Cholinergic receptors

Cholinergic Receptors their function and Mechanism of action

1. Cholinergic receptors Dr NAJM UL HASSAN KHAN PhD (Pharmaceutical Chemistry ) Maryum Khalid

2. introduction Cholinergic nerves found in peripheral and CNS and release acetylcholine. 2 distinct receptors for ACh (Nicotinic and Muscarinic) that differ in composition, location and pharmacological action having agonist and antagonist. ACh was 1 st identified by Henry Hallet Dale for action on heart tissue in 1914. Otto Loewi conformed ACh as neurotransmitter in 1921 and gave it name as “ vagusstoff ” because it was released from vagus nerve. Both received 1936 Nobel Prize in Physiology or Medicine for their work.

3. acetylcholine

4. Muscarinic receptors These are receptor sites where muscarine bind eliciting same qualitative effects as ACh . Muscarine is a toxic compound found in mushrooms. These are Gprotein coupled receptors also known as metabotropic receptors. Majorly 5 types of muscarinic recptors found in various organs M1, M2, M3, M4 and M5. M1,3,5 showed stimulatory pathway while M2 and 4 showed inhibitory pathway.

5. Location and functions of muscarinic receptors Receptor G protein Tissue location Cellular response Function M1 Gq CNS, Salivary and gastric glands, autonomic ganglion PLC activation, Ca+2 increase, PKC activation ↑ cognitive function,seizure activity, secretions M2 Gi/Go Heart, blood vessels, on presynaptic membranes of autonomic ganglion Inhibition of adenyl cyclase and Ca+2 channels, increase activation of K+ channels Dec. heart rate, ganglion transmission. Neuronal inhibition M3 Gq CNS, smooth muscles, glands Same as M1 ↑ secretions, smooth muscle contraction, inhibits dopamine release. M4 Gi/Go CNS Same as M2 Analgesia, facilitates dopamine release M5 Gq Low levels in CNS and periphery Same as M1 Facilitates dopamine release, mediates dilation of cerebral arteries

6. Action of M receptors Stimulatory action Inhibitory action

7. Nicotinic receptors The nicotinic acetylcholine receptors are receptor sites acted upon by nicotine eliciting the same qualitative effects as acetyl choline. These are the 1 st ACh receptor and 1 st neurotransmitter receptor to be fully characterized. These receptors are ligand gated ion channels, also called as ionotropic channels. The receptor creates a transmembrane channel(gate) and acetylcholine acts as gatekeeper by binding with the receptor to modulate passage of K+ and Na+. They are pentameric transmembrane protein made up of 2 α ,ꞵ, Ꝺ , Ꝩ subunits . The 5 subunits are arranged around a central pore that serves as ion channel. There are two subtypes of nicotinic receptors: Nm and Nn receptors.

8. Location and function Receptor Location Membrane response Molecular mechanism Agonists Antagonists Nm Neuromuscular junction Excitatory , end plate depolarization, contraction of muscle Increased Na+ and K+ permeability ACH,nicotine Atracurium , Vecuronium, pancuronium . Nn Autonomic ganglion, adrenal medulla Excitatory post synaptic potential, propagates action potential Increased Na+ and K+ permeability ACH, nicotine, dimethylphenyl piperazinum mecamylamine

9. Cholinomimetics The agents that bind to acetylcholine receptors and stimulate the parasympathetic nervous system. Actions of cholinomimetics: They dilate nearly all blood vessels and cause smooth muscle relaxation. In high dose may decrease heart rate and atrioventricular conduction velocity and cause varying degree of heart block, may decrease strength of atrial contractions. In therapeutic doses usually only vasodilation occurs and heart rate and contractility may increase. Stimulate gastrointestinal smooth muscles and increase peristalsis and decreasing bowel transit time. Contract smooth detrusor muscle of urinary bladder but relax trigonal sphincter thus causing urination. Stimulates iris causing miosis, decrease intraocular pressure in glaucoma. On glands show stimulation so excessive salivation, bronchorrhoea inc gastric and pancreatic secretions and copious sweating.

10. Sar of cholinomimetics Acyloxy group: Higher homologues of methyl group= less active Ester of aromatic of higher mol. Weight acids= anticholinergic activity Replacement of ester group with ether or ketone = chemically stable and potent Ethylene bridge: Chain length inc = dec. activity Acetyl ꞵ methyl choline= muscarinic receptor Acetyl α methyl choline= nicotinic receptor Quaternary ammonium group: Essential for activity Replacement of methyl by larger compounds= inactive compounds

11. Classification of cholinergic agonists Direct acting agonist: Acetylcholine chloride Bethanechol Carbachol Nicotine Pilocarpine Anticholinestrase (reversible) Neostigmine Physostigmine Rivastigmine Pyridostigmine Edrophonium Donepezil Galantamine Ambenonium Anticholinestrase (irreversible) Ecothiophate Parathion Malathion

12. Synthesis of acetylcholine chloride It is prototypical muscarinic and nicotinic agonist but a poor therapeutic agent because of its low chemical and enzymatic stability with low availability dur to poor absorption. It is a cardiac depressant and vasodilator Used in ocular surgery, causes miosis in seconds, instilled directly in anterior chamber. Properties: White crystalline powder, hygroscopic, soluble in water and alcohol. Dose: topically used as 1% solution.

13. anticholinestrases Acetylcholinesterase AChE is a serine dependent isoenzyme capable of hydrolyzing ACh to choline and acetic acid. On hydrolysis the acetyl group of ACh is transferred to serine –OH group. Spontaneous hydrolysis of serine acetyl group occurs rapidly. They are indirect acting cholinomimetics. Duration is for few minutes to few hours.

14. Uses: Mysthenia gravis Intestinal distention Agricultural insectidies Nerve gas warfare agent Physostigmine for antagonize toxic CNS affects antimuscarinic agents, tca antidepressants, h1 antihistamines and benzodiazepens . Also for alzheimers diseases. In eye for treatment of glaucoma.

15. neostigmine It is a quaternary amine so no CNS activity. Employed for the treatment of genitourinary, gastrointestinal and neuromuscular disease. Myasthenia gravis prophylaxis, reversal of neuromuscular blockage, prophylaxis of postoperative abdominal distension. Properties: 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. Dosage forms : neostigmine bromide tablets I.P., Neostigmine methyl sulphate injection I.P., Neostigmine tablets B.P

16. Synthesis of neostigmine

17. Anticholinergic agents They are mostly antimuscarinic that are competitive antagonists that act only on cholinergic receptors Therapeutically used as skeletal muscle relaxant adjuvants with anesthesia, intubation and orthopedic procedures Side effects are decreased gastric secretion, dry mouth, drying of mucous membrane, general mydriasis, loss of accommodation, urinary retention, decreased sweating, bronchial and biliary dilation and tachycardia.

18. Classification of anticholinergics Antimuscarinic agents Atropine Benztropine Cyclopentolate Ipratropium Scopolamine Tiotropium Tropicamide Oxybutinin Antinicotinic agents Nicotine Pancuronium Rocuronium Ciscuronium Succinylcholine

19. Antimuscarinic agents Competitive antagonists Uses: Topically to dilate pupil and paralyse accommodation Pre- anaesthetic medicine, to inhibit excessive salivary and mucous secretions Antisecretory effect is also sought in treatment of hay fever and rhinitis In bronchial asthma and peptic ulcers In treatment of parkinsons disease.

20. Classification of antimuscarinic Tertiary antimuscarinic Can penetrate cell membranes Nonionized, penetrate cornea and cause mydriasis and cycloplegia No nicotinic receptor affinity E.g , atropine sulphate, cyclopentolate, tropicamide Quaternary antimuscarinic Can't pass BBB lack CNS action Ionized,Poorly penetrate eye Greater affinity for nicotinic receptor e.g , anisotropine , ipratropium

21. atropine It is a white crystalline powder or colourless crystals, freely soluble in alcohol and well soluble in water. The greater molar potency of atropine helps it to block several moles of acetylcholine. The circled portion of the atropine molecule depicts the segment resembling acetylcholine The most potent compounds were those that possessed two lipophilic ring substituents on the carbon alpha to carbonyl of ester moiety for antimuscarinic activity Atropine has all the actions and uses of antimuscarinic drugs. Dose: In bradycardia: adult: 500 μg every 3–5 min totally 3 mg.

22. Atropine synthesis

23. Antinicotinic agents history: The neuromuscular blocking effects of extracts of curare were first reported as early as 1510, when explorers of the amazon river region of South America found natives using these plant extracts as arrow poisons. In 1856, however, Bernard demonstrated that curare extracts prevented skeletal muscle contractions by an effect at the neuromuscular junction, rather than the nerve innervating the muscle or the muscle itself. In 1935, King isolated a pure alkaloid, which he named d-tubocurarine, from a tube curare of unknown botanical origin. The word “tube” refers to the container in which the south american natives transported their plant extract.

24. Nicotine: Dose dependent At high dose bp falls and activity in GIT and bladder musculature ceases. Colorless, odourless , on air/light exposure turns slightly brown, soluble in alcohol, oils, ether and cholorform . Ganglionic blockers

25. NEUROMUSCULAR BLOCKING AGENTS SUCCINYLCHOLINE: D DIMER OF ACETYLCHOLINE

26. Rapid onset of action Useful when rapid endotracheal intubation is required during induction of anesthesia Also used in electroconvulsant shock treatment. Muscle relaxant Properties= white crystalline powder, hygroscopic and odourless , freely soluble in water and normal saline ADR: Hyperthermia Hyperkalemia so dangerous in burn patients and pt. with major tissue damage cz K+ has been rapidly lost from within cells. Postoperative muscle pain Cardiac arrythmias

27. refrences Foyes principles of medicinal chemistry Medicinal chemistry by d. Sriram Textbook of medicinal chemistry by v . Algarsmy Lippincotts illustrated review: pharmacology An introduction to medicinal chemistry 5 th edition graham. L. patrick