Dying in balance and my organ is more important than yours-managing treatments from different specialties
When I was an intern in Internal Medicine, my training director was highly influenced by House of God by Samuel Shem. His sense of humor was often not appropriate for patient consumption. He claimed that all patient problems could be summed up in two general categories, WTD1 and WTD2. WTD1 was short for "weak, tired and dizzy" while WTD2 was "waiting to die." The internist was successful when the patients' symptoms resolved or they "died in balance." The latter referred to all their lab values and numbers looking good just prior to the time of death. Samuel Shem became a psychiatrist and I believe he would agree with my goal, normalizing lab values is less important than the patient feeling better and if they happen to die, it is with a smile on their face for a life worth living.
I note the above because many efforts in modern medicine seem focused on "normalizing" numbers rather than treating the patient. Whenever a patient asks me the result of their lab tests, especially for medication blood levels, I always ask them "how are you doing?" The lab result is less important than the results of the treatment. Labs are for guidance. If the blood level of a medication are too high I might want to reduce the dose to prevent side effects. If the levels are too low and they are doing well, I don't care. I might ask if they are really taking the medication and if not, tell them that that's OK if you are doing well. I don't treat lab values, I treat patients. I don't get any satisfaction from patients being compliant with medications that are not helping them or are causing untoward effects.
Physicians have embraced using evidence-based treatments which on the surface is a noble aim. This means that physicians should prescribe the best treatments for each condition based upon the best scientific evidence. The best evidence is from large double blind studies in which active treatments are compared to each other and placebos. Unfortunately, these are very expensive studies to do, so most are funded by pharmaceutical companies who are able to design studies which can favor their medication by under or overdosing comparator medications or not enrolling enough patients to receive alternative medications so that true differences can't be proven. Additionally, it is difficult, if not impossible, to do statistical analyses of multiple variables in sub-populations of patients. For example, in studying a medication for high blood pressure they haven't differentiated patients with other conditions like depression or anxiety since the focus is on disease states associated with high blood pressure such as heart attack and stroke. Only recently was it demonstrated that depression was one of the greatest risk factors for heart attacks. This would suggest that additional studies should be done to look for the best anti-hypertension medications for the subpopulation of patients with depression and anxiety. Instead some of the most commonly used medications indicated by evidence based medicine to prevent heart attacks can worsen depression and interfere with antidepressants.
Jill was a 45 year old married woman with a long history of anxiety and depression. She was treated by her primary care doctor with Cymbalta (duloxetine) for her depression and pain from arthritis. She was doing well for several years but had a panic attack when her teenage son got into a car accident while texting his new girlfriend. No one was hurt but she thought she was having a heart attack and went to the hospital emergency room. She was given an extensive work up including EKG, blood work and was referred to a cardiologist. He ordered an echocardiogram and stress tests which were all normal. Her blood pressure and pulse were high so the ER physicians began her on metoprolol and the cardiologist raised the dose. She continued to feel ill and in fact was feeling worse with fatigue and loss of drive. She couldn't concentrate. Now worrying that doctors had missed some serious problem she complained to her primary care doctor who told her that everything was normal and that the only thing he could suggest to her was to see a psychiatrist.
Reluctantly, after several weeks of resistance, she made her appointment to see me. I reviewed all of her symptoms and history. She was not the best student in school but managed to get by because most subjects seemed easy for her. Her son was similar and was recently diagnosed with attention deficit disorder but was refusing to take medications. She saw some of the same obstinacy in herself agreeing to the Cymbalta only because she didn't want to get addicted to pain medications for her arthritis. The improvement in her mood was an added bonus which she appreciated. Careful questioning revealed that the worsening of her fatigue began after going to the emergency room and worsened more after seeing the cardiologist. This correlated with her beginning the metoprolol and the subsequent dosage increase. I suggested that this medication should be changed but she didn't want to call her doctors about this. Knowing that her cardiac work-up was negative I told her that I could give her an alternate medication that was similar to the metoprolol but would not get into the brain as easily. I prescribed atenolol as a substitute. She called me a week later telling me she was back to her old self.
Metoprolol and atenolol are both medications of the class of beta blockers that are selective to the heart (Beta 1 selective). Metoprolol was approved more recently and the manufacturer did more studies to prove its superiority for certain heart conditions. My impression of some of the studies and experience switching people between these medications is that the dosage equivalencies used were not accurate. Most reports suggest that atenolol should be dosed about half as much as the equivalent dose of metoprolol. In my experience patients needed the same dosage of each medication to get an equivalent effect on blood pressure and heart rate. More importantly, metoprolol is lipophilic, which means it dissolves in fats and thereby may enter the brain more easily than atenolol. Beta blockers block the effects of adrenaline which is a hormone that in the body raises heart rate and blood pressure. In the brain this neurohormone helps concentration, drive and mood. Metoprolol blocks some of the effects of Cymbalta which raises adrenaline in the brain. We give medications that enhance adrenaline to patients with depression and attention deficit disorder so a beta blocker in the brain can reverse these benefits.
Is metoprolol a more effective beta blocker than atenolol for preventing heart disease? Or would the depression worsening side effect of metoprolol make it less effective in patients with depression or for patients on antidepressants. As far as I know, no one has studied this. This leads me back to my internship. Do I follow evidence-based studies that call for metoprolol and have my patient "die in balance" having done everything by the book, or do I risk following a patient-centered approach that may cause my patient to die with a smile on her face? Having changed Jill's medication, she now can make a choice with personal evidence of her own trial comparing the effects and side effects of both medications. She can, with this firsthand knowledge, make a more informed decision about her own treatment.
Feeling better, Jill decided to have her primary care physician continue to prescribe all of her medications including the new medication I started her on. Five years later she returned for another evaluation. She has gone through menopause and now has a number of new problems. She has to urinate frequently and often can't make it to the bathroom in time. She was referred to an urologist who diagnosed her with over active bladder and prescribed oxybutynin for her. The urinary urgency is better but she has gotten more forgetful and more tired again. She associates her memory problems with menopause. Sleep has been poor due to night sweats and hot flashes. All of this is making her more depressed and she is anxious that she might lose her job due to poor performance. She needs this job as her husband's business has not been well lately. She went to her gynecologist who advised against hormone replacement therapy due to a family history of breast cancer.
Jill is typical in many ways and is a setup for bad pharmacology based upon evidence-based medicine. Oxybutinin is a standard medication for over active bladder that works as an anticholinergic medication. Many of our old antidepressant medications had anticholinergic side effects which included difficulty urinating, dry mouth, blurred vision, constipation and rapid heart rate. In the brain, anticholinergic medications cause memory loss and confusion. In Alzheimer's dementia the cholinergic system deteriorates. Several medications approved for Alzheimer's, such as Aricept work the opposite of Oxybutynin. Oxybutinin is another lipophilic medication that gets into the brain easily, worsening memory. I switched Jill's oxybutynin to trospium (Sanctura) , which is also anticholinergic but is not lipophilic and can effectively treat overactive bladder without the cognitive side effects, but is not widely marketed. Some medications seemed to have flopped due to bad timing in their release when cheaper equally effective medications were available. Only later, after a medication has gone generic, did we appreciate certain differences that gave some medications an advantage. When a medication has gone generic there is no drug company who will want to spend the money to market it to prescribers. This knowledge has to be spread by word of mouth or through small case reports.
Jill was happy with the change in medication. Her bladder symptoms were as well controlled on the trospium but she was still disturbed by her hot flashes and poor sleep. Sweating is another adrenaline symptom that can be helped by medications that block this hormone's action on the alpha receptor. Above we noted she was using a beta 1 adrenaline receptor blocker, atenolol, which controlled her rapid heart rate. There are several alpha blockers available and some psychiatric medications have this as a side effect. This mechanism was responsible for lowering patients' blood pressure causing dizziness. This may not be a problem if the dosage of the alpha blocker is low but might be a problem when combined with another blood pressure lowering medication like atenolol. There is a blood pressure medication, carvedilol, which has both alpha and beta adrenaline blocking activity so could help both sweating and rapid heart rate, but it gets into the brain more easily than atenolol. Terazocin (Hytrin) is an alpha blocker that is approved for both blood pressure and male urinary symptoms due to benign prostatic hypertrophy. At low doses it helps reduce sweating from multiple causes without lowering blood pressure significantly. Blocking the alpha receptor in the brain doesn't seem to cause the same psychiatric problems as the beta receptor.
I didn't go over all of the possible treatments with Jill, but she might have noticed the smoke coming from my ears as I ran through the multitude of possibilities and drug interactions affecting multiple bodily systems. I settled on a simple one, trazodone. This is a medication that came out before Prozac (BP) which never hit it off as an antidepressant. Its sedating side effect was so strong that few patients were able to tolerate enough to get an antidepressant effect. I was working at a Veterans hospital when I began using it for depressed veterans with post traumatic stress disorder and substance abuse. The sedation allowed me to taper patients off their sedating addicting medications and I published an article on this. What I didn't realize at the time was that trazodone's alpha blockade effect might also help sleep, nightmares and night sweats as much as the sedation in these patients. So I decided on low dose trazodone for Jill as it could help both her night sweats and sleep. This improved her sleep but she still complained of night sweats and hot flashes. Adding one milligram of terazocin twice a day resolved them. She was so pleased with the results that she referred her husband, George, to me as he was sleeping poorly and disturbing her now.
George was 55 years old and has always been a hyperactive independent guy. He ran his own business which had its ups and downs until he hired Jill to do his bookkeeping. When she was not doing as well he became more aware of his short comings. This caused him to become increasingly anxious which led to troublesome urinary frequency. He drank a lot of coffee to keep up with his workload but felt his need to leave meetings with clients to urinate was unprofessional. His primary care doctor told him that his prostate was not enlarged so diagnosed him also with overactive bladder. He gave him some Myrbetriq to try since he had samples in his closet. George felt that this didn't work and maybe made him worse. He was hoping that I could help him as I had his wife.
I have sympathy for primary care physicians. They have so many disease states to learn about and treat. They get bombarded with drug reps peddling the latest, greatest medications for existing and sometime new seemingly made up conditions. It is impossible to keep up let alone learn the differences between treatments based upon mechanisms of action. The FDA approves medications for specific conditions defined by a set of symptoms and the medications clearly help these conditions. This is the definition of evidenced-based medicine. Several years ago with the new healthcare program, ACA, I was incentivized to start prescribing electronically instead of by paper prescription. This had two effects besides making my prescriptions more legible. I needed to get internet access for my prescribing and I was able to see what other physicians had ordered for my patients. Once I had the internet, the power of Google allowed me to look up details about all the medications I was prescribing as well as what other doctors had given my patients.
I looked up Myrbetriq. It is an interesting medication as it is not anticholinergic like most of the medications for over active bladder. It works on adrenaline, cool. I know adrenaline and its effects. It happens to target a different adrenaline receptor the beta-3 receptor which is focused in the bladder but instead of blocking it like the medications noted above, it stimulates them. Looking at the side effect profile in the package insert, it might not be as specific as it professes since it may raise blood pressure as you would expect for a drug that stimulates adrenaline. I learned from a drug rep (see chapter Marketing of a slightly better medication) that medications that stimulate adrenaline produce a "pseudo anticholinergic" effect. In other words like the anticholinergic medications they slow urination and cause dry mouth. But they do not cause the memory problems associated with true anticholinergic medications.
Obtaining more history from George suggested that like his son, he probably also suffered from attention deficit disorder since childhood. He compensated for this by drinking a lot of coffee and when he was younger he was very active in sports. He would always do things at the last minute and thrived on the anxiety that it produced. All of these things raise adrenaline. His urinary problem was not caused by too little adrenaline, but by too much causing a pseudo anticholinergic side effect such that he never fully emptied his bladder. He needed a medication that blocked his adrenaline in his bladder but not his head. Tamsulosin is such a medication. Also the excessive amounts of caffeine were irritating his bladder and causing sleep difficulty. I gave him atomoxetine (Strattera) a medication that stimulates adrenaline, for his ADHD symptoms so he could reduce his caffeine intake and be less anxious. Without the tamsulosin, the atomoxetine would have worsened his bladder problem. I was able to give him the adrenaline he needed in his brain for concentration with atomoxetine, while blocking its effect in his bladder with tamsulosin. If his blood pressure went up or he developed sweating from the excess adrenaline, I could switch his tamsulosin to terazocin which would block the adrenaline effect in the bladder, blood vessels, and sweat glands without impacting the brain. If instead he had tremors and increased heart rate, I could give nadolol which is a beta adrenergic blocker that doesn't get into the brain easily. Isn't pharmacology fun?
In summary, I want to impress upon prescribers and patients that mechanism of actions as well as evidence-based studies comprise a starting point of medications that might be used to treat a specific problem. In order to find the best medications to treat individual patients we need to understand the pharmacology of each medication and how it might impact any concomitant medical or psychiatric conditions. Everyone is complicated by the fact that they have multiple conditions and different metabolisms which warrant individualized treatments. Medications have more than one action which can result in side effects, but sometimes these side effects can be used to benefit co-occurring problems. Alternatively, specific side effects might be ameliorated by other medications creating a cocktail of sorts. Specialists would be wise to consider co-occurring conditions when choosing medications rather than reflexively selecting the "best" "evidence-based" medication for the condition that they are called upon to fix or giving samples of the latest medication left by a pharmaceutical representative. When in doubt, Google is your friend that can help you rapidly find out all sorts of interesting facts not only about mechanism of action but also drug interactions, side effects, and duration of action which makes everyone a more informed prescriber.
And by the way, the brain is the most important organ!
Reference note:
As a psychiatrist I must note that the worst beta blocker for patients with psychiatric conditions is metoprolol. It penetrates the brain easily (highly lipophilic) causing fatigue and reverses the norepinephrine benefits of many antidepressants and stimulants (i.e. causing depression and cognitive impairment). Two good alternatives are atenolol for beta 1 selectivity and nadolol for non selective use (eg tremors). These beta blockers are hydrophilic and don't cross bbb as easily) The original studies comparing atenolol with metoprolol were flawed in that they under dosed atenolol. The potency should be 1:1 published in 2012https://www.ncbi.nlm.nih.gov/pubmed/2891183 vs earlier studies presumably paid for by manufacturer of Toprol in 1981 https://www.ncbi.nlm.nih.gov/pubmed/7308277 which dosed 2:1 metoprolol to atenolol.
