Cholinergics, anticholinergics and antcholinesterases Nervous System Peripheral NS Sensory nerves Motor nerves Central NS (Brain and Spinal cord) Sensory nerves: Carry messages from the body to the CNS. Motor nerves: Carry messages from the CNS to the rest of the body.

Motor nerves

Without motor nerves: No breathing. Digestion. Excretion. Muscle movement. Control of body temperature. Heart problems.

Motor nerves 1. Somatic motor NS: carry messages from CNS to the skeletal muscles. Acetylcholine is the neurotransmitter. Lead to muscle contraction.

Motor nerves 2. Autonomic motor NS: Carry messages from the CNS to smooth muscle, cardiac muscle and adrenal medulla. Two subsystems: I. Parasympathetic nerves: From CNS to smooth muscles. Acetylcholine is the N.T. II. Sympathetic nerves: To the cardiac muscles……. Contraction and heart rate Using noradrenalin and Acetylcholine as N.T

Motor nerves 3. Enteric NS: Located in the wall of intestine. Use serotonin, neuropeptide and NO as N.T Noradrenaline: increase heart rate. Relax GIT and UT muscles. Decrease salivation. Vasoconstriction of peripheral blood vessels.

The problem Is a result of either deficit or excess of the neurotransmitters. Treatment is either by cholinergic or adrenergic agonist or antagonist. Treatment should be selective either on acetylcholine receptors or noradrenalin receptors.

Cholinergic system

Cholinergic Agonist Why we can not give Acetylcholine in the case of deficiency? Orally unstable (hydrolyzed in water, why?). Hydrolyzed in the blood by esterase. Not selective.

Cholinergic receptors 1. Muscarinic receptors: Found in smooth muscles and cardiac muscles. Related to muscarine. 2. Nicotinic receptors: Found in skeletal muscles. Related to nicotine.

Cholinergic agonists Looking for selectivity: Targeting only cholinergic not adrenergic receptors. Targeting either Muscarinic or Nicotinic receptors. Muscarinic receptors of 5 subclasses: M1-M5 Nicotinic receptors of 10 subclasses:  1 -  10

Design of cholinergic agonists Acetylcholine as a lead: Acetylcholine in the Muscarinic receptor

SAR of Acetylcholine A positively charged amine is essential. The ester moiety is important. The two carbon linker between the amine and the ester is important for activity. Groups attached to the amino group not larger than methyl group.

Acetylcholine analogues To overcome the instability of Ach: Steric shield: add large group to change the conformation of Ach: 3X more stable than Ach. More selective on muscarinic over nicotinic receptors.

Acetylcholine analogues Electronic effect: to alter the electron density of Ach ester: Carbamate more stable ester toward hydrolysis (why?) Long acting cholinergic agonist. Can be administered orally. Not selective…… just used topically in glaucoma.

Acetylcholine analogues More stable. More selective on muscarinic receptor. Used to stimulate GIT and urinary bladder after surgery.

Muscarinic agonists Clinical uses: Treatment of glaucoma. Stimulate GIT and UT after surgery. In some heart defects. Pilocarpine: An alkaloids from pilocarpus shrubs. Used in glaucoma. Topically only (why?)

Muscarinic agonists Oxotremorine and Arecoline: Act on the muscarinic receptors in brain. Used in Alzheimer’s disease.

Nicotinic agonists Mainly used in myasthenia gravis: an autoimmune disorder in which the body produce antibodies against cholinergic receptors.

Muscarinic antagonists Antagonist: binds to the receptor and prevent Ach from binding without induce action. Clinical effect: Reduction of saliva and gastric secretion. Reduction of GIT and UT motility. Dilatation of pupil. Clinical Uses: Shutting down GIT and UT during surgery. Before ophthalmic examination. In Parkinson’s disease. In motion sickness.

Muscarinic antagonists Atropine (hyoscyamine): From atropa belladona. Used to decrease GIT motility and in bradycardia. Why it is an antagonist? Cause CNS side effects such as restlessness and hyperactivity (why?). Common side effects: urinary retention and blurred vision.

Muscarinic antagonists Hyoscine (scopolamine): Used in motion sickness and as antispasmodic. Same side effects as atropine. Is it more toxic than atropine?

Atropine analogues Is to reduce the CNS side effects of atropine (How?):

Ipratropium Used as bronchodilator Less CNS side effects than atropine (why?).

Muscarinic antagonists The general structure for them: Examples: Used in excessive sweating, spasms and nocturnal enuresis. What are the possible side effects?

Muscarinic antagonists Used to dilate pupils (mydriasis) before ophthalmic examination. CNS side effects….rare?

Muscarinic antagonists Selectively inhibits M 1 receptors in stomach. Used in peptic ulcer.

Nicotinic antagonists Targeting neuromuscular synapses (neuromuscular blocking agents). Mainly used as muscle relaxants.

Decamethonium and suxamethonium As muscle relaxant. Not selective… act on all cholinergic receptors… increase heart rate.

Pancuronium and vancuronium The distance bt nitrogen atoms is 1.09 nm. Widely used as muscle relaxant. Have long duration of action (why?)

Anticholinesterase agents Lead to Ach accumulation… have cholinergic effect.

Anticholinesterase agents Either reversible or irreversible inhibition. 1. Carbamate: Systemically toxic (why?). Use in Glaucoma, myasthenia gravis and Alzheimer’s. Used as antidote for atropine poisoning (why?) SAR: Carbamate is essential. Benzene ring is important. Pyrrolidine ring is important. What are the possible side effects?

Anticholinesterase agents Physostigmine analogues: has CNS side effects. Less CNS side effects and more stable than miotine (why). Both used in myasthenia gravis.

Anticholinesterase agents Same profile as neostigmine. was used by troops to protect against nerve gases. Is it orally available? In which dosage form will be administered?