بسم الله الرحمن الرحيم

Parasympathomimetic Dr. samia elshiaty

Parasympathomimetic An agent whose effects mimic those resulting from stimulation of the parasympathetic nerves. Acetyl choline is a major neurochemical transmitter in these sites: All autonomic ganglia (sympathetic & para- sympathetic). Nerve to adrenal medulla(modified sympathetic ganglion) Parasympathetic postganglionic neuro-effector cell synapses. Motor end plate of skeletal muscles Cholinergic sympathetic postganglionic fibers to sweat gland and some skeletal blood vessels. Some tracts in the CNS e.g. basal ganglia

Neurotransmission at Cholinergic Neurons Synthesis of acetylcholine. Storage of acetylcholine in vesicles. Release of acetylcholine. Binding to receptor. Degradation of acetylcholine. Recycling of choline.

The vesicles then become part of one of three pools, each varying in their availability ability for release 1% are immediately releasable. 80% are readily releasable and 19% the stationary store.

Synthesis,storage and destruction of Ach

Synthesis of Ach Choline is taken up into nerve terminals by special choline transport system mediated by a carrier that co- transports sodium. The choline transport appears to be the rate limiting step. It can be inhibited by hemicholinium. The choline acetylated by enzyme choline acetyl transferase to form Ach. The acetyl group source of acetyl-coA

Storage and release of Ach The Ach is packaged into vesicles by an active transport process coupled with the efflux of protons. The mature vesicles also contain ATP and proteoglycon. When an action potential propagated voltage sensitive calcium channels in the presynaptic membrane opens causes an intracellular increase of calcium. Elevated calcium levels promote the fusion of synaptic vesicles with the cell membrane and release of their contents into the synaptic cleft. This release can be blocked by botulinum toxin. Ach is degraded by acetylcholinestrase and forms choline and acetate in the synaptic cleft.

Choline eastrase enzymes Acetyl choline bind to the enzymeactive site. Then hydrolysed to acetylated enz.+ choline.Lastly, acetylated enz.---->>acetate + free enz. Two types: True choline estrase pseudo choline estrase * Spacific,essential for life * non spacific,hydrolysed ester Substrate Ach, methacholine * exogenous Ach, succinyl choline Present in cholinergic nerve, * in plasma, liver, intestine,CNS RBcs skin *To regenerate take 120 days * synthesized in liver * Slow turnover * rapid

Muscarinc receptor * Stimulated by muscrine, on the basis of their ability to be bound by natural occuring alkaloid from amanita muscarine mushrooms : *are G protein coupled receptor causing Activation of phospholipase c Inhibition of adenylate cyclase Activation of potassium channels Inhibition of calcium channels

Cholenergic muscarinic receptors

Muscarinc receptor Muscarinc receptor blocked by atropin *five types : M1 (neuronal) selectivity blocked by pirenzepine. M2(cardiac)decrease cardiac contractility and H R blocked by gallamine M3( glandular) causing secretion, smooth muscle contration and vascular relaxation M4-M5 largely confind to CNS,functional role not understood M1, 3,5 are stimulatory M2,4 are inhibitory

Cholenergic muscarinic receptors *If the efflux of K ion is increased,hyperpolarization results and the effect is inhibition *If the efflux of K ion is dencreased, depolarization results and the effect is excitation Examples: parasympathetic excitation GIT and inhibition heart blood vessel of penis and clitoris Examples: sympathetic Excitation Eccrine sweat gland inhibition of blood vessels of skeletal muscle

Nicotinic receptor *Stimulated by nicotine, on the basis of their ability to be bound by natural occurring alkaloid nicotine Has ligand gated ion ic channel----depolarization TWO types Nm (neuromuscular junction) blocked by d-Tubo-curar ine. Nn (postganglionic cell body ), blocked by hexamethonium

Nicotnic receptor

Nicotinc receptor

Classification of parasympathomimetic 1.Direct parasympathmimetic *Choline ester *Alkaloid acetyl choline muscarine Methacholine pilocarpine carbacol arecoline bethanechol

1.Direct parasympathmimetic muscarinic action of Ach

1.Direct parasympathmimetic nicotinic action of Ach On Nn nicotinic receptor Ach (small dose) stimulate M3 on blood vessel-----EDRF ---- vasodilation hypotension If inject atropine-----Ach ( large dose)-----hypertention Due to stimulation of adrenal medull and sympathetic ganglia On Nm nicotinic receptor twitch of Sk muscle Ach not used due to short, non spacific action Ach is quaternary ammonium, so not pass through membrane as intestine (not oral), BBB …..distributed extracellular

Direct parasympathomimetic Synthetic cholin ester (carbacol, methacoline and bathanecol) All are quaternary ammonium,So…. Resist to hydrolysis by cholinestrase…..long duration Not given IV#toxicity.. secretion, vomiting,diarrhea and B athma More specfic in action Methcholine Carbacol Bethanecol More muscarinic more nicotinic muscarinic,No nicotinic paroxysmal A tachycardia glucoma,urine urine retention,non Peripheral V disease retention,non obstructive paralytic obstructive paralytic ileus Contraindication: bronchial athma, thyrotoxicosis, coronary dse,peptic ulcer and obstruction of GIT or bladder

Alkaloid plant origin Tertiary amine,So can pass through membranes,oral,BBB. Not used in parkinsonism, aggravates condition Hydrolysis by cholinestreas,excreted in urine More muscrinic Uses:*Mitotic glucoma, adhesive iritis with lens alternative with medriatic counteract mydriatic after fundus exam. *in dry mouth(xerostomia)……increase saliva(sialagogue) *promotes Hair growth Direct parasympathomimetic Alkaloid (pilocarpine)

Classification of parasympathomimetic 2. Indirect parasympathmimetic Drugs inhibit cholinestrase, Ach Toxicity as incease Ach reversible irreversible Edrophonium parathion Neostigmine sarin&soman (nerve gas) pyridostigmine metrifonate( antibilharzial) physostigmine echothiophate( eye drop)

Reversaible anticholinestrase Neostigmine,pyridostigmine and physostigmine bind to anionic and esteratic sites of cholinestrase enzyme, so take time for hydrolysis,process lasts 3-4h. While edrophonium binds to anionic site, this complex rapidly hydrolysis Lasts 5min Physostigmine Tertiary amine passBBB Selective on eye glucoma, adhesive iritis with lens alternative with medriatic counteract mydriatic after fundus exam Atropine poisoning Alzheimer dse

Neostigmine Quaternary ammonium Selective on: *skeletal diagnosis & ttt of myasthenia gravis, curare poisoning *GIT :paralytic ileus *urinary bladder :retention of urine *paroxysmal A. tachycardia *diagnosis of pregnancy(1mg/d for 3days)contraction of nonpregnant uterus Pyridostimine More selective on skeletal M ttt of myasthenia gravis without atropine. long duration Edrophonium Quaternary ammonium Selective on: *skeletal diagnosis of myasthenia gravis (Improve) &dd with cholinergic crisis( worsen) *ganglion stimulant

Irreversaible anticholinestrase Organophosphorus poisoning: parathion, malathin,srin and soman Used as insecticides,pesticides and war (nerve gas) Bind to esteratic site only ( except echothiophate)to enzyme with phosphorylation of active site. This bond is stable. Undergoes to aging ( long duration)i.e. further strengthening of the covalent bond. So cholinestrase regenerator should be given as early as possible before aging occur.Accumulation of Ach on synases and receptor sites. Manifestation: lacrimation,miosis,rhinorhea,salivation,nausea, vomiting, bradycardia, twitches of skeletal M, paralysis,excitation, convulsion and coma death due to central and peripheral Respiratory failure.

Organophosphorus poisoning Treatment: Remove contaminated clothes,skin wash with soap. Endotracheal intubation,artificial respiration & aspiration of bronchial secretion. Atropine 1-2gm/ 5-15 min until mydriasis,dry mouth or tachycardia. Oxime as early as possible with atropine to reactivate cholinesterase before aging (pralidoxime “PAM”,diacetylmonoxime”DAM”) Anticonvulsant diazepam 1gmin 60ml saline

Organophosphorus poisoning Mechanism of Oxim ( choline esterase regenerator) has high affinity to phosphorous atom, attached unoccupies anionic site of enzyme and free oxim end attracts the phosphorous atom from esteratic site of the enzyme ( able to hydrolyse the bond if the complex not aging. PAM can regenerate cholinestrase at Nm junction. DAM can cross BBB and regenerate cholinestrase in CNS