Medicinal Chemistry I - Unit 3 - PDF

JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir UNIT-III Cholinergi...

JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir UNIT-III Cholinergic and Anticholinergic Drug The nervous system is divided into the somatic nervous system, which controls organs under voluntary control (mainly muscles) and the autonomic nervous system (ANS) which regulates individual organ function and homeostasis, and for the most part is not subject to voluntary control. The autonomic nervous system is also known as the visceral or automatic system. The ANS is predominantly an efferent system transmitting impulses from the central nervous system (CNS) to peripheral organ systems. The autonomic nervous system consists of sensory neurons and motor neurons that innervates between the central nervous system (especially the hypothalamus and medulla oblongata) and various internal organs such as the : heart, lungs, viscera, glands (both exocrine and endocrine). Thus it is responsible for monitoring conditions in the internal environment and bringing about appropriate changes in them. The ANS is divided into two separate divisions called the parasympathetic and sympathetic systems, on the basis of anatomical and functional differences. Both of these systems consist of myelinated preganglionic fibres which make synaptic connections with unmyelinated postganglionic fibres, and it is these which then innervate the effector organ. These synapses usually occur in clusters called ganglia. The main nerves of the parasympathetic system are the tenth cranial nerve, the vagus nerve, which originate in the medulla oblongata. Other preganglionic parasympathetic neurons also extend from the brain as well as from the lower tip of the spinal cord. Each preganglionic parasympathetic neuron synapses with just a few postganglionic neurons, which are located near or in the effector organ, a muscle or major gland. Acetylcholine (ACh) is the neurotransmitter of all the pre and many of the postganglionic neurons of the parasympathetic system. Parasympathetic stimulation causes slowing down of Page |1 ISI-15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir the heart beat, lowering of blood pressure, constriction of the pupils, increased blood flow to the skin and viscera, peristalsis of the GI tract Biosynthesis and catabolism of acetylcholine: acetylcholine The chemical transmitter at both pre and postganglionic synapses in the parasympathetic system is acetylcholine (Ach). Ach is also the neurotransmitter at sympathetic preganglionic synapses, some sympathetic sympathetic postganglionic synapses, the neuromuscular junction (somatic nervous system), and at some sites in the CNS. Acetylcholine is the most widespread autonomic transmitter present in the body. (a) Synthesis of acetylcholine (ACh). It was first synthesized by by Bayer in 1867. Acetylcholine virtually has no therapeutic effect because of its differences of action andsusceptability to hydrolysis by acetylcholinesterase and plasma butyrylcholinesterase. The synthesis of acetylcholine involves the reaction of cholinee with active acetyl (CoA). The active acetyl CoA being formed by the combination of acetate with Coenzyme A (CoA). The reactionbetween acetyl Coenzyme A and choline is catalyzed by the enzyme cholineacetylase. There is considerable evidence that the enzyme enzyme cholineacetylase is synthesized within the neuronal perikaryon, then transferred along the axon to its terminals where the formation of acetylcholine is believed to occur. Page |2 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir Metabolism Storage and release of ACh. ACh is stored in synaptic vesicles, which is released as discrete “Quanta” in response to depolarization of the nerve terminal and an increased influx of Ca++. When a nerve impulse occurs, depolarization of nerve terminal causes influx of Ca++, which facilitates facilitates the fusion of the axonal and vesicular storage membranes, and release formed acetylcholine into the synaptic cleft by exocytosis. The released acetylcholine combines with the receptors at target organ, remains bound for less than a millisecond and is quickly uickly hydrolysed by acetycholinesterase enzyme into choline and acetate. Page |3 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir Cholinergic receptors (Muscarinic & Nicotinic) and their distribution Acetylcholine Receptors. There are number of different ACh receptors throughout the body. Acetylcholine acts on on two different classes of receptors- receptors nicotinic receptors and muscarinic receptors (widely distributed within both peripheral and central nervous systems). Nicotinic Receptors. Nicotinic receptors are selectively activated by nicotine and blocked by tubocurarine or hexamethonium. These are rosette like pentameric structures which enclose a ligand gated cation channel, their activation causes opening of the channel and rapid flow of cations resulting in depolarization and generation of action potential. potential. On the basis of location and selectivity. They are divided into two types; N1 : These are present at skeletal muscle endplate and mediate skeletal muscle contractions. They are selectively stimulated by phenyltrimethyl ammonium and are blocked by tubocurarine. tubocur N2 : These are present in ganglionic cells, adrenal medullary cells, in spinal cord and in certain areas of brain. They are primarily stimulated by dimethylphenylpiperazine and blocked by hexamethonium. Page |4 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir Muscarinic Receptors. Although five muscarinic carinic receptors have been identified, helpfully labelled M1 to M5, only three are well-characterised. well characterised. The prototype agonist for these receptors is muscarine, derived from the poisonous fly agaric, Amanita muscaria. M1 receptors are mainly found in the nervous system. They mediate excitatory effects, lowering transmembrane potential by a decrease in K+ ion conductance; as an added wrinkle, they mediate increased gastric acid secretion seen with vagal stimulation. M1 receptors receptors work via phospholipase C, increasing IP3 and DAG levels. M2 receptors mediate the cardiac effects of vagal stimulation. They are inhibitory (hyperpolarizing membranes by increasing potassium conductance). M2 receptors are found presynaptically in a variety of situations. This fits on cardiac cells and smooth muscle. M2 receptors lower intracellular cAMP levels. Page |5 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir M3 receptors are responsible for all the other effects of parasympathetic stimulation, as they are the cholinergic excitatory receptors found found on glands and smooth muscle. M3 receptors are similar to M1 in their use of phospholipase C. Physiology is however never simple, vascular smooth muscle relaxes in some situations due to M3 receptor stimulation. This relaxation is mediated by endothelial release of nitric oxide (NO), and occurs in some vascular beds that appear devoid of parasympathetic innervation. M4 are similar to M2. M5 receptors seem similar to M1 and M3 in their effects. CHOLINOMIMETIC (PARASYMPATHOMIMETIC) DRUGS The cholinomimetic or parasympathomimetic or cholinergic drugs are those which cause a muscarinic action on the receptors of the effector organs provided by the post-ganglionic ganglionic cholinergic nerves. Invariably, these drugs exert their action in two different ways, way namely:: direct action, whereby they act on the cholinoceptive receptors like acetylcholine; indirect action, by rendering the cholinesterase enzymes inactive and preserving endogenously secreted acetylcholine, e.g., anticholinesterase drugs like physostigmine physostigmine (naturally occurring neostigmine and pyridostigmine (synthetic). SAR OF CHOLINERGIC DRUGS Page |6 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir carbon with respect to ester group 1. Substitutions at α-carbon 2. Changes at ester group Page |7 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir 3. Substitution at the amine group 4. Changes at R4 position Page |8 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir Classification:- Cholinomimetic drugs may be broadly classified under the following two categories. 1.Direct acting agents: a. choline ester: Acetylcholine, Carbachol*, Carbachol*, Bethanechol, Methacholine. b. Natural alkaloids: Pilocarpine. 2. Indirect acting/ Cholinesterase inhibitors a.Reversible: Physostigmine,Neostigmine*,Tacrine hydrochloride b.Irreversible:Pyridostigmine, stigmine, Edrophonium chloride, Ambenoniumchloride, Ambenonium Isofluorphate, Echothiophate iodide, Parathione, Malathion. Malathion Storage: It should be stored in well closed ampoules ampoules and protected from light.Dose: Dose: Topically as a 1% solution. Page |9 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir Carbachol* Properties and uses: It is a white crystalline, hygroscopic powder, soluble in water, sparingly soluble in alcohol, insoluble in acetone. acetone. It is an ester of carbamic acid, the terminal methyl group of Ach is replaced by amino group. It possesses both muscarinic and nicotinic properties by cholinergic receptor stimulation. It is more slowly hydrolyzed by acetylcholinesterase. It is used for its miotic actions in the treatment of glaucoma to reduce intraocular pressure. P a g e | 10 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir 3.Methacholine Properties and uses: It is highly deliquescent, deliqu has faint fishy fi odour, and aqueous solutions are neutral, soluble in water, alcohol, and CHCl3. It is used to treat Reynaud’s syndrome and glaucoma. Dose: For usual paroxysmal tachycardia, 10 to 25 mg; by S.C. for peripheral vascular disease 10 to 25 mg. P a g e | 11 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir 4. Pilocarpine. Properties and uses: It is a white or almost white crystalline powder or colourless crystals, hygroscopic, very soluble in water and in alcohol. Pilocarpine is an alkaloid obtained from the dried leaflets leaflets of Pilocarpus jaborandi and Pilocarpusmicrophyllus Pilocarpusmicrophyllus in which it occurs to the extent of about 0.5% together with other alkaloids. Pilocarpine is a nonselective agonist on the muscarinic receptors. It acts on M3 receptors in smooth muscles and cause contractions in the gut, trachea, and eyes. It is used for the treatment of symptoms of dry mouth caused by radiotherapy for cancer of head and neck and the symptoms associated ciated with Sjogren’ssyndrome. Storage: It should be stored in well-closed well closed airtight containers, and protected from light. Dose: Topically 0.1 ml of 0.5 to 6% solution into the conjunctivalsac conjunctival 1 to 5 times/day. Dosage forms: Pilocarpine hydrochloride eye drops B.P. 2. Reversible & Irreversible: 1.Physostigmine P a g e | 12 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir Properties and uses: It exists as a white or almost white crystalline powder, hygroscopic, very soluble in water, and freely soluble in alcohol. It gradually becomes red when exposed to air and light; the colour develops more quickly when the substance is also exposed to moisture. moisture. Aqueous solutions are unstable. It melts at about 145°C with decomposition. It is an alkaloid obtained from the dried ripe seeds of Physostigmavenenosum. It occurs as a white, odourless, microcrystalline powder, slightly soluble in H2O, freely soluble solub in alcohol, CHCl3 and fixed xed oils. Physostigmine is an oldest anticholinesterase agent. It is used in the treatment of glaucoma. It can penetrate the blood brain barrier and is employed to antagonize the toxic CNS effects of antimuscarinic drugs, tricyclic tricycli depressants, H1 antihistamines, and benzodiazepines. It is also used in the treatment of Alzheimer’s disease. Storage: It should be stored in well-closed well closed airtight glass container and protected from light. 2. Neostigmine* Synthesis P a g e | 13 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir Properties and uses: It exists as white, odourless, crystalline powder with a bitter taste, freely soluble in water, alcohol, and insoluble in ether. Its solutions are neutral to litmus. It acts as a cholinesterase inhibitor. Storage: It should be stored in well-closed well airtight ht container and protected from light. Dosage forms: Neostigmine bromide tablets I.P., Neostigmine methyl sulphate injection I.P., Neostigmine tablets B.P. P a g e | 14 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir 3. Pyridostigmine Properties and uses: It exists as white, crystalline powder with a characteristic odour and bitter taste, soluble in water, alcohol, chloroform, slightly soluble in hexane, and insoluble in ether. It is hygroscopic in nature. It is used in the treatment of myasthenia gravis and and it antagonizes the effects of neuromuscular blocking (NMB) agents. Storage: It should be stored in well-closed well closed airtight container, protected from light. The sterile substance should be stored in airtight, tamper-proof tamper proof containers, and protected from light. Dose: Initially, 60 mg every 4 to 8 h, but 120 to 300 mg 6 times/day is the usual dose. Dosage forms: Pyridostigmine tablets B.P. 4. Edrophonium chloride P a g e | 15 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir Properties and uses: It exists as a white crystalline powder, soluble in water and alcohol, insoluble in methylene chloride. On parenteral administration, edrophonium has a more rapid onset and shorter duration of action than neostigmine, pyridostigmine, or ambenonium. It is used as an antiarrhythmic drug in paroxymal atrial tachycardia. It is also used in the diagnosis of myasthenia gravis. Assay: Dissolve the sample in a mixture of equal volumes of acetic anhydride and anhydrous acetic acid. Titrate with 0.1 M perchloric acid and determine the end point potentiometrically. Storage: It should be stored in well-closed airtight containers and protected from light. Dose: By I.V. 2 to 10 mg; usually 2 mg is injected initially and if no adverse reaction takes place within 30 sec, the remaining 8 mg may be injected. Dosage form: Edrophonium injection B.P. 5. Tacrine hydrochloride P a g e | 16 ISI-15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir 6. Ambenonium chloride 7. Isofluorphate 8. Echothiaphate iodide Properties and uses: It exists as a white crystalline powder, soluble in water and alcohol, insoluble in methylene chloride. On parenteral administration, edrophonium has a more rapid onset and shorter duration of action than neostigmine, pyridostigmine, or ambenonium. It is used as an antiarrhythmic drug in paroxymal atrial tachycardia. It is also used in the diagnosis of glaucoma P a g e | 17 ISI-15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir 9. Parathione 10.Malathion. CHOLINESTERASE REACTIVATOR: Drugs used to reverse the inactivation of cholinesterase caused by organophosphates or sulfonates. They are an important important component of therapy in agricultural, industrial, and military poisonings by organophosphates and sulfonates. 1. Pralidoxime chloride. P a g e | 18 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir CHOLINERGIC BLOCKING AGENTS Cholinergic Blocking agents: Cholinergic nergic antagonists inhibit the actions of endogenous acetyl choline and muscarinic agonists at muscarnic receptor sites in peripheral tissues and in the CNS. These drugs are highly specific reversible competitive antagonists for muscarinic ACh receptors. The pharmacological effects are blockage of parasympathetic stimulation at effector organs. They are rapidly dly absorbed from the gastrointestinal tract, slowly absorbed when applied locally on eye or skin. The potent anticholinergics are used to control the secretion of saliva and gastric acid, slow down gut motility, and to prevent vomiting. They also have a limited limited therapeutic use for the treatment of Parkinson’s disease. SAR of cholinolytic agents 1. Anticholinergic agents are bulky. They combine with muscarinic receptors and shield the binding site from acetylcholine. The general structure of the compounds in this category is 2. Substituent R1 should be carbocyclic or heterocyclic ring for maximal antagonist activity. 3. Substituent R2 should be a hydrogen atom, hydroxy group, hydroxymethyl group, or methyl group. 4. The nature of the group X effects only the duration of action, the physicochemical properties and the side effects of the drug molecule but not its ability to bind with the receptor. receptor P a g e | 19 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir 5. There is a limitation for the N-substitution. N substitution. Optimal potency is associated with 2-3 ethyl groups. 6. Thee stereochemistry at the benzylic carbon is critical for muscarinic antagonist activity. Any compound that can place the phenyl group in the same absolute configuration as depicted in the general formula above will have potent muscarinic antagonist activity activit 7. The phenyl ring cannot tolerate any their substituent than F at the p-position p without losing its antagonist activity 8. A negative site for binding nding of the positive charged N; N; quaternary amines have formal positive charge while tertiary amines have a positive charged proton 9. Atropine is a racemic mixture (equal number of d- d and l-isomers) isomers) and like most chemicals acting on the peripheral nervous system, atropine is stereospecific; l-isomer isomer (l-hyoscyamine) (l hyoscyamine) is 250 times more active than the d- d isomer 10. The presence of an N-methyl methyl group on atropine or scopolamine changes the activity of the ligand, possibly by preventing a close interaction between the ligand and the membrane or lipophilic sites on the receptor. The methyl group also prevents the penetration enetration into the brain Therapeutic uses of anticholinergic drugs 1. Peripheral: Therapeutic uses following inhibition of parasympathetic transmission, e.g., mydriasis with cycloplegia, decrease saliva production, P a g e | 20 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir decrease motility of smooth muscle, inhibition inhibition of vagal transmission to heart, decrease bronchial secretions, decrease in urinary incontinence, etc. 2. Central: Anti-parkinson parkinson and anti-motion anti sickness 3. If anticholinergic drugs are non-quaternary non quaternary amine derivatives, they will cross the bloodbrain barrier. They may have therapeutic actions, or side effects, involving the central nervous system; if anticholinergic drugs are quaternary amines, they will not cross the blood brain barrier, thus they are devoid of CNS activity. 4. Expected ‘side ide effects’ of anticholinergic therapy include: peripheral- peripheral photophobia, cycloplegia, dry mouth, tachycardia, difficult urination, red skin (‘atropine flush’), and increase in skin temperature, central-sedation central or excitement. SOLANACEOUS ALKALOIDS AND ANALOGUES Scopolamine is an alkaloid isolated from various members of solanaceae. It is an optically active compound and levoform is potent. (–) ( ) Scopolamine is slightly water miscible viscous liquid. Scopolamine occurs as Scopolamine hydrobromide salt, which is a colorless, odorless, water soluble powder 1. Atropine sulphate Properties and uses: It is a white crystalline powder or colourless crystals, freely soluble in alcohol and well soluble in water. It is the tropine ester of racemic tropic acid and is optically inactive. The greater molar potency of P a g e | 21 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir atropine helps it to block several moles of acetylcholine. The umbrella-like umbrella atropine molecule may mechanically or electrostatically inactivate adjacent receptors on the cell surface so that these receptors are also unavailable for acetylcholine or other parasympathomimetic stimulants. Atropine has all the actions and uses of antimuscarinic drugs. Storage: It should be stored in well-closed well closed airtight containers and protected from light. Dose: In Bradycardia: Adult: 500 μg every 3–55 min totally 3 mg. Dosage forms: Atropine methonitrate injection I.P., Atropine sulphate injection I.P., Atropine sulphate tablets I.P., Atropine sulphate ointment I.P., Atropine Eye drops B.P., Atropine opine Eye ointment B.P., Atropine injection B.P., Atropine tablets B.P., Morphine and Atropine injection B.P. 2.Hyoscyamine sulphate Properties and uses:: Hyoscyamine sulphate is available as white, crystalline powder or colorless needles, very soluble soluble in water, sparingly soluble or soluble in alcohol, practically insoluble in ether. It melts at about 203°C, with decomposition. It should be stored in an airtight container, conta protected rotected from light. Use: Hyoscyamine is an anticholinergic drug used to treat peptic ulcers. ulcers P a g e | 22 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir 3. Scopolamine hydrobromide Properties and uses: It exists as colourless or white crystals or white granular powder, odourless, slightly efflorescent ef in dry air, and is an anhydrous salt, soluble in water or alcohol and in chloroform, insoluble in ether. Scopolamine is the levo component of the racemic mixture that is known as Hyoscine. It is effective in the prevention of motion sickness. It is a competitive competitive blocking agent of the parasympathetic nervous system like atropine, but it differs markedly from atropine in its action on the higher nerve centres. centres 4. Homatropine hydrobromide Properties and uses: It is a white crystalline powder or colourless crystals, sparingly soluble in alcohol, but freely soluble in water. It is used topically on the ciliary structure of the he eye and to effect mydriasis. Storage: It should be stored in well-closed well airtight containers, ners, protected from light. Dose: Topically for adult, to the conjunctiva, 1 drop of a 2%–5% 2% 5% solution given three times at 10 min intervals. Dosage forms: Homatropine eye drops B.P. P a g e | 23 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir 5. Ipratropium bromide*. Properties and uses:: It is a white or almost white crystalline powder, freely soluble in methanol, soluble in water, but slightly soluble in ethanol. It is used in the inhalation therapy to produce dilation of bronchial smooth muscle for acute asthmatic attacks. It produces broncho-dilation dilation by competitive inhibition of cholinergic receptors bound to the smooth muscles of the bronchioles. Assay: Dissolve the sample in water and add 3 ml of dilute nitric acid. Titrate with 0.1 M silver nitrate and determine the end point potentiometrically. potentiometrically. Dose: For inhalation reversible airways obstruction and COPD, maximum dose is 320 μgg daily as nebulized solution. Dosage forms: Ipratropium Nebuliser solution B.P., Ipratropium powder for inhalation B.P., Ipratropium pressurized inhalation B.P. B. P a g e | 24 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir Synthetic cholinergic blocking agents: 1.Tropicamide Properties and uses: Tropicamide is (RS)-N-ethyl ethyl-2-phenyl-N-(4- pyridylmethyl) hydrocrylamide. It is white, crystalline powder, slightly soluble in water, freely soluble in alcohol and in methylene methylene chloride. It is an effective anticholinergic drug for ophthalmic use. It antagonizes M4 receptors. 2. Cyclopentolate hydrochloride Properties and uses: It exists as white crystalline powder, soluble in water, methanol, and ethanol, but insoluble in toluene. Cyclopentolate is usually employed as eye drops to cause cycloplegia and mydriasis. It acts much faster than atropine and possesses a relatively relati shorter er duration of action. action Dose: Topically for adult, 1 drop of 1 or 2% solution to the conjunctiva; for refraction 1 drop of a 0.5% solution repeated after 5 to 15 min. Dosage forms: Cyclopentolate eye drops B.P. P a g e | 25 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir 3.Clidinium bromide Uses: Used as a bronchodilator dilator in asthmatic conditions. It has a longer lasting effect as compared to β-agonists agonists. 4. Dicyclomine hydrochloride* Properties and uses: It exists as a white, crystalline powder with a bitter taste, soluble in water and chloroform. Dicyclomine HCl behaves both as anantimuscarinic antimuscarinic and a nonspecific nonspeci antispasmodic agent. It was first introduced P a g e | 26 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir in 1950 and had minimized the adverse effects associated with the atropine type of compounds. Dicyclomine has spasmolytic spasmolytic effect on various smooth muscle spasms particularly articularly those associated with the gastrointestinal (GI) tract. It is also used in dysmenorrhoea, pylorospasm, and biliary dysfunction. Dose: By oral or I.M. 10 to 20 mg per day in four divided dose. 5. Glycopyrrolate Properties and uses: It exists as as a white, crystalline powder with a bitter taste, soluble in water and alcohol. It is used for suppressing gastric secretion and in the treatment of peptic ulcer and gastrointestinal disorder associated with spasm. 6. Methantheline bromide P a g e | 27 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir 7. Propantheline bromide Properties and uses: It is a white or yellowish-white white powder, slightly hygroscopic, soluble in water, in alcohol, and in methylene chloride. It is beneficial ficial for the treatment of peptic ulcer, due to the decreased gastric motility motilit by this drug, and it may relieve the pain in this condition. Assay: Dissolve the sample in acetic anhydride. Titrate with 0.1 M perchloric acid and determine the end point potentiometrically. Storage: It should be stored in well-closed well airtight container,, and protected from light. Dose: The usual initial dose is 15 mg thrice/day before meals; and 30 mg at bed time. Dosage forms: Propantheline bromide tablets I.P., Propantheline tablets B.P. 8. Benztropinemesylate Properties and uses: It is a white crystalline crystalline powder, insoluble in ether, but soluble in water and ethanol. It has anticholinergic, antihistaminic, and local anaesthetic activities. It is used in the treatment of Parkinsons’s disease. Dosage forms: Benzatropine injection B.P., Benzatropine tablets tablets B.P. P a g e | 28 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir 9. Orphenadrine citrate Properties and uses: It is a white or almost white crystalline powder, sparingly soluble in water, slightly soluble in alcohol. It is used for the symptomatic treatment of Parkinson’s disease. It is also used as a skeletal muscle relaxant. Storage: It should be stored in well-closed well closed containers. If the substance is sterile, it should be stored in a sterile, airtight, tamper-proof tamper proof container, and protected from light. Dose: The initial oral dose is 100 mg twice/day; I.M. I.M. or I.V. 60 mg every 12 hrs. 10. Biperidine hydrochloride Properties and uses: It is a white crystalline powder, slightly soluble in methylene chloride, in water, and in alcohol. It has a relatively strong musculotropic action, which is about equal to that of papaverine, in comparison with most synthetic anticholinergic drugs. It is used in all types of Parkinson’s disease. P a g e | 29 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir Assay: Dissolve the sample in alcohol and titrate with 0.1 M alcoholic potassium hydroxide and determine determine the end point potentiometrically. potentiometrically Storage: It should be stored in well-closed well closed airtight containers and protected from light. Dose: For parkinsonism, 2 mg 3 or 4 times/day. 11. Procyclidine hydrochloride* ochloride* Properties and uses: It exists as white crystalline powder, and it has been used for peripheral effects that are similar to methantheline. Its clinical usefulness lies in its ability to relieve voluntary muscle spasticity through its central action. Procyclidine is used in the treatment of Parkinson’s disease. Dose: The initial oral dose is 7.5 mg/day in 3 or 4 divided doses after meals; maintenance dose is usually 20 to 30 mg per day. Dosage forms: Procyclidine injection B.P., Procyclidine tablets B.P. P a g e | 30 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir 12. Tridihexethyl chloride ide Properties and uses: It is a white crystalline powder, slightly soluble in water, sparingly soluble in alcohol and in methylene chloride. It is used as antispasmodic and antiparkinsonian agent. T rihexylphenidyl is more effective than levodopa against st Parkinson’s tremor. Assay: Dissolve the sample in alcohol and add 0.01 M hydrochloric acid. Perform potentiometric titration using 0.1 M sodium hydroxide. Dose: Initial oral dose is 1 mg on fi rst day, followed by 2 mg daily after 3 to 5 days; maintenancee dose, 6 to 10 mg/day in 3 to 4 divided doses but not exceeding 20 mg/day. Dosage forms: Trihexylphenidyl tablets B.P. 13. Isopropamide iodide. Properties and uses: Isopropamide iodide is pale yellow coloured, bitter taste crystalline powder. It is sparingly soluble in water and freely soluble in chloroform and alcohol. Isopropamide is a potent anticholinergic drug. It has antispasmodic ic and antisecretory effects. It is used inn the treatment of peptic ulcer. P a g e | 31 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com  JAIPUR COLLEGE OF PHARMACY, JAIPUR B.PHARMACY, SECOND YEAR, FOURTH SEMESTER MEDICINAL CHEMISTRY-I Prepared by: Mrs. Nisha Dhir 14. Ethopropazine hydrochloride. P a g e | 32 15, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur - 302021 ISI-15, Email: [email protected] Website: jcpjaipur.com