Tag: Phenelzine

What is Phenelzine?

Published on by Andrew Marshall1 Comment

Introduction

Phenelzine, sold under the brand name Nardil, among others, is a non-selective and irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class which is used as an antidepressant and anxiolytic. Along with tranylcypromine and isocarboxazid, phenelzine is one of the few non-selective and irreversible MAOIs still in widespread clinical use. It is taken by mouth.

In June 2020, the Therapeutic Goods Administration (TGA) reported that the availability of phenelzine was discontinued in Australia due to global issues with the manufacture of the active pharmaceutical ingredient. However, unapproved phenelzine products may be accessed through alternative pathways, such as the Special Access Scheme (SAS) administered by the TGA. In October 2020, The TGA authorized two sponsors to supply an overseas-registered brand of phenelzine in Australia. In May 2020, the Specialist Pharmacy Service in the UK reported the unavailability of phenelzine from the sole supplier. In July 2020, supplies of unlicensed phenelzine 15mg capsule specials became available for UK patients. In February 2021, Phenelzine again became available in Australia as a subsidised medication through the Pharmaceutical Benefits Scheme.

Brief History

Synthesis of phenelzine was first described by Emil Votoček and Otakar Leminger in 1932.

Indications

Phenelzine is used primarily in the treatment of major depressive disorder (MDD). Patients with depressive symptomology characterised as “atypical”, “nonendogenous”, and/or “neurotic” respond particularly well to phenelzine. The medication is also useful in patients who do not respond favourably to first and second-line treatments for depression, or are “treatment-resistant”. In addition to being a recognised treatment for major depressive disorder, phenelzine is effective in treating dysthymia, bipolar depression (BD), panic disorder (PD), social anxiety disorder, bulimia, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD). Phenelzine showed promise in a phase II clinical trial from March 2020 in treating prostate cancer.

Pharmacology

Pharmacodynamics

Phenelzine is a non-selective and irreversible inhibitor of the enzyme monoamine oxidase (MAO). It inhibits both of the respective isoforms of MAO, MAO-A and MAO-B, and does so almost equally, with slight preference for the former. By inhibiting MAO, phenelzine prevents the breakdown of the monoamine neurotransmitters serotonin, melatonin, norepinephrine, epinephrine, and dopamine, as well as the trace amine neuromodulators such as phenethylamine, tyramine, octopamine, and tryptamine. This leads to an increase in the extracellular concentrations of these neurochemicals and therefore an alteration in neurochemistry and neurotransmission. This action is thought to be the primary mediator in phenelzine’s therapeutic benefits.

Phenelzine and its metabolites also inhibit at least two other enzymes to a lesser extent, of which are alanine transaminase (ALA-T), and γ-Aminobutyric acid transaminase (GABA-T), the latter of which is not caused by phenelzine itself, but by a phenelzine metabolite phenylethylidenehydrazine (PEH). By inhibiting ALA-T and GABA-T, phenelzine causes an increase in the alanine and GABA levels in the brain and body. GABA is the major inhibitory neurotransmitter in the mammalian central nervous system, and is very important for the normal suppression of anxiety, stress, and depression. Phenelzine’s action in increasing GABA concentrations may significantly contribute to its antidepressant, and especially, anxiolytic/antipanic properties, the latter of which have been considered superior to those of other antidepressants. As for ALA-T inhibition, though the consequences of disabling this enzyme are currently not well understood, there is some evidence to suggest that it is this action of the hydrazines (including phenelzine) which may be responsible for the occasional incidence of hepatitis and liver failure.

Phenelzine has also been shown to metabolise to phenethylamine (PEA). PEA acts as a releasing agent of norepinephrine and dopamine, and this occurs in the same manner as amphetamine (very similar in structure) by being taken up into vesicles, and displacing, and causing the release of those monoamines (though with markedly different pharmacokinetics such as a far shorter duration of action). Although this is indeed the same mechanism to which some (but not all) of amphetamine’s effects are attributable to, this is not all that uncommon a property among phenethylamines in general, many of which do not have psychoactive properties comparable to amphetamine. Amphetamine is different in that it binds with high affinity to the reuptake pumps of dopamine, norepinephrine, and serotonin, which phenethylamine and related molecules may as well to some extent, but with far less potency, such that it is basically insignificant in comparison. And, often being metabolized too quickly or not having the solubility to enable it to have a psychostimulant effect in humans. Claims that phenethylamine has comparable or roughly similar effects to psychostimulants such as amphetamine when administered are misconstrued. Phenethylamine does not have any obvious, easily discernible, reliably induced effects when administered to humans. Phenelzine’s enhancement of PEA levels may contribute further to its overall antidepressant effects to some degree. In addition, phenethylamine is a substrate for MAO-B, and treatment with MAOIs that inhibit MAO-B such as phenelzine have been shown to consistently and significantly elevate its concentrations.

Phenelzine usually requires six to eight weeks of treatment, and a minimum dose of 60 mg/day, to achieve therapeutic effects. The reason for the delay in therapeutic effect is not fully understood, but it is believed to be due to many factors, including achieving steady-state levels of MAO inhibition and the resulting adaptations in mean neurotransmitter levels, the possibility of necessary desensitisation of autoreceptors which normally inhibit the release of neurotransmitters like serotonin and dopamine, and also the upregulation of enzymes such as serotonin N-acetyltransferase. Typically, a therapeutic response to MAOIs is associated with an inhibition of at least 80-85% of monoamine oxidase activity.

Pharmacokinetics

Phenelzine is administered orally in the form of phenelzine sulfate and is rapidly absorbed from the gastrointestinal tract. Time to peak plasma concentration is 43 minutes and half-life is 11.6 hours. Unlike most other drugs, phenelzine irreversibly disables MAO, and as a result, it does not necessarily need to be present in the blood at all times for its effects to be sustained. Because of this, upon phenelzine treatment being ceased, its effects typically do not actually wear off until the body replenishes its enzyme stores, a process which can take as long as 2-3 weeks.

Phenelzine is metabolised primarily in the liver and its metabolites are excreted in the urine. Oxidation is the primary routine of metabolism, and the major metabolites are phenylacetic acid and parahydroxyphenylacetic acid, recovered as about 73% of the excreted dose of phenelzine in the urine over the course of 96 hours after single doses. Acetylation to N2-acetylphenelzine is a minor pathway. Phenelzine may also interact with cytochrome P450 enzymes, inactivating these enzymes through formation of a heme adduct. Two other minor metabolites of phenelzine, as mentioned above, include phenylethylidenehydrazine and phenethylamine.

Adverse Effects

Common side effects of phenelzine may include dizziness, blurry vision, dry mouth, headache, lethargy, sedation, somnolence, insomnia, anorexia, weight gain or loss, nausea and vomiting, diarrhoea, constipation, urinary retention, mydriasis, muscle tremors, hyperthermia, sweating, hypertension or hypotension, orthostatic hypotension, paraesthesia, hepatitis, and sexual dysfunction (consisting of loss of libido and anorgasmia). Rare side effects usually only seen in susceptible individuals may include hypomania or mania, psychosis and acute liver failure, the last of which is usually only seen in people with pre-existing liver damage, old age, long-term effects of alcohol consumption, or viral infection.

Interactions

The MAOIs have certain dietary restrictions and drug interactions. The amount of such restrictions and interactions is far less than previously thought, and MAOIs are generally safe medications when administered correctly. Hypertensive crisis is generally a rare occurrence while taking MAOIs, yet may result from the overconsumption of tyramine-containing foods. As a result, patients on phenelzine and other MAOIs must avoid excess quantities of certain foods that contain tyramine such as aged cheeses and cured meats, among others. Serotonin syndrome may result from an interaction with certain drugs which increase serotonin activity such as selective serotonin reuptake inhibitors, serotonin releasing agents, and serotonin agonists. Several deaths have been reported due to drug interaction-related serotonin syndrome such as the case of Libby Zion.

As is the case with other MAOIs, there is a concern regarding phenelzine and the use of both local and general anesthetics. Anyone taking phenelzine should inform their dentist before proceeding with dental surgery, and surgeon in any other contexts.

Phenelzine has also been linked to vitamin B6 deficiency. Transaminases such as GABA-transaminase have been shown to be dependent upon vitamin B6 and may be involved in a potentially related process, since the phenelzine metabolite phenylethylidenehydrazine (PEH) is a GABA transaminase inhibitor. Both phenelzine and vitamin B6 are rendered inactive upon these reactions occurring. For this reason, it may be recommended to supplement with vitamin B6 while taking phenelzine. The pyridoxine form of B6 is recommended for supplementation, since this form has been shown to reduce hydrazine toxicity from phenelzine and, in contrast, the pyridoxal form has been shown to increase the toxicity of hydrazines.

What is the Libby Zion Law?

Published on by Andrew Marshall1 Comment

Introduction

New York State Department of Health Code, Section 405, also known as the Libby Zion Law, is a regulation that limits the amount of resident physicians’ work in New York State hospitals to roughly 80 hours per week. The law was named after Libby Zion, who died in 1984 at the age of 18 under the care of what her father believed to be overworked resident physicians and intern physicians. In July 2003, the Accreditation Council for Graduate Medical Education adopted similar regulations for all accredited medical training institutions in the United States.

Although regulatory and civil proceedings found conflicting evidence about Zion’s death, today her death is widely believed to have been caused by serotonin syndrome from the drug interaction between the phenelzine she was taking prior to her hospital visit, and the pethidine administered by a resident physician. The lawsuits and regulatory investigations following her death, and their implications for working conditions and supervision of interns and residents, were highly publicised in both lay media and medical journals.

Death of Libby Zion

Libby Zion (November 1965 to 05 March 1984) was a freshman at Bennington College in Bennington, Vermont. She took a prescribed antidepressant, phenelzine, daily. A hospital autopsy revealed traces of cocaine, but other later tests showed no traces. She was the daughter of Sidney Zion, a lawyer who had been a writer for The New York Times. She had two brothers, Adam and Jed. Her obituary in The New York Times, written the day after her death, stated that she had been ill with a “flu-like ailment” for the past several days. The article stated that after being admitted to New York Hospital, she died of cardiac arrest, the cause of which was not known.

Libby Zion had been admitted to the hospital through the emergency room by the resident physician assigned to the ER on the night of 04 March. Raymond Sherman, the Zion family physician, agreed with their plan to hydrate and observe her. Zion was assigned to two residents, Luise Weinstein and Gregg Stone, who both evaluated her. Weinstein, a first-year resident physician (also referred to as intern or PGY-1), and Stone, a PGY-2 resident, were unable to determine the cause of Zion’s illness, though Stone tentatively suggested that her condition might be a simple overreaction to a normal illness. After consulting with Dr. Sherman, the two prescribed pethidine (meperidine) to control the “strange jerking motions” that Zion had been exhibiting when she was admitted.

Weinstein and Stone were both responsible for covering dozens of other patients. After evaluating Zion, they left. Luise Weinstein went to cover other patients, and Stone went to sleep in an on-call room in an adjacent building. Zion, however, did not improve, and continued to become more agitated. After being contacted by nurses by phone, Weinstein ordered medical restraints be placed on Zion. She also prescribed haloperidol by phone to control the agitation.

Zion finally managed to fall asleep, but by 6:30, her temperature was 107 °F (42 °C). Weinstein was once again called, and measures were quickly taken to try to reduce her temperature. However, before this could be done, Zion had a cardiac arrest and could not be resuscitated. Weinstein informed Zion’s parents by telephone.

Several years had gone by before a general agreement was reached regarding the cause of Zion’s death. Zion had been taking a prescribed antidepressant, phenelzine, before she was admitted to the hospital. The combination of that and the pethidine given to her by Stone and Weinstein contributed to the development of serotonin syndrome, a condition which led to increased agitation. This led Zion to pull on her intravenous tubes, causing Weinstein to order physical restraints, which Zion also fought against. By the time she finally fell asleep, her fever had already reached dangerous levels, and she died soon after of cardiac arrest.

Publicity and Trials

Grieving the loss of their child, Zion’s parents became convinced their daughter’s death was due to inadequate staffing at the teaching hospital. Sidney Zion questioned the staff’s competence for two reasons. The first was the administration of pethidine, which can cause fatal interactions with phenelzine, the antidepressant that Zion was taking. Said interaction was known to few clinicians at the time, though because of this case it is now widely known. The second issue was the use of restraints and emergency psychiatric medication. Sidney’s aggrieved words were: “They gave her a drug that was destined to kill her, then ignored her except to tie her down like a dog.” To the distress of the doctors, Sidney referred to his daughter’s death as a “murder”. Sidney also questioned the long hours that residents worked at the time. In a New York Times op-ed piece, he wrote: “You don’t need kindergarten to know that a resident working a 36-hour shift is in no condition to make any kind of judgment call—forget about life-and-death.” The case eventually became a protracted high-profile legal battle, with multiple abrupt reversals; case reports about it appeared in major medical journals.

State Investigation

In May 1986, Manhattan District Attorney Robert Morgenthau agreed to let a grand jury consider murder charges, an unusual decision for a medical malpractice case. Although the jury declined to indict for murder, in 1987 the intern and resident were charged with 38 counts of gross negligence and/or gross incompetence. The grand jury considered that a series of mistakes contributed to Zion’s death, including the improper prescription of drugs and the failure to perform adequate diagnostic tests. Under New York law, the investigative body for these charges was the Hearing Committee of the State Board for Professional Medical Conduct. Between April 1987 and January 1989, the committee conducted 30 hearings at which 33 witnesses testified, including expert witnesses in toxicology, emergency medicine, and chairmen of internal medicine departments at six prominent medical schools, several of whom stated under oath that they had never heard of the interaction between meperidine and phenelzine prior to this case. At the end of these proceedings, the committee unanimously decided that none of the 38 charges against the two residents were supported by evidence. Its findings were accepted by the full board, and by the state’s Health Commissioner, David Axelrod.

Under New York law, however, the final decision in this matter rested with another body, the Board of Regents, which was under no obligation to consider either the Commissioner’s or the Hearing Committee’s recommendations. The Board of Regents, which at the time had only one physician among its 16 members, voted to “censure and reprimand” the resident physicians for acts of gross negligence. This decision did not affect their right to practice. The verdict against the two residents was considered very surprising in medical circles. In no other case had the Board of Regents overruled the Commissioner’s recommendation. The hospital also admitted it had provided inadequate care and paid a $13,000 fine to the state. In 1991, however, the state’s appeals court completely cleared the records of the two doctors of findings that they had provided inadequate care to Zion.

Civil Trial

In parallel with the state investigation, Sidney Zion also filed a separate civil case against the doctors and the hospital. The civil trial came to a close in 1995 when a Manhattan jury found that the two residents and Libby Zion’s primary care doctor contributed to her death by prescribing the wrong drug, and ordered them to pay a total of $375,000 to Zion’s family for her pain and suffering. The jury also found that Raymond Sherman, the primary care physician, had lied on the witness stand in denying he knew that Libby Zion was to be given pethidine. Although the jury found the three doctors negligent, none of them were found guilty of “wanton” negligence, i.e. demonstrating utter disregard for the patient, as opposed to a simple mistake. Payouts for wanton negligence would not have been covered by the doctors’ malpractice insurance.

The emergency room physician, Maurice Leonard, as well as the hospital (as legal persona) were found not responsible for Zion’s death in the civil trial. The jury decided that the hospital was negligent for leaving Weinstein alone in charge of 40 patients that night, but they also concluded that this negligence did not directly contribute to Zion’s death. The trial was shown on Court TV.

Law and Regulations

After the grand jury’s indictment of the two residents, Axelrod decided to address the systemic problems in residency by establishing a blue-ribbon panel of experts headed by Bertrand M. Bell, a primary care physician at the Albert Einstein College of Medicine in the Bronx. Bell was well known for his critical stance regarding the lack of supervision of physicians-in-training. Formally known as the Ad Hoc Advisory Committee on Emergency Services, and more commonly known as the Bell Commission, the committee evaluated the training and supervision of doctors in the state, and developed a series of recommendations that addressed several patient-care issues, including restraint usage, medication systems, and resident work hours.

“In 1989, New York state adopted the Bell Commission’s recommendations that residents could not work more than 80 hours a week or more than 24 consecutive hours” and that attending physicians “needed to be physically present in the hospital at all times. Hospitals instituted so-called night floats, doctors who worked overnight to spell their colleagues, allowing them to adhere to the new rules.” Periodic follow-up audits have prompted the New York State Department of Health to crack down on violating hospitals. Similar limits have since been adopted in numerous other states. In July 2003 the Accreditation Council for Graduate Medical Education (ACGME) adopted similar regulations for all accredited medical training institutions in the United States.