Ormeloxifene does not affect ovulation. It has been shown to increase the rate of  blastocyst  development and to increase the speed at which the blastocyst is moved from the  fallopian tubes  into the uterus. Ormeloxifene also suppresses proliferation and  decidualization  of the  endometrium  (the transformation of the endometrium in preparation for possible implantation of an embryo). [ 32 ]  While they are believed to prevent  implantation  rather than  fertilization , exactly how these effects operate to prevent pregnancy is not understood


The use of emergency contraceptives (ECs) allows for the prevention of a pregnancy after unprotected sex or contraception failure. [ 37 ]  In the United States, there are currently four different methods available, including ulipristal acetate (UPA), an oral progesterone receptor agonist-antagonist; levonorgestrel (LNG), an oral progestin; off-label use of combined oral contraceptives (Yuzpe regimen); and the copper intrauterine device (Cu-IUD). [ 38 ]


UPA, a progesterone agonist-antagonist, was approved by the FDA in 2010 for use as an EC. [ 38 ]  UPA acts as a partial agonist and antagonist of the progesterone receptor and works by preventing both ovulation and fertilization. [ 39 ]  Users of UPA are likely to experience delayed menses after the expected date. [ 40 ]  In the United States, UPA is sold under the brand name Ella, which is a 30 mg single pill to be taken up to 120 hours after unprotected sex. [ 41 ]  /> UPA has emerged as the most effective EC pill, however, the access to UPA is very limited in US cities. [ 42 ] [ 43 ]  UPA is a prescription emergency contraceptive pill and a recent study has found that less than 10% of pharmacies indicated that a UPA prescription could be filled immediately. [ 44 ]  72% of pharmacies reported the ability to order UPA and the prescription to be filled in a median wait time of 24 hours. [ 44 ]


Plan B one step was the first levonorgestrel progestin-only EC approved by the FDA in 1999. [ 41 ]  Currently, there are many different brands of levonorgestrel EC pills, including Take Action, Next Choice One Dose, and My Way and regimens include a single 1.5 mg pill of levonorgestrel. [ 41 ]  Levonorgestrel EC pills should be taken up to 72 hours after unprotected sex due to the drug becoming less effective over time. [ 41 ]  Levonorgestrel acts as an agonist of the progesterone receptor, preventing ovulation. [ 39 ]  Users of levonorgestrel often experience menses before the expected date. [ 40 ]  A prescription for levonorgestrel is not needed and can be found over the counter at local pharmacies. [ 45 ]  Because levonorgestrel does not have any life-threatening side effects, it has been approved by the FDA for use by all age groups. [ 45 ]


The Yuzpe regimen used combination oral contraceptives for EC and has been used since 1974. [ 41 ]  This regimen is no longer commonly used due to side effects such as nausea and vomiting, as well as the discovery of more effective methods. [ 41 ]  The regimen consists of two pills, each containing a minimum 100 μg of ethinyl estradiol and a minimum of 500 μg of levonorgestrel. [ 41 ]  The first pill is taken 72 hours after unprotected sex and the second pill is taken 12 hours after the first. [ 41 ]  The Yuzpe regimen is often used in areas where dedicated EC methods are unavailable or where EC is not accepted. [ 46 ]


The most effective form of EC is the insertion of a Cu-IUD within 5 days of unprotected sex. [ 41 ]  Because the Cu-IUD is inserted into the uterus, it has the advantage of providing continued contraception for up to 10 years. [ 46 ] [ 47 ]  Cu-IUDs have been the only IUDs that have been approved as ECs due to the mechanism in hormonal and copper IUDs differing. [ 41 ]  Hormonal IUDs are used for the treatment of unplanned pregnancies by being placed in the uterus after an oral EC has been taken. [ 41 ]


Pills—combined and progestogen-only—are the most common form of hormonal contraception. Worldwide, they account for 12% of contraceptive use. 21% of users of reversible contraceptives choose COCPs or POPs. Pills are especially popular in more developed countries, where they account for 25% of contraceptive use. [ 48 ]


Injectable hormonal contraceptives are also used by a significant portion—about 6%—of the world's contraceptive users. [ 48 ] [ 49 ]  Other hormonal contraceptives are less common, accounting for less than 1% of contraceptive use. [ 48 ] [ 49 ]


In 1921,  Ludwig Haberlandt  demonstrated a temporary hormonal contraception in a female rabbit by transplanting ovaries from a second, pregnant, animal. [ 50 ]  By the 1930s, scientists had isolated and determined the structure of the  steroid hormones  and found that high doses of  androgens ,  estrogens , or  progesterone  inhibited  ovulation . [ 51 ] [ 52 ]  A number of economic, technological, and social obstacles had to be overcome before the development of the first hormonal contraceptive, the  combined oral contraceptive pill  (COCP). In 1957  Enovid , the first COCP, was approved in the  United States  for the treatment of menstrual disorders. In 1960, the U.S.  Food and Drug Administration  approved an application that allowed Enovid to be marketed as a contraceptive. [ 53 ]


The first progestogen-only contraceptive was introduced in 1969:  Depo-Provera , a high-dose progestin injection. [ 54 ]  Over the next decade and a half, other types of progestogen-only contraceptive were developed: a low-dose  progestogen only pill  (1973); [ 55 ]  Progestasert, the first  hormonal intrauterine device  (1976); [ 56 ]  and  Norplant , the first contraceptive implant (1983). [ 57 ]


Combined contraceptives have also been made available in a variety of forms. In the 1960s a few  combined injectable contraceptives  were introduced, notably Injectable Number 1 in  China  and Deladroxate in  Latin America . [ 58 ]  A third combined injection, Cyclo-Provera, was reformulated in the 1980s by lowering the dose and renamed Cyclofem (also called Lunelle). Cyclofem and Mesigyna, another formulation developed in the 1980s, were approved by the  World Health Organization  in 1993. [ 59 ]   NuvaRing , a contraceptive vaginal ring, was first marketed in 2002. [ 60 ]  2002 also saw the launch of Ortho Evra, the first  contraceptive patch . [ 61 ]


In 1991,  ormeloxifene  was introduced as a contraceptive in  India . [ 62 ]  While it acts on the estrogen hormonal system, it is atypical in that it is a  selective estrogen receptor modulator  rather than an estrogen, and has the capacity for both estrogenic and  antiestrogenic  effects. [ 62 ]


Mechanism of action COCs prevent fertilization and, therefore, qualify as contraceptives. There is no significant evidence that they work after fertilization. The progestins in all COCs provide most of the contraceptive effect by suppressing ovulation and thickening cervical mucus, although the estrogens also make a small contribution to ovulation suppression. Cycle control is enhanced by the estrogen. Because COCs so effectively suppress ovulation and block ascent of sperm into the upper genital tract, the potential impact on endometrial receptivity to implantation is almost academic. When the two primary mechanisms fail, the fact that pregnancy occurs despite the endometrial changes demonstrates that those endometrial changes do not significantly contribute to the pill's mechanism of action.


Party and play  ( PnP ), also known as  chemsex  or  wired play , refers to the practice of consuming drugs to enhance  sexual activity . [ 1 ] [ 2 ]  This  sexual subculture  involves  recreational drug  users engaging in high-risk sexual behaviors under the influence of drugs, often within specific sub-groups. [ 3 ]  Activities may include  unprotected sex  with multiple partners during sessions over extended periods, sometimes lasting days. The drug of choice is typically  methamphetamine , commonly referred to as  crystal meth ,  tina , or  T . [ 4 ]  Other substances like  mephedrone ,  GHB ,  GBL , [ 5 ] [ 6 ]   ketamine , and  alkyl nitrites  (known as  poppers ) are also used. [ 6 ] [ 7 ]  The term  slamsex  is used for  injection drug users . [ 8 ]


Studies indicate that individuals participating in such activities have a higher likelihood of acquiring  sexually transmitted infections , including  HIV/AIDS , due to unprotected sex with numerous partners. Consequently, addressing this issue is considered a significant  public health  priority. [ 5 ]


The practice is commonly referred to as "party 'n' play" (PNP or PnP) by some participants, while others use the term "high 'n' horny" (HnH). An academic study has labeled it "sexualized drug use" (SDU). [ 9 ]  The term PnP is widely used among  gay men [ 3 ] [ failed verification ]  and other  men who have sex with men  (MSM) in North America and Australia. Conversely, the term chemsex is more common in Europe. [ 10 ]  In certain Southeast Asian countries, it is commonly known as "chem fun" (CF or Cf).


Methamphetamine is often used recreationally for its effects as a potent  aphrodisiac ,  euphoriant , and  stimulant . [ 11 ]  It has been further described that "an entire subculture known as party and play is based around methamphetamine use." [ 11 ]   Gay men belonging to this subculture will typically meet up through internet dating sites to have sex. [ 11 ]   On such sites, men often include notations such as "chems" or "PnP". [ 11 ]   Since stimulant drugs such as methamphetamine drastically delay the need for  sleep , increase  sexual arousal , and tend to inhibit  ejaculation , PNP sexual encounters can continue for many hours or even days. [ 11 ]


Methamphetamine taken in excess of amounts prescribed or recommended will prolong symptoms of intoxication for up to eight hours. [ 12 ]  In some cases, these sexual encounters will sometimes occur continuously for several days along with repeated methamphetamine use. [ 11 ]  Methamphetamine is used to create euphoria, "heighten sexual appetite", and increase sexual stamina. [ 6 ]  The crash following the use of methamphetamine in this manner is very often severe, with marked  hypersomnia . [ 11 ]


Ketamine is very different from the main chemsex drugs, as it is a  dissociative hallucinogen  that distorts  perception  and causes  dissociation . Ketamine is used in chemsex encounters to "improve the experience of receptive  anal intercourse  or  fisting ". [ 6 ]


A study of sauna participants in Barcelona, Spain, in 2016, found that the most commonly used drugs in chemsex are "GHB/GBL, cocaine, ecstasy, silver bars ( MDMA ), poppers and Viagra". [ 13 ]


A 2014 study on chemsex in London, UK, indicated that the drugs associated with chemsex include mephedrone, GHB/GBL, crystal meth, ketamine, and cocaine. [ 6 ]


Internet posts by men seeking PnP experiences often resort to slang to identify what drug they are partying with. [ 14 ] [ 15 ]  These drugs tend to inhibit  penile erection , [ 11 ] [ 12 ]  a phenomenon known by the slang term  crystal penis  or  tweaker dick . Consequently, many men who engage in PnP use  erectile dysfunction  drugs such as  sildenafil ,  vardenafil , and  tadalafil . [ 16 ]   Imodium  is often taken by participants in passive  anal sex  in order to be clean for longer.


For some PnP participants, substance use may facilitate a process of "cognitive disengagement” or  moral disengagement  from the fears and stipulations associated with sex in the time of  HIV/AIDS . Popular discourses of " disinhibition " provide a commonly accepted alibi for activities engaged in when under the influence of stimulants. [ 16 ]


The use of drugs like mephedrone, GHB/GBL, and crystal meth before or during sex, can have physical effects. These can include dehydration, a higher risk of HIV and other sexually transmitted infections (STIs), and drug-related injuries. Dehydration is a widespread problem with chemsex. This can lead to serious health problems, including seizures and even death. GHB/GBL and crystal meth can also increase the risk of injuries due to accidents or sexual encounters that go wrong. These injuries can be as minor as cuts and bruises, but they can also be dangerous in severe cases, such as haemorrhages, anal fissures, ripped anuses, anal prolapse, suffocation, and more. Furthermore, the use of these drugs can affect erection and ejaculation. Gay/Bisexual men often will use Viagra or other ED drugs to overcome this issue. Unfortunately, this means that their body has to cope with drug interactions that very often go wrong leading, in many cases, to overdose, seizures, drug induced heart attacks, stroke, paralysis, neurological damage and even death. These physical risks are particularly higher in older men and those with pre-existing medical conditions. [ citation needed ]


The same drug-induced loss of inhibitions makes PNP enthusiasts more vulnerable to more immediate threats, such as  robbery ,  date rape ,  assault , or  murder , by someone whom they meet for sex. [ 17 ]  Men in the chemsex scene have stated that  sexual consent  is not clearly defined and there can be a perception that anyone at a "party and play" get-together is assumed to consent. [ 18 ]


The abuse of drugs such as methamphetamine may cause neurological damage. [ 19 ]  Impaired judgement due to intoxication may lead to  bareback sex , which increases the chances of contracting HIV. [ 14 ]


The use of crystal methamphetamine or mephedrone for chemsex is associated with "high-risk sexual behaviour… with little regard to consequences, poor [ antiretroviral drug ] adherence for HIV, poor use of condoms, extended episodes of (often traumatic) sexual pursuits (e.g. fisting) typically lasting two to three days, [and] multiple sexual partners. Men who have sex with men in the chemsex scene who inject drugs tend to use 'clumsy injecting practices and knowledge', which increases the risks of injection problems. As well, since most chemsex takes place in private home parties, it is hard for public health staff to reach these participants to inform them of safer practices, as compared to reaching gay men in nightclubs, who can be approached by outreach workers". [ 20 ]


Methamphetamine suppresses autonomic response and can cause sores and abrasions in the mouth. Open wounds or damaged mucous membranes can turn typically low-HIV-risk sex acts such as oral sex into much-higher-risk sexual activity [ 21 ]  unless all HIV-positive participants are undetectable on HAART, and all HIV-negative participants are taking  pre-exposure prophylaxis  in strict accordance with prescription instructions.


Men who PNP with methamphetamine,  cocaine ,  MDMA , and  ketamine  are twice as likely to have unprotected sex (meaning sex without using a condom or taking PrEP), according to British research from 2006. The study also found that up to 20% of gay men from central London gyms had tried methamphetamine, the drug most associated with PNPing. [ 22 ]


Subcultures of psychoactive drug use have long existed within urban gay communities, since the 1970s  disco  era and before.  These substances have been used for dancing, socializing, communal celebration and other purposes. [ 23 ]  The rise of online websites and hookup apps in the 1990s gave men new ways of  cruising  and meeting sexual partners, including the ability to arrange private sexual gatherings in their homes. [ 24 ]


From the early 2000s, historic venues of gay socialization such as bars, clubs, and dance events reduced in number in response to a range of factors, including  gentrification ,  zoning  laws, licensing restrictions, and the increased number of  closeted  or sexually labile men who are under the influence of drugs and the increasing popularity of digital technologies for sexual and social purposes. [ 25 ]


In this context, PNP emerged as an alternative form of sexualized partying that enabled participants to avoid the public scrutiny and potentially judgmental and anxiety-provoking nature of the "public space".  Newly popular drugs such as methamphetamine and GHB/GBL replaced  dance drugs  such as Ecstasy within this context. [ citation needed ]


While PNP sessions tend to be organized around sex, there is some evidence that they can serve a range of social purposes for their participants, including the opportunity to meet other gay men, become friends, and engage in erotic play and experimentation. In some instances, PNP sessions play a part in the formation of loose social networks that are valued and relied upon by participants. [ 24 ]  For other men, increasing reliance on  hookup apps  and websites to arrange sex may result in a sense of isolation that may exacerbate the risk of drug dependence, especially in the context of a lack of other venues for gay socializing and sexual community-formation. [ 25 ]


A 2014 study found that one of the key reasons for taking drugs before and during sex was to boost sexual confidence and reduce feelings of self-doubt, regarding feelings of "internalised  homophobia " from society, concerns about an HIV diagnosis, or "guilt related to having or desiring gay sex". A key self-confidence issue for study participants was " body image ", a concern that was heightened by the focus on social networking apps on appearance, because on these apps, there is a focus on idealized male bodies that are "toned and muscular". Men were also anxious about their sexual performance, and as such, taking drugs can reduce these anxieties and enable them to enjoy sex more. [ 6 ] [ 26 ]


It has been observed that reliable data and relevant research are generally lacking and this situation is generating a climate of  moral panic . In an opinion piece published by  The Guardian , it has been argued that an exaggerated reporting might give the public a distorted impression of the magnitude of this phenomenon and that may increase the level of collective anxiety. [ 27 ]


Poppers  (or  popper ) is a slang term referring to recreational drugs belonging to the  alkyl nitrite  family of  chemical compounds . When fumes from these substances are  inhaled , they act as potent  vasodilators , producing mild euphoria, warmth, and dizziness. Most effects have a rapid onset and are short-acting. [ 2 ]  Its  recreational use  is believed to be potentially dangerous for people with  heart problems ,  anaemia , or  glaucoma . Reported adverse effects include  fainting , retinal toxicity, and vision loss. [ 3 ] [ 4 ]


As poppers include a broad range of  chemical types , their legality differs across different jurisdictions. They are often packaged under the guise of room deodorizer, leather polish, nail polish remover, or  videotape head cleaner  to evade  anti-drug laws . [ 2 ]


The term  poppers  stems from the "popping" sound of  glass vials  containing the substance when crushed to release vapour for inhalation.  Amyl nitrite  was originally prescribed in the late 1800s for the medical management of  angina . [ 2 ]  Many analogues exist, such as  isoamyl nitrite, isopentyl nitrite ,  isopropyl nitrite , and  isobutyl nitrite . These substances are subject to different regulations; for example, isobutyl nitrite is banned in the  European Union .


Poppers act as  muscle relaxants , causing the relaxation of  involuntary smooth muscles  such as the  throat  and  anus . [ 5 ] [ 6 ]  Such physiological effects, along with others (such as mild euphoria), have resulted in poppers being used as  recreational drugs , sometimes during  sexual intercourse , as the effects can heighten arousal and help facilitate acts such as  anal intercourse . [ 7 ]  It has been reported that poppers were a part of the club culture which began during the mid-1970s  disco  scene, and surged in popularity during the  rave  scene of the 1980s and 1990s. [ 8 ] [ 9 ]


Poppers come in liquid form, but this liquid is not directly consumed. When the bottle is opened, the vapors are inhaled, rather than the liquid. This is typically done through the nasal cavities, commonly directly from the bottle (avoiding touching the bottle to the skin) or with the help of small inhalers.


Inhaling nitrites produces a fast-acting, short-lived and non-specific relaxation of  smooth muscles  (along with the  sphincter  muscles of the  anus  and the  vagina ). [ 10 ]  Blood vessels are surrounded by smooth musculature, which directly influences blood pressure by increasing or decreasing its inward pressure on the blood vessels.


With relaxation of the smooth muscles, the 'inward' pressure on the blood vessels decreases and they  dilate , resulting in  a drop in blood pressure  and an immediate (compensatory) increase in  heart rate  (reflex tachycardia). Vasodilation may cause giddiness, dizziness, headache, nausea, vomiting and flushing, and may produce a sensation of heat and excitement. Maximum vasodilatory effect is usually reached within 30 seconds, with (secondary) physiological effects lasting for 5 to 10 minutes. [ 11 ] [ 12 ] [ 13 ] [ 14 ]


Inhaling nitrites produces several psychological effects such as euphoria, increased sensual awareness, lowered inhibitions or increased confidence, and potential for impaired judgement and disorientation. [ 12 ]


Alkyl nitrites  interact  with other  vasodilators , such as  sildenafil  (Viagra),  vardenafil  (Levitra), and  tadalafil  (Cialis), to cause a serious  decrease in blood pressure , which can cause strokes, and low blood pressure leading to people fainting. [ 16 ]  Side effects of popper abuse include  tachycardia ,  headaches ,  migraines ,  dizziness  and  fainting . [ 17 ]


The  Merck Manual of Diagnosis and Therapy  reports insignificant hazard associated with inhalation of alkyl nitrites, [ 18 ]  and British governmental guidance on the relative harmfulness of alkyl nitrites places them among the less harmful of recreational drugs. [ 19 ]


If in contact with the skin, Butyl Nitrite poppers can cause  chemical burns  and contact  dermatitis  of the skin around the mouth and nose. [ 20 ]


Swallowing poppers (rather than inhaling the vapour) may cause  cyanosis ,  methemoglobinemia , unconsciousness, coma, and complications leading to death. [ 10 ] [ 21 ] [ 22 ] [ 23 ] [ 24 ]  Accidental aspiration of amyl or butyl nitrites may cause  lipoid pneumonia . [ 25 ]


Isopropyl nitrite poppers may be a cause of  maculopathy  (eye damage), as reported in France and the United Kingdom. [ 26 ]  Some studies have concluded that there may be increased risk for at least temporary retinal damage with habitual popper use in certain users; in a letter to the  New England Journal of Medicine , [ 27 ]  an ophthalmologist described four cases in which recreational users of isopropyl nitrite poppers suffered temporary changes in vision. [ 28 ]  In November 2014, it was observed  maculopathy  is a rare complication of isopropyl nitrite abuse. A full recovery of visual acuity in longterm abuse could be demonstrated after drug abstinence. [ 29 ]  Studies have shown that poppers users who have HIV and/or use Sildenafil in combination with poppers are at an increased risk of developing poppers‐associated maculopathy. [ 30 ]


Foveal (center-of-gaze) damage has also been described, in six habitual users of isopropyl nitrite poppers. [ 31 ]  Furthermore, in June 2014,  optometrists  and  ophthalmologists  reported having noticed an increase in vision loss in chronic popper users in the United Kingdom associated with isopropyl nitrite (substitute for isobutyl nitrite which was banned in 2007). [ 32 ] [ 33 ]


A working group in 2019 from the  International Agency for Research on Cancer  determined there to be "sufficient evidence" to suggest  carcinogenic  properties of isobutyl nitrite on experimental animals, and because they could not find any sufficient studies regarding its carcinogenic effects on humans, they determined that isobutyl nitrite is "possibly carcinogenic to humans". The group primarily looked at 2 studies on animals, one on rats and one on mice. Both of these involved the administration of doses of isobutyl nitrite at seemingly low doses (0, 37.5, 75, or 150 ppm) 6 hours a day, 5 days a week, for a total of 103 weeks. [ 34 ]  This is different from the relatively brief exposure to isobutyl nitrite that inhaling poppers recreationally usually provides. Nonetheless, in the studies there was shown to be no increase in death rates for the animals exposed to isobutyl nitrite, but there was shown to be an increase in tumors in the lungs of the males and females of both species in the groups exposed, as well as in the thyroids of the male mice exposed. [ 34 ]  Isobutyl Nitrite is no longer sold as 'Poppers' having been banned in the EU since 2007 and banned in the USA since 1990.  [ 35 ]


Early in the  AIDS  crisis, widespread use of poppers among AIDS patients led to the later disproved hypothesis that poppers contributed to the development of  Kaposi's sarcoma , a rare form of cancer that occurs in AIDS patients. [ 36 ] [ 37 ]  Modest, short-term reductions in immune function were observed in animal studies, but not replicated in human studies. [ 38 ] [ 39 ]


Amyl nitrites were part of some kits used to treat  cyanide poisoning , containing amyl nitrite,  sodium nitrite , and  sodium thiosulfate . The nitrites were administered to produce  methemoglobin  and induce  vasodilation . [ 40 ] [ 41 ]  Amyl nitrites were discontinued in 2012 in standard cyanide kits. [ 42 ]  Cyanide kits now use  hydroxocobalamin . [ 43 ]


Poppers contain a class of chemicals called alkyl nitrites. To the extent that poppers products contain alkyl nitrites, the following applies.


The following table summarizes alkyl nitrite chemical and physical properties, including chemical structure: [ 44 ]


The French chemist  Antoine Jérôme Balard  synthesized  amyl nitrite  in 1844. [ 46 ]   Sir Thomas Lauder Brunton , a Scottish physician born in the year of amyl nitrite's first synthesis, documented its clinical use to treat  angina pectoris  in 1867 when patients experiencing chest pains would experience complete relief after inhalation. [ 47 ]   Brunton was inspired by earlier work with the same agent, performed by  Arthur Gamgee  and  Benjamin Ward Richardson . [ 47 ]  Brunton reasoned that the angina sufferer's pain and discomfort could be reduced by administering amyl nitrite—to dilate the coronary arteries of patients, thus improving blood flow to the heart muscle. [ 47 ]


Amyl nitrites were originally enclosed in a glass mesh called "pearls". The usual administration of these pearls was done by crushing them between the fingers, followed by a popping sound. This administration process seems to be the origin of the  slang term  "poppers". It was then administered via direct inhalation of the vapors or inhalation through silk that covered the capsule.


Brunton found that amyl nitrites had effects of dilating blood vessels and flushing of the face. Isobutyl nitrites were also documented around the late 1890s by Brunton and despite being found to have generally the same effects as amyl nitrites, they were never used as a clinical alternative to amyl nitrates. Brunton also found that propyl nitrites had the same effects as well. [ 48 ] [ 49 ]


Although amyl nitrite is known for its practical therapeutic applications, the first documented case of recreational use was in 1964. [ 50 ] [ 51 ]  The poppers "craze" began in the early 1970s in the  gay male  community in  bars ,  discothèques  and  bathhouses . [ 52 ] [ 53 ]  It was packaged and sold pharmaceutically in fragile glass ampoules wrapped in cloth sleeves which, when crushed or "popped" in the fingers, released the amyl nitrite for inhalation, hence the colloquialism  poppers . [ 52 ]  The term extended to the drug in any form as well as to other drugs with similar effects, e.g.  butyl nitrite  which is packaged under a variety of trade names in small bottles. [ 52 ]


In the late 1970s,  Time  magazine [ 54 ]  and  The Wall Street Journal [ 55 ]  reported that popper use among  gay men  began as a way to enhance sexual pleasure, but "quickly spread to  avant-garde   heterosexuals ". A series of interviews conducted in the late 1970s revealed a wide spectrum of users. [ 54 ] [ failed verification ]


Poppers were well established in the gay community, with more than a third of gay men having used poppers at least once. [ 56 ]  Poppers were partial inspiration for songs such as  Troye Sivan 's  Rush . [ 57 ]


Poppers are legal in Australia, and from 2020, poppers can also be purchased as a schedule 3 substance from pharmacies, or a schedule 4 substance with a prescription. [ 58 ]


In June 2018, the  Therapeutic Goods Administration  (TGA) motioned to reschedule alkyl nitrites to be in the same category as heroin and cocaine ( Schedule 9 ). [ 59 ]  This was met by criticism from the LGBTQI community for being discriminatory and further evidence was demanded and further consultation sought. [ 60 ]


In October 2018, the  Australian Federation of AIDS Organisations  (AFAO) pointed out the lack of quality evidence provided by the TGA to justify the rescheduling [ 61 ]  and that use of amyl nitrites has been stable over the past decade with very little evidence of harm and has been in use by a high proportion of gay men over a long period.


A final decision was pushed back from 29 November 2018 to late January or early February 2019 for further consultation with the public. [ 62 ]


As of March 2019, two public meetings have taken place in Sydney and Melbourne with  The Kirby Institute  and the  Australian Research Centre in Sex, Health and Society  (ARCSHS). Along with 70 written public proposals, there was significant opposition to alkyl nitrites rescheduling. [ 63 ]  Banning alkyl nitrites was not considered acceptable as their use was said to help reduce harms such as anal injury and blood-borne disease transmission during anal sex. [ 64 ]


In June 2019, Australia decided not to ban poppers. [ 65 ]


Since 2013,  Health Canada  has banned all distribution and sales of poppers. [ 66 ]


Since 2007, reformulated poppers containing  isopropyl nitrite  are sold in the EU;  isobutyl nitrite  is prohibited. [ 67 ]


In  France , the sale of products containing  butyl nitrite  has been prohibited since 1990 on grounds of danger to consumers. [ 68 ]  In 2007, the government extended this prohibition to all  alkyl nitrites  that were not authorized for sale as  drugs . [ 69 ]  After litigation by  sex shop  owners, this extension was quashed by the  Council of State  on the grounds that the government had failed to justify such a blanket prohibition: according to the court, the risks cited, concerning rare accidents often following abnormal usage, rather justified compulsory warnings on the packaging. [ 70 ]


The possession in  Germany ,  Austria  and  Switzerland  is not subject to any regulations regarding  anesthetic  drugs and is therefore legal; however, the purchase, sale or trade of  amyl nitrite  without permission violates the drug laws of the corresponding countries. Occasionally, poppers were seized from sex shops, when sold there illegally. [ 71 ] [ 72 ]


Poppers are sold in  nightclubs ,  bars , sex shops,  drug paraphernalia   head shops , over the  Internet  and in markets. It is illegal under  Medicines Act 1968  to sell them advertised for human consumption. The  Advisory Council on the Misuse of Drugs  noted in 2011 that poppers, rather than being a psychoactive substance or a  legal high , "appear to fall within the scope of  The Intoxicating Substances (Supply) Act 1985 ". [ 73 ]


The  Psychoactive Substances Act 2016 , scheduled to be enacted 1 April 2016, was initially claimed to impose a blanket ban on the production, import and distribution of all poppers. [ 74 ]  On 20 January 2016 a motion to exempt poppers (alkyl nitrites) from this legislation was defeated. [ 75 ]  This was opposed by Conservative MP  Ben Howlett . Howlett's fellow Conservative MP  Crispin Blunt  declared that he has used and currently uses poppers. Manufacturers expressed concern over loss of business and potential unemployment. [ 76 ] [ 77 ]


In March 2016, the Advisory Council on the Misuse of Drugs stated that, because alkyl nitrites do not directly stimulate or depress the  central nervous system , poppers do not fall within the scope of the Psychoactive Substances Act 2016. [ 78 ]


Amyl nitrite  was originally marketed as a  prescription drug  in 1937. It remained so until 1960, when the  Food and Drug Administration  removed the prescription requirement due to its safety record. This requirement was reinstated in 1969, after observing an increase in  recreational use . There was a huge increase in the number of brands for  butyl nitrites  after the FDA put in the prescription requirement again in 1969. [ 47 ]


Butyl nitrites were outlawed in 1988 by the  Anti-Drug Abuse Act of 1988 . [ 79 ]  This prompted distributors to sell other  alkyl nitrites  not yet banned, like  isopropyl nitrite . In 1990, isopropyl nitrites and other nitrites not yet banned were outlawed by the  Crime Control Act of 1990 . [ 80 ]  Both of these laws include an exception for  commercial purpose , defined as any use other than for the production of consumer products containing volatile alkyl nitrites meant for inhaling or otherwise introducing volatile alkyl nitrites into the human body for euphoric or physical effects. [ 81 ]


" Wine, women, and song " is a  hendiatris  that endorses  hedonistic  lifestyles or behaviors. A more modern form of the idea is often expressed as " sex  and  drugs  and  rock 'n' roll ", a phrase popularized by British singer  Ian Dury  in  his song of the same title .


Similar  tripartite mottoes  have existed for a long time in many languages, for example:


Not all hendiatris including women are positive: in  Greek :  Πύρ, γυνή και θάλαττα ,  lit.   'fire, women and the sea' instead suggest three dangers rather than pleasures, and  Turkish :  At, Avrat, Silah ,  lit.   'horse, woman, weapon' offers the three essentials of quite another culture.


Roman inscriptions mention  Balnea vina Venus , ' Baths ,  wines ,  sex ', such as the ambivalent:


balnea vina Venus
corrumpunt corpora
nostra se<t> vitam faciunt
balnea vina Venus

"Baths, wine, and sex corrupt our bodies, but baths, wine, and sex make life worth living."


The following poem mentions similar ideas, using four concepts rather than three:


Omar Khayyam addressed the trio in 1120 in his  Rubaiyat, verse XII . For him singing was replaced by a book, but he acknowledged its importance for others.


Among rural Arabs in the days before Muhammed, free women "joined in the music of the family or tribal festivities with their instruments". [ 2 ]  It was a time of the " badawī  Arab". A secular people then, for them "love, wine, gambling, hunting, the pleasure of song and romance ... wit and wisdom" were all important. [ 2 ]


The Irish poet Edward Lysaght (1763–1810) used the phrase 'poetry and pistols, wine and women'. [ 3 ]


In 1816 the English poet John Keats composed a poem, 'Give Me Women, Wine, and Snuff'. [ 4 ]


The English  couplet  "Who loves not woman, wine, and song / Remains a fool his whole life long" appears in print as early as 1837, translated from German verse attributed to Martin Luther. [ 5 ]   John Addington Symonds  used the phrase "Wine, Women and Song" as the title for his 1884 book of translations of medieval Latin students' songs. [ 6 ]


The phrase in  German  is apparently older than in English. Symonds and the anonymous 1837 writer both provide the German text, attributing it to Luther. The attribution to Luther has been questioned, however, [ 7 ] [ 8 ]  and the earliest known reference in German is to a folksong first printed in 1602. [ 9 ]   Bartlett's Familiar Quotations  cites  Johann Heinrich Voss  (1751–1826) as a likely source, [ 7 ]  but any use by him would have to be a later use of the phrase.


The  waltz  "Wine, Women and Song" ( Wein, Weib und Gesang ) is Op. 333 (1869) of  Johann Strauss II .


The lines  Deutsche Frauen, deutsche Treue, / Deutscher Wein, und deutscher Sang  (German women, German loyalty, / German wine, and German song) are found in the second verse of  Das Lied der Deutschen ,  the third verse of which is the  German national anthem .


Alpha blockers , also known as  α-blockers  or  α-adrenoreceptor antagonists , are a class of   pharmacological agents  that act as  antagonists  on  α-adrenergic receptors  ( α-adrenoceptors ). [ 2 ]


Historically, alpha-blockers were used as a tool for pharmacologic research to develop a greater understanding of the autonomic nervous system. Using alpha blockers, scientists began characterizing arterial blood pressure and central vasomotor control in the autonomic nervous system. [ 3 ]  Today, they can be used as clinical treatments for a limited number of diseases. [ 2 ]


Alpha blockers can treat a small range of diseases such as  hypertension ,  Raynaud's disease ,  benign prostatic hyperplasia  (BPH) and  erectile dysfunction . [ 2 ]  Generally speaking, these treatments function by binding an α-blocker to α receptors in the arteries and smooth muscle. Ultimately, depending on the type of alpha receptor, this relaxes the smooth muscle or blood vessels, which increases fluid flow in these entities. [ 2 ]


When the term "alpha blocker" is used without further qualification, it can refer to an  α 1  blocker, an  α 2  blocker, a nonselective blocker (both  α 1  and  α 2  activity), or an  α  blocker with some β activity. [ 2 ]  However, the most common type of alpha blocker is usually an  α 1  blocker.


Non-selective α-adrenergic receptor antagonists include:


Selective α 1 -adrenergic receptor antagonists include:


Selective α 2 -adrenergic receptor antagonists include:


Finally, the agents  carvedilol  and  labetalol  are both α and  β-blockers .


Below are some of the most common drugs used in the clinic.


Irreversibly binds. [ 2 ] [ 10 ]


Blocks alpha induced vasconstriction. [ 2 ]


4 hours of action after initial administration. [ 2 ] [ 10 ]


Lowers blood pressure by decreasing peripheral resistance. [ 2 ] [ 10 ]


Cardura XL


Coreg CR


While there are limited clinical α-blocker uses, in which most α-blockers are used for  hypertension  or  benign prostatic hyperplasia , α-blockers can be used to treat a few other diseases, such as  Raynaud's disease ,  congestive heart failure  (CHF),  pheochromocytoma , and  erectile dysfunction . [ 15 ] [ 16 ] [ 17 ]


Furthermore, α-blockers can occasionally be used to treat anxiety and panic disorders, such as  posttraumatic stress disorder  (PTSD) induced  nightmares . [ 6 ]  Studies have also had great medical interest in testing alpha blockers, specifically α 2  blockers, to treat  type II diabetes  and  psychiatric depression . [ 2 ]


Hypertension  is due to an increase in vascular resistance and vasoconstriction. Using α 1  selective antagonists, such as  prazosin , has been efficacious in treating mild to moderate hypertension. This is because they can decrease vascular resistance and decrease pressure. [ 2 ] [ 18 ]  However, while these drugs are generally well tolerated, they have the potential to produce side effects such as orthostatic hypotension and dizziness. [ 2 ]  However, unlike other treatments for hypertension such as  ACE inhibitors ,  ARBs ,  calcium channel blockers ,  thiazide diuretics  or  beta blockers , alpha blockers have not demonstrated the same mortality and morbidity benefits, and are therefore not generally used as first or even second line agents.


Another treatment for hypertension is using drugs that have both α 1  blocking activity, as well as nonselective β activity, such as  Labetalol  or  carvedilol . [ 19 ]  In low doses, labetalol and carvedilol can decrease the peripheral resistance and block the effects of isoprenaline to reduce hypertensive symptoms. [ 19 ]


Pheochromocytoma  is a disease in which a catecholamine secreting tumor develops. [ 2 ] [ 20 ]  Specifically, norepinephrine and epinephrine are secreted by these tumors, either continuously or intermittently. [ 21 ]  The excess release of these catecholamines increases central nervous system stimulation, thus causing blood vessels to increase in vascular resistance, and ultimately giving rise to hypertension. [ 20 ]  In addition, patients with these rare tumors are often subject to headaches, heart palpitations, and increased sweating. [ 2 ]


Phenoxybenzamine , a nonselective α 1  and α 2  blocker, has been used to treat pheochromocytoma. [ 21 ]  This drug blocks the activity of epinephrine and norepinephrine by antagonizing the alpha receptors, thus decreasing vascular resistance, increasing vasodilation, and decreasing blood pressure overall. [ 21 ]


Blockers that have both the ability to block both α and β receptors, such as  carvedilol ,  bucindolol , and  labetalol , have the ability to mitigate the symptoms in  congestive heart failure . [ 22 ]  By binding to both the α and β receptors, these drugs can decrease the cardiac output and stimulate the dilation of blood vessels to promote a reduction in blood pressure. [ 22 ]


Yohimbine , an α 2  blocker derived from the bark of the  Pausinystalia johimbe  tree, has been tested to increase libido and treat erectile dysfunction. The proposed mechanism for yohimbine is blockade of the adrenergic receptors that are associated with  neurotransmitters  inhibition, including  dopamine  and  nitric oxide , and thus aiding with penile erection and libido. [ 23 ]  By doing so, they can alter the blood flow in the penis to aid in achieving an erection. However, some side effects can occur, such as  palpitation ,  tremor ,  elevated blood pressure , and  anxiety . [ 23 ]
 Yohimbe bark  contains both α 1  and α 2   adrenergic receptors  blocking  alkaloids .


Phentolamine , a non-selective alpha blocker, has also been tested to treat erectile dysfunction. By reducing vasoconstriction in the penis, there appears to be increased blood flow that aids in penile erection. Side effects associated with phentolamine include headache, flushing, and nasal congestion. [ 23 ]


Phenoxybenzamine , a non-competitive α 1  and α 2  blocker was used by Dr.  Giles Brindley  in the first intracavernosal pharmacotherapy for erectile dysfunction. [ 24 ]


In  benign prostatic hyperplasia  (BPH), men experience urinary obstruction and are unable to urinate, thus leading to urinary retention. [ 2 ]  α 1  specific blockers have been used to relax the smooth muscle in the bladder and enlarged prostate. [ 25 ]   Prazosin ,  doxazosin , and  terazosin  have been particularly useful for patients with BPH, especially in patients with hypertension. [ 2 ]  In such patients, these drugs can treat both conditions at the same time. [ 2 ]  In patients without hypertension,  tamsulosin  can be used, as it has the ability to relax the bladder and prostate smooth muscle without causing major changes in blood pressure. [ 25 ]


Both α 1  blockers and α 2  blockers have been examined to treat  Raynaud's disease . Although α 1  blockers, such as  prazosin , have appeared to give slight improvement for the sclerotic symptoms of Raynaud's disease, there are many side effects that occur while taking this drug. Conversely, α 2  blockers, such as yohimbine, appear to provide significant improvement of the sclerotic symptoms in Raynaud's Disease without excessive side effects. [ 26 ]


Patients with  posttraumatic stress disorder  (PTSD) have often continued to be symptomatic despite being treated with PTSD-specific drugs. [ 27 ]  In addition, PTSD patients often have debilitating nightmares that continue, despite their treatments. [ 27 ]  High doses of the α 1  blocker,  prazosin , have been efficacious in treating patients with PTSD induced nightmares due to its ability to block the effects of norepinephrine. [ 27 ]


Adverse effects of prazosin to treat PTSD nightmares include  dizziness ,  first dose effect  (a sudden loss of consciousness),  weakness ,  nausea , and  fatigue . [ 27 ]


Although alpha blockers have the ability to reduce some disease pathology, there are some side effects that come with these alpha blockers. [ 28 ]  However, because there are several structural compositions that make each alpha blocker different, the side effects are different for each drug. Side effects that arise when taking alpha blockers can include the  first dose effect ,  cardiovascular side effects, genitourinary side effects, as well as other side effects. [ 28 ]


One of the most common side effects with alpha blockers is the  first dose effect . [ 29 ]  This is a phenomenon in which patients with hypertension take an alpha blocker for the first time, and suddenly experience an intense decrease in blood pressure. Ultimately, this gives rise to  orthostatic hypotension ,  dizziness , and a sudden loss of consciousness due to the drastic drop in blood pressure. [ 29 ]


Alpha blockers that possess these side effects include  prazosin ,  doxazosin , and  terazosin . [ 30 ]


There are some alpha blockers that can give rise to changes in the cardiovascular system, such as the induction of reflex tachycardia, orthostatic hypotension, or heart palpitations via alterations of the QT interval. [ 28 ] [ 31 ]  Alpha blockers that may have these side effects include  yohimbine ,  phenoxybenzamine , and  phentolamine . [ 2 ]


When alpha blockers are used to treat BPH, it causes vasodilation of blood vessels on the bladder and the prostate, thus increasing urination in general. [ 32 ]  However, these alpha blockers can produce the exact opposite side effect, in which  edema , or abnormal fluid retention, occurs. [ 33 ]


In addition, due to the relaxation of the prostate smooth muscle, another side effect that arises in men being treated for BPH is impotence, as well as the inability to ejaculate. [ 32 ] [ 34 ]  However, if any ejaculation activity does occur, oftentimes, it results in a phenomenon called  retrograde ejaculation , in which semen flows into the urinary bladder instead of exiting through the urethra. [ 34 ]


Drugs that may produce such side effects include  prazosin ,  terazosin ,  tamsulosin , and  doxazosin . [ 34 ]


Finally, there are other general side effects that can be caused by most alpha blockers (however, more frequently in alpha-1 blockers). Such side effects include  dizziness ,  drowsiness ,  weakness ,  fatigue , psychiatric  depression , and  dry mouth . [ 28 ] [ 34 ]


Priapism, an unwanted, painful long term erection not brought on by sexual arousal and lasting several hours has been associated with alpha blocker use. While this is extremely rare, particularly with tamsulosin, it can cause permanent impotence if not treated in a hospital setting. Male patients should be made aware of this as it can result from a single dose or develop over time.


There is only one compelling indication for alpha blockers, which is for  benign prostatic hyperplasia . [ 33 ]  Patients who need alpha blockers for BPH, but have a history of  hypotension  or  postural heart failure , should use these drugs with caution, as it may result in an even greater decrease in blood pressure or make heart failure even worse. [ 35 ] [ 36 ]  The most compelling  contraindication  is  urinary incontinence  and overall fluid retention. [ 35 ] [ 36 ]  To combat such fluid retention, patients can take a diuretic in combination with the alpha-blocker. [ 36 ]


In the absence of compelling indications or contraindications, patients should take alpha blockers as a  step 4 therapy  to reduce blood pressure, but only if the use of ACE inhibitors, angiotensin-II receptor blockers, calcium channel blockers, or thazide diuretics (in full dose or in combinations) have not been efficacious. [ 33 ] [ 35 ] [ 36 ]


As with any drug, there are drug interactions that can occur with alpha blockers. For instance, alpha blockers that are used for the reduction of blood pressure, such as  phenoxybenzamine  or  phentolamine  can have synergy with other drugs that affect smooth muscle, blood vessels, or drugs used for  erectile dysfunction  (i.e.  sildenafil ,  tamsulosin , etc.). This stimulates exaggerated  hypotension . [ 2 ]


Alternative alpha blockers, such as  prazosin ,  tamsulosin ,  doxazosin , or  terazosin  can have adverse interactions with  beta blockers ,  erectile dysfunction  drugs,  anxiolytics , and  antihistamines . [ 2 ]  Again, these interactions can cause dangerous  hypotension . Furthermore, in rare cases, drug interactions can cause irregular, rapid heartbeats or an increase blood pressure. [ 2 ]


Yohimbine  can interact with  stimulants ,  hypertension  drugs,  naloxone , and  clonidine . Interactions with such drugs can cause either an unintended increase in blood pressure or potentiate an increase in blood pressure. [ 2 ]


Finally, in drugs with both alpha and beta blocking properties, such as  carvedilol  and  labetalol , interactions with other alpha or beta blockers can exaggerate a decrease in blood pressure. [ 2 ]  Conversely, there are also drug interactions with carvedilol or labetalol in which blood pressure is increased unintentionally (such as with cough and cold medications). [ 2 ]  Finally, there may also be some alpha/beta blocker drug interactions that can worsen previous heart failure. [ 2 ]


Alpha blockers work by blocking the effect of nerves in the sympathetic nervous system. This is done by binding to the alpha receptors in smooth muscle or blood vessels. [ 37 ]  α-blockers can bind both reversibly and irreversibly. [ 2 ]


There are several α receptors throughout the body where these drugs can bind. Specifically, α 1  receptors can be found in most vascular smooth muscle, the pupillary dilator muscle, the heart, the prostate, and pilomotor smooth muscle. [ 2 ]  On the other hand, α 2  receptors can be found in platelets, cholinergic nerve terminals, some vascular smooth muscle, postsynaptic CNS neurons, and fat cells. [ 2 ]


The structure of α receptors is a classic  G protein–coupled receptors  (GPCRs) consisting of 7 transmembrane domains, which form three intracellular loops and three extracellular loops. [ 2 ]  These receptors couple to heterotrimeric G proteins composed of α, β, and γ subunits. [ 2 ]  Although both of the α receptors are GPCRs, there are large differences in their mechanism of action. Specifically,  α 1  receptors  are characterized as G q  GPCRs, signaling through  Phospholipase C  to increase  IP 3  and  DAG , thus increasing the release of calcium. Meanwhile,  α 2  receptors  are labeled as G i  GPCRs, which signal through  adenylyl cyclase  to decrease  cAMP . [ 38 ]


Because the α 1  and α 2  receptors have different mechanisms of action, their antagonists also have different effects. [ 39 ]  α 1  blockers can inhibit the release of  IP 3  and  DAG  to decrease calcium release, thus, decreasing overall signaling. On the other hand, α 2  blockers prevent the reduction of cAMP, thus leading to an increase in overall signaling.


Apomorphine , sold under the brand name  Apokyn  among others, is a type of  aporphine  having activity as a non- selective   dopamine agonist  which activates both  D 2 -like  and, to a much lesser extent,  D 1 -like receptors . [ 2 ]  It also acts as an  antagonist  of  5-HT 2  and  α-adrenergic receptors  with high  affinity . The compound is an alkaloid belonging to nymphaea caerulea, or blue lotus, but is also historically known as a  morphine  decomposition product made by boiling morphine with concentrated acid, hence the  -morphine  suffix. Contrary to its name, apomorphine does not actually contain morphine or its skeleton, nor does it bind to  opioid receptors . The  apo-  prefix relates to it being a  morphine  derivative ("[comes] from morphine").


Historically, apomorphine has been tried for a variety of uses, including as a way to relieve anxiety and craving in alcoholics, an emetic (to induce vomiting), for treating stereotypies (repeated behaviour) in farmyard animals, and more recently in treating  erectile dysfunction . Currently, apomorphine is used in the treatment of  Parkinson's disease . It is a potent  emetic  and should not be administered without an  antiemetic  such as  domperidone . The emetic properties of apomorphine are exploited in veterinary medicine to induce therapeutic  emesis  in canines that have recently ingested toxic or foreign substances.


Apomorphine was also used as a private treatment of  heroin addiction , a purpose for which it was championed by the author  William S. Burroughs . Burroughs and others claimed that it was a "metabolic regulator" with a restorative dimension to a damaged or dysfunctional dopaminergic system. Despite anecdotal evidence that this offers a plausible route to an abstinence-based mode, no clinical trials have ever tested this hypothesis. A recent study indicates that apomorphine might be a suitable marker for assessing central  dopamine  system alterations associated with chronic heroin consumption. [ 3 ]  There is, however, no clinical evidence that apomorphine is an effective and safe treatment regimen for  opiate addiction . [ 4 ]


Apomorphine is used in advanced  Parkinson's disease  intermittent hypomobility ("off" episodes), where a decreased response to an anti-Parkinson drug such as  L -DOPA  causes  muscle stiffness  and loss of muscle control. [ 5 ] [ 6 ]  While apomorphine can be used in combination with  L -DOPA , the intention is usually to reduce the  L -DOPA dosing, as by this stage the patient often has many of  dyskinesias  caused by  L -DOPA and hypermobility periods. [ 7 ] [ 8 ]  When an episode sets in, the apomorphine is injected  subcutaneously  or applied sublingually, [ 9 ]  and signs subside. It is used an average of three times a day. [ 7 ]  Some people use portable mini-pumps that continuously infuse them with apomorphine, allowing them to stay in the "on" state and using apomorphine as an effective  monotherapy . [ 8 ] [ 10 ]


The main and  absolute contraindication  to using apomorphine is the concurrent use of  adrenergic receptor  antagonists; combined, they cause a severe  drop in blood pressure  and  fainting . [ 7 ] [ 6 ]   Alcohol  causes an increased frequency of  orthostatic hypotension  (a sudden drop in blood pressure when getting up), and can also increase the chances of  pneumonia  and  heart attacks . [ 7 ]   Dopamine antagonists , by their nature of competing for sites at dopamine receptors, reduce the effectiveness of the agonistic apomorphine. [ 7 ] [ 6 ]


IV administration  of apomorphine is highly discouraged, as it can crystallize in the veins and create a blood clot ( thrombus ) and block a pulmonary artery ( pulmonary embolism ). [ 7 ] [ 6 ]


Nausea and vomiting are common side effects when first beginning therapy with apomorphine; [ 11 ]  antiemetics such as trimethobenzamide or domperidone, dopamine antagonists, [ 12 ]  are often used while first starting apomorphine. Around 50% of people grow tolerant enough to apomorphine's emetic effects that they can discontinue the antiemetic. [ 6 ] [ 7 ]


Other side effects include orthostatic hypotension and resultant fainting,  sleepiness ,  dizziness ,  runny nose ,  sweating ,  paleness , and  flushing . More serious side effects include dyskinesias (especially when taking  L -DOPA), fluid accumulation in the limbs ( edema ), suddenly falling asleep,  confusion  and  hallucinations ,  increased heart rate  and  heart palpitations , and persistent  erections  ( priapism ). [ 6 ] [ 7 ] [ 13 ]  The priapism is caused by apomorphine increasing arterial blood supply to the  penis . This side effect has been exploited in studies attempting to treat  erectile dysfunction . [ 14 ]


Apomorphine's  R-enantiomer  is an  agonist  of both  D 1  and  D 2  dopamine receptors , with higher activity at D 2 . [ 7 ] [ 12 ]  The members of the D 2  subfamily, consisting of D 2 ,  D 3 , and  D 4  receptors, are inhibitory  G protein–coupled receptors . The D 4  receptor in particular is an important target in the signaling pathway, and is connected to several neurological disorders. [ 15 ]  Shortage or excess of dopamine can prevent proper function and signaling of these receptors leading to disease states. [ 16 ]


Apomorphine improves motor function by activating dopamine receptors in the  nigrostriatal pathway , the  limbic system , the  hypothalamus , and the  pituitary gland . [ 17 ]  It also increases blood flow to the  supplementary motor area  and to the  dorsolateral prefrontal cortex  (stimulation of which has been found to reduce the  tardive dyskinesia  effects of  L -DOPA ). [ 18 ] [ 19 ]  Parkinson's has also been found to have excess  iron  at the sites of neurodegeneration; both the ( R )- and ( S )-enantiomers of apomorphine are potent iron  chelators  and  radical scavengers . [ 12 ] [ 20 ]


Apomorphine also decreases the breakdown of dopamine in the brain (though it inhibits its synthesis as well). [ 21 ] [ 22 ]  It is an upregulator of certain neural growth factors, [ 23 ]  in particular  NGF  but not  BDNF ,  epigenetic  downregulation of which has been associated with addictive behaviour in rats. [ 24 ] [ 25 ]


Apomorphine causes vomiting by acting on dopamine receptors in the  chemoreceptor trigger zone  of the  medulla ; this activates the nearby  vomiting center . [ 17 ] [ 22 ] [ 26 ]


While apomorphine has lower  bioavailability  when taken orally, due to not being absorbed well in the GI tract and undergoing heavy  first-pass metabolism , [ 20 ] [ 10 ]  it has a bioavailability of 100% when given subcutaneously. [ 7 ] [ 17 ]  It reaches peak plasma concentration in 10–60 minutes. Ten to twenty minutes after that, it reaches its peak concentration in the  cerebrospinal fluid . Its lipophilic structure allows it to cross the  blood–brain barrier . [ 7 ] [ 17 ]


Apomorphine possesses  affinity  for the following  receptors  (note that a  higher   K i  indicates a  lower  affinity): [ 27 ] [ 28 ] [ 29 ]


It has a  K i  of over 10,000 nM (and thus negligible affinity) for  β-adrenergic ,  H 1 , and  mACh . [ 2 ]


Apomorphine has a high  clearance rate  (3–5 L/kg/hr) and is mainly metabolized and excreted by the  liver . [ 17 ]  It is likely that while the  cytochrome P450 system  plays a minor role, most of apomorphine's metabolism happens via auto- oxidation ,  O -glucuronidation ,  O -methylation ,  N -demethylation , and  sulfation . [ 7 ] [ 17 ] [ 22 ]  Only 3–4% of the apomorphine is excreted unchanged and into the urine. The  half-life  is 30–60 minutes, and the effects of the injection last for up to 90 minutes. [ 7 ] [ 8 ] [ 17 ]


Toxicity depends on the route of administration; the  LD 50 s  in mice were 300 mg/kg for the oral route, 160 mg/kg for  intraperitoneal , and 56 mg/kg intravenous. [ 31 ]


Apomorphine has a  catechol  structure similar to that of dopamine. [ 21 ]


Several techniques exist for the creation of apomorphine from morphine. In the past,  morphine  had been combined with  hydrochloric acid  at high temperatures (around 150 °C) to achieve a low yield of apomorphine, ranging anywhere from 0.6% to 46%. [ 32 ]


More recent techniques create the apomorphine in a similar fashion, by heating it in the presence of any acid that will promote the essential dehydration rearrangement of morphine-type  alkaloids , such as  phosphoric acid . The method then deviates by including a water scavenger, which is essential to remove the water produced by the reaction that can react with the product and lead to decreased yield. The scavenger can be any reagent that will irreversibly react with water such as  phthalic anhydride  or  titanium chloride . The temperature required for the reaction varies based upon choice of acid and water scavenger. The yield of this reaction is much higher: at least 55%. [ 32 ]


The pharmacological effects of the naturally-occurring analog  aporphine  in the  blue lotus  ( Nymphaea caerulea ) [ 34 ]  were known to the ancient Egyptians and Mayans, [ 35 ]  with the plant featuring in tomb frescoes and associated with entheogenic rites. It is also observed in Egyptian erotic cartoons, suggesting that they were aware of its erectogenic properties.


The modern medical history of apomorphine begins with its synthesis by  Arppe  in 1845 [ 36 ]  from morphine and  sulfuric acid , although it was named  sulphomorphide  at first. Matthiesen and Wright (1869) used hydrochloric acid instead of sulfuric acid in the process, naming the resulting compound  apomorphine . Initial interest in the compound was as an emetic, tested and confirmed safe by London doctor  Samuel Gee , [ 37 ]  and for the treatment of stereotypies in farmyard animals. [ 38 ]  Key to the use of apomorphine as a behavioural modifier was the research of Erich Harnack, whose experiments in rabbits (which do not vomit) demonstrated that apomorphine had powerful effects on the activity of rabbits, inducing licking, gnawing and in very high doses convulsions and death.


Apomorphine was one of the earliest used pharmacotherapies for  alcoholism . The  Keeley Cure  (1870s to 1900) contained apomorphine, among other ingredients, but the first medical reports of its use for more than pure emesis come from James Tompkins [ 39 ]  and Charles Douglas. [ 40 ] [ 41 ]  Tompkins reported, after injection of 6.5 mg ("one tenth of a grain"):


In four minutes free emesis followed, rigidity gave way to relaxation, excitement to somnolence, and without further medication the patient, who before had been wild and delirious, went off into a quiet sleep.


Douglas saw two purposes for apomorphine:


[it can be used to treat] a paroxysm of dipsomania [an episode of intense alcoholic craving]...  in minute doses  it is much more rapidly efficient in stilling the dipsomaniac craving than strychnine or atropine… Four or even 3m [minim – roughly 60 microlitres] of the solution usually checks for some hours the incessant demands of the patient… when he awakes from the apomorphine sleep he may still be demanding alcohol, though he is never then so insistent as before. Accordingly it may be necessary to repeat the dose, and even to continue to give it twice or three times a day. Such repeated doses, however, do not require to be so large: 4 or even 3m is usually sufficient.


This use of small, continuous doses (1/30th of a grain, or 2.16 mg by Douglas) of apomorphine to reduce alcoholic craving comes some time before  Pavlov 's discovery and publication of the idea of the "conditioned reflex" in 1903. This method was not limited to Douglas; the Irish doctor Francis Hare, who worked in a sanatorium outside London from 1905 onward, also used low-dose apomorphine as a treatment, describing it as "the most useful single drug in the therapeutics of inebriety". [ 42 ]  He wrote:


In (the) sanatorium it is used in three different sets of circumstances: (1) in maniacal or hysterical drunkenness: (2) during the paroxysm of dipsomania,  in order to still the craving for alcohol;  and (3) in essential insomnia of a special variety... [after giving apomorphine] the patient's mental condition is entirely altered. He may be sober: he is free from the time being from any craving from alcohol. The craving may return, however, and then it is necessary to repeat the injection, it may be several times at intervals of a few hours. These succeeding injections should be quite small, 3 to 6 min. being sufficient.  Doses of this size are rarely emetic.  There is little facial pallor, a sensation as of the commencement of sea-sickness, perhaps a slight malaise with a sudden subsidence of the craving for alcohol, followed by a light and short doze.


He also noted there appeared to be a significant prejudice against the use of apomorphine, both from the associations of its name and doctors being reluctant to give hypodermic injections to alcoholics. In the US, the  Harrison Narcotics Tax Act  made working with any morphine derivatives extremely hard, despite apomorphine itself not being an opiate.


In the 1950s the neurotransmitter  dopamine  was discovered in the brain by  Katharine Montagu , and characterised as a neurotransmitter a year later by  Arvid Carlsson , for which he would be awarded the Nobel Prize. [ 43 ]  A. N. Ernst then discovered in 1965 that apomorphine was a powerful stimulant of dopamine receptors. [ 44 ]  This, along with the use of sublingual apomorphine tablets, led to a renewed interest in the use of apomorphine as a treatment for alcoholism. A series of studies of non-emetic apomorphine in the treatment of alcoholism were published, with mostly positive results. [ 45 ] [ 46 ] [ 47 ] [ 48 ] [ 49 ]  However, there was little clinical consequence.


The use of apomorphine to treat "the shakes" was first suggested by Weil in France in 1884, [ 50 ]  although seemingly not pursued until 1951. [ 51 ]  Its clinical use was first reported in 1970 by  Cotzias  et al., [ 52 ]  although its emetic properties and short half-life made oral use impractical. A later study found that combining the drug with the  antiemetic   domperidone  improved results significantly. [ 53 ]  The commercialization of apomorphine for Parkinson's disease followed its successful use in patients with refractory motor fluctuations using intermittent rescue injections and continuous infusions. [ 54 ]


Aversion therapy  in alcoholism had its roots in Russia in the early 1930s, [ 55 ]  with early papers by Pavlov, Galant and Sluchevsky and Friken, [ 56 ]  and would remain a strain in the Soviet treatment of alcoholism well into the 1980s. In the US a particularly notable devotee was Dr Voegtlin, [ 57 ]  who attempted aversion therapy using apomorphine in the mid to late 1930s. However, he found apomorphine less able to induce negative feelings in his subjects than the stronger and more unpleasant emetic  emetine .


In the UK, however, the publication of J. Y. Dent's (who later went on to treat Burroughs) 1934 paper "Apomorphine in the treatment of Anxiety States" [ 58 ]  laid out the main method by which apomorphine would be used to treat alcoholism in Britain. His method in that paper is clearly influenced by the then-novel idea of aversion:


He is given his favourite drink, and his favourite brand of that drink ... He takes it stronger than is usual to him ... The small dose of apomorphine, one-twentieth of a grain [3.24 mg], is now given subcutaneously into his thigh, and he is told that he will be sick in a quarter of an hour. A glass of whisky and water and a bottle of whisky are left by his bedside. At six o'clock (four hours later) he is again visited and the same treatment is again administered ... The nurse is told in confidence that if he does not drink, one-fortieth [1.62 mg] of a grain of apomorphine should be injected during the night at nine o'clock, one o'clock, and five o'clock, but that if he drinks the injection should be given soon after the drink and may be increased to two hourly intervals. In the morning at about ten he is again given one or two glasses of whisky and water ... and again one-twentieth of a grain [3.24 mg] of apomorphine is injected ... The next day he is allowed to eat what he likes, he may drink as much tea as he likes ... He will be strong enough to get up and two days later he leaves the home.


However, even in 1934 he was suspicious of the idea that the treatment was pure conditioned reflex – "though vomiting is one of the ways that apomorphine relives the patient, I do not believe it to be its main therapeutic effect." – and by 1948 he wrote: [ 4 ]


It is now twenty-five years since I began treating cases of anxiety and alcoholism with apomorphine, and I read my first paper before this Society fourteen years ago. Up till then I had thought, and, unfortunately, I said in my paper, that the virtue of the treatment lay in the conditioned reflex of aversion produced in the patient. This statement is not even a half truth… I have been forced to the conclusion that apomorphine has some further action than the production of a vomit.


This led to his development of lower-dose and non-aversive methods, which would inspire a positive trial of his method in Switzerland by Dr Harry Feldmann [ 59 ]  and later scientific testing in the 1970s, some time after his death. However, the use of apomorphine in aversion therapy had escaped alcoholism, with its use to treat homosexuality leading to the death of a British Army Captain Billy Clegg Hill in 1962, [ 60 ]  helping to cement its reputation as a dangerous drug used primarily in archaic behavioural therapies.


In his  Deposition: Testimony Concerning a Sickness  in the introduction to later editions of  Naked Lunch  (first published in 1959),  William S. Burroughs  wrote that apomorphine treatment was the only effective cure to  opioid addiction  he has encountered:


The apomorphine cure is qualitatively different from other methods of cure.  I have tried them all.  Short reduction, slow reduction,  cortisone ,  antihistamines ,  tranquilizers , sleeping cures, tolserol,  reserpine .  None of these cures lasted beyond the first opportunity to relapse.  I can say that I was never metabolically cured until I took the apomorphine cure... The doctor, John Yerbury Dent, explained to me that apomorphine acts on the back brain to regulate the metabolism and normalize the blood stream in such a way that the enzyme stream of addiction is destroyed over a period of four to five days.  Once the back brain is regulated apomorphine can be discontinued and only used in case of relapse.


He goes on to lament the fact that as of his writing, little to no research has been done on apomorphine or variations of the drug to study its effects on curing addiction, and perhaps the possibility of retaining the positive effects while removing the side effect of vomiting.


Despite his claims throughout his life, Burroughs never really cured his addiction and was back to using opiates within years of his apomorphine "cure". [ 61 ]  However, he insisted on apomorphine's effectiveness in several works and interviews. [ citation needed ]


There is renewed interest in the use of apomorphine to treat addiction, in both  smoking cessation [ 62 ]  and alcoholism. [ 63 ]  As the drug is known to be reasonably safe for use in humans, it is a viable target for repurposing.


Apomorphine has been researched as a possible treatment for erectile dysfunction and female hypoactive sexual desire disorder, though its efficacy has been limited. [ 14 ] [ 64 ]  Nonetheless, it  was under  development  as a treatment for  erectile dysfunction  by  TAP Pharmaceuticals  under the brand name Uprima. In 2000, TAP withdrew its  new drug application  after an FDA review panel raised questions about the drug's safety, due to many clinical trial subjects fainting after taking the drug. [ 65 ]


Apomorphine is reported to be an inhibitor of  amyloid beta  protein fiber formation, whose presence is a hallmark of  Alzheimer's disease , and a potential therapeutic under the  amyloid hypothesis . [ 66 ]


Two routes of administration are currently clinically utilized: subcutaneous (either as intermittent injections or continuous infusion) and sublingual. Other non-invasive administration routes were investigated as a substitute for parenteral administration, reaching different preclinical and clinical stages. These include: peroral, [ 67 ]  nasal, [ 68 ] [ 69 ] [ 70 ] [ 71 ]  pulmonary, [ 72 ]  transdermal, [ 73 ]  rectal, [ 74 ] [ 75 ]  and buccal, [ 76 ] [ 77 ]  as well as iontophoresis methods. [ 78 ]


Apomorphine is used to inducing vomiting in  dogs  after ingestion of various toxins or foreign bodies. It can be given subcutaneously, intramuscularly, intravenously, or, when a tablet is crushed, in the  conjunctiva  of the eye. [ 79 ] [ 80 ]  The oral route is ineffective, as apomorphine cannot cross the blood–brain barrier fast enough, and blood levels don't reach a high enough concentration to stimulate the chemoreceptor trigger zone. [ 79 ]  It can remove around 40–60% of the contents in the stomach. [ 81 ]


One of the reasons apomorphine is a preferred drug is its reversibility: [ 82 ]  in cases of prolonged vomiting, the apomorphine can be reversed with dopamine antagonists like the  phenothiazines  (for example,  acepromazine ). Giving apomorphine after giving acepromazine, however, will no longer stimulate vomiting, because apomorphine's target receptors are already occupied. [ 79 ]  An animal who undergoes severe  respiratory depression  due to apomorphine can be treated with  naloxone . [ 79 ] [ 80 ]


Apomorphine does not work in  cats , who have too few dopamine receptors. [ 79 ]


Mdo-npa, the  methylenedioxy   analog  of apomorphine, has greater  bioavailability  and a longer duration of action. [ citation needed ]


Benzoctamine  is a  drug  that possesses  sedative  and  anxiolytic  properties. Marketed as  Tacitin  by  Ciba-Geigy , it is different from most sedative drugs because in most  clinical trials  it does not produce  respiratory depression , but actually stimulates the  respiratory system . As a result, when compared to other  sedative  and  anxiolytic  drugs such as  benzodiazepines  like  diazepam , it is a safer form of  tranquilizing . However, when co-administered with other drugs that cause respiratory depression, like  morphine , it can cause increased respiratory depression.


Medically, benzoctamine is used as a treatment for anxious outpatients to control  aggression , [ 2 ]   enuresis , [ 3 ]  fear, and minor social maladjustment in children. [ 2 ]  re Its anxiolytic effects are most similar to  diazepam , another anxiolytic, but unlike  diazepam , benzoctamine has  antagonistic  effects on  epinephrine  and  norepinephrine , and appears to increase  serotonin  levels. While little is understood about how it carries out its effects, studies point to reduced serotonin, epinephrine, and  norepinephrine  as partial causes of its  pharmacologic  and behavioral effects.


Animal studies have shown sedative hypnotic drugs tend to show dependency in animals, but benzoctamine has been shown to not be addictive. Other animal studies also point to the drug as a possible mechanism by which to reduce blood pressure through the  adrenergic  system.


Chemically, benzoctamine belongs to the class of compounds called dibenzobicyclo-octadienes. It is a  tetracyclic compound , consisting of four rings in a three dimensional configuration, and is very closely related structurally to the  tetracyclic antidepressant  (TeCA)  maprotiline , differing only in the length of their  side chain .


Benzoctamine's main clinical use is for the treatment of  anxiety , and evidence points to it being as effective as other clinical anxiety drugs, in particular  diazepam . [ 4 ]  In the treatment of symptoms of mild anxiety due to  psychoneurosis , a daily dosage of 30 to 80 mg of benzoctamine was shown to be just as effective as 6–20 mg of diazepam. [ 4 ]  In another study one group of patients were given 10 mg of benzoctamine three times a day, while another group was given 5 mg of diazepam, and the treatments were equivalent. [ 4 ]  While these studies point to higher doses of benzoctamine being needed to exert the same pharmacological effects, the drug is still popular because of its ability to act as an anxiolytic without producing the common respiratory depression associated with other sedative drugs. Some studies have even shown that it stimulates the respiratory system. [ 5 ]


In a study used to compare benzoctamine to  sodium amylobarbitone  as a sleep promoter, it was found that during administration of both drugs, patients reported that their sleep was less restless, and drowsiness was diminished. [ 6 ]  The study further showed that while sodium amylobarbitone caused withdrawal rebound symptoms, benzoctamine did not. [ 6 ]  It was also found that benzoctamine reduced plasma corticosteroid hormone levels. [ 6 ]  There is a relationship between anxiety and adreno-corticosteroid activity, with raised levels commonly being reported as an indication of stress. [ 6 ]  The study showed that benzoctamine, a drug reported to reduce anxiety, was also able to reduce the hormones that potentially cause it. [ 6 ]  This points to a phenomenon often seen within pharmacology where drugs intended for other uses often have far-reaching and rarely considered effects.


Benzoctamine has been found to have the same efficacy as chlordiazepoxide when treating anxiety neurosis. [ 7 ]


While benzoctamine was made to be an alternative to the  benzodiazepine  line of anxiolytic drugs, other uses for the drug have been discovered. Due to benzoctamine's ability to  tranquilize  without causing respiratory depression, scientists are moving forward with studies that test its sedative effects in patients with respiratory failure. In one study that used benzoctamine in a clinical setting, researchers showed that the use of benzoctamine for sedation did not result in changes in  forced expiratory volume in one second  or  carbon dioxide partial pressure  ( p CO 2 ). [ 8 ]  This confirmed previous statements that claimed the drug did not cause respiratory failure. The main goal of this clinical study was to confirm the findings of another study that showed benzoctamine did not reduce CO 2  responsiveness, but instead increased the ventilatory response to CO 2 . [ 9 ]


There are usually many risks associated with using sedatives on patients who are suffering from respiratory failure, which has made it difficult to administer tranquillizing medications in situations when they are desirable. It is not known why this drug is safe and its benzodiazepine cousins are not, but a possible explanation for this phenomenon might come from its similarity in structure to  tricyclic antidepressants , which have also been shown to not cause respiratory failure. [ 8 ]  While further experimentation is necessary, this study points to benzoctamine's possible consideration for sedation in respiratory failure patients.


A possible treatment for  hypertension  is blocking peripheral vascular seretonergic neurons or alpha- adrenergic  neurons on  postsynaptic cell  sites. [ 10 ]  One study showed that benzoctamine, a serotonin and alpha-adrenergic  antagonist , does not reduce blood pressure through a seretonin mechanism but does reduce  blood pressure  by antagonizing alpha- adrenergic receptors  in rats. [ 10 ]  Rats were given 10 mg of benzoctamine and drops in their blood pressure were approximately 30mm Hg. [ 10 ]  The researchers further confirmed that  serotonin antagonism  was not sufficient to reduce blood pressure by using the highly selective serotonin antagonist  1-(1-naphthyl)piperazine , which was not able to decrease the blood pressure of the rats. [ 10 ]  These studies have yet to be repeated in humans.


Common side effects include drowsiness (incidence of 9%), gastro-intestinal upset, dry mouth, headache, and dizziness (incidence of 1-2% each). [ 11 ]


Studies have shown that benzoctamine increases level of serotonin. [ 12 ]  Scientists confirmed these results and proposed that the method of action was inhibition of serotonin uptake since the drug also blocked the serotonin depleting action of extra-neuronal monoamine transporters (EMT). [ 13 ]  This would lead to increased stimulation of serotonin receptors through a  negative feed back  mechanism, eventually decreasing serotonin out put. However, the study points out that other studies have shown that drugs combined with EMT cause a lowering of body temperature that in fact results in a decrease in  serotonin  turnover. [ 13 ]  This means that body temperature effects cannot be ruled out.


Not much is understood about how benzoctamine produces its anti-anxiety effects, but rat studies have shown that the possible mechanism of action is by way of increased turnover of  catecholamines . [ 14 ]  In addition to serotonin it has also been shown to decrease epinephrine,  dopamine , and norepinephrine turnover by antagonizing their receptors. [ 13 ]  When given intravenously in doses of 20–40 mg there are no significant differences in efficacy. [ 15 ]  Oral doses exceeding 10 mg three times daily do not increase the effects of the drug. [ 4 ]  Assuming serotonin postsynaptic antagonism is the main mechanism by which benzoctamine carries out its effects, studies have shown it to have an  IC 50  value of 115 mM at the serotonin receptor. [ 16 ]


Benzoctamine can be injected directly into the blood or given as tablets. When given as tablets, it is given in doses of 10 mg three times daily. [ 4 ]  And when given intravenously, patients are given the drug at a rate of 5 mg/minute until 20–40 mg of drug has been injected. [ 15 ]  Benzoctamine can be analyzed as the  3 H acetyl derivative and  N -methyl  metabolite  it gets broken down into using radioactive analysis. [ 17 ]  Benzoctamine has a half-life of 2–3 hours, [ 5 ]  with a  bioavailability  of  around >90% when given orally. [ 18 ]  The average time to achieve peak plasma concentrations is 1 hour [ 5 ]  and the  volume of distribution  for a 70 kg person is 1–2 L/kg. [ 5 ]


Bunazosin  ( INN ) is an  α 1 -adrenergic receptor   antagonist . [ 1 ]  Bunazosin was initially developed to treat benign prostatic hyperplasia (BPH). It has been approved in Japan in a topical form to treat  glaucoma . The mechanism of action is a reduction of aqueous outflow through the uveoscleral pathway resulting in lowering the intraocular pressure. It also may act to improve blood flow to the ocular nerve. Systemic Alpha-1 adrenergic receptor antagonists have been implicated in Intraoperative Floppy Iris Syndrome (IFIS). Bunazosin potentially could have the same effect but there has been no research to substantiate this as a risk for cataract surgery.


This  antihypertensive -related article is a  stub . You can help Wikipedia by  expanding it .


Idazoxan  ( INN ) is a  drug  which is used in  scientific research . It acts as both a selective  α 2   adrenergic receptor   antagonist , and an antagonist for the  imidazoline receptor . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  Idazoxan has been under investigation as an  antidepressant , but it did not reach the market as such. More recently, it is under investigation as an adjunctive treatment in  schizophrenia . Due to its α 2  receptor antagonism it is capable of enhancing therapeutic effects of  antipsychotics , possibly by enhancing  dopamine   neurotransmission  in the  prefrontal cortex  of the brain, a brain area thought to be involved in the  pathogenesis  of schizophrenia.


Mice treated with idazoxan, which blocks the  α 2A  receptor  which regulates  norepinephrine , behaved similarly to control animals despite still having amyloid-beta plaques in the brain, as a proof-of-concept experiment that dramatically reduced  Alzheimer's  pathology and symptoms in two mouse models, potentially offering an immediate treatment for this devastating disease. [ 5 ]


Note that the literature method claims that the old original patented procedure gives a different reaction product formed through a rearrangement.


The reaction of catechol ( 1 ) with 2-Chloroacrylonitrile [920-37-6] ( 2 ) gives 2-cyano-1,4-benzodioxan [1008-92-0] ( 3 ).  Pinner reaction  with alcoholic hydrogen chloride leads to the iminoether, [ 11 ]  ( 4 ). Treatment with  ethylenediamine  [107-15-3] ( 5 ) gives the imidazoline ring affording  Idazoxin  ( 6 ).


Ifenprodil , sold under the brand names  Cerocral ,  Dilvax , and  Vadilex , is a  cerebral vasodilator  that has been marketed in some countries, including in  Japan ,  Hong Kong , and  France . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  It is currently under development for treatment of a variety of additional indications. [ 5 ]


Ifenprodil has multiple known  pharmacological actions . [ 5 ]  It is an  inhibitor  of the  NMDA receptor , [ 6 ]  specifically of NMDA receptors containing  GluN1  and  GluN2B   subunits , the "ifenprodil binding site". [ 7 ]  Additionally, ifenprodil inhibits  GIRK channels [ 8 ]  and interacts with  α 1 -adrenergic , [ 5 ]   serotonin , [ 9 ]  and  sigma   receptors . [ 10 ] [ 11 ] [ 12 ] [ 5 ]


Chemically, ifenprodil is a  substituted phenethylamine  and  β-hydroxyamphetamine   derivative . [ 2 ] [ 3 ]  It is used  pharmaceutically  as the  tartrate   salt . [ 1 ] [ 2 ] [ 3 ]


Ifenprodil has been studied as a possible medication to prevent  tinnitus  after  acoustic trauma . [ 13 ]


It is currently in  phase II  trials for  cough  and  idiopathic pulmonary fibrosis , among other investigational uses. [ 5 ]


Imiloxan  is a drug which is used in  scientific research . It acts as a selective  antagonist  for the  α 2B   adrenergic receptor , [ 1 ]  and has been useful for distinguishing the actions of the different α 2  adrenergic subtypes. [ 2 ] [ 3 ]


The  imidazole  portion of imiloxan is prepared by the reaction of an  imidate  with the diethyl acetal of  aminoacetaldehyde .  N -Alkylation of the imidazole with  ethyl iodide  gives imiloxan.


Isoxaprolol  is an  adrenergic antagonist  with  antiarrhythmic  and  antihypertensive  properties. [ 1 ]


This  drug  article relating to the  cardiovascular system  is a  stub . You can help Wikipedia by  expanding it .


Neldazosin  is an  α-adrenoreceptor antagonist . [ 1 ]


Nordoxepin , also known as  N -desmethyldoxepin , is an  organic compound .  A colorless solid, it attracted attention as the major  active metabolite  of the  tricyclic antidepressant  (TCA)  doxepin  (Sinequan). [ 2 ]  It has been found to play a significant role in the  antidepressant  effects of doxepin. [ 3 ]


Nordoxepin is a  mixture  of  ( E ) and ( Z )   stereoisomers . [ 2 ]  Whereas  pharmaceutical  doxepin is supplied in an approximate 85:15 ratio mixture of ( E )- and ( Z )-stereoisomers and plasma concentrations of doxepin remain roughly the same as this ratio with treatment, plasma levels of the ( E )- and ( Z )-stereoisomers of nordoxepin, due to  stereoselective   metabolism  of doxepin by  cytochrome P450   enzymes , are approximately 1:1. [ 2 ]


Nordoxepin is  pharmacologically active  similarly to doxepin, [ 4 ]  but relative to doxepin, is much more  potent  and  selective  as a  norepinephrine reuptake inhibitor . [ 2 ] [ 5 ] [ 6 ]  In general, the demethylated variants of  tertiary amine  TCAs like doxepin are much more potent  inhibitors  of  norepinephrine   reuptake , less potent inhibitors of  serotonin  reuptake, and less potent in their  antiadrenergic ,  antihistamine , and  anticholinergic  activities. [ 5 ] [ 6 ] [ 7 ]


Nordoxepin is formed from doxepin mainly by  CYP2C19  (>50% contribution), while  CYP1A2  and  CYP2C9  are involved to a lesser extent, and  CYP2D6  and  CYP3A4  are not involved. [ 8 ]   Hydroxylation  of doxepin and nordoxepin is mediated mainly by CYP2D6. [ 3 ]  Total exposures to both doxepin and nordoxepin differ by almost 10-fold in CYP2D6  ultra-rapid  versus  poor metabolizers . [ 3 ]  Both doxepin and nordoxepin are also  transformed  into  glucuronide   conjugates . [ 3 ]  The  elimination half-life  of nordoxepin is approximately 31 hours, which is almost twice that of doxepin (mean 17 hours). [ 1 ]


Ocaperidone  ( R 79598 ) is a  benzisoxazole   antipsychotic . [ 1 ]  It was initially developed by  Janssen , later licensed to French laboratory Neuro3D and then acquired in 2007 by German company  Evotec . It was found to be more potent than  risperidone  in animal studies, [ 2 ]  but its testing was abandoned in 2010 after unfavorable results in human Phase II trials, [ 3 ]  as while it was effective at controlling symptoms of  schizophrenia , ocaperidone produced an unacceptable amount of  extrapyramidal  side effects. [ 4 ]


The last step requires attachment of the sidechain between 3-(2-bromoethyl)-2,9-dimethyl 4 H -pyrido[1,2-a]pyrimidin-4-one ( 1 ) and 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole ( 2 ) completing the  convergent synthesis  of ocaperidone ( 3 ).


Oxetorone  ( INN Tooltip International Nonproprietary Name ), as  oxetorone fumarate  ( USAN Tooltip United States Adopted Name ) (brand names  Nocertone ,  Oxedix ), is a  serotonin antagonist ,  antihistamine , and  alpha blocker  used as an  antimigraine drug . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  Association with  hyperprolactinemia  has been described [ 5 ]  and  antidopaminergic  actions are also suspected. [ 6 ]


Piperoxan , also known as  benodaine , was the first  antihistamine  to be discovered. [ 1 ] [ 2 ]  This compound, derived from  benzodioxan , was prepared in the early 1930s by  Daniel Bovet  and  Ernest Fourneau  at the  Pasteur Institute  in  France . [ 1 ] [ 2 ]  Formerly investigated by Fourneau as an  α-adrenergic - blocking  agent, they demonstrated that it also  antagonized   histamine -induced  bronchospasm  in  guinea pigs , and published their findings in 1933. [ 1 ] [ 2 ] [ 3 ]  Bovet went on to win the 1957  Nobel Prize in Physiology or Medicine  for his contribution. [ 4 ]  One of Bovet and Fourneau's students,  Anne-Marie Staub , published the first  structure–activity relationship  (SAR) study of antihistamines in 1939. [ 1 ]  Piperoxan and  analogues  themselves were not clinically useful due to the production of  toxic  effects in humans and were followed by  phenbenzamine  (Antergan) in the early 1940s, which was the first antihistamine to be marketed for medical use. [ 5 ]


Condensation of  catechol  [120-80-9] ( 1 ) with  epichlorohydrin  in the presence of an aqueous base can be visualized as proceeding initially with the epoxide ( 2 ) Opening of the oxirane ring by the phenoxide anion then leads to 2-hydroxymethyl-1,4-benzodioxane [3663-82-9] ( 3 ). Halogenation with  thionyl chloride  gives 2-chloromethyl-1,4-benzodioxane [2164-33-2] ( 4 ). Displacement of the leaving group by piperidine completed the synthesis of piperoxan ( 5 ).


In  pharmacology  and  toxicology , a  route of administration  is the way by which a  drug , fluid, poison, or other substance is taken into the body. [ 1 ]


Routes of administration are generally classified by the  location at which the substance is applied.  Common examples include  oral  and  intravenous  administration. Routes can also be classified based on where the target of action is.  Action may be  topical  (local),  enteral  (system-wide effect, but delivered through the  gastrointestinal tract ), or  parenteral  (systemic action, but is delivered by routes other than the GI tract). Route of administration and  dosage form  are aspects of  drug delivery .


Routes of administration are usually classified by application location (or exposition).


The route or course the active substance takes from application location to the location where it has its target effect is usually rather a matter of  pharmacokinetics  (concerning the processes of uptake, distribution, and elimination of drugs). Exceptions include the  transdermal  or transmucosal routes, which are still commonly referred to as  routes of administration .


The location of the target effect of active substances is usually rather a matter of  pharmacodynamics  (concerning, for example, the physiological effects of drugs [ 2 ] ). An exception is  topical administration , which generally means that both the application location and the effect thereof is local. [ 3 ]


Topical administration  is sometimes defined as both a local application location and local  pharmacodynamic  effect, [ 3 ]  and sometimes merely as a local application location regardless of location of the effects. [ 4 ] [ 5 ]


Through the  gastrointestinal tract  is sometimes termed  enteral or enteric administration  (literally meaning 'through the  intestines ').  Enteral/enteric administration  usually includes  oral [ 6 ]  (through the  mouth ) and  rectal  (into the  rectum ) [ 6 ]  administration, in the sense that these are taken up by the intestines. However, uptake of drugs administered orally may also occur already in the  stomach , and as such  gastrointestinal  (along the  gastrointestinal tract ) may be a more fitting term for this route of administration. Furthermore, some application locations often classified as  enteral , such as  sublingual [ 6 ]  (under the tongue) and  sublabial  or  buccal  (between the cheek and gums/ gingiva ), are taken up in the proximal part of the  gastrointestinal tract  without reaching the intestines. Strictly  enteral administration  (directly into the intestines) can be used for systemic administration, as well as local (sometimes termed  topical ), such as in a contrast  enema , whereby contrast media are infused into the intestines for imaging. However, for the purposes of classification based on location of effects, the term enteral is reserved for substances with systemic effects.


Many drugs as  tablets ,  capsules , or drops are taken orally. Administration methods directly into the stomach include those by  gastric feeding tube  or  gastrostomy . Substances may also be placed into the  small intestines , as with a  duodenal  feeding tube and  enteral nutrition . Enteric coated tablets are designed to dissolve in the intestine, not the stomach, because the drug present in the tablet causes irritation in the stomach.


The  rectal  route is an effective route of administration for many medications, especially those used at the  end of life . [ 7 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ]  The walls of the rectum absorb many medications quickly and effectively. [ 14 ]  Medications delivered to the distal one-third of the rectum at least partially avoid the " first pass effect " through the liver, which allows for greater  bio-availability  of many medications than that of the oral route. Rectal  mucosa  is highly  vascularized  tissue that allows for rapid and effective absorption of medications. [ 15 ]  A  suppository  is a solid  dosage form  that fits for  rectal administration . In  hospice care , a specialized rectal  catheter , designed to provide comfortable and discreet administration of ongoing medications provides a practical way to deliver and retain liquid formulations in the  distal  rectum, giving health practitioners a way to leverage the established benefits of rectal administration. The  Murphy drip  is an example of rectal infusion.


The parenteral route is any route that is not  enteral  ( par-  +  enteral ).


Parenteral administration can be performed by  injection , that is, using a needle (usually a  hypodermic needle ) and a  syringe , [ 16 ]  or by the insertion of an  indwelling catheter .


Locations of application of parenteral administration include:


The definition of the topical route of administration sometimes states that both the application location and the  pharmacodynamic  effect thereof is local. [ 3 ]


In other cases,  topical  is defined as applied to a localized area of the body or to the surface of a body part regardless of the location of the effect. [ 4 ] [ 5 ]  By this definition,  topical administration  also includes  transdermal  application, where the substance is administered onto the skin but is  absorbed  into the body to attain  systemic  distribution.


If defined strictly as having local effect, the topical route of administration can also include  enteral administration  of medications that are poorly absorbable by the  gastrointestinal tract . One such medication is the antibiotic  vancomycin , which cannot be absorbed in the gastrointestinal tract and is used orally only as a treatment for  Clostridioides difficile  colitis . [ 24 ]


The reason for choice of routes of drug administration are governing by various factors:


In acute situations, in  emergency medicine  and  intensive care medicine , drugs are most often given intravenously. This is the most reliable route, as in acutely ill patients the absorption of substances from the tissues and from the digestive tract can often be unpredictable due to altered blood flow or bowel motility.


Enteral routes are generally the most convenient for the patient, as no punctures or  sterile  procedures are necessary. Enteral medications are therefore often preferred in the treatment of chronic disease. However, some drugs can not be used enterally because their absorption in the digestive tract is low or unpredictable. Transdermal administration is a comfortable alternative; there are, however, only a few drug preparations that are suitable for transdermal administration.


Identical drugs can produce different results depending on the route of administration. For example, some drugs are not significantly absorbed into the bloodstream from the gastrointestinal tract and their action after enteral administration is therefore different from that after parenteral administration. This can be illustrated by the action of  naloxone  (Narcan), an antagonist of  opiates  such as  morphine . Naloxone counteracts opiate action in the  central nervous system  when given intravenously and is therefore used in the treatment of opiate overdose. The same drug, when swallowed, acts exclusively on the bowels; it is here used to treat constipation under opiate pain therapy and does not affect the pain-reducing effect of the opiate.


The oral route is generally the most convenient and costs the least. [ 25 ]  However, some drugs can cause  gastrointestinal tract  irritation. [ 26 ]  For drugs that come in  delayed release  or  time-release  formulations, breaking the tablets or capsules can lead to more rapid delivery of the drug than intended. [ 25 ]  The oral route is limited to  formulations  containing  small molecules  only while biopharmaceuticals (usually proteins) would be  digested in the stomach and thereby become ineffective. Biopharmaceuticals have to be given by injection or infusion. However, recent research found various ways to improve oral bioavailability of these drugs. In particular permeation enhancers, [ 27 ]   ionic liquids , [ 28 ]  lipid-based nanocarriers, [ 29 ]  enzyme inhibitors and microneedles [ 30 ]  have shown potential.


Oral administration  is often denoted "PO" from "per os", the Latin for "by mouth".


The bioavailability of oral administration is affected by the amount of drug that is absorbed across the  intestinal epithelium  and  first-pass metabolism . [ 31 ]


The  oral mucosa  is the mucous membrane lining the inside of the  mouth .


Buccally administered  medication is achieved by placing the drug between  gums  and the inner lining of the  cheek . [ 32 ] [ 33 ]  In comparison with sublingual tissue, buccal tissue is less permeable resulting in slower  absorption . [ 33 ]


Sublingual administration  is fulfilled by placing the drug between the tongue and the lower surface of the mouth. [ 33 ]  The  sublingual mucosa  is highly permeable and thereby provides access to the underlying expansive network composed of capillaries, leading to rapid drug absorption. [ 33 ]


Drug administration via the nasal cavity yields rapid drug absorption and therapeutic effects. [ 33 ]  This is because drug absorption through the nasal passages does not go through the gut before entering  capillaries  situated at  tissue cells  and then systemic circulation and such absorption route allows transport of drugs into the  central nervous system  via the pathways of  olfactory  and  trigeminal nerve . [ 33 ]