The Practice of Medicine. My relevant background with respect to this presentation includes: With a show of hands, please indicate which you are:

Transcription

1 The Practice of Medicine Clinical Psychopharmacology and Malpractice: What Clinically Relevant Lessons Can Be Learned? Sheldon H. Preskorn, MD Professor of Psychiatry, Kansas University School of Medicine President and CEO World-wide Psychiatric Drug Development Consultants, Inc. Wichita, Kansas Professor of Psychiatry, Laureate Institute for Brain Research Tulsa, Oklahoma A physician is by no means physician to living beings in general, not even physician to the human race, but rather, physician to a human individual, and still more physician to an individual in certain morbid conditions peculiar to himself and forming what is called his idiosyncrasy Claude Bernard, An Introduction to the Study of Experimental Medicine, 1865 With a show of hands, please indicate which you are: a) Psychiatrist b) Resident psychiatry c) Another type of physician d) APRN or PA e) RN, MSW, or other mental health care professional f) None of the above My relevant background with respect to this presentation includes: Psychiatrist Clinical pharmacologist Preclinical pharmacologist Neuropathology General medical internship Expert witness principally on causation Tommy 6-year-old, weighed 55 lbs What are the 4 Ds of a malpractice lawsuit? Diagnosed with ADHD Originally treated with amphetamine and methylphenidate, but inadequate improvement Next treated with imipramine beginning with 50 mg/day and gradually titrated over 3 months to 200 mg/day based on clinical assessment of response ADHD = attention-deficit/hyperactivity disorder. Preskorn SH. J Psychiatr Pract. 2011;17(2):

2 Tommy (continued) Tommy (continued) One day at school, he collapsed His teachers initiated CPR and called an ambulance His heartbeat was re-established, but he had fixed dilated pupils and no spontaneous respirations In the ED, he was maintained on a ventilator and found to have Ventricular tachycardia and fibrillation One measurable QTc that was 580 msec long A plasma drug concentration drawn revealed a total concentration of 1000 ng/ml He experienced a recurrent bout of ventricular fibrillation and cardiac arrest and was pronounced dead An autopsy revealed no anatomical cause for sudden death Preskorn SH. J Psychiatr Pract. 2011;17(2): ED = emergency department. Preskorn SH. J Psychiatr Pract. 2011;17(2): Package Insert Learning Objective #2: Examine the relevance of the package insert in malpractice suits 1. Who writes it? 2. Why do they write it? 3. Upon what is it based? 4. Why will it generally be a document brought up in a malpractice lawsuit involving the alleged misuse of a medication? McMahon D, et al. J Psychiatr Pract. 2014;20(4): Package Insert Where does the PI time-wise fit in the drug development process? What are class warnings? Warnings that are included in the PI for a drug not because the adverse events were observed with the drug necessarily but because they were observed with other members of the class.

3 Can a drug avoid class warnings? Does failure to follow the PI necessarily mean that the practitioner was derelict? What about the case of Tommy? What about the case of Tommy? The PI for imipramine warned against exceeding 2.5 mg/kg in a child. He was on 8 mg/kg. The imipramine PI recommended to measure an ECG before starting the drug and after each dose increase. That was not done. Tommy (continued) Beyond the malpractice lawsuit, did this prescriber face any other consequence? Learning Objective #3: Discuss clinical pharmacology principles, which have been pivotal to the outcomes of malpractice cases, to improve your care of patients

4 3 Variables That Determine Drug Effect Concentration = Dosing Rate Drug concentration at its site(s) of action Patient s biology Clearance Affinity Intrinsic Activity Absorption Distribution Genetics Age mg/min ml/min Professional Communications, Inc; Variables That Determine Drug Effect Drug concentration at its site(s) of action Patient s biology Preskorn SH, et al. Use of tricyclic antidepressant blood levels. N Engl J Med. 1978;298(3):166. Affinity Intrinsic Activity Absorption Distribution Genetics Age Professional Communications, Inc; Genetics of CYP 2D6: Metabolizing Effects on Nortriptyline 3 Variables That Determine Drug Effect MR= MR Nortriptyline dose requirement (mg day 1 ) > Nortriptyline (mg) MR = metabolic ratio. Meyer UA. Nat Rev Genet. 2004;5(9): Number of Patients Genotype Phenotype Frequency (Caucasian) or or or or Ultra-rapid metabolizers Extensive metabolizers Intermediate metabolizers Poor metabolizers 5% 10% 80% 65% 10% 15% 5% 10% Affinity Intrinsic Activity Drug concentration at its site(s) of action Absorption Distribution Patient s biology Genetics Age Professional Communications, Inc; 1996.

5 Time Course: Fluoxetine Effect on CYP 2D6 Preskorn SH, et al. Serious adverse effects of combining fluoxetine and tricyclic antidepressants. Am J Psychiatry. 1990;147(4):532. Preskorn SH. J Clin Psychopharmacol. 1994;14(2): What does phenoconversion mean to you? Number of Patients Frequency Distribution Histograms: ODMR in Healthy Controls Before After 40 mg/day fluoxetine (a substantial CYP 2D6 inhibitor) -4.0 UM EM IM PM Log ODMR ODMR = O-demethylation ratio of dextromethorphan; UM = ultra-rapid metabolizer; EM = extensive metabolizer; IM = intermediate metabolizer; PM = poor metabolizer. Preskorn SH. J Psychiatr Pract. 2003;9(3): Variables That Determine Drug Effect Familial QTc Prolongation Syndrome and Variant of the K+ Rectifying Channel Drug concentration Underlying biology of at its site(s) of action the patient Affinity Absorption Genetics Intrinsic activity Distribution Age Professional Communications, Inc.; 1996.

6 3 Variables That Determine Drug Effect 3 Variables That Determine Drug Effect Drug concentration Underlying biology of at its site(s) of action the patient Affinity Absorption Genetics Intrinsic activity Distribution Age Drug concentration Underlying biology of at its site(s) of action the patient Affinity Absorption Genetics Intrinsic activity Distribution Age Professional Communications, Inc.; Professional Communications, Inc.; year-old Male with Tourette Syndrome and Bronchitis Cases Had been on a stable dose of pimozide for several years by neurologist Clarithromycin is added for bronchitis by his internist Goes to the ED complaining of intermittent episodes of dizziness Is checked out and nothing its found Next day he dies suddenly and autopsy reveals no anatomical cause of death Flockhart DA, et al. Clin Pharmacol Ther. 1996;59(2): year-old Male with Tourette Syndrome and Bronchitis (continued) Why did he die? Which prescriber if any was culpable? Michael 18-year-old high school senior, valedictorian, and highly regarded long-distance runner His beloved grandmother was dying because of an aggressive cancer He is seen by 3 different PCPs in an 11-day period of time Flockhart DA, et al. Clin Pharmacol Ther. 1996;59(2):189. PCP = primary care physician.

7 Michael (continued) Michael (continued) Day of Care HCP Reason for Visit 1 PCP 1 Depression / anxiety 1 ER Hyperventilation Headache 4 PCP 2 Depression / anxiety Work-up Drug Prescribed Dose Notes Hx & PE Sertraline 50 mg/day Generic Hx, PE, rebreather Alprazolam Acetaminophen or ibuprofen 0.25 mg, 1-2 TID PRN PRN Generic OTC Hx & PE Continue medications Headache Rizatriptan PRN Samples given 8 PCP 2 Depression / anxiety TSH, CBC, chem 20, UA Hx & PE & lab: Start quetiapine - XR 50 mg/day Samples given Titrate to 300 mg/day as tolerated Day of Care HCP 10 PCP 2 11 PCP Urgent Care Reason for Visit Depression / anxiety Itching Work-up Drug Prescribed Dose Notes Hx & PE & lab: All normal Switched to quetiapine - IR Stop sertraline, start paroxetine Diphenhydramine Dehydration Hx & PE Continue medications Continue same dose 20 mg/day 25 mg/day PRN Out of samples. Insurance did not approve XR. B/C of complaints of itching Mouth dry - stressed importance of fluids Consider giving fluids as outpatient or inpatient Somewhat dried mucous membranes, some moisture Encourage fluids even a teaspoon at a time Consider IV fluids if no improvement HCP = health care provider. Michael (continued) Michael (continued) Day of Care Location Body wt Blood Pulse Respiratory Rate (lbs) Pressure Rate (bpm) Temperature (F) 1 PCP /90 76 NA NA 1 ER NA 148/ / NR 4 PCP /80 NA NA " /70 NA NA " /70 NA NA PCP /76 92 NA NA He takes his medication that evening Goes to sleep in a recliner in a semi-recumbent position In the morning, his mother goes down to awaken him She finds a small amount of vomitus on his cheek He is unarousable with labored breathing He was resuscitated but now is in a vegetative state Michael (continued) What caused this catastrophic outcome? Hint: Look at the data and think physiologically Which prescriber if any is culpable? 66-year-old Male with MDD Presents with Dizziness 66-year-old male successfully treated for psychotic major depression with paroxetine, 40 mg/day, and iloperidone, 24 mg/day administered once a day, and now on maintenance therapy He develops bronchitis and his internist treats him with clarithromycin, 250 mg twice daily for 14 days. He comes for his routine psychiatric follow-up at the end of the first week of antibiotic therapy. He is doing well except for a couple of incidences of intermittent dizziness and an episode of near syncope His comorbid medical conditions include type 2 diabetes mellitus well controlled with metformin, moderate obesity, and status post quadruple coronary bypass surgery 4 years ago MDD = major depressive disorder.

8 66-year-old Male with MDD Presents with Dizziness (continued) How do you conceptualize this case? What is your differential diagnosis of his new chief complaint? What do you do? A 75-year-old Male with Partially Responsive MDD Psychiatrist prescribes 2 mg/day of aripiprazole Pharmacy fills prescription for 20 mg/day One month later, patient has akathisia on his return visit Psychiatrist tells him to cut tablets in half (10 mg/day) Preskorn SH. J Psychiatr Pract. 2013;19(5): Preskorn S, et al. J Psychiatr Pract. 2015;21(5): A 75-year-old Male with Partially Responsive MDD (continued) 2 months later, the patient runs out of first prescription and asks for a refill Psychiatrist writes for 2 mg/day Patient notices the difference in tablet appearance and brings it to the attention of the psychiatrist Psychiatrist notifies pharmacy and the error is confirmed A 75-year-old Male with Partially Responsive MDD (continued) Patient continues on 2 mg/day of aripiprazole for next 3 months and is doing well He then develops an orofacial dyskinesia Lawsuit is filed against the pharmacy What was the outcome? Take-Home Messages Remember 1. The 4 Ds of a malpractice lawsuit 2. Clinical pharmacology principles 3. The role of the package insert 4. Not to jump to conclusions Document to explain what you did and why You can sometimes make a physiological measurement of the adverse effect of a drug before an adverse event occurs. I believe these take-homes are good medicine, not just defensive