Procyclidine
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Procyclidine is an
anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the acetylcholine (ACh) neurotransmitter at synapses in the central nervous system, central and peripheral nervous system. These agents inhibit the parasympatheti ...
drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...
principally used for the treatment of drug-induced
parkinsonism Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), Rigidity (neurology), rigidity, and balance disorder, postural instability. Both hypokinetic features (bradykinesia and akinesia) and hyperkinetic f ...
,
akathisia Akathisia (IPA: /æ.kə.ˈθɪ.si.ə/) is a movement disorder characterized by a subjective feeling of inner restlessness accompanied by mental distress and/or an inability to sit still. Usually, the legs are most prominently affected. Those a ...
and acute
dystonia Dystonia is a neurology, neurological Hyperkinesia, hyperkinetic Movement disorders, movement disorder in which sustained or repetitive muscle contractions occur involuntarily, resulting in twisting and repetitive movements or abnormal fixed po ...
,
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
, and
idiopathic An idiopathic disease is any disease with an unknown cause or mechanism of apparent spontaneous origin. For some medical conditions, one or more causes are somewhat understood, but in a certain percentage of people with the condition, the cause ...
or secondary
dystonia Dystonia is a neurology, neurological Hyperkinesia, hyperkinetic Movement disorders, movement disorder in which sustained or repetitive muscle contractions occur involuntarily, resulting in twisting and repetitive movements or abnormal fixed po ...
.


Medical uses

It is used in patients with
parkinsonism Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), Rigidity (neurology), rigidity, and balance disorder, postural instability. Both hypokinetic features (bradykinesia and akinesia) and hyperkinetic f ...
and
akathisia Akathisia (IPA: /æ.kə.ˈθɪ.si.ə/) is a movement disorder characterized by a subjective feeling of inner restlessness accompanied by mental distress and/or an inability to sit still. Usually, the legs are most prominently affected. Those a ...
, and to reduce the side effects of
antipsychotic Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), p ...
treatment given for
schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
. Procyclidine is also a second-line drug for the treatment of
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
. It improves
tremor A tremor is an involuntary, somewhat rhythmic muscle contraction and relaxation involving neural oscillations, oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the h ...
but not rigidity or
bradykinesia Hypokinesia is one of the classifications of movement disorders, and refers to decreased bodily movement. Hypokinesia is characterized by a partial or complete loss of muscle movement due to a disruption in the basal ganglia. Hypokinesia is a sy ...
. Procyclidine is also sometimes used for the treatment of
dystonia Dystonia is a neurology, neurological Hyperkinesia, hyperkinetic Movement disorders, movement disorder in which sustained or repetitive muscle contractions occur involuntarily, resulting in twisting and repetitive movements or abnormal fixed po ...
(but not
tardive dyskinesia Tardive dyskinesia (TD) is an iatrogenic disorder that results in involuntary repetitive body movements, which may include grimacing, sticking out the tongue or smacking the lips, which occurs following treatment with medication. Additional mo ...
), a rare disorder that causes abnormal muscle contraction, resulting in twisting postures of limbs, trunk, or face.


Side Effects

Side effects include nausea, constipation, urinary retention, blurred vision, anxiety, cognitive impairment, confusion, dizziness, gingivitis, hallucination, memory loss, rash and vomiting.


Overdose

Signs of procyclidine overdose are those of an
anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the acetylcholine (ACh) neurotransmitter at synapses in the central nervous system, central and peripheral nervous system. These agents inhibit the parasympatheti ...
and include confusion, agitation and sleeplessness that can last up to or more than 24 hours. Pupils become dilated and unreactive to light.
Tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ...
(fast heart beat), as well as auditory and visual hallucinations have also been reported. Other known symptoms of overdose are: clumsiness or unsteadiness, being severely drowsy, having a severely dry mouth, nose, or throat, having an altered mood or other mental changes, seizures, being short of breath or having troubled breathing, a dry and warm, flushed skin. A suspected overdose with severe life-threatening symptoms should immediately be brought to medical attention, where reversal can be attempted with
physostigmine Physostigmine (also known as eserine from ''éséré'', the West African name for the Calabar bean) is a highly toxic parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean and ...
administered intravenously or subcutaneously.


Pharmacology


Pharmacodynamics

Procyclidine is an
anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the acetylcholine (ACh) neurotransmitter at synapses in the central nervous system, central and peripheral nervous system. These agents inhibit the parasympatheti ...
. It is specifically an
antimuscarinic A muscarinic acetylcholine receptor antagonist, also simply known as a muscarinic antagonist or as an antimuscarinic agent, is a type of anticholinergic drug that blocks the activity of the muscarinic acetylcholine receptors (mAChRs). The muscarin ...
. The drug acts as a non-selective
antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.muscarinic acetylcholine M1, M2, and M4 receptors, whereas its activities at the M3 and M5 receptors are reportedly unknown.


Chemistry


Synthesis

Procyclidine, 1-cyclohexyl-1-phenyl-3-pyrrolidinopropan-1-ol, is synthesized in exactly the same manner as was seen for
trihexyphenidyl Trihexyphenidyl (THP, benzhexol, trihex, marketed as Artane and others) is an antispasmodic drug used to treat stiffness, tremors, spasms, and poor muscle control. It is an agent of the antimuscarinic class and is often used in management of P ...
, except this time the linear synthesis begins with the preparation of 3-(1-pyrrolidino)propiophenone. In an interesting variation, the ketone is first reacted with phenylmagnesium bromide.
Catalytic hydrogenation Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a catalyst such as nickel, palladium or platinum. The process is commonly employed to reduce or saturate organic ...
of the carbinol thus obtained can be stopped after the reduction of only one aromatic ring. Morton method:, GB773748 (1957 to Wellcome Foundation Ltd). The Reformatsky reaction between Cyclohexyl phenyl ketone (BzCy) 12-50-5(1) and Ethyl Bromoacetate 05-36-2(2) gives ethyl 3-cyclohexyl-3-hydroxy-3-phenylpropanoate
PC12565684
(3). The reduction of the ester gives 1-cyclohexyl-1-phenylpropane-1,3-diol
PC13841193
(4). FGI of the primary alcohol to the Tosyl leaving group gives 3-Cyclohexyl-3-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate 02473-43-8(5). Alkylation with pyrrolidine 23-75-1completes the synthesis of procyclidine.


See also

*
Benzatropine Benzatropine ( INN), known as benztropine in the United States and Japan, is a medication used to treat movement disorders like parkinsonism and dystonia, as well as extrapyramidal side effects of antipsychotics, including akathisia. It is n ...
*
Biperiden Biperiden, sold under the brand name Akineton among others, is a medication used to treat Parkinson disease, certain drug-induced movement disorders and Tourette Syndrome. It is not recommended for tardive dyskinesias. It is taken by mouth, in ...
*
Cycrimine Cycrimine (trade name Pagitane) is a central anticholinergic drug designed to reduce the levels of acetylcholine in the treatment of Parkinson's disease. Its mechanism of action is to bind to the muscarinic acetylcholine receptor M1. Synthesis ...


References


Further reading

* {{Muscarinic acetylcholine receptor modulators 1-Pyrrolidinyl compounds Hydrochlorides Cyclohexyl compounds M1 receptor antagonists M2 receptor antagonists M3 receptor antagonists M4 receptor antagonists M5 receptor antagonists Tardive dyskinesia Tertiary alcohols