Anticholinergics

1. Anticholinergics PS postganglionic Ganglionic & Neuromuscular blocking agents

2. Cholinergic blocking agents • Muscarinic & Nicotinic antagonists • Muscarinic – Para sympatholytics • Nic – N2 ganglionic blockers -hexamethonium • N1 - neuromuscular jn blockers eg tubocurarine • Atropine & related compounds • Atropa belladona, A. accuminata, Datura Strammonium, synthetic & semisyn compounds

3. MECHANISM OF ACTION  • Reduces the no. of free receptors that can interact with Ach. • The cholinergic blocking agents competitively inhibit the cholinergic receptors and prevent the binding of acetyl choline to the receptors due to the size of acyl group through ‘umbrella effect’. • The large group (alkyl or aryl) present in cholinergic blocking agents increase the affinity of the blocking agent and also block the approach of acetyl choline to the receptor.

4. Ach Ach Antagonist Ach Postsynaptic nerve Postsynaptic nerve Cholinergic Antagonists (Muscarinic receptor) • Drugs which bind to cholinergic receptor but do not activate it • Prevent acetylcholine from binding • Opposite clinical effect to agonists - lower activity of • acetylcholine

5. CLASSIFICATION1. Solanaceous alkaloids and Analogues - Atropine Sulfate, Hyoscyamine sulfate, Scopalamine HBr, Homatropine HBr, Ipratropium bromide.  • 2. Amino alcohol esters - Cyclopentolate. HCl, Clidinium bromide, Dicyclomine HCl, Glycopyrrolate, Methanthelin bromide, Propanthelin bromide, Mepenzolate.  • 3. Amino Alcohols- Biperidine HCl, Procyclidine HCl . 4. Amino alcohol ethers Benztropine mesylate, Orphenadrine  5. Amino amides - Tropicamide, Isopropamide iodide. • 6. Diamides – Ethopropazine HCl, Diethazine • 7. Papaveraceous – Papaverine alkaloids • 8. Miscellaneous - Pirenzepine, methixine HCl 

6. SAR • A quarternary ammonium function / tertiary amines protonated in biophase to form cationic species • N is separated from pivotal C by a chain- ester, ether or hydrocarbon moiety • A & B contain atleast 1 aromatic moiety for vander waals interaction, & 1 cycloaliphatic /hydrocarbon moiety for hydrophobic bonding interactions • C – may be hydroxyl or carboxamide – hydrogen bonding or can be component of A & B ring system, more potent if hydroxyl or hydroxymethyl

7. Alkyl substitution in N usually methyl, ethyl, propyl, isopropyl. The nitrogen in tertiary atom should contain alkyl group not larger than butyl for effective antagonist activity. • Groups A & B should be hydrophobic in nature • Distance b/w ring sub C & N – not critical may be 2-4 carbons • Most potent with 2 methylene units.

8. Highly potent antimuscarinic agents have ester grp (but not necessary for activity). The acyl group is always larger than acyl group in acetyl choline for good activity. • Hydrophobic substituents increase the affinity to binding the receptors and have good antagonist property. • C -The presence of free hydroxyl or carbamide is also important for hydrogen bonding with receptor. • Naturally occurring l-hyocyamine is more active than d-isomer.

9. Parasympathetic postganglionic Blocking agents • Competetive antagonism of Ach binding to muscarinic receptors • Potent agents – derived from muscarinic agonists - one or two bulky grps • Additional binding interaction - high affinity – low intrinsic activity

10. Therapeutic effects • Mydriatic effect • Dialation of pupil of the eye, cycloplegia, • Antispasmodic effect • Lowered tone, motility of GI tract, genitourinary tract • Antisecretory effect • Reduced salivation, perspiration, acid & gastric secretions – used as preanaesthetic medication Side effects: mydriasis, dryness of mouth, urinary retention Used in treatment of Parkinson’s disease

11. Cvs PS tachycardia • Heart sym vasodilation • Arterioles sym dilation Eye PS Mydriasis GI tract PS Relaxation Urinary B PS Urinary retention Salivary G PS Dry mouth Sweat G sym anhidrosis

12. Cholinergic Antagonists (Muscarinic receptor) • Clinical Effects • Decrease of saliva and gastric secretions • Relaxation of smooth muscle • Decrease in motility of GIT and urinary tract • Dilation of pupils • Uses • Shutting down digestion for surgery • Ophthalmic examinations • Relief of peptic ulcers • Treatment of Parkinson’s Disease • Anticholinesterase poisoning • Motion sickness

13. Solanaceous alkaloids and analogs • Also known as the Deadly Nightshade Family. • Hyoscyamus niger • Atropa belladonna. • Datura stramonium • Have been used as poisons and hallucinogens (witches and sorcerers) Solanaceous Plants

14. Solanaceous alkaloids & analogues SAR • Chemistry • Esters of bicyclic aminoalcohol 3-hydroxytropane • Piperidine ring system in stable chair confirmation • Isomers exist due to rigidity imparted to the molecule by ethylene chain across 1,5 positions

15. Greater molar potency of atropine – blocks several moles of ACh • Umbrella-like artopine molecule inactivates adjacent receptors mechanically or electrostatically – unavailable • Amine grp seperated frm ester O by more than 2 C, but conformation by tropanal rings orients the molecule in a way that the distance is similar to Ach. • Most potent compounds – 2 lipophilic ring substitutions on C alpha to carbonyl of ester grp for mus activity

16. Comparison of atropine with acetylcholine • Relative positions of ester and nitrogen similar in both molecules • Nitrogen in atropine is ionised • Amine and ester are important binding groups (ionic + H-bonds) • Aromatic ring of atropine is an extra binding group (vdW) • Atropine binds with a different induced fit - no activation • Atropine binds more strongly than acetylcholine Fully ionised • analogues unable to cross the blood brain barrier No CNS side effects

17. Atropine USP • 8-methyl-8-aza-bicyclo[3.2.1]octan-3-yl-3-hydroxy-2-phenyl propanoate • Tropine ester of racemic tropic acid –optically inactive, white odourless crystals bitter taste • Piperidine ring in chair conformation • Racemic form of hyoscyamine • Source - roots of belladonna (1831) (deadly nightshade) • Used as a poison • Used as a medicine decreases GIT motility antidote for anticholinesterase poisoning dilation of eye pupils • CNS side effects – hallucinations

18. Opthalmic use of atropine a as mydriatic (dilating) agent has been largely replaced by use of analogs tropicamide and cyclopenatolate • Also these antagonists can be used to treat the symptoms of an excess of acetylcholine, - exposure to an inhibitor of the enzyme acetylcholinesterase (such as a nerve gas).

19. Atropine serves as an antagonist of acetycholine at the M2 receptor of the sinoatrial node. • Used to treat some arrhythmias. (↑ ses HR by blocking effect of ACh on vagus. • Atropine is also used to avoid bradycardia (too slow heart rate) during some surgical procedures.

20. Hyoscyamine USP • Levorotatory form of racemic mixture atropine, obtained from solanaceous sp. (egyptian henbane) • Dextro form does not exist naturally • Uses: Disorders of urinary tract, treat spasms of bladder, as an antispasmodic

21. Scopolamine • Scopine ester found in H. Niger, Duboisia Myoporoides, Datura metel etc) • Levo component of racemic mixture atroscine, • β- oriented epoxy grp bridged across 6,7 positions • Uses: Effective in prevention of morning sickness, (action on vestibular apparatus & cortex, depressant action) • Atropine stimulates CNS. • Given as hydrobromide, transdermal systems

22. Papaverine alkaloids 6,7 dimethoxy-1-veratrylisoquinoline • Papaverine- Benzylisoquinoline alkaloids • From opium poppy • Muscarinic blocking action- spasmolytic on SM cardiac, vascular and other SM- non specific antagonist • used as antispasmodicfor GIT spasms andin bronchial asthma in a dose up to 600 mg of papaverine HCl daily.

23. Ethaverine • A homologue of papaverine, • More potent than papaverine IUPAC: 1-[(3,4-diethoxyphenyl)methyl]-6,7-diethoxyisoquinoline

24. 3-hydroxy-1-methylquinuclidinium bromide benzilate (Quarzan) Marketed alone & in combination with chlordiazepoxide (Librax) Use: peptic ulcer, hyperchlorhydria, Dicyclomine hydrochloride (Bentyl) – binds more firmly to M1 & M3 Spasmolytic effect on SM spasms mainly of GI tract. Useful in dysmenorrhoea, spasm of GI tract. Amino alcohol esters

25. Aminoalcohol ethers Diphenhydramine, benztropine mesylate, orphenadrine citrate Higher anticholinergic & low antihistaminic activity Used as anti parkinsonian drug. Aminoalcohols Posses bulky grps Procyclidine HCl etc Used as Antiparkinsonian drugs

26. Ganglionic blocking agents • The Ganglionic blocking agents are drugs which act by competition with Acetyl choline (Ach) from the cholinergic receptors present in the autonomic post ganglionic neurons. • The ganglia of both the sympathetic and parasympathetic nervous systems are cholinergic, these drugs interrupt the outflow through both system • Used mostly for their interruption of the sympathetic outflow in hypertension, vasopastic disorders and peripheral vascular disease. Thus lowering the B.P and increasing the peripheral blood flow.

27. Depolarizing blocking agents • By prolonged depolarization e.g. Nicotine • Nondepolarising competitive GB agents • MOA: Affinity to attach to nicotinic Ach receptors but no intrinsic activity, Acts by competing with ACh for receptors • Hexamethonium, Tetraethylammonium salts, Trimethaphan camsylate. Nondepolarizing non competetive GB agents MOA: Produce effect not at specific receptor site but at some point far along the chain of events for impulse transmission has been imposed,. Once blocked increasing conc. Of Ach has no effect. Mecamylamine Hydrochloride etc.

28. SAR • n = 5-6 active as ganglionic blocker (weak curariform activity) • n = 9-12 weak GB (strong curariform activity) Drug –Hexamethonium bromide

29. Trimethaphan Camsylate (Arfonad) • 1,3-dibenzyldecahydro-2-oxoimidazo-4,5-thieno-1,2-thiolium-2-oxo-10-boranesulphonate • Short acting – used for neurosurgical procedures where chances of excessive bleeding may make difficulty in operative field, (moa- antihypertensive) • Indications for use: treatment of HT emergencies to reduce BP.

30. Mecamylamine HCl (Inversine) • N,2,3,3-tetramethy-2-norbornanamine hydrochloride • Powerful GB agent, effect same as that of hexamethonium br • Orally active. • Use: moderate – severe HT (adr- severe orthostatic hypotension

31. Neuromuscular blocking agents • Agents that block the transmission of Ach at the motor end plate, and bring about voluntary muscle relaxation are called NM blocking agents • Used mainly for relaxation of skeletal muscles during surgical anaesthesia. • The absence of lipophilic barrier in NMJ causes ready access to quaternary ammonium compds. Variations in quatnry str – no effect

32. Non-depolarising blocking agents • MOA: compete with Ach for the nicotinic receptorbinding site by preventing depolarization of end plate by NT. Causes antagonistic action – no intrinsic effect • Drugs: d-Tubocurarine, dimethyltubocurarine, pancuronium and gallamine.

33. Tubocurarine Chloride USP • Curare alkaloids Source: Chondodendron tomentosum • MOA; Competitive NM blocking, nondepolarizing blocking agent used for its paralysing action on skeletal muscles. • Action reversed by AChE inhibitors- Neostigmine, Tensilon • Higher doses produce noncompetitive block • Orally inactive, given as IV, action – 2 hrs. • Use: As muscle relaxant in during shock therapy for mental disorders, prevents fracture,dislocation due to convulsions produced during shock • Muscle relaxation during surgical aneathesia.

34. Metocurine iodide • (+)-O,O’-dimethylchondrocurarine diodide • Prepared by extracting crude curare with ethanolic KOH, and treated with methyl iodide. • MOA; same as d-Tc, but more potent, and less paralysing effect on respiration.

35. Papaverine alkaloids

36. SAR

38. CLASSIFICATION • Based on the mechanism these are classified as follows.1.By Interfering with Ach release - Triethyl choline, Hemicholinium • 2. By interference with post synaptic action of Ach - Eg : Hexamethonium • 3. By prolonged depolarization - Eg : Nicotin

39. phenethanol-amino Aryloxypropanolamines Figure.1:the similarity in the spatial relationship of the two typical structures

40. Most derivatives of this series of the aryloxypropanolamines possess various substituted phenyl rings rather than the naphthyl ring. Substitution of methyl, chloro, methoxy, or nitro groups on the ring was most favored at the 2 and 3 positions and least favored in the 4 position. When dimethyl substitutions were made, the 3,5-disubstituted compound was best and the 2,6- or 2,3,6-substituted compounds show the least activity. Presumably, this was due to steric hindrance to rotation about the side chain. • Stereochemistry: Compounds with phenethenolamine structure possess high –receptor blockade when the β–C attached to the OH group is in (R) configuration. The (S)-isomer, however, has much lower activity. In the structure of Aryloxypropanolamines, the stereochemistry is just opposite to that of the former type due to the insert of an O which changes the priorities of the substituents attached to the stereogenic center (β-C). Therefore, the (S)-isomer is more active. In fact, the two types of enantiomer are consistent in the arbitrary spatial configuration. (Figure 2.)

41. Selectivity: Compounds with enhanced selectivity of the β1response are characterized chiefly by para substitution rather than ortho substitution in the phenoxypropanolamine series. Practolol (our object compound), for example, is reported to inhibit the β1receptor at lower doses than those required to inhibit the β2receptor. (S)-isomer (R) -isomer Figure2.the consistence in spatial configuration of the two structures

42. Structure-Activity Study A Brief Review of Pharmacology of β-Adrenergic Blocker Literature Information of Practolol Route of Synthesis The Procedure of Laboratory Synthesis Discussion Reference Catalogue

43. Pharmcologic Study • Effects on the Cardiovascular System: Beta-blocking drugs lower blood pressure. This effect is the result of several factors, including effects on the heart and blood vessels, the renin-angiotensin system, and possibly the central nervous system. Beta-receptor antagonists have prominent effects on the heart. The negative inotropic and chronotropic effects are predictable from the role of adrenergic receptors in regulating these functions. In the vascular system, beta-receptor blockade opposes β2-mediated effects. Beta-blocking drugs antagonize the release of renin caused by the sympathetic nervous system. • Effects on the Respiratory Tract :Blockade of the β2 receptors bronchial smooth muscle may lead to an increase in airway resistance, particularly in patients with asthma. β1 receptor-selective antagonists when blockade of β1 receptors in the heart is desired and β2 –receptor blockade is undesirable.

44. Effects on the Eye :Several nonselective beta-blocking agents reduce intraocular pressure, especially in glaucomatous eyes. • Effects Not Related to Beta Blockade:Partial beta-agonist activity was significant in the first beta-blocking drug synthesized. It has been suggested that retention of some intrinsic sympathomimetic activity is desirable to prevent untoward effects such as precipitation of asthma. Local anesthetic action, also known as “membrane-stabilizing” action, is a prominent effect of several beta-blockers. This action is the result of typical local anesthetic blockade of sodium channels and can be demonstrated in neurons, heart muscle, and skeletal muscle membrane.

45. Decision making in choosing object compound acebutolol diacetolol practolol

46. Structure-Activity Study A Brief Review of Pharmacology of β-Adrenergic Blocker Literature Information of Practolol Route of Synthesis The Procedure of Laboratory Synthesis Discussion Reference Catalogue

47. Literature Information of Practolol • Structure： • CA Name：N-[4-[2-Hydroxy-3-[(1-methylethyl)amino]propoxy]pheyl]acetamide • Formula and Molecular Weight： • Physical Property：fine,white or almost white, ordourless powder. soluble in alcohol (1:40), slightly soluble in acetone and acetic acid Aqueous solution is most stable at PH6(protected from light)

48. Structure-Activity Study A Brief Review of Pharmacology of β-Adrenergic Blocker Literature Information of Practolol Route of Synthesis The Procedure of Laboratory Synthesis Discussion Reference Catalogue

49. Route of Synthesis （Ⅰ）condensation （Ⅱ）amination

50. Reagents and Apparatus Reagents Raw Materials: 4-acetamidophenol (impure), epichlorohydrin, isopropylamine Other Reagent: glacial acetate acid, alcohol absolute, activated charcoal Apparatus Apparatus for reflux: three-necked boiling flask(250ml,500ml), mechanical stirrer, iron rings, clamps, reflux condenser, Apparatus for vacuum filtration: Buchner funnel, suction flask, water aspirator Apparatus for distillation: distilling flask, condenser, distillation adapter, water aspirator Others: beakers (several ), stirring rod, drying tube, infrared light, filter paper, boiling stones