Haloperidol

Haloperidol does not produce a high; it produces a subtraction. Within thirty to sixty minutes of administration, the emotional landscape begins to flatten, as though someone is slowly turning down the volume on every feeling simultaneously. Joy, anger, anxiety, curiosity -- all of them lose their amplitude, their peaks shaved down to a uniform, low-grade hum that barely registers as feeling at all. The world does not change, but your relationship to it does: things that mattered intensely an hour ago now seem distant, theoretical, belonging to someone else.

The physical effects arrive alongside the emotional flattening and are difficult to ignore. A profound restlessness seizes the body -- akathisia, an inner agitation that demands movement even as the medication makes movement feel laborious and uncoordinated. The legs want to pace. The arms want to shift position. Sitting still becomes an exercise in endurance, but standing and moving provides only momentary relief before the restlessness reasserts itself. This is the cruel paradox of haloperidol: it suppresses the mind's capacity for distress while simultaneously generating a physical distress that the suppressed mind cannot adequately process or express.

At higher doses, the body begins to feel alien. Muscles stiffen, losing their natural fluidity and acquiring a wooden, resistant quality that makes every movement feel effortful and mechanical. The face may freeze into a mask-like expression, the usual micro-movements that convey emotion and intention suppressed by the compound's dopaminergic blockade. The jaw clenches or drifts open. The tongue may move of its own accord. These are the extrapyramidal effects, the movement disturbances that are haloperidol's most recognizable signature, and they produce a deeply unsettling sensation of losing ownership of your own body.

Cognitively, the experience is one of diminishment. Thoughts come more slowly, with less color and less energy. Creativity evaporates. The ability to generate motivation for any activity -- conversation, work, recreation -- dwindles to near zero. There is no stupor exactly; consciousness remains clear, but it is a consciousness stripped of its driving forces, an engine with the fuel lines disconnected. The world is perceived accurately but responded to minimally, as though through bulletproof glass.

The duration depends on the formulation -- oral doses last six to eight hours, while depot injections can maintain these effects for weeks. The offset brings a gradual return of emotional color and physical spontaneity, a slow repopulation of the inner landscape that had been pharmacologically evacuated. The experience of haloperidol is not one that anyone describes as pleasant; it is an experience of reduction, of neural quieting carried past the point of therapeutic benefit into a territory that feels like a diminished version of oneself.

Haloperidol is a typical butyrophenone-type antipsychotic that exhibits high-affinity dopamine D2 receptor antagonism and slow receptor dissociation kinetics. It has effects similar to the phenothiazines. The drug binds preferentially to D2 and α1 receptors at low dose (ED50 = 0.13 and 0.42mg/kg, respectively), and 5-HT2 receptors at a higher dose (ED50 = 2.6mg/kg). Given that antagonism of D2 receptors is more beneficial on the positive symptoms of schizophrenia and antagonism of 5-HT2 receptors on the negative symptoms, this characteristic underlies haloperidol's greater effect on delusions, hallucinations and other manifestations of psychosis. Haloperidol's negligible affinity for histamine H1 receptors and muscarinic M1 acetylcholine receptors yields an antipsychotic with a lower incidence of sedation, weight gain, and orthostatic hypotension though having higher rates of treatment emergent extrapyramidal symptoms.

Pharmacokinetics By mouth The bioavailability of oral haloperidol ranges from 60 to 70%. However, there is a wide variance in reported mean Tmax and T1/2 in different studies, ranging from 1.7 to 6.1 hours and 14.5 to 36.7 hours respectively.

Intramuscular injections The drug is well and rapidly absorbed with a high bioavailability when injected intramuscularly. The Tmax is 20 minutes in healthy individuals and 33.8 minutes in patients with schizophrenia. The mean T1/2 is 20.7 hours. The decanoate injectable formulation is for intramuscular administration only and is not intended to be used intravenously. The plasma concentrations of haloperidol decanoate reach a peak at about six days after the injection, falling thereafter, with an approximate half-life of three weeks.

Intravenous injections The bioavailability is 100% in intravenous (IV) injection, and the very rapid onset of action is seen within seconds. The T1/2 is 14.1 to 26.2 hours. The apparent volume of distribution is between 9.5 and 21.7 L/kg. The duration of action is four to six hours.

Therapeutic concentrations Plasma levels of five to 15 micrograms per liter are typically seen for therapeutic response (Ulrich S, et al. Clin Pharmacokinet. 1998). The determination of plasma levels is rarely used to calculate dose adjustments but can be useful to check compliance.

The concentration of haloperidol in brain tissue is about 20-fold higher compared to blood levels. It is slowly eliminated from brain tissue, which may explain the slow disappearance of side effects when the medication is stopped.

Distribution and metabolism Haloperidol is heavily protein bound in human plasma, with a free fraction of only 7.5 to 11.6%. It is also extensively metabolized in the liver with only about 1% of the administered dose excreted unchanged in the urine. The greatest proportion of the hepatic clearance is by glucuronidation, followed by reduction and CYP-mediated oxidation, primarily by CYP3A4. Haloperidol is metabolized into HPP, a monoaminergic neurotoxin related to MPTP, by CYP3A enzymes.

According to Francisco López-Munoz, the "discovery of haloperidol at the end of the 1950s constitutes one of the greatest advances of 20th century psychiatry." This antipsychotic drug has their origin in the research process of central analgesic molecules derived from pethidine and methadone, carried out by the Belgian company Janssen Phamaceutica. After the synthesis of phenoperidine, numerous analogues of this compound were studied, and chemists at Janssen took the decision to substitute the propiophenone group for a butyrophenone group. One of these compounds went the R-1625, a stronger agent with specifically neuroleptic properties but lacking morphine-like activity.

Haloperidal was synthesized on the 11th February 1958 and received the generic name of haloperidol because of the two halogenated substitutes incorporated into the molecule. Clinical development of haloperidol was conducted, primarily, by psychiatric research team at the University of Liège that confirmed its efficacy in the treatment of various psychiatric disorders such as acute and chronic paranoid psychosis, mania, or chronic treatment-resistant schizophrenia. Under the brand name Haldol((R)), haloperidol was licensed and marketed in Belgium in October 1959.

can have serious side effects at higher dosages,risk of having severe extrapyramidal symptoms and muscle rigidity, which can last for hours.

Both typical and atypical antipsychotics can cause tardive dyskinesia. Rates are lower with the atypicals at 3.9% as opposed to the typicals at 5.5%. Switching to these atypicals is an option to minimize symptoms of tardive dyskinesia caused by other atypicals.

It is strongly recommended that one use harm reduction practices when using this drug.

• Australia:** The drug is available via prescription only.

• Canada:** The drug is available via prescription only.

• Germany:** Haloperidol is a prescription medicine, according to Anlage 1 AMVV.

• Switzerland:** Haloperidol is listed as a "Abgabekategorie B" pharmaceutical, which requires a prescription.

• United Kingdom:** Haloperidol is a prescription-only medication.

• United States:** The drug is available via prescription only.

• Responsible use

• Antipsychotic

• Quetiapine

• Pethidine

• Risperidone

• Haloperidol (Wikipedia)

• Haloperidol (TiHKAL / Isomer Design)

• Haloperidol decanoate (Isomer Design)

• Haloperidol propionate (Isomer Design)

• Haloperidol (DrugBank)

• Haloperidol (Drugs.com)