The cholinergic drug

The cholinergic drugA cholinergic drug is a drug that acts on the peripheral nervous system, the primeval nervous system, or both and enhances the tack togethers that are mediated by acetylcholine. It is to a fault known as cholinergic agent, parasympathomimetic drug or cholinergic agonist. 12 It can work in two ways each acting involvely by mimicking the effects of acetylcholine at one or more acetylcholine receptors consecrate in the body, or acting indirectly by blocking/inhibiting the enzyme acetylcholine that is responsible for the degradation/ hydrolysis of acetylcholine. 12Depending on the type of receptor to act on, cholinergic drugs are either classified as muscarinic agonists or nicotinic agonists. 6Anticholinergic drugsAn anticholinergic drug is a drug or an agent that competes with the neurotransmitter acetylcholine for its binding sites at synaptic junctions thereby suppressing or inhibiting its activity and thus preventing the transmission of parasympathetic nerve impulses. 34Depending on the type of receptor to act on, anticholinergic drugs are either classified as muscarinic antagonists or nicotinic antagonists. 6Pilocarpine (Chemical formula=C11H16N2O2)IntroductionPilocarpine is a naturally occur isthmus alkaloid which is extracted from the South American shrub named Pilocarpus jaborandi. It is a non-selective cholinergic parasympathomimetic agonist that binds to muscarinic-M3 receptors and results in contraction of smooth muscles and stimulation of various exocrine glands. 5The drug is available in the form of eye drops, tablets, suspensions and gel. It has a slow onset of action which is about 10 to 15 proceeding entirely has a longer eon of action of about 6 to 8 hours, and therefore can be given thrice a day. It is inactivated at neuronal synapses and in plasma and is excreted in urine.Pilocarpine can be subroutined in combination with other sympathomimetics, carbonic anhydrase inhibitors, miotics, beta-blockers, or hyperosmotic a gents. 8HistoryIn 1875, Mr. Gerrard find pilocarpine from the leaves of Pilocarpus jaborandi. At that time, he believed that there were at least two alkaloids present in this plant. At the same time, M. Hardy isolated pilocarpine.In 1876, the isolated pilocarpine alkaloid was introduced to formal ophthalmology for the treatment of glaucoma.1879, Straws, sequence doing an active research concerning the sudoriferous secretion in cases of facial paralysis, was the first to employ local medication with pilocarpine and published relevant results.Chemical implication of pilocarpineAlthough pilocarpine looks like a simple molecule but it has a complex chemic synthesis. This is because of the stereospecific construction of the imidazole moiety that is cis to the ethyl group on the butyrolactone ring which makes its synthesis difficult and challenging. The starting reagent for its synthesis is 2-acetylbutyrolactone which undergoes selenenylation by reacting with phenylaelenenyl chloride to produce a seleno lactone 2-acetyl-2-(phenylselenyl) butyrolactone with a gestate of 94%. This is then subjected to oxidative elimination of selenoxide in the nominal head of cyclo-pentadiene and hydrogen peroxide to produce a mixture of endo and exo bicycle ketones in a ratio of 2.31. Pyrolysis (flash vacuum thermolysis) of these ketones produces a white solid 3-acetyl-2(5H)-furanone with a yield of 95%. This ketone is then reduced under mild conditions by treating it with an asymmetric reducing agent (+)-?-chlorodiisopinocamphenylborane, which is used particularly for chiral reductions, to produce (3R)-3-(1-hydroxyethyl)-2(5H)-furanone in 60% chemical yield and an optical purity of 92% that was determined by NMR analysis. Next, a stereocentre is introduced at C4 of the (3R)-3-(1-hydroxyethyl)-2(5H)-furanone by the Claisen rearrangement at its vinyl ether which produces an exocyclic double bond and the (4R)-acetaldehyde place chain. Both of them are necessary for the formatio n of the imidazole ring. This will result in a 21 mixture of (4R)-(Z)-dehydrohomopilopic aldehyde and (4S)-E-diastereomer in 71% yield. Hydrogenation of (4R)-(Z)-dehydrohomopilopic aldehyde in the presence of pyridine/benzene (11) solution at 25?C at 1atm for 1 hour produces (3s,cis)-Homopilopic aldehyde. Finally, when (3s,cis)-Homopilopic aldehyde is reacted with 1,5-disubstituted imidazole under aprotic conditions, it results in the formation of pilocarpine in 61% yield. 9Structure-activity relationship (SAR)The unsandedton on the imidazole ring is protonated before interacting with the muscarinic receptor. There is a strong ionic interaction between the charged newton share and an anionic side group of an aspartate resiimputable in the receptor. The methyl radical substitute on the nitrogen is positioned in an open region of the binding site. Hydrogen bind interactions exist between the ester group of pilocarpine and an asparagines residue of the cholinergic receptor. A sma ll hydrophobic pocket exists in the receptor site which can accommodate the methyl group of pilocarpine. The drug has a correct pharmacophore for the muscarinic receptor with a separation between nitrogen and oxygen being 4.4?A. 6Mechanism of actionPilocarpine is a direct acting cholinergic agent that resembles acetylcholine and therefore binds to the same muscarinic neuroreceptor and results in its stimulation. In eye, it causes contraction of the iris sphincter muscle and therefore results in miosis (pupil constriction).clinical usesPilocarpine has been used in the treatment of both acute closed-angle and chronic open-angle glaucoma. 8 Glaucoma is a condition when the aqueous contents of the eye cannot be drained. This result in increase intraocular pressure which causes optic nerve damage and can lead to side vision damage (peripheral vision damage) and if not treated, can result in central vision damage and leads to irreversible blindness. 6Pilocarpine is also used to treat xero stomia which is a condition characterised by dryness of the oral mucosa. The drug acts on cholinergic receptors in the glandular parenchyma thereby increasing the salivary secretion. 7Pilocarpine hydrochloride (Salagen) tablets are prescribed to the patients suffering from Sjgren syndrome (SS) in order to treat their symptoms of xerostomia (dry mouth) and xerophthalmia (dry eyes). Sjgren syndrome (SS) is a chronic, autoimmune, rheumatoid disorder in which immune cells attack and destroy the exocrine glands that produce tears and saliva. This in turn makes the individual susceptible to various infections and if untreated whitethorn also lead to other complications like bacterial sialadenitis, bacterial conjunctivitis, stomatopyrosis (burning mouth), oral candidiasis, oral ulcers, periodontal disease, accelerated dental caries, corneal ulceration or perforation, malnutrition, angle loss and sleep disruption. 5Pilocarpine is also used to diagnose cystic fibrosis (CF). 8 Cystic fibros is is a common hereditary disease which is characterised by scarring (fibrosis) and formation of cyst within the pancreas. The disease is characterised by shortness of breath, frequent chest infections, sinus infections, salty tasting skin, normal appetite but poor growth and poor metric weight unit gain, excess mucus production, diarrhea and infertility in males. 14 Sweat test method acting is used to diagnose of disease in which the drug stimulates sweat glands in order to measure the concentration of chloride and sodium that is excreted in the sweat.Pilocarpine is often used as an antidote for Atropine, Hyoscyamine and Scopolamine insobriety. 8Adverse effectsSince pilocarpine is a non-selective muscarinic receptor anonist, its use can result in a wide variety of side-effects which can include lacrimation, excessive perspiration, excessive salivation, bronchospasm, increased bronchial mucus secretion, muscle tremors, tachycardia, hypertension, diarrhea, dazed vision and eye pa in, browache and miosis when used chronically as an eye drop. When pilocarpine is used in the form systemic injection, it can cross the blood-brain barrier and hap the brain where it can lead to chronic epilepsy. 13Suggestions for rule of new drugsPilocarpine has significant legal transfer problems associated with its low lipophilicity. Its bioavailability in the eye is low, duration of action is fast due to its rapid elimination from the eye and above all, it has serious side effects like miosis and myopia. Based on the knowledge of dependence of drug delivery with physicochemical properties of the drug, a prodrug approach can be used to improve the delivery characteristics of pilocarpine. A prodrug should be designed such(prenominal) that it has a higher lipophilicity than pilocarpine which would alter it to cross the corneal membrane with ease, should have sufficient aqueous solubility so that it could be formulated as eyedrops, should be able to convert backward to the acti ve parent drug within the cornea, should have a controlled release and a prolonged duration of action. 10CurareIntroductionCurare is a nicotinic antagonist. It is a crude, dried extract from a plant called Chondrodendron tomentosum. 6 It is a mixture of 70 alkaloids. 11 The active principle in curare is tubocurarine (C37H41N2O6). 6The antidote for curare poisoning is an acetylcholinesterase (AChE) inhibitor (anti-cholinesterase), such as physostigmine or neostigmine. 15The drug is available in the form of solutions and intravenous injections. It has an onset of action of about 4 to 6 minutes and duration of action of about 80 to 120 minutes. It is eliminated through kidney and liver.History of curareDuring the sixteenth century, the South American indigenous people used curare as a paralyzing poison where they killed the prey by dipping the arrows or blowgun darts in curare. 16The prey is killed due to asphyxia in which the respiratory muscles fail to contract. 16In 1780, Abbe Felix Fontana studied the effects of curare on midsection, voluntary muscles and nerves and found that it affects the voluntary muscles of the body as compared to the other two. 15In 1800, Alexander von Humboldt reported the method used by the Orinoco River natives to prepare the curare toxin from its plant source.16During 1811-1812 Benjamin Collins Brodie (1783-1862), a leading English surgeon, experimented with curare. 16He found that curare paralysed the respiratory muscles but the heart continued to beat for a while. 16He was the first to show that if the animals respiration is maintained artificially, recovery is complete. 16In 1850, George Harley found that tetanus or strychnine poisoning can be cured by using curare. 15From 1887 the Burroughs Wellcome catalogue listed under its Tabloids brand name, tablets of curare at 1/12 grain (price 8 shillings) for use in preparing a solution for hypodermic injection. 15In 1939, Henry Hallett Dale reported the antagonistic effect of curare o n acetylcholine. 15Mechanism of actionCurare is a non-depolarizing muscle relaxant that blocks the nicotinic acetylcholine receptor. The main toxin of curare, d-tubocurarine, is a competitive antagonist of acetylcholine and so occupies the same position on the receptor as the neurotransmitter but does not switch it on. The overall effect on the body is the same as it would be in the absence of acetylcholine. 15History of tubocurarineIn 1935, Harold King of London was experimenting on a standard of curare in Sir Henry Dales laboratory and was not only able to isolate tubocurarine in its pure form from the crude drug but also discovered its chemical structure. 16In 1912, tubocurarine was used for the first time in medicine. 15In 1942, tubocurarine was used along with anaesthetics in functional procedures to relax muscles. 15Structure-activity relationshipThe structure of tubocurarine is shown in fig. Although the molecule does not have an ester group to bind to the nicotinic recepto r, but it has two positively charged nitrogen atoms, one of which is a tertiary nitrogen atom while the other is a quaternity nitrogen. One of them binds to the anionic binding region of the nicotinic receptor while the other binds to a nearby cysteine residue that is 0.9-1.2nm away. Such an intreraction is so strong that it makes up for the lack of the ester binding interaction. Also, the distance between the two positive centres is 1.15nm which is also important for the activity of the drug. 6IndicationCurare is used in the diagnosis of myasthenia gravis, 17which is an autoimmune disease in which antibodies are produced against acetylcholine nicotinic post synaptic receptors at the neuro-muscular junction. 18Curare is also used in surgical procedures in association with general anesthesia in order to facilitate in the relaxation of abdominal muscles when it is not possible with inhalation anesthesia. 12Adverse effectsCurare has undesirable side-effects, the most common of which include hypotension (by ganglion-block and histamine release), bronchoconstriction (by histamine release), skeletal muscles paralysis and asphyxia (impaired breathing). 15Suggestions for design of new drugsTubocurarine has undesirable side effects because it also acts as an antagonist at the nicotinic receptors of the autonomic nervous system. Also, its defusing depends on metabolic mechanisms involving enzymatic deactivation and/or excretion, the efficiency of which varies from patient to patient and is particularly poor for patients with low levels of plasma esterases or kidney failure. Therefore, a self-destruct mechanism can be introduced into the design of a new drug for its sufficiently rapid breakdown. If a good electron withdrawing group is introduced on to a carbon that is beta to the quaternary nitrogen centre, Hofmann elimination is possible under the slightly alkaline pH of blood (pH = 7.4) and body temperature. The electron-withdrawing groups will function to increase the acidity of the hydrogen on the beta-carbon such that it is easily lost. Thus by introducing such a group, the drug is inactivated and is unable to bind to its receptor due to the loss of the positive charge on the quaternary centre and is split into two molecules. Thus deactivation occurs at a constant rate between patients. 6