with. Client X’s background is a single parent home, consisting of her mother and grandmother whom she has spent the majority of her live with. She claims she is very close to both ladies and has always had a loving relationship between all three of them. She shares that she hopes she could one day be a great mother; however, she was warned by her doctor her medical condition may play as a risk factor. Client X had symptoms of light-headedness, fatigue, and occasionally felt her heart “flip-flop quickly”. Her doctor diagnosed X with atrial fibrillation. Client X, her mother and grandmother all have atrial fibrillation, and  X’s grandmother recently suffered from a stroke due to her condition. This has, in turn, increased X’s feelings of anxiety and depression. Just like her own mother and grandmother, Client X has been prescribed Warfarin two years ago to help maintain her atrial fibrillation.

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Client X also had a miscarriage three years ago which is when the onset of her depressive symptoms began. For about six months post tragedy, Client X reported self-medicating through  alcohol and other substances such as marijuana and, occasionally, cocaine. Her boyfriend convinced her to begin a rehabilitation process and it has proven to be successful for the past two and a half years, but she still struggles with the depression. She began group counseling, but she eventually lost all desire to attend meetings since they brought back painful memories for her. Client X had been working full time as an assistant secretary, but after the unfortunate event, she struggled with getting out of bed and coming to work. She went on a medical leave of absence and saw a psychiatrist who diagnosed her with Major Depressive Disorder with anxious distress and prescribed Cymbalta. Client X reports that she still occasionally struggles with her depressive thoughts, lack of pleasure, drowsiness, dizziness, but also has some days where she feels “over the moon” and has so much energy she will work an extra day or two to ensure she is staying productive.

Client X reports feeling hopeless and wishes she could get her life back on track. Client X also reported feeling the same symptoms she felt when she found out she was pregnant the first time. She recently took a pregnancy test and it showed positive. Client X says she is excited but also terrified she will suffer the same heartbreak once again and wants to take every necessary precaution everything is done the right way this time. Client X is worried that her depression and heart condition may get in the way.

Atrial Fibrillation

Atrial fibrillation is a form of heart arrythmia, or heart beat irregularity. Atrial fibrillation, as defined by the American Heart Association, is when the upper chambers of the heart beat irregularly disrupting the movement of blood into the ventricles (2016). The National Heart, Lung and Blood Institute elaborates that atrial fibrillation causes the heart to beat much faster than normal, resulting in the discordance of the upper and lower chambers of the heart working together (2019). Consequently, the lower chambers cannot fill completely to pump enough blood to the lungs and rest of the body which can have a detrimental impact.

There are a few factors that may be considered possible causes for atrial fibrillation. These include changes in heart tissue or changes in electrical signaling. Changes in heart tissue may be the effect of aging, heart disease, infection, or genetics that all can break down the pattern of the heart’s cells (NHLBI, 2019). Electrical signals also fire from trigger heartbeats that can set off atrial fibrillation. These signals can, then, change the rhythm of heart beats either faster or slower than usual. The signals can also create an abnormal loop, sending the message to the heart to contract, repeatedly. Differences in heart anatomy, premature or extra heartbeats, normal heart rate adjustments, patches of faster or slower tissue and repeated stimulation of certain tissue patches can all contribute to variations in the heart’s electrical signaling (NHLBI, 2019).

The physiological effects of lack of blood flow leaves an individual fatigued or dizzy, and, in some instances, experiencing heart palpitations or chest pain. Another risk is the possibility of blood pooling in the heart, which increases the risk of stroke among other complications. Atrial fibrillation can occur without any obvious signs or symptoms, so many individuals can, unknowingly, have this condition. When left untreated, atrial fibrillation can have life-threatening complications.

While in some occurrences, atrial fibrillation can diminish on its own, atrial fibrillation can be an ongoing heart problem that lasts for a lifetime. Over time, frequency and duration of atrial fibrillation symptoms may increase. Treatment would attempt to restore normal heart rhythms, helps control symptoms, and prevent any further complications. Treatment may come in the form of recommended medicines, medical procedures, and lifestyle changes to treat atrial fibrillation. Particular medicines involved in atrial fibrillation treatment include Beta blockers, blood thinners, calcium channel blockers, digitalis, or digoxin, among countless other heart rhythm medicines (NHLBI, 2019). Blood thinners, specifically, act to prevent blood clots and lower the risk of stroke. Such medicines include Warfarin, Dabigatran, Heparin, and Clopidogrel. Blood-thinning medicines, typically, carry a risk of bleeding with other side effects including indigestion and heart attack. For the purpose of the case of Client X, Warfarin will be examined in detail.

Warfarin

Warfarin Sodium, also known as Coumadin, is either utilized in the form of tablets or injections. Coumadin tablets, involve the crystallization of warfarin sodium to eliminate trace impurities present in amorphous warfarin. Crystalline warfarin sodium occurs as a white, odorless, crystalline powder, is discolored by light and is very soluble in water; freely soluble in alcohol; very slightly soluble in chloroform and in ether. This crystalline warfarin sodium is an anticoagulant that inhibits vitamin K-dependent coagulation factors. The injection version of Coumadin is supplied as a sterile, lyophilized powder that is reconstituted with 2.7 mL of sterile water (FDA, 2007).

Coumadin and other coumarin anticoagulants act by hindering the production of vitamin K-dependent clotting factors, which include Factors II, VII, IX and X, and the anticoagulant proteins C and S. Half-lives of these clotting factors are 60 hours for Factor II, 4 to 6 hours for Factor VII, 24 hours for Factor IX, and for Factor X, the half-life can be between 48-72 hours. Proteins C and S have half-lives of approximately 8 hours and 30 hours. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K dependent clotting factors. This vitamin further supports the biosynthesis in proteins that are essential for biological activity (FDA, 2007).

Warfarin can interfere with clotting by inhibiting the C1 subunit of the vitamin K epoxide reductase enzyme complex, in turn, reducing vitamin K1 epoxide redevelopment. Dosage effects the degree of depression. Therapeutic doses of warfarin aim to decrease the total amount of the active form of each vitamin K-dependent clotting factor that the liver produces by approximately 30% to 50% (FDA, 2007).

Within 24 hours after drug administration, anticoagulation can be expected to occur. The duration of action of a single dose of warfarin is between 2 and 5 days. Anticoagulants cannot  reverse ischemic tissue damage. However, once a blood clot has occurred, anticoagulation prevents further additional clotting and prevents other clotting from forming. If such clotting were to occur, it could possibly lead to fatal consequences (FDA, 2007).

Coumadin is a mixture of the R- and S-enantiomers with the S-enantiomer exhibiting between 2 to 5 times more anticoagulant activity than the R-enantiomer with more efficient clearance action. Coumadin is essentially completely absorbed after oral administration with peak concentration generally attained within the first 4 hours. Warfarin is eliminated by metabolism. Coumadin is metabolized by enzymes to reduce metabolites. The metabolites are excreted in the form of urine or bile (FDA, 2007).

Side effects of Coumadin include pain, swelling or discomfort, headaches, dizziness, weakness, unusual bruising, nose bleeds, bleeding gums, bleeding taking a long time to stop, pink or brown urine, red or black stools, coughing up blood, vomiting blood, death of skin tissue, “purple toe syndrome” allergic reactions, liver problems, low blood pressure, swelling, low red blood cells, paleness, fever, and rash (FDA, 2007).

Coumadin is contraindicated in women who are or may become pregnant because the drug passes through the placental barrier and can cause fatal hemorrhage to the fetus in utero. Birth malformations have been reported among children whose mothers who have been treated with warfarin during pregnancy. Embryopathy has also been reported in pregnant women exposed to warfarin during the first trimester. Central nervous system abnormalities also have been reported, as well as dorsal midline dysplasia, Dandy-Walker malformation, midline cerebellar atrophy, ventral midline dysplasia and eye abnormalities (FDA, 2007).  In other cases examining consumption during the second and third trimesters, mental retardation, blindness, and other abnormalities have been reported. Severe cases have found single kidney, asplenia, anencephaly, spina bifida, cranial nerve palsy, hydrocephalus, cardiac defects and congenital heart disease, polydactyly, deformities of toes, diaphragmatic hernia, corneal leukoma, cleft palate, cleft lip, schizencephaly, and microcephaly (FDA, 2007).

Women pregnant taking Warfarin have also been subject to spontaneous abortion, stillbirth, and fetal mortality. If babies have survived labor, they risk low birth weight and stunts in physical growth. Women who are or may become pregnant taking anticoagulation treatment should be informed of these potential risks. The possibility of termination of the pregnancy should be discussed when considering the potential risks to both mother and child (FDA, 2007).

Major Depressive Disorder

Major Depressive Disorder is characterized as a change from previous functioning with symptoms of either depressed mood or loss of interest or pleasure. Diagnostic criteria include Depressed mood most of the day, nearly every day, as indicated by either subjective report or observations made by others, markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day, significant weight loss, insomnia, psychomotor agitation, fatigue, loss of energy, feelings of worthlessness or inappropriate guilt, diminished ability to think or concentrate, recurrent thoughts of death. Twelve-month prevalence of major depressive disorder in the United States is approximately 7%, with marked differences by age group such that the prevalence in 18- to 29-year-old individuals is threefold higher than the prevalence in individuals age 60 years or older. Females have been found to experience significantly higher rates than males beginning in early adolescence. Major depressive disorder can arise at any age, but the period of puberty can begin the onset of depressive symptoms. In the United States, individuals typically begin experiencing the onset of depression in their 20s, however, it can also occur later in life, or following traumatic events (American Psychiatric Association, 2013).

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As there can be many factors, either biological or socioemotional, that can trigger the onset of depression, there can be various methods to treat depression. Psychotherapies such as cognitive, interpersonal, and behavioral therapies have been established as empirically supported treatments and antidepressant medications have been shown to be effective as well, with selective serotonin reuptake inhibitors being the most widely used especially with more severe depression (Khalsa, et. al, 2011). Antidepressants are frequently prescribed medications used to depression and other mental health condition including selective serotonin reuptake inhibitors SSRIs, serotonin and norepinephrine reuptake inhibitors, SNRIs, atypical antidepressants, tricyclic antidepressants TCAs, and monoamine oxidase inhibitors MAOIs. Antidepressant medications aim to balance neurotransmitters affecting temper and emotions (Smith, et. al, 2019). Duloxetine, or Cymbalta, is an example of an SNRI, and is the main form of treatment for Client X’s depression (Mayo Clinic, 2017).

Cymbalta

Cymbalta, usually utilized in the treatment of Major Depressive Disorder, Generalized Anxiety Disorder, Diabetic Peripheral Neuropathic Pain, Fibromyalgia, and Chronic Musculoskeletal Pain, is administered once daily, orally, in patients suffering from such illnesses. The target dosage of Cymbalta in patients treated with Major Depressive Disorder should be 60 milligrams per day never exceeding 120 milligrams per day. Contraindications exist for those using a monoamine oxidase inhibitor concomitantly or in patients with narrow-angle glaucoma. Warnings and precautions for Cymbalta include suicidality, hepatoxicity, orthostatic hypotension and syncope, serotonin syndrome, neuroleptic malignant syndrome, abnormal bleeding, activation of mania or hypomania, seizures, and issues with blood pressure.  Other adverse reactions include nausea, dry mouth, somnolence, fatigue, constipation, decreased appetite, and hyperhidrosis (FDA, 2017).

Although the exact mechanisms of the antidepressant actions of duloxetine in humans are unknown, they are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS. Studies have demonstrated duloxetine to be a strong inhibitor of neuronal serotonin and norepinephrine reuptake, while interfering less with dopamine reuptake. Duloxetine has an elimination half-life of approximately 12 hours with the earliest half-life of 8 hours and the maximum, 17 hours. Duloxetine’s effect on the body depend on dosage. Steady-state plasma concentrations usually occur within 3 days of dosing. Elimination of duloxetine is mainly through hepatic metabolism (FDA, 2017).

Duloxetine hydrochloride is well absorbed when taken orally with 2 hours between the beginning of absorption. Peak plasma concentrations of duloxetine occur 6 hours after ingestion. Food can delay the peak concentration time from 6 to 10 hours, and it decreases the absorption rates by about 10%. Morning doses are recommended due to a difference in absorption rate. The apparent volume of distribution averages about 1640 L. Interaction between duloxetine and other highly protein bound drugs has not been determined. (FDA, 2017).

Trace amounts of unchanged duloxetine have been found in urine, the rest is found in fecal matter. Duloxetine undergoes extensive metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine (FDA, 2017).

Drug-Drug Interactions

While the Food and Drug Administration does not specifically list Cymbalta under the specific list of identified drug to drug interactions, it does warn against the interactions that may occur with antidepressants, in general. The Food and Drug Administration warns of abnormal bleeding in individuals taking Cymbalta. SSRIs such as duloxetine, can increase the chance of bleeding and continuous use of anticoagulants such as aspirin or warfarin can further increase this risk. Case reports and other studies have shown an relationship between drugs interfering with serotonin reuptake and gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have occurred in the form of ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Demographic Dilemma

Warfarin on Gender, Race and Pregnancy

Warfarin has not been found to have significant differences between genders or various races. However, it is considered a contraindication in women who are or may become pregnant. As mentioned before, the drug can pass through the placental barrier and cause fatal hemorrhage to the fetus in utero. Birth malformations can also occur to Client X’s child . The baby can have other serious health risks including spinal bifida, heart disease, single kidney or even cranial nerve palsy. Client X also risks a spontaneous abortion or giving labor stillbirth. Even if Client X’s child survives the labor, the consumption of warfarin may increase the bleeding within the baby. There may also be complications in terms of breatfeeding.

Cymbalta on Gender, Race and Pregnancy

In the usage of Cymbalta, the half-life has been found to be similar in men and women. Dosage adjustment based on gender is not necessary. There have also been no specific pharmacokinetic studies conducted to investigate the effects of race as listed on the FDA fact sheet, however other studies have been conducted and have found that the magnitude of duloxetine’s treatment effects did not differ significantly between African-American and Caucasian patients (Bailey, et. al, 2006). Consuming Cymbalta while pregnant is unadvised as there are no adequate studies conducted with pregnant women. As advised by the Food and Drug Administration,  Cymbalta should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because the safety of duloxetine in infants is not known, nursing while on Cymbalta is also not recommended (FDA, 2017).

Though human studies were not conducted, animal reproduction studies found that duloxetine has been shown to have adverse effects on embryo/fetal and postnatal development.

Human neonates exposed to SSRIs or SNRIs late in the third trimester have developed complications leading to hospitalization, respiratory support, and tube feeding. Clinical findings have reported respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying (FDA, 2017). These events occurred due to either a direct effect of SSRIs and SNRIs or, a drug discontinuation syndrome. In treatment of pregnant women with Cymbalta, a physician should warn the individual of potential risks and seriously recommend decreasing the usage especially in the third trimester. Duloxetine effects on labor and delivery is still uncertain.

Duloxetine is excreted into the milk of lactating women and because the safety of duloxetine in infants is unknown, nursing while on Cymbalta is not recommended. However, if the physician determines that duloxetine therapy is more beneficial than harmful for the mother and infant, no dosage adjustment is required since lactation has not been found to interfere with duloxetine pharmacokinetics.

Conclusion

First and foremost, I would recommend Client X to see her physician for consultation about taking both medications simultaneously. I, personally, would immediately recommend the discontinuation of Warfarin seeing as how the Food and Drug Administration has fully deemed pregnancy as a contraindication and severe health risks are possible for both Client X and her unborn baby and this blood thinner may cause severe complications. Since there are other medications that treat atrial fibrillation, I would highly advise consulting her doctor about other medical options that may not interfere with her pregnancy or antidepressant medication, should she still choose to take that medication, of course. Additionally, having a baby while having atrial fibrillation is a complication, in and of itself, therefore I would also recommend her to research with her doctor the risks of that, alone.

I would also advise Client X to discuss with her psychiatrist if the Cymbalta is also absolutely necessary to take during the pregnancy and while breastfeeding. While no adequate human studies were conducted to conclude whether or not Cymbalta was safe for pregnant and nursing women, I still feel as though there might be a potential risk as evidenced by the animal studies. If the depression can be contained by other, safer medication, or simply by counseling, at least until labor and nursing are complete, then I would highly suggest doing so. The recommendation on the Food and Drug Administration also explained that in the case of pregnant and nursing women should only take the duloxetine if the potential benefit justifies the potential risk to the fetus, meaning if taking the medication will not risk the overall life of the fetus, it is alright. However, the justification, I feel, is up to the mother at this point in time. It is her body, her fetus, and her child. All decisions, at the end, must be made by Client X, along with the information and recommendations given to her by her physicians and psychiatrists.

References

• American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.).
• Antidepressants: Selecting one that’s right for you. (2017, November 17). Retrieved June 20, 2019, from https://www.mayoclinic.org/diseases-conditions/depression/in-depth/antidepressants/art-20046273
• Atrial Fibrillation. National Heart Lung and Blood Institute. Retrieved June 19, 2019, from https://www.nhlbi.nih.gov/health-topics/atrial-fibrillation
• Bailey, R.K., Mallinckrodt, C.H., Wohlreich, M.M., Watkin, J. G., & Plewes, J.M. (2006).  Duloxetine in the treatment of major depressive disorder: Comparisons of safety and efficacy. Journal of the National Medical Association (98), 437–447.
• Bristol-Myers Squibb Company. Coumadin. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/009218s105lblv2.pdf. Revised August 2007. Accessed June 2019.
• Eli Lilly and Company. Cymbalta. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021427s049lbl.pdf. Revised January 2017. Accessed June 2019.
• Khalsa, S., McCarthy, K. S., Sharpless, B. A., Barrett, M. S., & Barber, J. P. (2011). Beliefs about the causes of depression and treatment preferences. Journal of Clinical Psychology, 67(6), 539–549. https://doi.org/10.1002/jclp.20785
• Smith, M., Robinson, L., & Segal, J. (2019, June 11). Antidepressant Medication. Retrieved June 21, 2019, from https://www.helpguide.org/articles/depression/antidepressant-medication.htm
• What is Atrial Fibrillation (A Fib or AF)? (2016, July 31) American Heart Association. Retrieved June 20, 2019, from https://www.heart.org/en/health-topics/atrial-fibrillation/what-is-atrial-fibrillation-afib-or-              af