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Trihexyphenidyl (Artane, Apo-Trihex, Parkin, Pacitane), also known as benzhexol, Ariane, and trihex, is an antiparkinsonian agent of the antimuscarinic class. It has been in clinical usage for decades.

History
Artane, or its generic form Trihexyphenidyl HCL, was approved by the FDA on June 25th, 2003 for the clinical use of all types of parkinsonism. However, it has been clinically relevant in trials pertaining to Parkinson's disease since 1949. Artane is an anticholinergic drug which is prescribed by doctors to patients throughout the world. It is also abused by psychotic patients and non psychotic young people, typically in combination with other drugs or delicate pharmaceutical agents. Prisons in Iraq were among the places where abuse was obvious, along with within communities of Iraqi soldiers. There has already been an effort in psychiatric units in that area to survey the origins of this specific form of substance abuse. One of the goals of this research is to elucidate the decision making algorithm for treating these communities as patients on their road to recovery. The research found 146 (28.7%) of the 508 Interviewed [in a Kurdistan federal prison] to be dependent on substances. Artane was found to be the main drug that was abused by inmates. They were mostly young, single and were addicted on other substances with Artane. Some scholars believe that this uprising of substance abuse is merely due to more options taking part in criminal aspects of substance abuse. Similar cases have been arising in Brazil.

Uses
Trihexyphenidyl is used for the symptomatic treatment of Parkinson's disease in mono and combination therapy. It is active in postencephalitic, arteriosclerotic, and idiopathic forms. The drug is also commonly used to treat extrapyramidal side effects occurring during antipsychotic treatment. It reduces the frequency and duration of oculogyric crises as well as of dyskinetic movements and spastic contractions. Excessive salivation may also respond. Trihexyphenidyl may improve psychotic depression and mental inertia frequently associated with Parkinson's disease and symptomatic problems caused by antipsychotic treatment.

The drug cannot cure Parkinson's disease, but may provide substantial alleviation of symptoms. An estimated 50 to 75% of patients with Parkinson's disease will react positively and experience a 20 to 30% symptomatic improvement. To increase therapeutic activity trihexyphenidyl is often given concomitantly with levodopa, other antimuscarinic or antihistaminic (e.g. diphenhydramine) agents. Combination treatment with dopaminergic agonists such as cabergoline is also possible. This is often termed a 'multidimensional approach'. It has also been prescribed for essential tremor and akathisia.

Recreational use
In a 2008 news report, trihexyphenidyl was seen to be used for recreational purposes among Iraqi soldiers and police, among other prescription drugs. The report states that the drugs were taken to relieve combat stress. Although that may be the case for some, others used Artane as a substitute or more intense version of LSD. This was especially prevalent in the 1960's, according to a report in "The New Yorker". Similarly to those in Iraqi forces, some of the appeal was that the individual may retain partial control while under the influence.

The neurologist Oliver Sacks reports using the drug recreationally in the 1960s. He states to have taken upwards of twenty pills knowing full well the drug was intended for Parkinson's patients. More recounts of Dr. Sack's experiences - including experimentation with mescaline, psilocybin, LSD, and probably DMT - have been compared in his novel Hallucinations (book)

Symptoms and Side Effects
Dose-dependent side effects are frequent, but typically lessen over time as the body adapts to the medication. All of the following symptoms considered, Artane has been shown to dramatically and consistently improve neurologic defects in patients aged 16-86 over the course of five years. Geriatric or psychiatric patients may become confused or develop delirium. Side effects include but are not limited to:


 * Central nervous system: drowsiness, vertigo, headache, and dizziness are frequent. With high doses nervousness, agitation, anxiety, delirium, and confusion are noted. Trihexyphenidyl may be abused due to a short acting mood-elevating and euphoric effect. The normal sleep architecture may be altered (REM sleep depression). Trihexyphenidyl may lower the seizure-threshold.
 * Peripheral side effects: dry mouth, impaired sweating (diaphoresis), abdominal discomfort, nausea, and constipation are frequent. Tachycardia or heart palpitations (fast heart rate) may be noted. Allergic reactions are rare, but may occur. Many of these peripheral symptoms, especially considering an acute increase in anxiety with various physical complaints, as well as evidence of orthostatic hypotension and tachycardia are indicative of withdrawal, especially in psychiatric patients
 * Eyes: trihexyphenidyl causes mydriasis with or without photophobia. It may precipitate narrow angle glaucoma or cause blurred vision.
 * Tolerance may develop during therapy which requires dose adjustments.
 * Striated musculature and weight gain.

Trihexyphenidyl is a pregnancy category C drug for patients whom this may apply. It is advised to only use with caution if benefits outweigh risks.

Overdose
Trihexyphenidyl (THP) and other antiparkinsonian drugs are known to be substances of abuse. This is true both in abusers of other substances and in chronic schizophrenics, the latter being infrequent abusers of other drugs. Trihexyphenidyl mimics an atropine intoxication with mydriasis, dryness of mucous membranes, red face, atonic states of bowels and bladder, and hyperthermia in high doses. Central consequences are agitation, confusion, and hallucinations. An untreated overdose may be fatal, particularly in children. Premortal signs are respiratory depression and cardiac arrest. A specific antagonist is physostigmine which combines a peripheral and a central action. Carbachol can be used to treat atonic bowel and bladder. The vital functions should be monitored and stabilized. It may be necessary to treat hyperthermia with cooling blankets. Clinical case reports have repeatedly shown overdose of Trihexyphenidyl alongside other substances. The co-ingestion of Risperidone, Ziprasidone, Valproate, Trihexyphenidyl, and Clonazepam for instance would likely present unconscious, requiring intubation, intravenous fluids, and management of vital signs, electrolytes, and orientation status. Although many of these medications are neurologically oriented, patients are not required to be seizing post-consumption of anti-epileptics or antiparkinsonian medications.

Antidote
Physostigmine is indicated to reverse the central nervous system effects caused by clinical or toxic dosages of agents capable of producing anticholinergic syndrome such as Artane ; however, long lasting reversal of anticholinergic signs and symptoms is generally not achieved because of the relatively short duration of action of physostigmine (45 to 60 minutes). It is most often used diagnostically to distinguish anticholinergic delirium from other causes of altered mental status. CAUTION: If tricyclic antidepressants are co-ingested, physostigmine may precipitate seizures and dysrhythmias.

ADULT: BOLUS: The manufacturer recommends 2 mg IV at a slow controlled rate, no more than 1 mg/min. May repeat doses at intervals of 10 to 30 min, if severe symptoms recur.

ALTERNATE DOSAGE REGIMEN: 1 to 2 mg infused IV over at least 5 minutes. May repeat dosage at 10 to 15 min intervals as long as the toxic effect persists and there are no signs of cholinergic effects. For patients with prolonged anticholinergic delirium, consider a continuous infusion, start at 2 mg/hr an titrate to effect.

CHILD: 0.02 mg/kg (maximum 0.5 mg) by slow IV injection, at a rate no more than 0.5 mg/minute (manufacturer recommendation) or over at least 5 minutes. Repeat dosage at 5 to 15 minute intervals as long as the toxic effect persists and there are no signs of cholinergic effects.

MAXIMUM DOSAGE: 2 mg total. CAUTION: Too rapid IV administration of physostigmine can result in bradycardia, hypersalivation leading to respiratory difficulties, and seizures.

Pharmacology
The exact mechanism of action in parkinsonian syndromes is not precisely understood, but it is known that trihexyphenidyl blocks efferent impulses in parasympathetically innervated structures like smooth muscles (spasmolytic activity), salivary glands, and eyes (mydriasis). In higher doses direct central inhibition of cerebral motor centers may contribute. In very high doses central toxicity as seen in atropine overdose is noted. It binds to the M1 muscarinic receptor and possibly the dopamine receptor. Trihexyphenidyl is rapidly absorbed from the gastrointestinal tract. The onset of action is within 1 hour after oral dosing. The peak activity is noted after 2 to 3 hours. The duration of action of one single dose is 6 to 12 hours in a dose dependent manner. It is excreted in the urine, probably as unchanged drug. More precise data in animals and humans have so far not been determined.

Investigational Studies
Equivocal preliminary results from small studies exist for:


 * Other dyskinesias
 * Huntington's chorea
 * Spasmodic torticollis
 * Dystonia
 * Trihexyphenidyl has been shown to improve cerebral palsy and hemiplegia in pediatric patients.
 * Treatment of hypersalivation in patients suffering from Amyotrophic Lateral Sclerosis (ALS)

Interactions

 * Other anticholinergic drugs (e.g. spasmolytics, antihistamines, TCAs) : Side effects of trihexyphenidyl may be increased.
 * Quinidine : Increased anticholinergic action (particular on AV conduction).
 * Antipsychotics : Long term use of trihexyphenidyl may mask or increase the risk of tardive dyskinesia.
 * Pethidine (meperidine) : Central effects and side effects of pethidine may be increased.
 * Metoclopramide : Action of metoclopramide is decreased.
 * Alcohol : Risk of serious intoxication.

Contraindications and cautions

 * Hypersensitivity to trihexyphenidyl
 * Narrow angle glaucoma
 * Ileus
 * Caution : Patients with obstructive diseases of the urogenital tract, patients with a known history of seizures and those with potentially dangerous tachycardia
 * Patients under 18 yrs. of age should not be treated due to a lack of clinical experience.
 * Patients should allow a period to adjust to the dose when first starting trihexyphenidyl and when the dose has been increased or added to a regimen with other drugs because acute somnolence and accumulated fatigue can make it particularly dangerous to operate an automobile, heavy machinery etc.

Synthesis
Trihexyphenidyl can be synthesized in two ways, one linear and one convergent synthesis.

In the first way, the initial 2-(1-piperidino)propiophenone is synthesized in turn by the aminomethylation of acetophenone using paraformaldehyde and piperidine in a Mannich reaction. In the second step the 2-(1-piperidino)propiophenone is reacted with cyclohexylmagnesium bromide in a Grignard reaction.