Dr: Samah Gaafar Al-shaygi بسم الله الرحمن الرحيم

Nervous system Peripheral NS Central NS Afferent divisionEfferent division Somatic systemAutonomic NS enteric parasympathetic sympathetic

Anatomy of the ANS: Efferent neurons. Afferent neurons.

Cholinergic Agonist Ach transmission has 6 steps: Synthesis, storage, release, binding, degradation & choline recycling.

Cholinergic agonist: 1. Direct-acting cholinergic agonist. 2. Indirect-acting cholinergic agonist. (anti- cholinestrase).

Direct-acting cholinergic agonist: Binds directly to cholinoceptors. Synthetic esters of choline or natural alkaloids. Longer action than Ach. Acetylcholine: Has no therapeutic importance due to the multiplicity of action & the rapid inactivation. Has both muscarinic & nicotinic activity.

Action: the heart rate, COP & the BP. the GIT secretions & motility. the bronchial secretion. the tone of detrosur muscle. leads to ciliary muscle contraction & pupilary constriction. Bethanechol: Related structurally to ACH. It has no nicotinic action but a strong muscarinic one.

Action: 1. In the GIT, it increases motility & tone. 2. In the bladder, it stimulates the detruser muscle causing urine expulsion ( used for PO atonic bladder). A.E: As generalized cholinergic stimulation. Carbachol: Muscarinic & nicotinic action.

Action: 1. On the CVS. 2. On the GIT. 3. Epinephrine release from the adrenal medulla (nicotinic action). 4. In the eye it causes miosis & spasm of accommodation. is used as a miotic agent to treat glaucoma (pupilary constriction & the IOP).

pilocaroine: Less potent than Ach & it’s derivatives. Has muscarinic activity. Used in the eye to produce miosis & accommodation spasm. The drug of choice in emergency lowering of the IOP. A.E: CNS disturbances. Profuse sweating & salivation.

Reversible -anticholinestrase They inhibit Ach-esterase so prolong the action of Ach. Act on all cholinoceptors in the body (nicotinic & muscarinic).

Physostigmine: A tertiary amine. intestinal & bladder motility so is used in atony. Used in glaucoma. To treat overdose of anti-cholinergic action as atropine. A.E: 1. Convulsions. 2. Bradycardia & COP. 3. Skeletal muscle paralysis (rare with therapeutic dose).

Neostigmine: A quaternary amine. Stronger action than physo. On skeletal muscles (contraction then paralysis). Used to stimulate the bladder & GIT, myasthenia gravis (edrophonium for Δ). A.E: generalized cholinergic stimulation.

Irreversible anticholinesterase Are synthetic organophosphorus compound. Extremely toxic (as pesticides). Isoflurophate: Generalized cholinergic stimulation. Paralysis of motor function (breathing difficulties). Convulsions. Intense miosis (topically to treat open-angle glaucoma) ecothiophate replace it. Pralidoxime is an antidote (except for the CNS).

Cholinergic antagonists 1-Antimuscarinic They block the muscarinic receptors inhibiting their function. Atropine: Binds competitively. Acts centrally & peripherally. Action: In the eye it causes persistent mydriasis & cycloplegia. GIT : it’s an antispasmodic.

Urinary system: it decrease the bladder motility. CVS: In low dose bradycardia (blocks M1 in the inhibitory prejunctional neurons. In higher doses HR (blocks M2 in SA node). It blocks the salivary, lacrimal & sweat glands (as antiscretory prior to surgery). Used as an antidote for cholinergic agonist.

A.E: Tachycardia, dry mouth, constipation, blurred vision, restlessness, confusion hallucinations & glaucoma precipitation. Scopalamine: It has greater CNS action, longer duration, anti- motion sickness, sedation & blocks short term memory. Ipratropium: Quaternary derivative of atropine & is positively charged. As an inhaler in asthma & COPD.

Ganglionic Blockers Work on the nicotinic receptors in the autonomic ganglia. Are non-depolarizing competitive blockers. Has no selectivity for sympathetic or parasympathetic ganglia (so rarely used therapeutically only experimentally). Nicotine: Stimulation & then paralysis of all the ganglia. It causes transmitter release. It BP, HR, secretions & peristalsis. At higher doses the opposite happens due to ganglionic block.

Trimethophan short acting, used as an alternative drug to lower the BP in emergency situations. Neuromuscular blocking drugs: Either antagonist (non-depolarizing), or agonist (depolarizing). Non-depolarizing (competitive) blockers: At low dose they compete with Ach & prevent muscle contraction (action is overcomed by e.g. cholinesterase inhibitors).

At high doses, they can block the ion-channels so further weakening the NMJ transmission. Used in surgery for muscle relaxation. They don’t cross the BBB. A.E: release of histamine, BP& HR, malignant hyperthermia, hyperkalemia. Drug interactions: 1. Cholinesterase inhibitors overcome the action. 2. Halothane stabilizes their action. 3. Aminoglycosides antibiotics enhance the blockade by inhibiting Ach release. 4. Calcium -channel blockers may enhance their action.

Depolarizing agents: Act as ach, they depolarize the receptors. The sustained depolarization renders the receptor unable to transmit further impulses, so gradual repolarization. E.g. is succinylcholine, has a rapid onset & short duration of action so used in anesthesia & in ECT. A.E: hyperthermia & apnea.