The British Pharmacopoeia (BP) is the national pharmacopoeia of the United Kingdom (UK). It is an annually published collection of quality standards for medicinal substances in the UK, which is used by individuals and organisations involved in pharmaceutical research, development, manufacture and testing.
Pharmacopoeial standards are publicly available and legally enforceable standards of quality for medicinal products and their constituents. The British Pharmacopoeia is an important statutory component in the control of medicines, which complements and assists the licensing and inspection processes of the UK’s Medicines and Healthcare products Regulatory Agency (MHRA). Together with the British National Formulary (BNF), the British Pharmacopoeia defines the UK’s pharmaceutical standards.
Pharmacopoeial standards are compliance requirements; that is, they provide the means for an independent judgement as to the overall quality of an article, and apply throughout the shelf-life of a product. Inclusion of a substance in a pharmacopoeia does not indicate that it is either safe or effective for the treatment of any disease.
Legal Basis
The British Pharmacopoeia is published on behalf of the Health Ministers of the United Kingdom; on the recommendation of the Commission on Human Medicines, in accordance with section 99(6) of the Medicines Act 1968, and notified in draft to the European Commission (EC) in accordance with Directive 98/34/EEC.
The monographs of the European Pharmacopoeia (as amended by Supplements published by the Council of Europe) are reproduced either in the British Pharmacopoeia, or in the associated edition of the British Pharmacopoeia (Veterinary).
In the pharmacopoeia, certain drugs and preparations are included regardless of the existence of actual or potential patent rights. Where substances are protected by letters patent, their inclusion in the pharmacopoeia neither conveys, nor implies, licence to manufacture.
Brief History
The regulation of medicinal products by officials in the United Kingdom dates back to the reign of King Henry VIII (1491-1547). The Royal College of Physicians of London had the power to inspect apothecaries’ products in the London area, and to destroy defective stock. The first list of approved drugs, with information on how they should be prepared, was the London Pharmacopoeia, published in 1618. The first edition of what is now known as the British Pharmacopoeia was published in 1864, and was one of the first attempts to harmonise pharmaceutical standards, through the merger of the London, Edinburgh and Dublin Pharmacopoeias. The New Latin name that had some currency at the time was Pharmacopoeia Britannica (Ph. Br.).
In 1844, concern about the dangers of unregulated manufacture and use led William Flockhart – who had provided chloroform to Doctor (later Sir) James Young Simpson for his experiment on anaesthesia – to recommend the creation of a ‘Universal Phamacopoeia for Great Britain’ in his inaugural speech as president of the Northern British branch of the Pharmaceutical Society.
A commission was first appointed by the General Medical Council (GMC), when the body was made statutorily responsible under the Medical Act 1858 for producing a British pharmacopoeia on a national basis. In 1907, the British Pharmacopoeia was supplemented by the British Pharmaceutical Codex, which gave information on drugs and other pharmaceutical substances not included in the BP, and provided standards for these.
The Medicines Act 1968 established the legal status of the British Pharmacopoeia Commission, and of the British Pharmacopoeia, as the UK standard for medicinal products under section 4 of the Act. The British Pharmacopoeia Commission continues the work of the earlier Commissions appointed by the GMC, and is responsible for preparing new editions of the British Pharmacopoeia and the British Pharmacopoeia (Veterinary), and for keeping them up to date. Under Section 100 of the Medicines Act, the Commission is also responsible for selecting and devising British Approved Names.
Since its first publication in 1864, the distribution of the British Pharmacopoeia has grown throughout the world and it is now used in over 100 countries. Australia and Canada are two of the countries that have adopted the BP as their national standard; in other countries, such as South Korea, the BP is recognised as an acceptable reference standard.
Content
The current edition of the British Pharmacopoeia comprises six volumes, which contain nearly 3,000 monographs for drug substances, excipients, and formulated preparation, together with supporting general notices, appendices (test methods, reagents etc.), and reference spectra, used in the practice of medicine, all comprehensively indexed and cross-referenced for easy reference. Items used exclusively in veterinary medicine in the UK are included in the BP (Veterinary).
The British Pharmacopoeia is available as a printed volume and electronically in both on-line and CD-ROM versions; the electronic products use sophisticated search techniques to locate information quickly. For example, pharmacists referring to a monograph can immediately link to other related substances and appendices referenced in the content by using 130,000+ hypertext links within the text.
Production
The British Pharmacopoeia is prepared by the Pharmacopoeial Secretariat, working in collaboration with the British Pharmacopoeia Laboratory, the British Pharmacopoeia Commission (BPC), and its Expert Advisory Groups (EAG) and Advisory Panels. The development of pharmacopoeial standards receives input from relevant industries, hospitals, academia, professional bodies and governmental sources, both within and outside the UK.
The British Pharmacopoeia Laboratory provides analytical and technical support to the British Pharmacopoeia. Its major functions are:
Development of new pharmacopoeial monographs: the laboratory undertakes the development and validation of qualitative and quantitative test methods for new BP monograph specifications, and refines and revalidates test methods for existing British Pharmacopoeia monographs.
British Pharmacopoeia Chemical Reference Substances (BPCRS): the laboratory is responsible for the procurement, establishment, maintenance and sale of BPCRS. The catalogue currently contains nearly 500 BPCRS, which are needed as standards for monograph tests in both the British Pharmacopoeia and the British Pharmacopoeia (Veterinary).
The current edition of the British Pharmacopoeia is available from The Stationery Office Bookshop.
Guidance
Detailed information and guidance on various aspects of current pharmacopoeial policy and practice is provided in supplementary chapters of the British Pharmacopoeia. This includes explanation of the basis of pharmacopoeial specifications, and information on the development of monographs including guidance to manufacturers.
British Approved Names (BANs) are devised or selected by the British Pharmacopoeia Commission (BPC), and published by the Health Ministers, on the recommendation of the Commission on Human Medicines, to provide a list of names of substances or articles referred to in Section 100 of the Medicines Act 1968. BANs are short, distinctive names for substances, where the systematic chemical or other scientific names are too complex for convenient general use.
As a consequence of Directive 2001/83/EC, as amended, the British Approved Names, since 2002, may be assumed to be the recommended International Non-proprietary Name (rINN), except where otherwise stated. A World Health Organisation (WHO) INN identifies a pharmaceutical substance or active pharmaceutical ingredient by a unique name that is globally recognised, and in which no party can claim any proprietary rights. A non-proprietary name is also known as a generic name.
The British National Formulary (BNF) and its related publications contain information on prescribing, indications, side effects and costs of all medication available on the National Health Service.
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Pharmacists – also known as chemists (Commonwealth English) or druggists (North American and, archaically, Commonwealth English) – are health professionals who control, formulate, preserve and dispense medications and provide advice and counselling on how medicines should be used to achieve maximum benefit, minimal side effects and to avoid drug interactions.
They also serve as primary care providers in the community. Pharmacists undergo university or graduate-level education to understand the biochemical mechanisms and actions of drugs, drug uses, therapeutic roles, side effects, potential drug interactions, and monitoring parameters. This is mated to anatomy, physiology, and pathophysiology. Pharmacists interpret and communicate this specialised knowledge to patients, physicians, and other health care providers.
Among other licensing requirements, different countries require pharmacists to hold either a Bachelor of Pharmacy, Master of Pharmacy, or Doctor of Pharmacy degree.
The most common pharmacist positions are that of a community pharmacist (also referred to as a retail pharmacist, first-line pharmacist or dispensing chemist), or a hospital pharmacist, where they instruct and counsel on the proper use and adverse effects of medically prescribed drugs and medicines. In most countries, the profession is subject to professional regulation. Depending on the legal scope of practice, pharmacists may contribute to prescribing (also referred to as “pharmacist prescriber”) and administering certain medications (e.g. immunisations) in some jurisdictions. Pharmacists may also practice in a variety of other settings, including industry, wholesaling, research, academia, formulary management, military, and government.
Nature of Work
Historically, the fundamental role of pharmacists as a healthcare practitioner was to check and distribute drugs to doctors for medication that had been prescribed to patients. In more modern times, pharmacists advise patients and health care providers on the selection, dosages, interactions, and side effects of medications, and act as a learned intermediary between a prescriber and a patient. Pharmacists monitor the health and progress of patients to ensure the safe and effective use of medication. Pharmacists may practice compounding; however, many medicines are now produced by pharmaceutical companies in a standard dosage and drug delivery form. In some jurisdictions, pharmacists have prescriptive authority to either independently prescribe under their own authority or in collaboration with a primary care physician through an agreed upon protocol called a collaborative practice agreement.
Increased numbers of drug therapies, aging but more knowledgeable and demanding populations, and deficiencies in other areas of the health care system seem to be driving increased demand for the clinical counselling skills of the pharmacist. One of the most important roles that pharmacists are currently taking on is one of pharmaceutical care. Pharmaceutical care involves taking direct responsibility for patients and their disease states, medications, and management of each to improve outcomes. Pharmaceutical care has many benefits that may include but are not limited to: decreased medication errors; increased patient compliance in medication regimen; better chronic disease state management, including hypertension and other cardiovascular disease risk factors; strong pharmacist–patient relationship; and decreased long-term costs of medical care.
Pharmacists are often the first point-of-contact for patients with health inquiries. Thus pharmacists have a significant role in assessing medication management in patients, and in referring patients to physicians. These roles may include, but are not limited to:
Clinical medication management, including reviewing and monitoring of medication regimens.
Assessment of patients with undiagnosed or diagnosed conditions, and ascertaining clinical medication management needs.
Specialised monitoring of disease states, such as dosing drugs in kidney and liver failure.
Compounding medicines.
Providing pharmaceutical information.
Providing patients with health monitoring and advice, including advice and treatment of common ailments and disease states.
Supervising pharmacy technicians and other staff.
Oversight of dispensing medicines on prescription.
Provision of and counselling about non-prescription or over-the-counter drugs.
Education and counselling for patients and other health care providers on optimal use of medicines (e.g. proper use, avoidance of overmedication).
Referrals to other health professionals if necessary.
Pharmacokinetic evaluation.
Promoting public health by administering immunisations.
Constructing drug formularies.
Designing clinical trials for drug development.
Working with federal, state, or local regulatory agencies to develop safe drug policies.
Ensuring correctness of all medication labels including auxiliary labels.
Member of inter-professional care team for critical care patients.
Symptom assessment leading to medication provision and lifestyle advice for community-based health concerns (e.g. head colds, or smoking cessation).
The role of pharmacy education, pharmacist licensing, and continuing education vary from country to country and between regions/localities within countries. In most countries, pharmacists must obtain a university degree at a pharmacy school or related institution, and/or satisfy other national/local credentialing requirements. In many contexts, students must first complete pre-professional (undergraduate) coursework, followed by about four years of professional academic studies to obtain a degree in pharmacy (such as Doctorate of Pharmacy). In the European Union, pharmacists are required to hold a Masters of Pharmacy, which allows them to practice in any other EU country, pending professional examinations and language tests in the country in which they want to practice. Pharmacists are educated in pharmacology, pharmacognosy, chemistry, organic chemistry, biochemistry, pharmaceutical chemistry, microbiology, pharmacy practice (including drug interactions, medicine monitoring, medication management), pharmaceutics, pharmacy law, pathophysiology, physiology, anatomy, pharmacokinetics, pharmacodynamics, drug delivery, pharmaceutical care, nephrology, hepatology, and compounding of medications. Additional curriculum may cover diagnosis with emphasis on laboratory tests, disease state management, therapeutics and prescribing (selecting the most appropriate medication for a given patient).
Upon graduation, pharmacists are licensed, either nationally or regionally, to dispense medication of various types in the areas they have trained for.
Some may undergo further specialised training, such as in cardiology or oncology. Specialties include:
Academic pharmacist.
Clinical pharmacy specialist.
Community pharmacist.
Compounding pharmacist.
Consultant pharmacist.
Drug information pharmacist.
Home health pharmacist.
Hospital pharmacist.
Industrial pharmacist.
Informatics pharmacist.
Managed care pharmacist.
Military pharmacist.
Nuclear pharmacist.
Oncology pharmacist.
Regulatory-affairs pharmacist.
Veterinary pharmacist.
Pharmacist clinical pathologist.
Pharmacist clinical.
Training and Practice by Country
Armenia
The Ministry of Education and Ministry of Health oversee pharmacy school accreditation in Armenia. Pharmacists are expected to have competency in the WHO Model List of Essential Medicines (EML), the use of Standard Treatment Guidelines, drug information, clinical pharmacy, and medicine supply management. There are currently no laws requiring pharmacists to be registered, but all pharmacies must have a license to conduct business. According to a World Health Organisation (WHO) report from 2010, there are 0.53 licensed pharmacists and 7.82 licensed pharmacies per 10,000 people in Armenia. Pharmacists are able to substitute for generic equivalents at point of dispensing.
Australia
The Australian Pharmacy Council is the independent accreditation agency for Australian pharmacists. The accreditation standards for Australian pharmacy degrees include compulsory clinical placements, with an emphasis on encouraging rural experiences to develop a rural workforce. It conducts examinations on behalf of the Pharmacy Board of Australia towards eligibility for registration. The Australian College of Pharmacy provides continuing education programmes for pharmacists. The number of full-time equivalent pharmacists working in Australia over the past decade has remained stable. Pharmacy practice is described by the practice standards and guidelines including those from the Pharmaceutical Society of Australia.
Wages for pharmacists in Australia appear to have stagnated, and even gone backwards. As of 2007, the award wages for a pharmacist is $812 a week. Pharmacist graduates are the lowest paid university graduates most years. Most pharmacists do earn above the award wage; the average male pharmacist earns $65,000, a female pharmacist averages $56,500. Contract and casual work is becoming more common. A contract pharmacist is self-employed and often called a locum; these pharmacists may be hired for one shift or for a longer period of time. There are accounts of underemployment and unemployment emerging recently.
Canada
The Canadian Pharmacists Association (CPhA) is the national professional organisation for pharmacists in Canada. Specific requirements for practice vary across provinces, but generally include a bachelor’s (BSc Pharm) or Doctor of Pharmacy (PharmD) degree from one of 10 Canadian universities offering a pharmacy programme, successful completion of a national board examination through the Pharmacy Examining Board of Canada (PEBC) (Quebec being the exception), practical experience through an apprenticeship/internship programme, and fluency in French or English. International pharmacy graduates can begin their journey of becoming licensed to practice in Canada by enrolling with the National Association of Pharmacy Regulatory Authorities (NAPRA) Pharmacists’ Gateway Canada. The vast majority (~70%) of Canada’s licensed pharmacists work in community pharmacies, another 15% work in hospital, and the remainder work in other settings such as industry, government, or universities. Pharmacists’ scope of practice varies widely among the 13 provinces and territories and continues to evolve with time. As a result of pharmacists’ expanding scope and knowledge application, there has been a purposeful effort to transition the professional programs in Canadian pharmacy schools to offer doctors of pharmacy over baccalaureate curriculums to ensure graduates have the most up to date level of training to match the increasing practice requirements.
Germany
In Germany, the education and training is divided into three sections, each ending with a state examination:
University: Basic studies (at least four semesters).
University: Main studies (at least four semesters).
Community Pharmacy / Hospital Pharmacy / Industry: Practical training (12 months; 6 months in a Community Pharmacy).
After the third state examination a person must become licensed as an RPh (“registered pharmacist”) for a licence to practice pharmacy. Today, many pharmacists work as employees in public pharmacies. They will be paid according to the labour agreement of Adexa and employer associations.
Japan
Brief History
In ancient Japan, the men who fulfilled roles similar to pharmacists were respected. The place of pharmacists in society was settled in the Taihō Code (701) and re-stated in the Yōrō Code (718). Ranked positions in the pre-Heian Imperial court were established; and this organisational structure remained largely intact until the Meiji Restoration (1868). In this highly stable hierarchy, the pharmacists – and even pharmacist assistants – were assigned status superior to all others in health-related fields such as physicians and acupuncturists. In the Imperial household, the pharmacist was even ranked above the two personal physicians of the Emperor.
Contemporary
As of 1997, 46 universities of pharmacy in Japan graduated about 8000 students annually. Contemporary practice of clinical pharmacists in Japan (as evaluated in September 2000) focuses on dispensing of drugs, consultation with patients, supplying drug information, advising on prescription changes and amending prescriptions. These practices have been linked to decreases in the average number of drugs in prescriptions, drug costs and incidence of adverse drug events.
Nigeria
Training to become a registered pharmacist in Nigeria involves a five-year course after six years of secondary/high school or four years after eight years of secondary/high school (i.e. after two (2) years of Advanced-level studies in accredited Universities). The degree awarded by most pharmacy schools is a Bachelor of Pharmacy Degree (B.Pharm.) However, in the near future, all schools will offer a 6-year first Degree course leading to the award of a Pharm.D (Doctor of Pharmacy Degree). The University of Benin has started the Pharm.D programme with other pharmacy schools planning to start soon. The Pharmacy Degree in Nigeria is unclassified i.e. awarded without first class, second class upper, etc., however graduates could be awarded Pass with Distinctions in specific fields such as Pharmaceutics, Pharmacology, medicinal chemistry etc. Pharmacy Graduates are required to undergo one (1) year of Tutelage under the supervision of an already Registered Pharmacist(a preceptor) in a recognised and designated Institution before they can become Registered Pharmacists. The Profession is Regulated by a Government Statutory body called the Pharmacists Council of Nigeria. The West African Post Graduate College of Pharmacy runs post-registration courses on advanced-level practice in various fields of pharmacy. It is a college jointly funded by a number of Countries in the West Africa sub-region. There are thousands of Nigerian-trained pharmacists registered and practicing in countries such as the US, the UK, Canada etc., due to the relatively poor public sector salaries in Nigeria.
Pakistan
In Pakistan, the Pharm.D. (Doctor of Pharmacy) degree is a graduate-level professional doctorate degree. Twenty-one universities are registered with the Pharmacy Council of Pakistan for imparting Pharmacy courses. In 2004 the Higher Education Commission of Pakistan and the Pharmacy Council of Pakistan revised the syllabus and changed the 4-year B.Pharmacy (Bachelor of Pharmacy) Programme to a 5-year Pharm.D. (Doctor of Pharmacy) programme. All 21 universities have started the 5-year Pharm.D Programme. In 2011 the Pharmacy Council of Pakistan approved the awarding of a Doctor of Pharmacy degree, a five-year programme at the Department of Pharmacy, University of Peshawar.
Poland
Polish pharmacists have to complete a 5+1⁄2-year Master of Pharmacy Programme at medical university and obtain the right to practice as a pharmacist in Poland from District Pharmaceutical Council. The Programme includes 6 months of pharmacy training. The Polish name for the Master of Pharmacy Degree (M.Pharm.) is magister farmacji (mgr farm). Not only pharmacists, but also pharmaceutical technicians are allowed to dispense prescription medicines, except for narcotics, psychotropics and very potent medicines. Pharmacists approve prescriptions fulfilled by pharmaceutical technicians subsequently. Pharmaceutical technicians have to complete 2 years of post-secondary occupational school and 2 years of pharmacy training afterwards. Pharmacists are eligible to prescribe medicines in exceptional circumstances. All Polish pharmacies are obliged to produce compound medicines. Most pharmacists in Poland are pharmacy managers and are responsible for pharmacy marketing in addition to traditional activities. To become a pharmacy manager in Poland, a pharmacist is expected to have at least 5 years of professional experience. All pharmacists in Poland have to maintain an adequate knowledge level by participating in various university- and industry-based courses and arrangements or by undergoing postgraduate specialisation.
Sweden
In Sweden, the national board of health and welfare regulates the practice of all legislated health care professionals, and is also responsible for registration of pharmacists in the country. The education to become a licensed pharmacist is regulated by the European Union, and states that minimum educational requirements are five years of university studies in a pharmacy programme, of which six months must be a pharmacy internship. To be admitted to pharmacy studies, students must complete a minimum of three years of gymnasium, similar to high school (school for about 15 to 20-year-old students) program in natural science after elementary school (6 to 16-year-olds). Only three universities in the whole of Sweden offer a pharmacy education, Uppsala University, where the Faculty of Pharmacy is located, the University of Gothenburg, and Umeå University. In Sweden, pharmacists are called Apotekare. At pharmacies in Sweden, pharmacists work together with another class of legislated health care professionals called Receptarier, in English so-called prescriptionists, who have completed studies equal to a Bachelor of Science in pharmacy, i.e. three years of university. Prescriptionists also have dispensing rights in Sweden, Norway, Finland and Iceland. The majority of the staff in a pharmacy are Apotekstekniker or “pharmacy technicians” with a three -semester education at a vocational college. Pharmacy technicians do not have dispensing rights in Sweden but are allowed to advise on and sell over-the-counter medicines.
Switzerland
In Switzerland, the federal office of public health regulates pharmacy practice. Four Swiss universities offer a major in pharmaceutical studies, the University of Basel, the University of Geneva, the University of Lausanne and the ETH Zurich. To major in pharmaceutical studies takes at least five years. Students spend their last year as interns in a pharmacy combined with courses at the university, with focus on the validation of prescriptions and the manufacturing of pharmaceutical formulations. Since all public health professions are regulated by the government it is also necessary to acquire a federal diploma in order to work in a pharmacy. It is not unusual for pharmaceutical studies majors to work in other fields such as the pharmaceutical industry or in hospitals. Pharmacists work alongside pharma assistants, an apprenticeship that takes three years to complete. Pharmacists can further specialise in various fields; this is organised by PharmaSuisse, the pharmacists’ association of Switzerland.
Tanzania
In Tanzania, pharmacy practice is regulated by the national Pharmacy Board, which is also responsible for registration of pharmacists in the country. By international standards, the density of pharmacists is very low, with a mean of 0.18 per 10,000 population. The majority of pharmacists are found in urban areas, with some underserved regions having only 2 pharmacists per region. According to 2007-2009 data, the largest group of pharmacists was employed in the public sector (44%). Those working in private retail pharmacies were 23%, and the rest were mostly working for private wholesalers, pharmaceutical manufacturers, in academia/teaching, or with faith-based or non-governmental facilities. The salaries of pharmacists varied significantly depending on the place of work. Those who worked in the academia were the highest paid followed by those who worked in the multilateral non-governmental organisations. The public sector including public retail pharmacies and faith based organisations paid much less. The Ministry of Health salary scale for medical doctors was considerably higher than that of pharmacists despite having a difference of only one year of training.
Trinidad and Tobago
In Trinidad and Tobago, pharmacy practice is regulated by the Pharmacy Board of Trinidad and Tobago, which is responsible for the registration of pharmacists in the twin islands. The University of the West Indies in St. Augustine offers a 4-year Bachelor of Science in Pharmacy as the sole practicing degree of pharmacy. Graduates undertake a 6-month internship, known as pre-registration, under the supervision of a registered pharmacist, at a pharmacy of their choosing, whether community or institutional. After completion of the required pre-registration period, the graduate can then apply to the Pharmacy Board to become a registered pharmacist. After working one (1) calendar year as a registered pharmacist, the individual can become a registered, responsible pharmacist. Being a registered, responsible pharmacist allows the individual to license a pharmacy and be a pharmacist-in-charge.
United Kingdom
In British English (and to some extent Australian English), the professional title known as “pharmacist” is also known as “dispensing chemist” or, more commonly, “chemist”. A dispensing chemist usually operates from a pharmacy or chemist’s shop, and is allowed to fulfil medical prescriptions and sell over-the-counter drugs and other health-related goods. Pharmacists can undertake additional training to allow them to prescribe medicines for specific conditions.
Practices
In the United Kingdom, most pharmacists working in the National Health Service practice in hospital pharmacy or community pharmacy. The Royal Commission on the National Health Service in 1979 reported that there were nearly 3,000 pharmacists employed in the hospital and community health service in the UK at that time. They were enthusiastic about the idea that pharmacists might develop their role of giving advice to the public.
The new professional role for pharmacist as prescriber has been recognised in the UK since May 2006, called the “Pharmacist Independent Prescriber”. Once qualified, a pharmacist independent prescriber can prescribe any licensed medicine for any medical condition within their competence. This includes controlled drugs except schedule 1 and prescribing certain drugs for the treatment of addiction (cocaine, diamorphine and dipipanone).
Education and Registration
Pharmacists, pharmacy technicians and pharmacy premises in the United Kingdom are regulated by the General Pharmaceutical Council (GPhC) for England, Scotland and Wales and by the Pharmaceutical Society of Northern Ireland for Northern Ireland. The role of regulatory and professional body on the mainland was previously carried out by the Royal Pharmaceutical Society of Great Britain, which remained as a professional body after handing over the regulatory role to the GPhC in 2010.
The following criteria must be met for qualification as a pharmacist in the United Kingdom (the Northern Irish body and the GPhC operate separately but have broadly similar registration requirements):
Successful completion of a 4-year Master of Pharmacy degree at a GPhC accredited university. Pharmacists holding degrees in Pharmacy from overseas institutions are able to fulfil this stage by undertaking the Overseas Pharmacist Assessment Programme (OSPAP), which is a one-year postgraduate diploma. On completion of the OSPAP, the candidate would proceed with the other stages of the registration process in the same manner as a UK student.
Completion of a 52-week preregistration training period. This is a period of paid or unpaid employment, in an approved hospital or community pharmacy under the supervision of a pharmacist tutor. During this time the student must collect evidence of having met certain competency standards set by the GPhC.
A pass mark in the GPhC registration assessment (formally an exam). This includes a closed-book paper and an open-book/mental calculations paper (using the British National Formulary and the GPhC’s “Standards of Conduct, Ethics and Performance” document as reference sources). The student must achieve an overall mark of 70%, which must include at least 70% in the calculations section of the open-book paper. From June 2016, the assessment will involve two papers, as before but the use of a calculator will now be allowed. However, reference sources will no longer be allowed in the assessment. Instead, relevant extracts of the British National Formulary will be provided within the assessment paper.
Satisfactorily meeting the GPhC’s Fitness to Practice Standards.
United States
In 2014 the United States Bureau of Labour Statistics revealed that there were 297,100 American pharmacist jobs. By 2024 that number is projected to grow by 3%. The majority (65%) of those pharmacists work in retail settings, mostly as salaried employees but some as self-employed owners. About 22% work in hospitals, and the rest mainly in mail-order or Internet pharmacies, pharmaceutical wholesalers, practices of physicians, and the Federal Government.
All graduating pharmacists must now obtain the Doctor of Pharmacy (Pharm.D.) degree before they are eligible to sit for the North American Pharmacist Licensure Examination (NAPLEX) to enter into pharmacy practice. In addition, pharmacists are subject to state-level jurisprudence exams in order to practice from state to state.
Pharmacy School Accreditation
The Accreditation Council for Pharmacy Education (ACPE) has operated since 1932 as the accrediting body for schools of pharmacy in the United States. The mission of ACPE is “To assure and advance excellence in education for the profession of pharmacy”. ACPE is recognised for the accreditation of professional degree programmes by the United States Department of Education (USDE) and the Council for Higher Education Accreditation (CHEA). Since 1975, ACPE has also been the accrediting body for continuing pharmacy education. The ACPE board of directors are appointed by the American Association of Colleges of Pharmacy (AACP), the American Pharmacists Association (APhA), the National Association of Boards of Pharmacy (NABP) (three appointments each), and the American Council on Education (one appointment). To obtain licensure in the United States, applicants for the North American Pharmacist Licensure Examination (NAPLEX) must graduate from an ACPE accredited school of pharmacy. ACPE publishes standards that schools of pharmacy must comply with to gain accreditation.
A Pharmacy school pursuing accreditation must first apply and be granted Pre-candidate status. These schools have met all the requirements for accreditation, but have not yet enrolled any students. This status indicates that the school of pharmacy has developed its programme in accordance with the ACPE standards and guidelines. Once a school has enrolled students, but has not yet had a graduating class, they may be granted Candidate status. The expectations of a Candidate programme are that they continue to mature in accordance with stated plans. The graduates of a Candidate programme are the same as those of fully accredited programmes. Full accreditation is granted to a programme once they have demonstrated they comply with the standards set forth by ACPE.
The customary review cycle for established accredited programmes is six years, whereas for programmes achieving their initial accreditation this cycle is two years. These are comprehensive on-site evaluations of the programmes. Additional evaluations may be conducted at the discretion of ACPE in the interim between comprehensive evaluations.
Education
Acceptance into a doctorate of pharmacy program depends upon completing specific prerequisites or obtaining a transferable bachelor’s degree. Pharmacy school is four years of graduate school (accelerated Pharmacy Schools go January to January and are only 3 years), which include at least one year of practical experience. Graduates receive a Doctorate of Pharmacy (PharmD) upon graduation. Most schools require students to take a Pharmacy College Admissions Test PCAT and complete 90 credit hours of university coursework in the sciences, mathematics, composition, and humanities before entry into the PharmD program. Due to the large admittance requirements and highly competitive nature of the field, most pharmacy students complete a bachelor’s degree before entry to pharmacy school.
Possible prerequisites:
Anatomy.
Physiology.
Biochemistry.
Biology.
Immunology.
Chemical engineering.
Economics.
Pathophysiology.
Physics.
Humanities.
Microbiology.
Molecular biology.
Organic chemistry.
Physical chemistry.
Statistics.
Calculus.
Besides taking classes, additional requirements before graduating may include a certain number of hours for community service, e.g. working in hospitals, clinics, and retail.
Estimated timeline: 4 years undergraduate + 4 years doctorate + 1–2 years residency + 1–3 years fellowship = 8 to 13 years.
A doctorate of pharmacy (except non-traditional, i.e. transferring a license from another country) is the only degree accepted by the National Associate of Boards of Pharmacy NABP to be eligible to “sit” for the North American Pharmacist Licensure Examination (NAPLEX). Previously the United States had a 5-year bachelor’s degree in pharmacy. For BS Pharmacy graduates currently licensed in US, there are 10 Universities offering non-traditional doctorate degree programmes via part-time, weekend or on-line programmes. These are programs fully accredited by Accreditation Council for Pharmacy Education (ACPE) but only available to current BS Pharmacy graduates with a license to practice pharmacy. Some institutions still offer 6 year accelerated PharmD programmes.
The current Pharm.D. degree curriculum is considerably different from that of the prior BS in pharmacy. It now includes extensive didactic clinical preparation, a full year of hands-on practice experience in a wider array of healthcare settings, and a greater emphasis on clinical pharmacy practice pertaining to pharmacotherapy optimisation. Legal requirements in the US to becoming a pharmacist include: graduating from an accredited PharmD programme, conducting a specified number of internship hours under a licensed pharmacist (i.e. 1,800 hours in some states), passing the NAPLEX, and passing a Multi-state Pharmacy Jurisprudence Exam MPJE. Arkansas, California, and Virginia have their own exams instead of the MPJE; in those states, pharmacists must pass the Arkansas Jurisprudence Exam, the California Jurisprudence Exam, or the Virginia Pharmacy Law Exam.
Residency is an option for post-graduates that is typically 1-2 years in length. A residency gives licensed pharmacists decades of clinical experience in an extremely condensed timeframe of only a few short years. In order for new graduates to remain competitive, employers generally favour residency trained applicants for clinical positions. The profession is moving toward resident-trained pharmacists who wish to provide direct patient care clinical services. In 1990, the American Association of Colleges of Pharmacy (AACP) required the new professional degree. Graduates from a PharmD program may also elect to do a fellowship that is geared toward research. Fellowships can varying in length but last 1-3 years depending on the programme and usually require one (1) year of residency at minimum.
Specialisation and Credentialing
American pharmacists can become certified in recognized specialty practice areas by passing an examination administered by one of several credentialing boards.
The Board of Pharmacy Specialties certifies pharmacists in thirteen specialties:
Ambulatory care pharmacy.
Cardiology pharmacy.
Compounded sterile preparations pharmacy.
Critical care pharmacy.
Geriatric pharmacy.
Infectious diseases pharmacy.
Nuclear pharmacy.
Nutrition support pharmacy.
Oncology pharmacy.
Paediatric pharmacy.
Pharmacotherapy.
Psychiatric pharmacy.
Solid organ transplant pharmacy.
The American Board of Applied Toxicology certifies pharmacists and other medical professionals in applied toxicology.
Vaccinations
As of 2016, all 50 states and the District of Columbia permit pharmacists to provide vaccination services, but specific protocols vary between states.
California
All licensed California pharmacists can perform the following:
Order and interpret drug therapy related tests.
Furnish smoking cessation aids (such as nicotine replacement therapy).
Furnish oral self-administered contraception (birth control pills).
Furnish travel medications recommended by the CDC.
Administer vaccinations pursuant to the latest CDC standards for anyone ages 3+.
The passage of Assembly Bill 1535 (2014) authorises pharmacists in California to furnish naloxone without a physician’s prescription.
With the passage of Senate Bill 159 in 2019, pharmacists in California are authorised to furnish pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) to patients without a physician’s prescription. In order to be eligible to dispense, a pharmacists must first “complete a training program approved by the” California State Board of Pharmacy.
California pharmacists can apply for Advanced Practice Pharmacist (APh) licenses from the California State Board of Pharmacy. Senate Bill 493, written by Senator Ed Hernandez, established a section on the Advanced Practice Pharmacist and outlines the definition, scope of practice, qualifications, and regulations of those holding this license. An APh can:
Perform patient assessments.
Refer patients to other healthcare providers.
Participate in the evaluation and management of diseases and health conditions in collaboration with other health care providers.
Initiate, adjust, or discontinue therapy pursuant to the regulations outlined in the bill.
To qualify for an advanced practice pharmacist license in California, the applicant must be in good standing with the State Board of pharmacy, have an active pharmacist license, and fulfil two of three requirements, including certification in their area clinical practice. The license must be renewed every 2 years, and the APh applying for renewal must complete 10 hours of continuing education in at least one area relevant to their clinical practice.
Vietnam
School students must take a national exam to enter a university of pharmacy or the pharmacy department of a university of medicine and pharmacy. About 5-7% of students can pass the exam. There are 3 aspects to the exam. These are on math, chemistry, and physics or biology. After being trained at the university for 5 years, successful students receive a bachelor’s degree in pharmacy. Or they are university pharmacists (university pharmacist to discriminate between college pharmacist or vocational pharmacist in some countries of the world these trainee pharmacists are called pharmacist assistants). An alternative method of obtaining a bachelor’s degree is as follows. School pupils study at a college of pharmacy or a vocational school of pharmacy. After attending the school or college they go to work in a pharmacy, and with two years of practice they could take an exam to enter university of pharmacy or the pharmacy department of a university of medicine and pharmacy. This exam is easier than the national one. Passing the exam they continue studying to gain 3-year bachelor’s degrees or 4-year bachelor’s degrees. This degree is considered equivalent to a 5-year bachelor’s degree.
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A British Approved Name (BAN) is the official, non-proprietary, or generic name given to a pharmaceutical substance, as defined in the British Pharmacopoeia (BP).
The BAN is also the official name used in some countries around the world, because starting in 1953, proposed new names were evaluated by a panel of experts from WHO in conjunction with the BP commission to ensure naming consistency worldwide (an effort leading to the International Nonproprietary Name system).
There is also a British Approved Name (Modified) (BANM).
Combination Preparations
BANs are unique in that names are assigned for combination preparations as well as single-drug preparations. For example, the BAN Co-amoxiclav is assigned to preparations containing amoxicillin and clavulanic acid. Most other pharmacopoeias simply refer to combination products by both ingredients in the preparation, in this example “amoxicillin with clavulanic acid”.
The prefix of “co-” is used for many combination drugs, including opioid with paracetamol or aspirin analgesics (e.g. Co-codamol, Co-codaprin, Co-dydramol, Co-proxamol). The other commonly encountered opioid combination is the anti-diarrhoeal, non-analgesic mixture of diphenoxylate and atropine, Co-phenotrope (aka Lomotil). Also antibiotics (e.g. Co-fluampicil and Co-trimoxazole), drugs to lower blood pressure (e.g. Co-tenidone), diuretics (e.g. Co-amilofruse and Co-amilozide), gastrointestinal drugs (e.g. Co-danthrusate), and anti-Parkinsonism agents such as Co-careldopa, Co-beneldopa, and others (e.g. Co-cyprindiol).
BAN Harmonisation
European Union legislation from 2001 required harmonisation of the BP with the European Pharmacopoeia (EP), as well as the adoption of International Nonproprietary Names through directives (2001/82/EC and 2001/83/EC, as amended, and 2003/63/EC). Across the EU has meant that, with the notable exception of adrenaline/epinephrine, BANs are now the same as the INNs. For example, the old BAN methicillin was replaced with the current BAN meticillin, matching the INN.
This has resulted in an interesting situation in other countries that use BANs. While the British Pharmacopoeia and BANs are the official pharmacopoeia/names defined by legislation in many of these countries, the former BANs often continue to be used, purportedly because of the difficulty of changeover. Despite the importance of the BP, there appears to be little or no movement in the direction of changing these names. In Australia, the Australian Approved Names are generally the same as BANs, but a few exceptions remain.
This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/British_Approved_Name >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.
Clozapine is a psychiatric medication and is the first atypical antipsychotic (also called second-generation antipsychotic). It is primarily used to treat people with schizophrenia and schizoaffective disorders who have had an inadequate response to other antipsychotics or who have been unable to tolerate other drugs due to extrapyramidal side effects. It is also used for the treatment of psychosis in Parkinson’s disease. Clozapine is regarded as the gold-standard treatment when other medication has been insufficiently effective and its use is recommended by multiple international treatment guidelines, after resistance to earlier neuroleptic treatment is established.
The role of clozapine in treatment-resistant schizophrenia was established by a 1988 landmark study in which clozapine showed marked benefits compared to chlorpromazine in a group of patients with protracted psychosis who had already shown an inadequate response to other antipsychotics. While there are significant side effects, clozapine remains the most effective treatment when one or more other antipsychotics have had an inadequate response. The use of clozapine is associated with multiple improved outcomes, including a reduced rate of all-cause mortality, suicide and hospitalisation. In a 2013 network comparative meta-analysis of 15 antipsychotic drugs, clozapine was found to be significantly more effective than all other drugs. In a 2021 UK study, the majority of patients (over 85% of respondents) who took clozapine preferred it to their previous therapies, felt better on it and wanted to keep taking it. In a 2000 Canadian survey of 130 patients, the majority reported better satisfaction, quality of life, compliance with treatment, thinking, mood, and alertness.
Compared to other antipsychotics, clozapine has an increased risk of blood dyscrasias, in particular agranulocytosis, in the first 18 weeks of treatment. After one year, this risk reduces to that associated with most antipsychotics. Clozapine’s use is therefore reserved for people who have not responded to two other antipsychotics and is only done with stringent blood monitoring. Overall, despite the concerns relating to blood and other side effects, clozapine use is associated with a reduced mortality, especially from suicide which is a major cause of premature death in people with schizophrenia. The risk of clozapine related agranulocytosis and neutropenia warranted the mandatory use of stringent risk monitoring and management systems, which have reduced the risk of death from these adverse events to around 1 in 7,700. The association between clozapine use and specific bloods dyscrasias was first noted in the 1970s when eight deaths from agranulocytosis were noted in Finland. At the time it was not clear if this exceeded the established rate of this side effect which is also found in other antipsychotics and although the drug was not completely withdrawn, its use became limited. Clozapine became widely available in the early 1990s and remains the only treatment likely to be effective in treating resistant schizophrenia.
Common adverse effects include drowsiness, constipation, hypersalivation (increased saliva production), tachycardia, low blood pressure, blurred vision, weight gain, and dizziness. Clozapine is not normally associated with tardive dyskinesia (TD) and is recommended as the drug of choice when this is present, although some case reports describe clozapine-induced TD. Other serious risks include seizures, inflammation of the heart, high blood sugar levels, constipation. The use of this drug can rarely result in clozapine-induced gastric hypomotility syndrome which may lead to bowel obstruction and death, and in older people with psychosis, as a result of dementia it may lead to an increased risk of death. The mechanism of action is not entirely clear in the current medical literature. Clozapine is on the World Health Organization’s List of Essential Medicines. It is available as a generic medication.
Brief History
Clozapine was synthesized in 1958 by Wander AG, a Swiss pharmaceutical company, based on the chemical structure of the tricyclic antidepressant imipramine. The first test in humans in 1962 was considered a failure. Trials in Germany in 1965 and 1966 as well as a trial in Vienna in 1966 were successful. In 1967 Wander AG was acquired by Sandoz. Further trials took place in 1972 when clozapine was released in Switzerland and Austria as Leponex. Two years later it was released in West Germany and in Finland in 1975. Early testing was performed in the United States around the same time. In 1975, 16 cases of agranulocytosis leading to 8 deaths in clozapine-treated patients, reported from 6 hospitals mostly in southwestern Finland, led to concern. Analysis of the Finnish cases revealed that all the agranulocytosis cases had occurred within the first 18 weeks of treatment and the authors proposed blood monitoring during this period. The rate of agranulocytosis in Finland appeared to be 20 times higher than in the rest of the world and there was speculation that this may have been due a unique genetic diversity in the region. Whilst the drug continued to be manufactured by Sandoz, and remained available in Europe, development in the US halted.
Interest in clozapine continued in an investigational capacity in the United States because, even in the 1980s, the duration of hospitalisation, especially in State Hospitals for those with treatment resistant schizophrenia might often be measured in years rather than days. The role of clozapine in treatment resistant schizophrenia was established by the landmark Clozaril Collaborative Study Group Study #30 in which clozapine showed marked benefits compared to chlorpromazine in a group of patients with protracted psychosis and who had already shown an inadequate response to other antipsychotics. This involved both stringent blood monitoring and a double-blind design with the power to demonstrate superiority over standard antipsychotic treatment. The inclusion criteria were patients who had failed to respond to at least three previous antipsychotics and had then not responded to a single blind treatment with haloperidol (mean dose 61 mg +/- 14 mg/d). Two hundred and sixty-eight were randomised were to double blind trials of clozapine (up to 900 mg/d) or chlorpromazine (up to 1800 mg/d). 30% of the clozapine patients responded compared to 4% of the controls, with significantly greater improvement on the Brief Psychiatric Rating Scale, Clinical Global Impression Scale, and Nurses’ Observation Scale for Inpatient Evaluation; this improvement included “negative” as well as positive symptom areas. Following this study, the US Food and Drug Administration (FDA) approved its use in 1990. Cautious of this risk, however, the FDA required a black box warning for specific side effects including agranulocytosis, and took the unique step of requiring patients to be registered in a formal system of tracking so that blood count levels could be evaluated on a systematic basis.
In December 2002, clozapine was approved in the US for reducing the risk of suicide in people with schizophrenia or schizoaffective judged to be at chronic risk for suicidal behaviour. In 2005, the FDA approved criteria to allow reduced blood monitoring frequency. In 2015, the individual manufacturer Patient Registries were consolidated by request of the FDA into a single shared Patient Registry Called The Clozapine REMS Registry. Despite the demonstrated safety of the new FDA monitoring requirements, which have lower neutrophil levels and do not include total white cell counts, international monitoring has not been standardised.
Chemistry
Clozapine is a dibenzodiazepine that is structurally very similar to loxapine (originally deemed a typical antipsychotic). It is slightly soluble in water, soluble in acetone, and highly soluble in chloroform. Its solubility in water is 0.1889 mg/L (25 °C).[3] Its manufacturer, Novartis, claims a solubility of <0.01% in water (<100 mg/L).
Clinical Uses
Schizophrenia
Clozapine is usually used for people diagnosed with schizophrenia who have had an inadequate response to other antipsychotics or who have been unable to tolerate other drugs due to extrapyramidal side effects. It is also used for the treatment of psychosis in Parkinson’s Disease. It is regarded as the gold-standard treatment when other medication has been insufficiently effective and its use is recommended by multiple international treatment guidelines, supported by systematic reviews and meta-analysis. Whilst all current guidelines reserve clozapine to individuals when two other antipsychotics evidence indicates that clozapine might be used as a second line drug. Clozapine treatment has been demonstrated to produced improved outcomes in multiple domains including; a reduced risk of hospitalisation, a reduced risk of drug discontinuation, a reduction in overall symptoms and has improved efficacy in the treatment of positive psychotic symptoms of schizophrenia. Despite a range of side effects patients report good levels of satisfaction and long term adherence is favourable compared to other antipsychotics. Very long term follow-up studies reveal multiple benefits in terms of reduced mortality, with a particularly strong effect for reduced death by suicide, clozapine is the only antipsychotic known to have an effect reducing the risk of suicide or attempted suicide. Clozapine has a significant anti-aggressive effect. Clozapine is widely used in secure and forensic mental health settings where improvements in aggression, shortened admission and reductions in restrictive practice such as seclusion have been found. In secure hospitals and other settings clozapine has also been used in the treatment of borderline and antisocial personality disorder when this has been associated with violence or self-harm. Although oral treatment is almost universal clozapine has on occasion been enforced using either nasogastric or a short acting injection although in almost 50% of the approximately 100 reported cases patients agreed to take oral medication prior to the use of a coercive intervention. Clozapine has also been used off-label to treat catatonia with success in over 80% of cases.
Bipolar Disorder
On the basis of systematic reviews clozapine is recommended in some treatment guidelines as a third or fourth line treatment for bipolar disorder. Bipolar disorder is an unlicensed indication for clozapine.
Severe Personality Disorders
Clozapine is also used in emotionally unstable personality disorder and a randomised controlled trial is currently underway. The use of clozapine to treat personality disorder is uncommon and unlicensed.
Initiation
Whilst clozapine is usually initiated in hospital setting community initiation is also available. Before clozapine can be initiated multiple assessments and baseline investigations are performed. In the UK and Ireland there must be an assessment that the patient satisfies the criteria for prescription; treatment resistant schizophrenia, intolerance due to extrapyramidal symptoms of other antipsychotics or psychosis in Parkinson’s disease. Establishing a history of treatment resistance may include careful review of the medication history including the durations, doses and compliance of previous antipsychotic therapy and that these did not have an adequate clinical effect. A diagnostic review may also be performed. That could include review of antipsychotic plasma concentrations if available. The prescriber, patient, pharmacy and the laboratory performing blood counts are all registered with a specified clozapine provider who must be advised that there is no history of neutropenia from any cause. The clozapine providers collaborate by sharing information regarding patients who have had clozapine related neutropenia or agranulocytosis so that clozapine cannot be used again on license. Clozapine may only be dispensed after a satisfactory blood result has been received by the risk monitoring agency at which point an individual prescription may be released to an individual patient only.
Baseline tests usually also include; a physical examination including baseline weight, waist circumference and BMI, assessments of renal function and liver function, an ECG and other baseline bloods may also be taken to facilitate monitoring of possible myocarditis, these might include C reactive protein (CRP) and troponin. In Australia and New Zealand pre-clozapine echocardiograms are also commonly performed. A number of service protocols are available and there are variations in the extent of preclozapine work ups. Some might also include fasting lipids, HbA1c and prolactin. At the Maudsley Hospital in the UK the Treat service also routinely performs a wide variety of other investigations including multiple investigations for other causes of psychosis and comorbidities including; MRI brain imaging, thyroid function tests, B12, folate and serum calcium levels, infection screening for blood borne viruses including Hepatitis B and C, HIV and syphilis as well as screening for autoimmune psychosis by anti-NMDA, anti-VGKC and Anti-nuclear Antibody screening. Investigations used to monitor the possibility of clozapine related side effects such as myocarditis are also performed including baseline troponin, CRP and BNP and for neuroleptic malignant syndrome CK.
The dose of clozapine is initially low and gradually increased over a number of weeks. Initial doses may range from 6.5 to 12.5 mg/d increasing stepwise typically to doses in the range of 250-350 mg per day at which point an assessment of response will be performed. In the UK the average clozapine dose is 450 mg/d. But response is highly variable and some patients respond at much lower doses and vice versa.
Monitoring
During the initial dose titration phase the following are typically monitored; usually daily at first; pulse, blood pressure and since orthostatic hypotension can be problematic this should be monitored both sitting and standing. If there is a significant drop then the rate of the dose increase may be slowed, temperature.
Weekly tests include; Mandatory full blood counts are performed weekly for the first 18 weeks. In some services there will also be monitoring of markers that might indicate myocarditis; troponin, CRP and BNP although the exact tests and frequency vary between services. Weight is usually measured weekly.
Thereon other investigations and monitoring will always include full blood counts (fortnightly for 1 year then monthly). Weight, waist circumference, lipids and glucose or HbA1c may also be monitored.
Clozapine Response and Treatment Optimisation
As with other antipsychotics, and in contrast to received wisdom, responses to clozapine are typically seen soon after initiation and often within the first week. That said responses, especially those which are partial, can be delayed. Quite what an adequate trial of clozapine is, is uncertain but a recommendation is that this should be for at least 8 weeks on a plasma trough level above 350-400 micro g/L. There is considerable inter-individual variation. A significant number of patients respond at lower and also much higher plasma concentrations and some patients, especially young male smokers may never achieve these plasma levels even at doses of 900 mg/day. Options then include either increasing the dose above the licensed maximum or the addition of a drug that inhibits clozapine metabolism. Avoiding unnecessary polypharmacy is a general principle in drug treatment.
Optimising Blood Sampling
The neutrophil cut off for clozapine have shown an exceptional ability to mitigate the risk of neutropenia and agranulocytosis. There is a significant margin of safety. Some patients may have marginal neutrophil counts before and after initiation and they are at risk of premature clozapine discontinuation. A knowledge of neutrophil biology allows blood sampling optimisation. Neutrophils show a diurnal variation in response to the natural cycle of G-CSF production, they are increased in the afternoons, they are also mobilised into the circulation after exercise and smoking. Simply shifting blood sampling has been shown to avoid unnecessary discontinuations, especially in black populations. However this is a disruption to usual hospital practice. Other practical steps are to ensure that blood results become available in hours and when senior staff are available.
Underuse of Clozapine
Clozapine is widely recognised as being underused with wide variation in prescribing, especially in patients with African heritage.
Psychiatrists prescribing practices have been found to be the most significant variable regarding variance in its use. Surveys of psychiatrists attitudes to clozapine have found that many had little experience in its use, over estimated the incidence and were fearful of side effects, and did not appreciate that many patients prefer to take clozapine than other antipsychotics, are reluctant to prescribe clozapine, had little experience in its use and believed that patients treated with clozapine were less satisfied than those treated with other antipsychotics. In contrast to many psychiatrists expectations most patients believe that the blood testing and other difficulties are worth the multiple benefits that they perceive. Whilst psychiatrists fear the severe adverse effects such as agranulocytosis, patients are more concerned about hypersalivation. Clozapine is no longer actively marketed and this may also be one of the explanations for its underuse.
Despite the strong evidence and universal endorsement by national and international treatment guidelines and the experiences of patients themselves, most people eligible for clozapine are not treated with it. A large study in England found that approximately 30% of those eligible for clozapine were being treated with it. Those patients that do start clozapine usually face prolonged delay, multiple episodes of psychosis and treatments such as high dose antipsychotics or polypharmacy. Instead of two previous antipsychotics many will have been exposed to ten or more drugs which were not effective. In a study of 120 patients conducted in four hospitals in South-East London, found a mean of 9.2 episodes of antipsychotic prescription before clozapine was initiated and the mean delay in using clozapine was 5 years. Treatments that have no evidence base or are regarded as actively harmful are used instead multiple and or high-dose treatment.
Racial Disparity in the Use of Clozapine
A general finding in healthcare provision is that minority groups receive inferior treatment; this is a particular finding in the US. In the US a general finding is that compared to their white peers African American people are less likely to be prescribed the second generation antipsychotics, which are more expensive than alternatives and this was even apparent and especially so for clozapine when comparison was made in the Veterans Affairs medical system and when differences regarding socioeconomic factors were taken into account. As well as being less likely to start clozapine black patients are more likely to stop clozapine, possibly on account of benign ethnic neutropenia.
Benign Ethnic Neutropenia
Benign reductions in neutrophils are observed in individuals of all ethnic backgrounds ethnic neutropenia (BEN), neutropenia without immune dysfunction or increased liability to infection is not due to abnormal neutrophil production; although, the exact aetiology of the reduction in circulating cells remains unknown. BEN is associated with several ethnic groups, but in particular those with Black African and West African ancestry. A difficulty with the use of clozapine is that neutrophil counts have been standardised on white populations. For significant numbers of black patients the standard neutrophil count thresholds did not permit clozapine use as the thresholds did not take BEN into account. Since 2002, clozapine monitoring services in the UK have used reference ranges 0.5 × 109/l lower for patients with haematologically confirmed BEN and similar adjustments are available in the current US criteria, although with lower permissible minima. But even then significant numbers of black patients will not be eligible even though the low neutrophil counts do not in their case reflect disease. The Duffy-Null polymorphism, which protects against some types of malaria, is predictive of BEN.
Adverse Effects
Clozapine may cause serious and potentially fatal adverse effects. Clozapine carries five black box warnings, including:
Severe neutropenia (low levels of neutrophils);
Orthostatic hypotension (low blood pressure upon changing positions), including slow heart rate and fainting;
Seizures;
Myocarditis (inflammation of the heart); and
Risk of death when used in elderly people with dementia-related psychosis.
Lowering of the seizure threshold may be dose related. Increasing the dose slowly may decrease the risk for seizures and orthostatic hypotension.
Common effects include constipation, bed-wetting, night-time drooling, muscle stiffness, sedation, tremors, orthostatic hypotension, high blood sugar, and weight gain. The risk of developing extrapyramidal symptoms, such as tardive dyskinesia, is below that of typical antipsychotics; this may be due to clozapine’s anticholinergic effects. Extrapyramidal symptoms may subside somewhat after a person switches from another antipsychotic to clozapine. Sexual problems, like retrograde ejaculation, have been reported while taking clozapine. Despite the risk for numerous side effects, many side effects can be managed while continuing to take clozapine.
Neutropenia and Agranulocytosis
Clozapine Induced Neutropenia (CIN) occurs in approximately 3.8% of cases and Clozapine Induced Agranulocytosis (CIA) in 0.4%. These are potentially serious side effects and agranulocytosis can result in death. To mitigate this risk clozapine is only used with mandatory absolute neutrophil count (ANC) monitoring (neutrophils are the most abundant of the granulocytes); for example, in the United States, the Risk Evaluation and Mitigation Strategy (REMS). The exact schedules and blood count thresholds vary internationally and the thresholds at which clozapine can be used in the US has been lower than those currently used in the UK and Australasia for some time. The effectiveness of the risk management strategies used is such that deaths from these side effects are very rare occurring at approximately 1 in 7,700 patients treated. Almost all the adverse blood reactions occur within the first year of treatment and the majority within the first 18 weeks. After one year of treatment these risks reduce markedly to that seen in other antipsychotic drugs 0.01% or about 1 in 10,000 and the risk of death is markedly lower still. When reductions in neutrophil levels are noted on regular blood monitoring then, depending on the value, monitoring may be increased or, if the neutrophil count is sufficiently low, then clozapine is stopped immediately and can then no longer be used within the medicinal licence. Stopping clozapine almost always results in resolution of the neutrophil reduction. However severe agranulocytosis can result in spontaneous infection and death, is a severe decrease in the amount of a specific kind of white blood cell called granulocytes. Clozapine carries a black box warning for drug-induced agranulocytosis. Rapid point-of-care tests may simplify the monitoring for agranulocytosis.
Clozapine Rechallenge
A clozapine “rechallenge” is when someone that experienced agranulocytosis while taking clozapine starts taking the medication again. In countries in which the neutrophil thresholds are higher than those used in the US a simple approach is, if the lowest ANC had been above the US cut off, to reintroduce clozapine but with the US monitoring regime. This has been demonstrated in a large cohort of patients in a hospital in London in which it was found that of 115 patients who had had clozapine stopped according to the US criteria only 7 would have had clozapine stopped if the US cut offs had been used. Of these 62 were rechallenged, 59 continued to use clozapine without difficulty and only 1 had a fall in neutrophils below the US cut off. Other approaches have included the use of other drugs to support neutrophil counts including lithium or granulocyte colony-stimulating factor (G-CSF). However, if agranulocytosis still occurs during a rechallenge, the alternative options are limited.
Cardiac Toxicity
Clozapine can rarely cause myocarditis and cardiomyopathy. A large meta-analysis of clozapine exposure to over 250,000 people revealed that these occurred in approximately 7 in 1,000 patients treated and resulted in death in 3 and 4 in 10,000 patients exposed respectively and although myocarditis occurred almost exclusively within the first 8 weeks of treatment, cardiomyopathy can occur much later on. First manifestations of illness are fever which may be accompanied by symptoms associated with upper respiratory tract, gastrointestinal or urinary tract infection. Typically C-reactive protein (CRP) increases with the onset of fever and rises in the cardiac enzyme, troponin, occur up to 5 days later. Monitoring guidelines advise checking CRP and troponin at baseline and weekly for the first 4 weeks after clozapine initiation and observing the patient for signs and symptoms of illness. Signs of heart failure are less common and may develop with the rise in troponin. A recent case-control study found that the risk of clozapine-induced myocarditis is increased with increasing rate of clozapine dose titration, increasing age and concomitant sodium valproate. A large electronic health register study has revealed that nearly 90% of cases of suspected clozapine related myocarditis are false positives. Rechallenge after clozapine induced myocarditis has been performed and a protocol for this specialist approach has been published. A systematic review of rechallenge after myocarditis has show success in over 60% of reported cases.
Gastrointestinal Hypomotility
Another under-recognised and potentially life-threatening effect spectrum is gastrointestinal hypomotility, which may manifest as severe constipation, faecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis. Colonic hypomotility has been shown to occur in up to 80% of people prescribed clozapine when gastrointestinal function is measured objectively using radiopaque markers. Clozapine-induced gastrointestinal hypomotility currently has a higher mortality rate than the better known side effect of agranulocytosis. A Cochrane review found little evidence to help guide decisions about the best treatment for gastrointestinal hypomotility caused by clozapine and other antipsychotic medication. Monitoring bowel function and the pre-emptive use of laxatives for all clozapine-treated people has been shown to improve colonic transit times and reduce serious sequelae.
Hypersalivation
Hypersalivation, or the excessive production of saliva, is one of the most common adverse effects of clozapine (30-80%). The saliva production is especially bothersome at night and first thing in the morning, as the immobility of sleep precludes the normal clearance of saliva by swallowing that occurs throughout the day. While clozapine is a muscarinic antagonist at the M1, M2, M3, and M5 receptors, clozapine is a full agonist at the M4 subset. Because M4 is highly expressed in the salivary gland, its M4 agonist activity is thought to be responsible for hypersalivation. Clozapine-induced hypersalivation is likely a dose-related phenomenon, and tends to be worse when first starting the medication. Besides decreasing the dose or slowing the initial dose titration, other interventions that have shown some benefit include systemically absorbed anticholinergic medications such as hyoscine, diphenhydramine and topical anticholinergic medications like ipratropium bromide. Mild hypersalivation may be managed by sleeping with a towel over the pillow at night.
Central Nervous System
CNS side effects include drowsiness, vertigo, headache, tremor, syncope, sleep disturbances, nightmares, restlessness, akinesia, agitation, seizures, rigidity, akathisia, confusion, fatigue, insomnia, hyperkinesia, weakness, lethargy, ataxia, slurred speech, depression, myoclonic jerks, and anxiety. Rarely seen are delusions, hallucinations, delirium, amnesia, libido increase or decrease, paranoia and irritability, abnormal EEG, worsening of psychosis, paraesthesia, status epilepticus, and obsessive compulsive symptoms. Similar to other antipsychotics clozapine rarely has been known to cause neuroleptic malignant syndrome.
Urinary Incontinence
Clozapine is linked to urinary incontinence, though its appearance may be under-recognised.
Withdrawal Effects
Abrupt withdrawal may lead to cholinergic rebound effects, such as indigestion, diarrhoea, nausea/vomiting, overabundance of saliva, profuse sweating, insomnia, and agitation. Abrupt withdrawal can also cause severe movement disorders, catatonia, and psychosis. Doctors have recommended that patients, families, and caregivers be made aware of the symptoms and risks of abrupt withdrawal of clozapine. When discontinuing clozapine, gradual dose reduction is recommended to reduce the intensity of withdrawal effects.
Weight Gain and Diabetes
In addition to hyperglycaemia, significant weight gain is frequently experienced by patients treated with clozapine. Impaired glucose metabolism and obesity have been shown to be constituents of the metabolic syndrome and may increase the risk of cardiovascular disease. The data suggest that clozapine may be more likely to cause adverse metabolic effects than some of the other atypical antipsychotics.
Pneumonia
International adverse drug effect databases indicate that clozapine use is associated with a significantly increased incidence of and death from pneumonia and this may be one of the most significant adverse events. The mechanisms for this are unknown although it has been speculated that it may be related to hypersalivation, immune effects of clozapine’s effects on the resolution of inflammation.
Overdose
Symptoms of overdose can be variable, but often include; sedation, confusion, tachycardia, seizures and ataxia. Fatalities have been reported due to clozapine overdose, though overdoses of greater than 5000 mg have been survived.
Drug Interactions
Fluvoxamine inhibits the metabolism of clozapine leading to significantly increased blood levels of clozapine.
When carbamazepine is concurrently used with clozapine, it has been shown to decrease plasma levels of clozapine significantly thereby decreasing the beneficial effects of clozapine. Patients should be monitored for “decreased therapeutic effects of clozapine if carbamazepine” is started or increased. If carbamazepine is discontinued or the dose of carbamazepine is decreased, therapeutic effects of clozapine should be monitored. The study recommends carbamazepine to not be used concurrently with clozapine due to increased risk of agranulocytosis.
Ciprofloxacin is an inhibitor of CYP1A2 and clozapine is a major CYP1A2 substrate. Randomized study reported elevation in clozapine concentration in subjects concurrently taking ciprofloxacin. Thus, the prescribing information for clozapine recommends “reducing the dose of clozapine by one-third of original dose” when ciprofloxacin and other CYP1A2 inhibitors are added to therapy, but once ciprofloxacin is removed from therapy, it is recommended to return clozapine to original dose.
Pharmacology
Pharmacodynamics
Clozapine is classified as an atypical antipsychotic drug because it binds to serotonin as well as dopamine receptors.
Clozapine is an antagonist at the 5-HT2A subunit of the serotonin receptor, putatively improving depression, anxiety, and the negative cognitive symptoms associated with schizophrenia.
A direct interaction of clozapine with the GABAB receptor has also been shown. GABAB receptor-deficient mice exhibit increased extracellular dopamine levels and altered locomotor behaviour equivalent to that in schizophrenia animal models. GABAB receptor agonists and positive allosteric modulators reduce the locomotor changes in these models.
Clozapine induces the release of glutamate and D-serine, an agonist at the glycine site of the NMDA receptor, from astrocytes, and reduces the expression of astrocytic glutamate transporters. These are direct effects that are also present in astrocyte cell cultures not containing neurons. Clozapine prevents impaired NMDA receptor expression caused by NMDA receptor antagonists.
Pharmacokinetics
The absorption of clozapine is almost complete following oral administration, but the oral bioavailability is only 60 to 70% due to first-pass metabolism. The time to peak concentration after oral dosing is about 2.5 hours, and food does not appear to affect the bioavailability of clozapine. However, it was shown that co-administration of food decreases the rate of absorption. The elimination half-life of clozapine is about 14 hours at steady state conditions (varying with daily dose).
Clozapine is extensively metabolized in the liver, via the cytochrome P450 system, to polar metabolites suitable for elimination in the urine and faeces. The major metabolite, norclozapine (desmethyl-clozapine), is pharmacologically active. The cytochrome P450 isoenzyme 1A2 is primarily responsible for clozapine metabolism, but 2C, 2D6, 2E1 and 3A3/4 appear to play roles as well. Agents that induce (e.g. cigarette smoke) or inhibit (e.g. theophylline, ciprofloxacin, fluvoxamine) CYP1A2 may increase or decrease, respectively, the metabolism of clozapine. For example, the induction of metabolism caused by smoking means that smokers require up to double the dose of clozapine compared with non-smokers to achieve an equivalent plasma concentration.
Clozapine and norclozapine (desmethyl-clozapine) plasma levels may also be monitored, though they show a significant degree of variation and are higher in women and increase with age. Monitoring of plasma levels of clozapine and norclozapine has been shown to be useful in assessment of compliance, metabolic status, prevention of toxicity, and in dose optimisation.
Society and Culture
Economics
Despite the expense of the risk monitoring and management systems required, clozapine use is highly cost effective; with a number of studies suggesting savings of tens of thousands of dollars per patient per year compared to other antipsychotics as well as advantages regarding improvements in quality of life. Clozapine is available as a generic medication.
Clozapine in the Arts
Carrie Mathison, a fictional CIA operative in the television series Homeland, secretly takes clozapine supplied by her sister for the treatment of bipolar disorder.
In the film Out of Darkness, Diana Ross played the protagonist Paulie Cooper, “a paranoid schizophrenic” who is depicted as having a dramatic improvement on clozapine.
In the television series Last Man On Earth (2015) the character Melissa has a psychotic episode and returns home and starts acting how she did pre-pandemic. Her boyfriend Todd sees her take a medication in the morning and asks her what it is. All she will say is “Santas Penis”. Todd searches medication books and finds clozapine = Clause a peen.
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Clorazepate, sold under the brand name Tranxene among others, is a benzodiazepine medication. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. Clorazepate is an unusually long-lasting benzodiazepine and serves as a majoritive prodrug for the equally long-lasting desmethyldiazepam, which is rapidly produced as an active metabolite. Desmethyldiazepam is responsible for most of the therapeutic effects of clorazepate.
It was patented in 1965 and approved for medical use in 1967.
Medical Uses
Clorazepate is used in the treatment of anxiety disorders and insomnia. It may also be prescribed as an anticonvulsant or muscle relaxant. It is also used as a premedication.
Clorazepate is prescribed principally in the treatment of alcohol withdrawal and epilepsy, although it is also a useful anxiolytic because of its long half-life. The normal starting dosage range of Clorazepate is 15 to 60 mg per day. The drug is to be taken two to four times per day. Dosages as high as 90 to 120 mg per day may be used in the treatment of acute alcohol withdrawal. In the United States and Canada, Clorazepate is available in 3.75, 7.5, and 15 mg capsules or tablets. In Europe, tablet formations are 5 mg, 10 mg, 20 mg and 50 mg. Clorazepate SD (controlled release) is available and may have a reduced incidence of adverse effects. The sustained-release formulation of clorazepate has some advantages in that, if a dose is missed, less profound fluctuations in blood plasma levels occur, which may be helpful to some people with epilepsy at risk of break-through seizures.
Adverse Effects
Adverse effects of clorazepate include tolerance, dependence, withdrawal reactions, cognitive impairment, confusion, anterograde amnesia, falls in the elderly, ataxia, hangover effects, and drowsiness. It is unclear whether cognitive deficits resulting from the long-term use of benzodiazepines return to normal or persist indefinitely after withdrawal from benzodiazepines. Benzodiazepines are also known to cause or worsen depression. Paradoxical effects including excitement and paradoxical worsening of seizures can sometimes result from the use of benzodiazepines. Children, the elderly, individuals with a history of alcohol use disorder or a history of aggressive behaviour and anger are at greater risk of developing paradoxical reactions to benzodiazepines.
In September 2020, the US Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of non-medical use, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.
Delirium has been noted from discontinuation from clorazepate. A benzodiazepine dependence occurs in approximately one third of patients who take benzodiazepines for longer than 4 weeks, which is characterised by a withdrawal syndrome upon dose reduction. When used for seizure control, tolerance may manifest itself with an increased rate of seizures as well an increased risk of withdrawal seizures. In humans, tolerance to the anticonvulsant effects of clorazepate occurs frequently with regular use. Due to the development of tolerance, benzodiazepines are, in general, not considered appropriate for the long-term management of epilepsy; increasing the dose may result only in the developing of tolerance to the higher dose combined with worsened adverse effects. Cross-tolerance occurs between benzodiazepines, meaning that, if individuals are tolerant to one benzodiazepine, they will display a tolerance to equivalent doses of other benzodiazepines. Withdrawal symptoms from benzodiazepines include a worsening of pre-existing symptoms as well as the appearance of new symptoms that were not pre-existing. The withdrawal symptoms may range from mild anxiety and insomnia to severe withdrawal symptoms such as seizures and psychosis. Withdrawal symptoms can be difficult in some cases to differentiate between pre-existing symptoms and withdrawal symptoms. Use of high doses, long-term use and abrupt or over-rapid withdrawal increases increase the severity of withdrawal syndrome. However, tolerance to the active metabolite of clorazepate may occur more slowly than with other benzodiazepines. Regular use of benzodiazepines causes the development of dependence characterised by tolerance to the therapeutic effects of benzodiazepines and the development of the benzodiazepine withdrawal syndrome including symptoms such as anxiety, apprehension, tremor, insomnia, nausea, and vomiting upon cessation of benzodiazepine use. Withdrawal from benzodiazepines should be gradual as abrupt withdrawal from high doses of benzodiazepines may cause confusion, toxic psychosis, convulsions, or a condition resembling delirium tremens. Abrupt withdrawal from lower doses may cause depression, nervousness, rebound insomnia, irritability, sweating, and diarrhoea.
Interactions
All sedatives or hypnotics e.g. other benzodiazepines, barbiturates, antiepileptic drugs, alcohol, antihistamines, opioids, neuroleptics, sleep aids are likely to magnify the effects of clorazepate on the central nervous system. Drugs that may interact with clorazepate include, digoxin, disulfiram, fluoxetine, isoniazid, ketoconazole, levodopa, metoprolol, hormonal contraceptives, probenecid, propranolol, rifampin, theophylline, valproic acid. Selective serotonin reuptake inhibitors (SSRI), cimetidine, macrolide antibiotics and antimycotics inhibit the metabolism of benzodiazepines and may result in increased plasma levels with resultant enhancement of adverse effects. Phenytoin, phenobarbital, and carbamazepine have the opposite effect, with coadministration leading to increased metabolism and decreased therapeutic effects of clorazepate.
Contraindications and Special Caution
Benzodiazepines require special precaution if used in the elderly, children, alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders.
Clorazepate if used late in pregnancy, the third trimester, causes a definite risk of severe benzodiazepine withdrawal syndrome in the neonate with symptoms including hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Floppy infant syndrome and sedation in the newborn may also occur. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.
Special precaution is required when using clorazepate in the elderly because the elderly metabolise clorazepate more slowly, which may result in excessive drug accumulation. Additionally the elderly are more sensitive to the adverse effects of benzodiazepines compared to younger individuals even when blood plasma levels are the same. Use of benzodiazepines in the elderly is only recommended for 2 weeks and it is also recommended that half of the usual daily dose is prescribed.
Pharmacology
Clorazepate is a “classical” benzodiazepine. Other classical benzodiazepines include chlordiazepoxide, diazepam, clonazepam, oxazepam, lorazepam, nitrazepam, bromazepam and flurazepam. Clorazepate is a long-acting benzodiazepine drug. Clorazepate produces the active metabolite desmethyl-diazepam, which is a partial agonist of the GABAA receptor and has a half life of 20-179 hours; a small amount of desmethyldiazepam is further metabolised into oxazepam. Clorazepate exerts its pharmacological properties via increasing the opening frequency of the chloride ion channel of GABAA receptors. This effect of benzodiazepines requires the presence of the neurotransmitter GABA and results in enhanced inhibitory effects of the neurotransmitter GABA acting on GABAA receptors. Clorazepate, like other benzodiazepines, is widely distributed and is highly bound to plasma proteins; clorazepate also crosses readily over the placenta and into breast milk. Peak plasma levels of the active metabolite desmethyl-diazepam are seen between 30 minutes and 2 hours after oral administration of clorazepate. Clorazepate is completely metabolised to desmethyl-diazepam in the gastrointestinal tract and thus the pharmacological properties of clorazepate are largely due to desmethyldiazepam.
Chemistry
Clorazepate is used in the form of a dipotassium salt. It is unusual among benzodiazepines in that it is freely soluble in water.
Clorazepate can be synthesized starting from 2-amino-5-chlorobenzonitrile, which upon reaction with phenylmagnesium bromide is transformed into 2-amino-5-chlorbenzophenone imine. Reacting this with aminomalonic ester gives a heterocyclisation product, 7-chloro-1,3-dihydro-3-carbethoxy-5-phenyl-2H-benzodiazepin-2-one. Upon hydrolysis using an alcoholic solution of potassium hydroxide forms a dipotassium salt, chlorazepate.
Legal Status
In the United States, clorazepate is listed under Schedule IV of the Controlled Substances Act.
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Clonazepam, sold under the brand name Klonopin among others, is a medication used to prevent and treat seizures, panic disorder, anxiety, and the movement disorder known as akathisia. It is a tranquiliser of the benzodiazepine class. It is typically taken by mouth. Effects begin within one hour and last between six and twelve hours.
Common side effects include sleepiness, poor coordination, and agitation. Long-term use may result in tolerance, dependence, and withdrawal symptoms if stopped abruptly. Dependence occurs in one-third of people who take clonazepam for longer than four weeks. There is an increased risk of suicide, particularly in people who are already depressed. If used during pregnancy it may result in harm to the foetus. Clonazepam binds to GABAA receptors, thus increasing the effect of the chief inhibitory neurotransmitter γ-aminobutyric acid (GABA).
Clonazepam was patented in 1960 and went on sale in 1975 in the United States from Roche. It is available as a generic medication. In 2019, it was the 46th most commonly prescribed medication in the United States, with more than 15 million prescriptions. In many areas of the world it is commonly used as a recreational drug.
Medical Uses
Clonazepam is prescribed for short term management of epilepsy, anxiety, and panic disorder with or without agoraphobia.
Seizures
Clonazepam, like other benzodiazepines, while being a first-line treatment for acute seizures, is not suitable for the long-term treatment of seizures due to the development of tolerance to the anticonvulsant effects.
Clonazepam has been found effective in treating epilepsy in children, and the inhibition of seizure activity seemed to be achieved at low plasma levels of clonazepam. As a result, clonazepam is sometimes used for certain rare childhood epilepsies; however, it has been found to be ineffective in the control of infantile spasms. Clonazepam is mainly prescribed for the acute management of epilepsies. Clonazepam has been found to be effective in the acute control of non-convulsive status epilepticus; however, the benefits tended to be transient in many people, and the addition of phenytoin for lasting control was required in these patients.
It is also approved for treatment of typical and atypical absences (seizures), infantile myoclonic, myoclonic, and akinetic seizures. A subgroup of people with treatment resistant epilepsy may benefit from long-term use of clonazepam; the benzodiazepine clorazepate may be an alternative due to its slow onset of tolerance.
Anxiety Disorders
Panic disorder with or without agoraphobia.
Clonazepam has also been found effective in treating other anxiety disorders, such as social phobia, but this is an off-label use.
The effectiveness of clonazepam in the short-term treatment of panic disorder has been demonstrated in controlled clinical trials. Some long-term trials have suggested a benefit of clonazepam for up to three years without the development of tolerance but these trials were not placebo-controlled. Clonazepam is also effective in the management of acute mania.
Muscle Disorders
Restless legs syndrome can be treated using clonazepam as a third-line treatment option as the use of clonazepam is still investigational. Bruxism also responds to clonazepam in the short-term. Rapid eye movement sleep behaviour disorder responds well to low doses of clonazepam.
The treatment of acute and chronic akathisia induced by neuroleptics, also called antipsychotics.
Spasticity related to amyotrophic lateral sclerosis.
Alcohol withdrawal syndrome
Other
Benzodiazepines, such as clonazepam, are sometimes used for the treatment of mania or acute psychosis-induced aggression. In this context, benzodiazepines are given either alone, or in combination with other first-line drugs such as lithium, haloperidol, or risperidone. The effectiveness of taking benzodiazepines along with antipsychotic medication is unknown, and more research is needed to determine if benzodiazepines are more effective than antipsychotics when urgent sedation is required.
Hyperekplexia: A very rare neurologic disorder classically characterised by pronounced startle responses to tactile or acoustic stimuli and hypertonia.
Many forms of parasomnia and other sleep disorders are treated with clonazepam..
It is not effective for preventing migraines.
Contraindications
Coma.
Current alcohol use disorder.
Current substance use disorder.
Respiratory depression.
Adverse Effects
In September 2020, the US Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.
Common
Sedation.
Motor impairment.
Less Common
Confusion.
Irritability and aggression.
Psychomotor agitation.
Lack of motivation.
Loss of libido.
Impaired motor function.
Impaired coordination.
Impaired balance.
Dizziness.
Cognitive impairments.
Hallucinations.
Short-term memory loss.
Anterograde amnesia (common with higher doses).
Some users report hangover-like symptoms of drowsiness, headaches, sluggishness, and irritability upon waking up if the medication was taken before sleep.
This is likely the result of the medication’s long half-life, which continues to affect the user after waking up.
While benzodiazepines induce sleep, they tend to reduce the quality of sleep by suppressing or disrupting REM sleep.
After regular use, rebound insomnia may occur when discontinuing clonazepam.
Benzodiazepines may cause or worsen depression.
Occasional
Dysphoria.
Induction of seizures or increased frequency of seizures.
Personality changes.
Behavioural disturbances.
Ataxia.
Rare
Cognitive Euphoria.
Suicide through disinhibition.
Psychosis.
Incontinence.
Liver damage.
Paradoxical behavioural disinhibition (most frequently in children, the elderly, and in persons with developmental disabilities).
Rage.
Excitement.
Impulsivity.
The long-term effects of clonazepam can include depression, disinhibition, and sexual dysfunction.
Drowsiness
Clonazepam, like other benzodiazepines, may impair a person’s ability to drive or operate machinery. The central nervous system depressing effects of the drug can be intensified by alcohol consumption, and therefore alcohol should be avoided while taking this medication. Benzodiazepines have been shown to cause dependence. Patients dependent on clonazepam should be slowly titrated off under the supervision of a qualified healthcare professional to reduce the intensity of withdrawal or rebound symptoms.
Withdrawal-Related
Anxiety.
Irritability.
Insomnia.
Tremors.
Headaches.
Stomach pain.
Hallucinations.
Suicidal thoughts or urges.
Depression.
Fatigue.
Dizziness.
Sweating.
Confusion.
Potential to exacerbate existing panic disorder upon discontinuation.
Seizures similar to delirium tremens (with long-term use of excessive doses).
Benzodiazepines such as clonazepam can be very effective in controlling status epilepticus, but, when used for longer periods of time, some potentially serious side-effects may develop, such as interference with cognitive functions and behaviour. Many individuals treated on a long-term basis develop a dependence. Physiological dependence was demonstrated by flumazenil-precipitated withdrawal. Use of alcohol or other central nervous system (CNS)-depressants while taking clonazepam greatly intensifies the effects (and side effects) of the drug.
A recurrence of symptoms of the underlying disease should be separated from withdrawal symptoms.
Like all benzodiazepines, clonazepam is a GABA-positive allosteric modulator. One-third of individuals treated with benzodiazepines for longer than four weeks develop a dependence on the drug and experience a withdrawal syndrome upon dose reduction. High dosage and long-term use increase the risk and severity of dependence and withdrawal symptoms. Withdrawal seizures and psychosis can occur in severe cases of withdrawal, and anxiety and insomnia can occur in less severe cases of withdrawal. A gradual reduction in dosage reduces the severity of the benzodiazepine withdrawal syndrome. Due to the risks of tolerance and withdrawal seizures, clonazepam is generally not recommended for the long-term management of epilepsies. Increasing the dose can overcome the effects of tolerance, but tolerance to the higher dose may occur and adverse effects may intensify. The mechanism of tolerance includes receptor desensitisation, down regulation, receptor decoupling, and alterations in subunit composition and in gene transcription coding.
Tolerance to the anticonvulsant effects of clonazepam occurs in both animals and humans. In humans, tolerance to the anticonvulsant effects of clonazepam occurs frequently. Chronic use of benzodiazepines can lead to the development of tolerance with a decrease of benzodiazepine binding sites. The degree of tolerance is more pronounced with clonazepam than with chlordiazepoxide. In general, short-term therapy is more effective than long-term therapy with clonazepam for the treatment of epilepsy. Many studies have found that tolerance develops to the anticonvulsant properties of clonazepam with chronic use, which limits its long-term effectiveness as an anticonvulsant.
Abrupt or over-rapid withdrawal from clonazepam may result in the development of the benzodiazepine withdrawal syndrome, causing psychosis characterised by dysphoric manifestations, irritability, aggressiveness, anxiety, and hallucinations. Sudden withdrawal may also induce the potentially life-threatening condition, status epilepticus. Anti-epileptic drugs, benzodiazepines such as clonazepam in particular, should be reduced in dose slowly and gradually when discontinuing the drug to mitigate withdrawal effects. Carbamazepine has been tested in the treatment of clonazepam withdrawal but was found to be ineffective in preventing clonazepam withdrawal-induced status epilepticus from occurring.
Coma can be cyclic, with the individual alternating from a comatose state to a hyper-alert state of consciousness, which occurred in a four-year-old boy who overdosed on clonazepam. The combination of clonazepam and certain barbiturates (for example, amobarbital), at prescribed doses has resulted in a synergistic potentiation of the effects of each drug, leading to serious respiratory depression.
Overdose symptoms may include extreme drowsiness, confusion, muscle weakness, and fainting.
Detection in Biological Fluids
Clonazepam and 7-aminoclonazepam may be quantified in plasma, serum, or whole blood in order to monitor compliance in those receiving the drug therapeutically. Results from such tests can be used to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage. Both the parent drug and 7-aminoclonazepam are unstable in biofluids, and therefore specimens should be preserved with sodium fluoride, stored at the lowest possible temperature and analysed quickly to minimise losses.
Special Precautions
The elderly metabolise benzodiazepines more slowly than younger people and are also more sensitive to the effects of benzodiazepines, even at similar blood plasma levels. Doses for the elderly are recommended to be about half of that given to younger adults and are to be administered for no longer than two weeks. Long-acting benzodiazepines such as clonazepam are not generally recommended for the elderly due to the risk of drug accumulation.
The elderly are especially susceptible to increased risk of harm from motor impairments and drug accumulation side effects. Benzodiazepines also require special precaution if used by individuals that may be pregnant, alcohol- or drug-dependent, or may have comorbid psychiatric disorders. Clonazepam is generally not recommended for use in elderly people for insomnia due to its high potency relative to other benzodiazepines.
Clonazepam is not recommended for use in those under 18. Use in very young children may be especially hazardous. Of anticonvulsant drugs, behavioural disturbances occur most frequently with clonazepam and phenobarbital.
Doses higher than 0.5-1 mg per day are associated with significant sedation.
Clonazepam may aggravate hepatic porphyria.
Clonazepam is not recommended for patients with chronic schizophrenia. A 1982 double-blinded, placebo-controlled study found clonazepam increases violent behaviour in individuals with chronic schizophrenia.
Clonazepam has similar effectiveness to other benzodiazepines at often a lower dose.
Interactions
Clonazepam decreases the levels of carbamazepine, and, likewise, clonazepam’s level is reduced by carbamazepine. Azole antifungals, such as ketoconazole, may inhibit the metabolism of clonazepam. Clonazepam may affect levels of phenytoin (diphenylhydantoin). In turn, Phenytoin may lower clonazepam plasma levels by increasing the speed of clonazepam clearance by approximately 50% and decreasing its half-life by 31%. Clonazepam increases the levels of primidone and phenobarbital.
Combined use of clonazepam with certain antidepressants, anticonvulsants (such as phenobarbital, phenytoin, and carbamazepine), sedative antihistamines, opiates, and antipsychotics, nonbenzodiazepines (such as zolpidem), and alcohol may result in enhanced sedative effects.
Pregnancy
There is some medical evidence of various malformations (for example, cardiac or facial deformations when used in early pregnancy); however, the data is not conclusive. The data are also inconclusive on whether benzodiazepines such as clonazepam cause developmental deficits or decreases in IQ in the developing foetus when taken by the mother during pregnancy. Clonazepam, when used late in pregnancy, may result in the development of a severe benzodiazepine withdrawal syndrome in the neonate. Withdrawal symptoms from benzodiazepines in the neonate may include hypotonia, apnoeic spells, cyanosis, and impaired metabolic responses to cold stress.
The safety profile of clonazepam during pregnancy is less clear than that of other benzodiazepines, and if benzodiazepines are indicated during pregnancy, chlordiazepoxide and diazepam may be a safer choice. The use of clonazepam during pregnancy should only occur if the clinical benefits are believed to outweigh the clinical risks to the foetus. Caution is also required if clonazepam is used during breastfeeding. Possible adverse effects of use of benzodiazepines such as clonazepam during pregnancy include: miscarriage, malformation, intrauterine growth retardation, functional deficits, carcinogenesis, and mutagenesis. Neonatal withdrawal syndrome associated with benzodiazepines include hypertonia, hyperreflexia, restlessness, irritability, abnormal sleep patterns, inconsolable crying, tremors, or jerking of the extremities, bradycardia, cyanosis, suckling difficulties, apnoea, risk of aspiration of feeds, diarrhoea and vomiting, and growth retardation. This syndrome can develop between three days to three weeks after birth and can have a duration of up to several months. The pathway by which clonazepam is metabolised is usually impaired in newborns. If clonazepam is used during pregnancy or breastfeeding, it is recommended that serum levels of clonazepam are monitored and that signs of central nervous system depression and apnoea are also checked for. In many cases, non-pharmacological treatments, such as relaxation therapy, psychotherapy, and avoidance of caffeine, can be an effective and safer alternative to the use of benzodiazepines for anxiety in pregnant women.
Pharmacology
Mechanism of Action
Clonazepam enhances the activity of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the central nervous system to give its anticonvulsant, skeletal muscle relaxant, and anxiolytic effects. It acts by binding to the benzodiazepine site of the GABA receptors, which enhances the electric effect of GABA binding on neurons, resulting in an increased influx of chloride ions into the neurons. This further results in an inhibition of synaptic transmission across the central nervous system.
Benzodiazepines do not have any effect on the levels of GABA in the brain. Clonazepam has no effect on GABA levels and has no effect on gamma-aminobutyric acid transaminase. Clonazepam does, however, affect glutamate decarboxylase activity. It differs from other anticonvulsant drugs it was compared to in a study.
Clonazepam’s primary mechanism of action is the modulation of GABA function in the brain, by the benzodiazepine receptor, located on GABAA receptors, which, in turn, leads to enhanced GABAergic inhibition of neuronal firing. Benzodiazepines do not replace GABA, but instead enhance the effect of GABA at the GABAA receptor by increasing the opening frequency of chloride ion channels, which leads to an increase in GABA’s inhibitory effects and resultant central nervous system depression. In addition, clonazepam decreases the utilisation of 5-HT (serotonin) by neurons and has been shown to bind tightly to central-type benzodiazepine receptors. Because clonazepam is effective in low milligram doses (0.5 mg clonazepam = 10 mg diazepam), it is said to be among the class of “highly potent” benzodiazepines. The anticonvulsant properties of benzodiazepines are due to the enhancement of synaptic GABA responses, and the inhibition of sustained, high-frequency repetitive firing.
Benzodiazepines, including clonazepam, bind to mouse glial cell membranes with high affinity. Clonazepam decreases release of acetylcholine in the feline brain and decreases prolactin release in rats. Benzodiazepines inhibit cold-induced thyroid-stimulating hormone (also known as TSH or thyrotropin) release. Benzodiazepines act via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarisation-sensitive calcium uptake in experimentation on rat brain cell components. This has been conjectured as a mechanism for high-dose effects on seizures in the study.
Clonazepam is a 2′-chlorinated derivative of nitrazepam, which increases its potency due to electron-attracting effect of the halogen in the ortho-position.
Pharmacokinetics
Clonazepam is lipid-soluble, rapidly crosses the blood-brain barrier, and penetrates the placenta. It is extensively metabolised into pharmacologically inactive metabolites, with only 2% of the unchanged drug excreted in the urine. Clonazepam is metabolised extensively via nitroreduction by cytochrome P450 enzymes, including CYP3A4. Erythromycin, clarithromycin, ritonavir, itraconazole, ketoconazole, nefazodone, cimetidine, and grapefruit juice are inhibitors of CYP3A4 and can affect the metabolism of benzodiazepines. It has an elimination half-life of 19-60 hours. Peak blood concentrations of 6.5-13.5 ng/mL were usually reached within 1-2 hours following a single 2 mg oral dose of micronized clonazepam in healthy adults. In some individuals, however, peak blood concentrations were reached at 4-8 hours.
Clonazepam passes rapidly into the central nervous system, with levels in the brain corresponding with levels of unbound clonazepam in the blood serum. Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients.
Clonazepam has plasma protein binding of 85%. Clonazepam passes through the blood-brain barrier easily, with blood and brain levels corresponding equally with each other. The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam. These metabolites are excreted by the kidney.
It is effective for 6-8 hours in children, and 6-12 in adults.
A 2006 US government study of hospital emergency department (ED) visits found that sedative-hypnotics were the most frequently implicated pharmaceutical drug in visits, with benzodiazepines accounting for the majority of these. Clonazepam was the second most frequently implicated benzodiazepine in ED visits. Alcohol alone was responsible for over twice as many ED visits as clonazepam in the same study. The study examined the number of times the non-medical use of certain drugs was implicated in an ED visit. The criteria for non-medical use in this study were purposefully broad, and include, for example, drug abuse, accidental or intentional overdose, or adverse reactions resulting from legitimate use of the medication.
Formulations
Clonazepam was approved in the United States as a generic drug in 1997 and is now manufactured and marketed by several companies.
Clonazepam is available as tablets and orally disintegrating tablets (wafers) an oral solution (drops), and as a solution for injection or intravenous infusion.
Brand Names
It is marketed under the trade name Rivotril by Roche in Argentina, Australia, Austria, Bangladesh, Belgium, Brazil, Bulgaria, Canada, Colombia, Costa Rica, Croatia, the Czech Republic, Denmark, Estonia,[136] Germany, Hungary, Iceland, Ireland, Italy, China, Mexico, the Netherlands, Norway, Portugal, Peru, Pakistan, Romania, Serbia, South Africa, South Korea, Spain, Turkey, and the United States; Emcloz, Linotril and Clonotril in India and other parts of Europe; under the name Riklona in Indonesia and Malaysia; and under the trade name Klonopin by Roche in the United States. Other names, such as Clonoten, Ravotril, Rivotril, Iktorivil, Clonex (Israel), Paxam, Petril, Naze, Zilepam and Kriadex, are known throughout the world.
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Butriptyline, sold under the brand name Evadyne among others, is a tricyclic antidepressant (TCA) that has been used in the United Kingdom and several other European countries for the treatment of depression but appears to no longer be marketed. Along with trimipramine, iprindole, and amoxapine, it has been described as an “atypical” or “second-generation” TCA due to its relatively late introduction and atypical pharmacology. It was very little-used compared to other TCAs, with the number of prescriptions dispensed only in the thousands.
Brief History
Butriptyline was developed by Wyeth, an American pharmaceutical company, and introduced in the United Kingdom in either 1974 or 1975.
Medical Uses
Butriptyline was used in the treatment of depression. It was usually used at dosages of 150-300 mg/day.
Side Effects
Butriptyline is closely related to amitriptyline, and produces similar effects as other TCAs, but its side effects like sedation are said to be reduced in severity and it has a lower risk of interactions with other medications.
Butriptyline has potent antihistamine effects, resulting in sedation and somnolence. It also has potent anticholinergic effects, resulting in side effects like dry mouth, constipation, urinary retention, blurred vision, and cognitive/memory impairment. The drug has relatively weak effects as an alpha-1 blocker and has no effects as a norepinephrine reuptake inhibitor, so is associated with little to no antiadrenergic and adrenergic side effects.
Overdose
Refer to Tricyclic Antidepressant Overdose.
Pharmacology
Pharmacodynamics
In vitro, butriptyline is a strong antihistamine and anticholinergic, moderate 5-HT2 and α1-adrenergic receptor antagonist, and very weak or negligible monoamine reuptake inhibitor. These actions appear to confer a profile similar to that of iprindole and trimipramine with serotonin-blocking effects as the apparent predominant mediator of mood-lifting efficacy.
However, in small clinical trials, using similar doses, butriptyline was found to be similarly effective to amitriptyline and imipramine as an antidepressant, despite the fact that both of these TCAs are far stronger as both 5-HT2 antagonists and serotonin–norepinephrine reuptake inhibitors. As a result, it may be that butriptyline has a different mechanism of action, or perhaps functions as a prodrug in the body to a metabolite with different pharmacodynamics.
Pharmacokinetics
Therapeutic concentrations of butriptyline are in the range of 60-280 ng/mL (204-954 nmol/L). Its plasma protein binding is greater than 90%.
Chemistry
Butriptyline is a tricyclic compound, specifically a dibenzocycloheptadiene, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzocycloheptadiene TCAs include amitriptyline, nortriptyline, and protriptyline. Butriptyline is an analogue of amitriptyline with an isobutyl side chain instead of a propylidene side chain. It is a tertiary amine TCA, with its side chain-demethylated metabolite norbutriptyline being a secondary amine. Other tertiary amine TCAs include amitriptyline, imipramine, clomipramine, dosulepin (dothiepin), doxepin, and trimipramine. The chemical name of butriptyline is 3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-yl)-N,N,2-trimethylpropan-1-amine and its free base form has a chemical formula of C21H27N with a molecular weight of 293.446 g/mol. The drug has been used commercially both as the free base and as the hydrochloride salt. The CAS Registry Number of the free base is 15686-37-0 and of the hydrochloride is 5585-73-9.
Society and Culture
Generic Names
Butriptyline is the English and French generic name of the drug and its International Non-Propriety Name (INN), British Approved Name (BAN), and Denomination Commune Francaise (DCF), while butriptyline hydrochloride is its BANM and (United States Adopted Name (USAN). Its generic name in Latin is butriptylinum, in German is butriptylin, and in Spanish is butriptylina.
Brand Names
Butriptyline has been marketed under the brand names Evadene, Evadyne, Evasidol, and Centrolese.
Availability
Butriptyline has been marketed in Europe, including in the United Kingdom, Belgium, Luxembourg, Austria, and Italy.
This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Butriptyline >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.
Bromazolam (XLI-268) is a triazolobenzodiazepine (TBZD) which was first synthesised in 1976, but was never marketed. It has subsequently been sold as a designer drug, first being definitively identified by the EMCDDA in Sweden in 2016.
Outline
It is the bromo instead of chloro analogue of alprazolam and has similar sedative and anxiolytic effects to it and other benzodiazepines. Bromazolam is a non subtype selective agonist at the benzodiazepine site of GABAA receptors, with a binding affinity of 2.81nM at the α1 subtype, 0.69nM at α2 and 0.62nM at α5.
This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Bromazolam >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.
Aripiprazole, sold under the brand names Abilify and Aristada among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder. Other uses include as an add-on treatment in major depressive disorder (MDD), tic disorders and irritability associated with autism. It is taken by mouth or injection into a muscle. A Cochrane review found low-quality evidence of effectiveness in treating schizophrenia.
In adults, side effects with greater than 10% incidence include weight gain, headache, akathisia, insomnia, and gastro-intestinal effects like nausea and constipation, and lightheadedness. Side effects in children are similar, and include sleepiness, increased appetite, and stuffy nose. A strong desire to gamble, binge eat, shop, and engage in sexual activity may also occur.
Common side effects include vomiting, constipation, sleepiness, dizziness, weight gain and movement disorders. Serious side effects may include neuroleptic malignant syndrome, tardive dyskinesia and anaphylaxis. It is not recommended for older people with dementia-related psychosis due to an increased risk of death. In pregnancy, there is evidence of possible harm to the baby. It is not recommended in women who are breastfeeding. It has not been very well studied in people less than 18 years old. The exact mode of action is not entirely clear but may involve effects on dopamine and serotonin.
Aripiprazole was approved for medical use in the United States in 2002. It is available as a generic medication. In 2019, it was the 101st most commonly prescribed medication in the United States, with more than 6 million prescriptions. Aripiprazole was discovered in 1988 by scientists at the Japanese firm Otsuka Pharmaceutical.
Aripiprazole was discovered by scientists at Otsuka Pharmaceutical and was called OPC-14597. It was first published in 1995. Otsuka initially developed the drug, and partnered with Bristol-Myers Squibb (BMS) in 1999 to complete development, obtain approvals, and market aripiprazole.
It was approved by the US Food and Drug Administration (FDA) for schizophrenia in November 2002, and the European Medicines Agency in June 2004; for acute manic and mixed episodes associated with bipolar disorder on 01 October 2004; as an adjunct for major depressive disorder on 20 November 2007; and to treat irritability in children with autism on 20 November 2009. Likewise it was approved for use as a treatment for schizophrenia by the TGA of Australia in May 2003.
Aripiprazole has been approved by the FDA for the treatment of both acute manic and mixed episodes, in people older than ten years.
In 2006, the FDA required manufacturers to add a black box warning to the label, warning that older people who were given the drug for dementia-related psychosis were at greater risk of death.
In 2007, aripiprazole was approved by the FDA for the treatment of unipolar depression when used adjunctively with an antidepressant medication. That same year, BMS settled a case with the US government in which it paid $515 million; the case covered several drugs but the focus was on BMS’s off-label marketing of aripiprazole for children and older people with dementia.
In 2011 Otsuka and Lundbeck signed a collaboration to develop a depot formulation of apripiprazole.
As of 2013, Abilify had annual sales of US$7 billion. In 2013 BMS returned marketing rights to Otsuka, but kept manufacturing the drug. Also in 2013, Otsuka and Lundbeck received US and European marketing approval for an injectable depot formulation of aripiprazole.
Otsuka’s US patent on aripiprazole expired on 20 October 2014, but due to a paediatric extension, a generic did not become available until 20 April 2015. Barr Laboratories (now Teva Pharmaceuticals) initiated a patent challenge under the Hatch-Waxman Act in March 2007. On 15 November 2010, this challenge was rejected by the US District Court in New Jersey.
Otsuka’s European patent EP0367141 which would have expired on 26 October 2009, was extended by a Supplementary Protection Certificate (SPC) to 26 October 2014. The UK Intellectual Property Office decided on 04 March 2015 that the SPC could not be further extended by six months under Regulation (EC) No 1901/2006. Even if the decision is successfully appealed, protection in Europe will not extend beyond 26 April 2015.
From April 2013 to March 2014, sales of Abilify amounted to almost $6.9 billion.
In April 2015, the FDA announced the first generic versions. In October 2015, aripiprazole lauroxil, a prodrug of aripiprazole that is administered via intramuscular injection once every four to six weeks for the treatment of schizophrenia, was approved by the FDA.
In 2016, BMS settled cases with 42 US states that had charged BMS with off-label marketing to older people with dementia; BMS agreed to pay $19.5 million.
In November 2017, the FDA approved Abilify MyCite, a digital pill containing a sensor intended to record when its consumer takes their medication.
Medical Uses
Aripiprazole is primarily used for the treatment of schizophrenia or bipolar disorder.
Schizophrenia
The 2016 NICE guidance for treating psychosis and schizophrenia in children and young people recommended aripiprazole as a second line treatment after risperidone for people between 15 and 17 who are having an acute exacerbation or recurrence of psychosis or schizophrenia. A 2014 NICE review of the depot formulation of the drug found that it might have a role in treatment as an alternative to other depot formulations of second generation antipsychotics for people who have trouble taking medication as directed or who prefer it.
A 2014 Cochrane review comparing aripiprazole and other atypical antipsychotics found that it is difficult to determine differences as data quality is poor. A 2011 Cochrane review comparing aripiprazole with placebo concluded that high dropout rates in clinical trials, and a lack of outcome data regarding general functioning, behaviour, mortality, economic outcomes, or cognitive functioning make it difficult to definitively conclude that aripiprazole is useful for the prevention of relapse. A Cochrane review found only low quality evidence of effectiveness in treating schizophrenia. Accordingly, part of its methodology on quality of evidence is based on quantity of qualified studies.
A 2013 review found that it is in the middle range of 15 antipsychotics for effectiveness, approximately as effective as haloperidol and quetiapine and slightly more effective than ziprasidone, chlorpromazine, and asenapine, with better tolerability compared to the other antipsychotic drugs (4th best for weight gain, 5th best for extrapyramidal symptoms, best for prolactin elevation, 2nd best for QTc prolongation, and 5th best for sedation). The authors concluded that for acute psychotic episodes aripiprazole results in benefits in some aspects of the condition.
In 2013 the World Federation of Societies for Biological Psychiatry recommended aripiprazole for the treatment of acute exacerbations of schizophrenia as a Grade 1 recommendation and evidence level A.
The British Association for Psychopharmacology similarly recommends that all persons presenting with psychosis receive treatment with an antipsychotic, and that such treatment should continue for at least 1-2 years, as “There is no doubt that antipsychotic discontinuation is strongly associated with relapse during this period”. The guideline further notes that “Established schizophrenia requires continued maintenance with doses of antipsychotic medication within the recommended range (Evidence level A)”.
The British Association for Psychopharmacology and the World Federation of Societies for Biological Psychiatry suggest that there is little difference in effectiveness between antipsychotics in prevention of relapse, and recommend that the specific choice of antipsychotic be chosen based on each person’s preference and side effect profile. The latter group recommends switching to aripiprazole when excessive weight gain is encountered during treatment with other antipsychotics
Bipolar Disorder
Aripiprazole is effective for the treatment of acute manic episodes of bipolar disorder in adults, children, and adolescents. Used as maintenance therapy, it is useful for the prevention of manic episodes, but is not useful for bipolar depression. Thus, it is often used in combination with an additional mood stabiliser; however, co-administration with a mood stabiliser increases the risk of extrapyramidal side effects.
Major Depression
Aripiprazole is an effective add-on treatment for major depressive disorder; however, there is a greater rate of side effects such as weight gain and movement disorders. The overall benefit is small to moderate and its use appears to neither improve quality of life nor functioning. Aripiprazole may interact with some antidepressants, especially selective serotonin reuptake inhibitors (SSRIs). There are interactions with fluoxetine and paroxetine and lesser interactions with sertraline, escitalopram, citalopram, and fluvoxamine, which inhibit CYP2D6, for which aripiprazole is a substrate. CYP2D6 inhibitors increase aripiprazole concentrations to 2-3 times their normal level.
Autism
Short-term data (8 weeks) shows reduced irritability, hyperactivity, inappropriate speech, and stereotypy, but no change in lethargic behaviours. Adverse effects include weight gain, sleepiness, drooling and tremors. It is suggested that children and adolescents need to be monitored regularly while taking this medication, to evaluate if this treatment option is still effective after long-term use and note if side effects are worsening. Further studies are needed to understand if this drug is helpful for children after long term use.
Tic Disorders
Aripiprazole is approved for the treatment of Tourette’s syndrome. It is effective, safe, and well-tolerated for this use per systematic reviews and meta-analyses
Obsessive-Compulsive Disorder
A 2014 systematic review and meta-analysis concluded that add-on therapy with low dose aripiprazole is an effective treatment for obsessive-compulsive disorder (OCD) that does not improve with selective serotonin reuptake inhibitors (SSRIs) alone. The conclusion was based on the results of two relatively small, short-term trials, each of which demonstrated improvements in symptoms. Risperidone, another second-generation antipsychotic, appears to be superior to aripiprazole for this indication, and is recommended by the 2007 American Psychiatric Association guidelines. However, aripiprazole is cautiously recommended by a 2017 review on antipsychotics for OCD. Aripiprazole is not currently approved for the treatment of OCD and is instead used off-label for this indication.
Adverse Effects
In adults, side effects with greater than 10% incidence include weight gain, headache, akathisia, insomnia, and gastro-intestinal effects like nausea and constipation, and lightheadedness. Side effects in children are similar, and include sleepiness, increased appetite, and stuffy nose. A strong desire to gamble, binge eat, shop, and engage in sexual activity may also occur.
Uncontrolled movement such as restlessness, tremors, and muscle stiffness may occur.
Discontinuation
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.
There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.
Overdose
Children or adults who ingested acute overdoses have usually manifested central nervous system depression ranging from mild sedation to coma; serum concentrations of aripiprazole and dehydroaripiprazole in these people were elevated by up to 3-4 fold over normal therapeutic levels; as of 2008 no deaths had been recorded.
Interactions
Aripiprazole is a substrate of CYP2D6 and CYP3A4. Coadministration with medications that inhibit (e.g. paroxetine, fluoxetine) or induce (e.g. carbamazepine) these metabolic enzymes are known to increase and decrease, respectively, plasma levels of aripiprazole.
Precautions should be taken in people with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics along with other medications that affect blood sugar levels and should be monitored regularly for worsening of glucose control. The liquid form (oral solution) of this medication may contain up to 15 grams of sugar per dose.
Antipsychotics like aripiprazole and stimulant medications, such as amphetamine, are traditionally thought to have opposing effects to their effects on dopamine receptors: stimulants are thought to increase dopamine in the synaptic cleft, whereas antipsychotics are thought to decrease dopamine. However, it is an oversimplification to state the interaction as such, due to the differing actions of antipsychotics and stimulants in different parts of the brain, as well as the effects of antipsychotics on non-dopaminergic receptors. This interaction frequently occurs in the setting of comorbid attention-deficit hyperactivity disorder (ADHD) (for which stimulants are commonly prescribed) and off-label treatment of aggression with antipsychotics. Aripiprazole has been reported to provide some benefit in improving cognitive functioning in people with ADHD without other psychiatric comorbidities, though the results have been disputed. The combination of antipsychotics like aripiprazole with stimulants should not be considered an absolute contraindication.
Pharmacology
Pharmacodynamics
Aripiprazole’s mechanism of action is different from those of the other FDA-approved atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine, ziprasidone, and risperidone). It shows differential engagement at the dopamine receptor (D2). It appears to show predominantly antagonist activity on postsynaptic D2 receptors and partial agonist activity on presynaptic D2 receptors, D3, and partially D4 and is a partial activator of serotonin (5-HT1A, 5-HT2A, 5-HT2B, 5-HT6, and 5-HT7). It also shows lower and likely insignificant effect on histamine (H1), epinephrine/norepinephrine (α), and otherwise dopamine (D4), as well as the serotonin transporter. Aripiprazole acts by modulating neurotransmission overactivity of dopamine, which is thought to mitigate schizophrenia symptoms.
As a pharmacologically unique antipsychotic with pronounced functional selectivity, characterization of this dopamine D2 partial agonist (with an intrinsic activity of ~25%) as being similar to a full agonist but at a reduced level of activity presents a misleading oversimplification of its actions; for example, among other effects, aripiprazole has been shown, in vitro, to bind to and/or induce receptor conformations (i.e. facilitate receptor shapes) in such a way as to not only prevent receptor internalisation (and, thus, lower receptor density) but even to lower the rate of receptor internalisation below that of neurons not in the presence of agonists (including dopamine) or antagonists. It is often the nature of partial agonists, including aripiprazole, to display a stabilising effect (such as on mood in this case) with agonistic activity when there are low levels of endogenous neurotransmitters (such as dopamine) and antagonistic activity in the presence of high levels of agonists associated with events such as mania, psychosis, and drug use. In addition to aripiprazole’s partial agonism and functional selectivity characteristics, its effectiveness may be mediated by its very high dopamine D2 receptor occupancy (approximately 32%, 53%, 72%, 80%, and 97% at daily dosages of 0.5 mg, 1 mg, 2 mg, 10 mg, and 40 mg respectively) as well as balanced selectivity for pre- and postsynaptic receptors (as suggested by its equal affinity for both D2S and D2L receptor forms). Aripiprazole has been characterised as possessing predominantly antagonistic activity on postsynaptic D2 receptors and partial agonist activity on presynaptic D2 receptors; however, while this explanation intuitively explains the drug’s efficacy as an antipsychotic, as degree of agonism is a function of more than a drug’s inherent properties as well as in vitro demonstration of aripiprazole’s partial agonism in cells expressing postsynaptic (D2L) receptors, it was noted that “It is unlikely that the differential actions of aripiprazole as an agonist, antagonist, or partial agonist were entirely due to differences in relative D2 receptor expression since aripiprazole was an antagonist in cells with the highest level of expression (4.6 pmol/mg) and a partial agonist in cells with an intermediate level of expression (0.5-1 pmol/mg). Instead, the current data are most parsimoniously explained by the ‘functional selectivity’ hypothesis of Lawler et al (1999)”. Aripiprazole is also a partial agonist of the D3 receptor. In healthy human volunteers, D2 and D3 receptor occupancy levels are high, with average levels ranging between approximately 71% at 2 mg/day to approximately 96% at 40 mg/day. Most atypical antipsychotics bind preferentially to extrastriatal receptors, but aripiprazole appears to be less preferential in this regard, as binding rates are high throughout the brain.
Aripiprazole is also a partial agonist of the serotonin 5-HT1A receptor (intrinsic activity = 68%). Casting doubt on the significance of aripiprazole’s agonism of 5-HT1A receptors, a PET scan study of 12 patients receiving doses ranging from 10 to 30 mg found 5-HT1A receptor occupancy to be only 16% compared to ~90% for D2. It is a very weak partial agonist of the 5-HT2A receptor (intrinsic activity = 12.7%), and like other atypical antipsychotics, displays a functional antagonist profile at this receptor. The drug differs from other atypical antipsychotics in having higher affinity for the D2 receptor than for the 5-HT2A receptor. At the 5-HT2B receptor, aripiprazole has both great binding affinity and acts as a potent inverse agonist, “Aripiprazole decreased PI hydrolysis from a basal level of 61% down to a low of 30% at 1000 nM, with an EC50 of 11 nM”. Unlike other antipsychotics, aripiprazole is a high-efficacy partial agonist of the 5-HT2C receptor (intrinsic activity = 82%) and with relatively weak affinity; this property may underlie the minimal weight gain seen in the course of therapy. At the 5-HT7 receptor, aripiprazole is a very weak partial agonist with barely measurable intrinsic activity, and hence is a functional antagonist of this receptor. Aripiprazole also shows lower but likely clinically insignificant affinity for a number of other sites, such as the histamine H1, α-adrenergic, and dopamine D4 receptors as well as the serotonin transporter, while it has negligible affinity for the muscarinic acetylcholine receptors.
Since the actions of aripiprazole differ markedly across receptor systems aripiprazole was sometimes an antagonist (e.g. at 5-HT6 and D2L), sometimes an inverse agonist (e.g. 5-HT2B), sometimes a partial agonist (e.g. D2L), and sometimes a full agonist (D3, D4). Aripiprazole was frequently found to be a partial agonist, with an intrinsic activity that could be low (D2L, 5-HT2A, 5-HT7), intermediate (5-HT1A), or high (D4, 5-HT2C). This mixture of agonist actions at D2-dopamine receptors is consistent with the hypothesis that aripiprazole has ‘functionally selective’ actions. The ‘functional-selectivity’ hypothesis proposes that a mixture of agonist/partial agonist/antagonist actions are likely. According to this hypothesis, agonists may induce structural changes in receptor conformations that are differentially ‘sensed’ by the local complement of G proteins to induce a variety of functional actions depending upon the precise cellular milieu. The diverse actions of aripiprazole at D2-dopamine receptors are clearly cell-type specific (e.g. agonism, antagonism, partial agonism), and are most parsimoniously explained by the ‘functional selectivity’ hypothesis.
Since 5-HT2C receptors have been implicated in the control of depression, OCD, and appetite, agonism at the 5-HT2C receptor might be associated with therapeutic potential in obsessive compulsive disorder, obesity, and depression. 5-HT2C agonism has been demonstrated to induce anorexia via enhancement of serotonergic neurotransmission via activation of 5-HT2C receptors; it is conceivable that the 5-HT2C agonist actions of aripiprazole may, thus, be partly responsible for the minimal weight gain associated with this compound in clinical trials. In terms of potential action as an anti-obsessional agent, it is worthwhile noting that a variety of 5-HT2A/5-HT2C agonists have shown promise as anti-obsessional agents, yet many of these compounds are hallucinogenic, presumably due to 5-HT2A activation. Aripiprazole has a favourable pharmacological profile in being a 5-HT2A antagonist and a 5-HT2C partial agonist. Based on this profile, one can predict that aripiprazole may have anti-obsessional and anorectic actions in humans.
Wood and Reavill’s (2007) review of published and unpublished data proposed that, at therapeutically relevant doses, aripiprazole may act essentially as a selective partial agonist of the D2 receptor without significantly affecting the majority of serotonin receptors. A positron emission tomography imaging study found that 10 to 30 mg/day aripiprazole resulted in 85 to 95% occupancy of the D2 receptor in various brain areas (putamen, caudate, ventral striatum) versus 54 to 60% occupancy of the 5-HT2A receptor and only 16% occupancy of the 5-HT1A receptor. It has been suggested that the low occupancy of the 5-HT1A receptor by aripiprazole may have been an erroneous measurement however.
Aripiprazole acts by modulating neurotransmission overactivity on the dopaminergic mesolimbic pathway, which is thought to be a cause of positive schizophrenia symptoms. Due to its agonist activity on D2 receptors, aripiprazole may also increase dopaminergic activity to optimal levels in the mesocortical pathways where it is reduce.
Pharmacokinetics
Aripiprazole displays linear kinetics and has an elimination half-life of approximately 75 hours. Steady-state plasma concentrations are achieved in about 14 days. Cmax (maximum plasma concentration) is achieved 3-5 hours after oral dosing. Bioavailability of the oral tablets is about 90% and the drug undergoes extensive hepatic metabolization (dehydrogenation, hydroxylation, and N-dealkylation), principally by the enzymes CYP2D6 and CYP3A4. Its only known active metabolite is dehydro-aripiprazole, which typically accumulates to approximately 40% of the aripiprazole concentration. The parenteral drug is excreted only in traces, and its metabolites, active or not, are excreted via faeces and urine.
Chemistry
Aripiprazole is a phenylpiperazine and is chemically related to nefazodone, etoperidone, and trazodone. It is unusual in having twelve known crystalline polymorphs.
Society and Culture
Classification
Aripiprazole has been described as the prototypical third-generation antipsychotic, as opposed to first-generation (typical) antipsychotics like haloperidol and second-generation (atypical) antipsychotics like clozapine. It has received this classification due to its partial agonism of dopamine receptors, and is the first of its kind in this regard among antipsychotics, which before aripiprazole acted only as dopamine receptor antagonists. The introduction of aripiprazole has led to a paradigm shift from a dopamine antagonist-based approach to a dopamine agonist-based approach for antipsychotic drug development.
Research
Attention Deficit Hyperactivity Disorder
Aripiprazole was under development for the treatment of attention-deficit hyperactivity disorder (ADHD), but development for this indication was discontinued. A 2017 meta review found only preliminary evidence (studies with small sample sizes and methodological problems) for aripiprazole in the treatment of ADHD. A 2013 systematic review of aripiprazole for ADHD similarly reported that there is insufficient evidence of effectiveness to support aripiprazole as a treatment for the condition. Although all 6 non-controlled open-label studies in the review reported effectiveness, two small randomised controlled trials found that aripiprazole did not significantly decrease ADHD symptoms. A high rate of adverse effects with aripiprazole such as weight gain, sedation, and headache was noted. Most research on aripiprazole for ADHD is in children and adolescents. Evidence on aripiprazole specifically for adult ADHD appears to be limited to a single case report.
Substance Dependence
Aripiprazole has been studied for the treatment of amphetamine dependence and other substance use disorders, but more research is needed to support aripiprazole for these potential uses. Available evidence of aripiprazole for amphetamine dependence is mixed. Some studies have reported attenuation of the effects of amphetamines by aripiprazole, whereas other studies have reported both enhancement of the effects of amphetamines and increased use of amphetamines by aripiprazole. As such, aripiprazole may not only be ineffective but potentially harmful for treatment of amphetamine dependence, and caution is warranted with regard to its use for such purposes.
Other Uses
Aripiprazole is under development for the treatment of agitation and pervasive child development disorders. As of May 2021, it is in phase 3 clinical trials for these indications.
This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Aripiprazole >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.
Amoxapine, sold under the brand name Asendin among others, is a tricyclic antidepressant (TCAs). It is the N-demethylated metabolite of loxapine. Amoxapine first received marketing approval in the United States in 1992 (approximately 30 to 40 years after most of the other TCAs were introduced in the United States).
Medical Uses
Moxapine is used in the treatment of major depressive disorder (MDD). Compared to other antidepressants it is believed to have a faster onset of action, with therapeutic effects seen within four to seven days. In excess of 80% of patients that do respond to amoxapine are reported to respond within two weeks of the beginning of treatment. It also has properties similar to those of the atypical antipsychotics, and may behave as one and may be used in the treatment of schizophrenia off-label. Despite its apparent lack of extrapyramidal side effects in patients with schizophrenia it has been found to exacerbate motor symptoms in patients with Parkinson’s disease and psychosis.
Contraindications
As with all US Food and Drug Administration (FDA)-approved antidepressants it carries a black-box warning about the potential of an increase in suicidal thoughts or behaviour in children, adolescents and young adults under the age of 25. Its use is also advised against in individuals with known hypersensitivities to either amoxapine or other ingredients in its oral formulations. Its use is also recommended against in the following disease states:
Severe cardiovascular disorders (potential of cardiotoxic adverse effects such as QT interval prolongation).
Its use in breastfeeding mothers not recommended as it is excreted in breast milk and the concentration found in breast milk is approximately a quarter that of the maternal serum level.
Side Effects
Very Common (>10% Incidence) Adverse Effects Include:
Constipation.
Dry mouth.
Sedation.
Common (1–10% Incidence) Adverse Effects Include:
Anxiety.
Ataxia.
Blurred vision.
Confusion.
Dizziness.
Headache.
Fatigue.
Nausea.
Nervousness/restlessness.
Excessive appetite.
Rash.
Increased perspiration (sweating).
Tremor.
Palpitations.
Nightmares.
Excitement.
Weakness.
ECG changes.
Oedema.
An abnormal accumulation of fluids in the tissues of the body leading to swelling.
Prolactin levels increased.
Prolactin is a hormone that regulates the generation of breast milk.
Prolactin elevation is not as significant as with risperidone or haloperidol.
Orthostatic hypotension (a drop in blood pressure that occurs upon standing up).
Seizure.
Urinary retention (being unable to pass urine).
Urticaria (hives).
Vomiting.
Nasal congestion.
Photosensitisation
Hypomania (a dangerously elated/irritable mood).
Tingling.
Paresthaesias of the extremities.
Tinnitus.
Disorientation.
Numbness.
Incoordination.
Disturbed concentration.
Epigastric distress.
Peculiar taste in the mouth.
Increased or decreased libido.
Impotence (difficulty achieving an erection).
Painful ejaculation.
Lacrimation (crying without an emotional cause).
Weight gain.
Altered liver function.
Breast enlargement.
Drug fever.
Pruritus (itchiness).
Vasculitis a disorder where blood vessels are destroyed by inflammation.
Can be life-threatening if it affects the right blood vessels.
Galactorrhoea:
Lactation that is not associated with pregnancy or breast feeding.
Delayed micturition:
That is, delays in urination from when a conscious effort to urinate is made.
Hyperthermia:
Elevation of body temperature; its seriousness depends on the extent of the hyperthermia.
Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) this is basically when the body’s level of the hormone, antidiuretic hormone, which regulates the conservation of water and the restriction of blood vessels, is elevated.
This is potentially fatal as it can cause electrolyte abnormalities including hyponatraemia (low blood sodium), hypokalaemia (low blood potassium) and hypocalcaemia (low blood calcium) which can be life-threatening.
Agranulocytosis a drop in white blood cell counts.
The white blood cells are the cells of the immune system that fight off foreign invaders.
Hence agranulocytosis leaves an individual open to life-threatening infections.
Leukopaenia the same as agranulocytosis but less severe.
Neuroleptic malignant syndrome (a potentially fatal reaction to antidopaminergic agents, most often antipsychotics.
It is characterised by hyperthermia, diarrhoea, tachycardia, mental status changes [e.g. confusion], rigidity, extrapyramidal side effects)
Tardive dyskinesia a most often irreversible neurologic reaction to antidopaminergic treatment, characterised by involuntary movements of facial muscles, tongue, lips, and other muscles.
It develops most often only after prolonged (months, years or even decades) exposure to antidopaminergics.
Extrapyramidal side effects.
Motor symptoms such as tremor, parkinsonism, involuntary movements, reduced ability to move one’s voluntary muscles, etc.
Unknown Incidence or Relationship to Drug Treatment Adverse Effects Include:
Paralytic ileus (paralysed bowel).
Atrial arrhythmias including atrial fibrillation.
Myocardial infarction (heart attack).
Stroke.
Heart block.
Hallucinations.
Purpura.
Petechiae.
Parotid swelling.
Changes in blood glucose levels.
Pancreatitis swelling of the pancreas.
Hepatitis swelling of the liver.
Urinary frequency.
Testicular swelling.
Anorexia (weight loss).
Alopecia (hair loss).
Thrombocytopenia:
A significant drop in platelet count that leaves one open to life-threatening bleeds.
Eosinophilia an elevated level of the eosinophils of the body.
Eosinophils are the type of immune cell that’s job is to fight off parasitic invaders.
Jaundice:
yellowing of the skin, eyes and mucous membranes due to an impaired ability of the body to clear the by product of haem breakdown, bilirubin, most often the result of liver damage as it is the liver’s responsibility to clear bilirubin.
It tends to produce less anticholinergic effects, sedation and weight gain than some of the earlier TCAs (e.g. amitriptyline, clomipramine, doxepin, imipramine, trimipramine). It may also be less cardiotoxic than its predecessors.
It is considered particularly toxic in overdose, with a high rate of renal failure (which usually takes 2-5 days), rhabdomyolysis, coma, seizures and even status epilepticus. Some believe it to be less cardiotoxic than other TCAs in overdose, although reports of cardiotoxic overdoses have been made.
Pharmacology
Pharmacodynamics
Amoxapine possesses a wide array of pharmacological effects. It is a moderate and strong reuptake inhibitor of serotonin and norepinephrine, respectively, and binds to the 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT6, 5-HT7, D2, α1-adrenergic, D3, D4, and H1 receptors with varying but significant affinity, where it acts as an antagonist (or inverse agonist depending on the receptor in question) at all sites. It has weak but negligible affinity for the dopamine transporter and the 5-HT1A, 5-HT1B, D1, α2-adrenergic, H4, mACh, and GABAA receptors, and no affinity for the β-adrenergic receptors or the allosteric benzodiazepine site on the GABAA receptor. Amoxapine is also a weak GlyT2 blocker, as well as a weak (Ki = 2.5 μM, EC50 = 0.98 μM) δ-opioid receptor partial agonist.
7-Hydroxyamoxapine, a major active metabolite of amoxapine, is a more potent dopamine receptor antagonist and contributes to its neuroleptic efficacy, whereas 8-hydroxyamoxapine is a norepinephrine reuptake inhibitor but a stronger serotonin reuptake inhibitor and helps to balance amoxapine’s ratio of serotonin to norepinephrine transporter blockade
Pharmacokinetics
Amoxapine is metabolised into two main active metabolites: 7-hydroxyamoxapine and 8-hydroxyamoxapine.
Society and Culture
Brand Names
Brand names for amoxapine include (where † denotes discontinued brands):
Adisen (KR).
Amolife (IN).
Amoxan (JP).
Asendin† (previously marketed in CA, NZ, US).
Asendis† (previously marketed in IE, UK).
Défanyl (FR).
Demolox (DK†, IN, ES†).
Oxamine (IN).
Oxcap.
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