Trihexyphenidyl
Encyclopedia
Trihexyphenidyl also known as benzhexol, is an antiparkinsonian agent of the antimuscarinic class. It has been in clinical usage for decades. The drug is available as the hydrochloride salt.
). 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
.
. 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.
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 Tremors.
Trihexyphenidyl does not improve cerebral palsy
and hemiplegia
.
s are frequent. Particularly geriatric patients may react with confusional states or develop delirium
.
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.
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 so-called Mannich reaction
. In the second step the 2-(1-piperidino)propiophenone is reacted with cyclohexylmagnesiumbromide in a Grignard reaction
.
Linear vs Convergent syntheses. Although the convergent synthesis is used on an industrial
scale, it is uses hazardous reagents and is not as desirable as the linear procedure for small-scale preparations.
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 (mydriasisMydriasis
Mydriasis is a dilation of the pupil due to disease, trauma or the use of drugs. Normally, the pupil dilates in the dark and constricts in the light to respectively improve vividity at night and to protect the retina from sunlight damage during the day...
). In higher doses direct central inhibition of cerebral motor centers may contribute. In very high doses central toxicity as seen in atropine
Atropine
Atropine is a naturally occurring tropane alkaloid extracted from deadly nightshade , Jimson weed , mandrake and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects...
overdose is noted.
It binds to the M1 muscarinic receptor and possibly the dopamine receptor
Dopamine receptor
Dopamine receptors are a class of metabotropic G protein-coupled receptors that are prominent in the vertebrate central nervous system . The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors....
.
Pharmacokinetics
Trihexyphenidyl is rapidly absorbed from the gastrointestinal tractGastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
. 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.
Uses
Trihexyphenidyl is used for the symptomatic treatment of Parkinson's diseaseParkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
in mono- and combination therapy. It is active in postencephalitic, arteriosclerotic, and idiopathic forms. The drug is also commonly used to treat extrapyramidal
Extrapyramidal symptoms
The extrapyramidal system can be affected in a number of ways, which are revealed in a range of extrapyramidal symptoms , also known as extrapyramidal side-effects , such as akinesia and akathisia .Extrapyramidal symptoms are various movement disorders such as acute dystonic reactions,...
side effects occurring during antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
treatment. It reduces the frequency and duration of oculogyric crises
Oculogyric crisis
Oculogyric crisis is the name of a dystonic reaction to certain drugs or medical conditions. The term "Oculogyric" refers to rotating of eyeballs, but several other responses are associated with the crisis.-Causes:...
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
Levodopa
L-DOPA is a chemical that is made and used as part of the normal biology of some animals and plants. Some animals including humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine , and epinephrine collectively...
, other antimuscarinic or antihistaminic (e.g. diphenhydramine
Diphenhydramine
Diphenhydramine hydrochloride is a first-generation antihistamine possessing anticholinergic, antitussive, antiemetic, and sedative properties which is mainly used to treat allergies. Like most other first-generation antihistamines, the drug also has a powerful hypnotic effect, and for this reason...
) agents. Combination treatment with dopaminergic agonists such as cabergoline
Cabergoline
Cabergoline , an ergot derivative, is a potent dopamine receptor agonist on D2 receptors. In vitro, rat studies show cabergoline has a direct inhibitory effect on pituitary lactotroph cells...
is also possible. This is often termed a 'multidimensional approach'.
It has also been prescribed for Essential Tremors.
Investigational
Equivocal preliminary results from small studies exist for:- Other dyskinesias
- Huntington's chorea
- Spasmodic torticollisTorticollisTorticollis, or wryneck, is a stiff neck associated with muscle spasm, classically causing lateral flexion contracture of the cervical spine musculature...
- DystoniaDystoniaDystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...
Trihexyphenidyl does not improve cerebral palsy
Cerebral palsy
Cerebral palsy is an umbrella term encompassing a group of non-progressive, non-contagious motor conditions that cause physical disability in human development, chiefly in the various areas of body movement....
and hemiplegia
Hemiplegia
Hemiplegia /he.mə.pliː.dʒiə/ is total paralysis of the arm, leg, and trunk on the same side of the body. Hemiplegia is more severe than hemiparesis, wherein one half of the body has less marked weakness....
.
Contraindications and cautions
- Hypersensitivity to trihexyphenidyl
- Narrow angle glaucomaGlaucomaGlaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
- IleusIleusIleus is a disruption of the normal propulsive ability of the gastrointestinal tract.Ileus is commonly defined simply as bowel obstruction. However, authoritative sources define it as decreased motor activity of the GI tract due to non-mechanical causes...
- Caution : Patients with obstructive diseases of the urogenital tract, patients with a known history of seizures and those with potentially dangerous tachycardiaTachycardiaTachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
- 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.
Pregnancy and lactation
The safe use of Trihexyphenidyl during pregnancy and lactation has not been established.Side effects
Dose-dependent side effectAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s are frequent. Particularly geriatric patients may react with confusional states or develop delirium
Delirium
Delirium or acute confusional state is a common and severe neuropsychiatric syndrome with core features of acute onset and fluctuating course, attentional deficits and generalized severe disorganization of behavior...
.
- CNS : Drowsiness, vertigoVertigo (medical)Vertigo is a type of dizziness, where there is a feeling of motion when one is stationary. The symptoms are due to a dysfunction of the vestibular system in the inner ear...
, headacheHeadacheA headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
, and dizzinessDizzinessDizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
are frequent. With high doses nervousness, agitation, anxietyAnxietyAnxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, delirium, and confusion are noted. Trihexyphenidyl may be abused due to a short acting mood-elevating and euphoriant effect. The normal sleep architecture may be altered (REM sleep depression). Trihexyphenidyl may lower the seizure-threshold. - Peripheral side effects : Blurred vision, dry mouth, impaired sweating, abdominal discomfort, and obstipation are frequent. Tachycardia may be noted. Allergic skin reactions may occur. Parenteral use may cause orthostatic hypotension.
- Eyes : Trihexyphenidyl causes mydriasisMydriasisMydriasis is a dilation of the pupil due to disease, trauma or the use of drugs. Normally, the pupil dilates in the dark and constricts in the light to respectively improve vividity at night and to protect the retina from sunlight damage during the day...
with or without photophobiaPhotophobiaPhotophobia is a symptom of abnormal intolerance to visual perception of light. As a medical symptom photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to the eyes due to light exposure or by presence of actual physical photosensitivity of the eyes, though the term...
. It may precipitate narrow angle glaucoma. - Tolerance may develop during therapy which requires dose adjustments.
Interactions
- Other anticholinergic drugs (e.g. spasmolytics, antihistamineAntihistamineAn H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...
s, TCAs) : Side effects of trihexyphenidyl may be increased. - QuinidineQuinidineQuinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree.-Mechanism:...
: Increased anticholinergic action (particular on AV conduction). - Antipsychotics : Long term use of trihexyphenidyl may mask or increase the risk of tardive dyskinesiaTardive dyskinesiaTardive dyskinesia is a difficult-to-treat form of dyskinesia that can be tardive...
. - PethidinePethidinePethidine or meperidine Pethidine (INN) or meperidine (USAN) Pethidine (INN) or meperidine (USAN) (commonly referred to as Demerol but also referred to as: isonipecaine; lidol; pethanol; piridosal; Algil; Alodan; Centralgin; Dispadol; Dolantin; Mialgin (in Indonesia); Petidin Dolargan (in Poland);...
(meperidine) : Central effects and side effects of pethidine may be increased. - MetoclopramideMetoclopramideMetoclopramide is an antiemetic and gastroprokinetic agent. It is commonly used to treat nausea and vomiting, to facilitate gastric emptying in people with gastroparesis, and as a treatment for the gastric stasis often associated with migraine headaches.-Medical uses:Metoclopramide is commonly...
: Action of metoclopramide is decreased. - Alcohol : Risk of serious intoxication.
Dosage
- Parkinson's disease : One mg is given on the first day. Increments are usually 2 mg every 3 days until 6 to 10 mg are reached. In postencephalitic cases up to 15 mg might be necessary, but then excessive dryness of mouth or nausea could be a problem. To increase tolerability Trihexyphenidyl may be given in 3 divided doses.
- Extrapyramidal side effects : Usually, 5 to 15 mg daily are needed in 2 or 3 divided doses. Some patients, however, are successfully treated with as little as 1 mg daily.
Overdose
Trihexyphenidyl mimics an atropine intoxication with mydriasis, dryness of mucous membranes, red face, atonic states of bowels and bladder, and hyperthermiaHyperthermia
Hyperthermia is an elevated body temperature due to failed thermoregulation. Hyperthermia occurs when the body produces or absorbs more heat than it can dissipate...
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
Physostigmine
Physostigmine is a parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean....
which combines a peripheral and a central action. Carbachol
Carbachol
Carbachol , also known as carbamylcholine, is a drug that binds and activates the acetylcholine receptor. Thus it is classified as a cholinergic agonist. It is primarily used for various ophthalmic purposes, such as for treating glaucoma, or for use during ophthalmic surgery...
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.
Recreational use
In a 2008 news report, trihexyphenidyl has been used recreationally among Iraqi soldiers and police, among other prescription drugs. The report states that the drugs were taken to relieve combat stress..Dosage forms
- Elixir, as hydrochloride: 2 mg/5 mL (480 mL)
- Tablet, as hydrochloride: 2 mg, 5 mg
Chemistry
Trihexyphenidyl, 1-cyclohexyl-1-phenyl-3-piperidineopropan-1-ol, is synthesized in two ways (linear and convergent synthesis):In the first way, the initial 2-(1-piperidino)propiophenone is synthesized in turn by the aminomethylation of acetophenone
Acetophenone
Acetophenone is the organic compound with the formula C6H5CCH3. It is the simplest aromatic ketone. This colourless, viscous liquid is a precursor to useful resins and fragrances.-Production:Acetophenone can be obtained by a variety of methods...
using paraformaldehyde
Paraformaldehyde
Paraformaldehyde is the smallest polyoxymethylene, it is the condensation reaction product of formaldehyde with a typical degree of polymerization of 8–100 units. Paraformaldehyde commonly has a slight odor of formaldehyde due to decomposition...
and piperidine
Piperidine
Piperidine is an organic compound with the molecular formula 5NH. This heterocyclic amine consists of a six-membered ring containing five methylene units and one nitrogen atom...
in a so-called Mannich reaction
Mannich reaction
The Mannich reaction is an organic reaction which consists of an amino alkylation of an acidic proton placed next to a carbonyl functional group with formaldehyde and ammonia or any primary or secondary amine. The final product is a β-amino-carbonyl compound also known as a Mannich base...
. In the second step the 2-(1-piperidino)propiophenone is reacted with cyclohexylmagnesiumbromide in a Grignard reaction
Grignard reaction
The Grignard reaction is an organometallic chemical reaction in which alkyl- or aryl-magnesium halides add to a carbonyl group in an aldehyde or ketone. This reaction is an important tool for the formation of carbon–carbon bonds...
.
Linear vs Convergent syntheses. Although the convergent synthesis is used on an industrial
Industry
Industry refers to the production of an economic good or service within an economy.-Industrial sectors:There are four key industrial economic sectors: the primary sector, largely raw material extraction industries such as mining and farming; the secondary sector, involving refining, construction,...
scale, it is uses hazardous reagents and is not as desirable as the linear procedure for small-scale preparations.