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Parasympathomimetics

y The main effect produced by these drugs resemble the

effect of parasympathetic stimulation. y On the basis of their mode of action they can be divided into two groups.
y Direct acting Parasympathomimetics (muscarinic

receptor agonists) y Indirectly acting Parasympathomimetics (anticholinesterases)

Directly acting parasympathomimetics


They act directly on cholinergic receptors and activate them. y Acetylcholine (prototype) y Bethanechol y Pilocarpine

Indirectly acting parasympathomimetics ( Anticholinestrases)


They competitively inhibit the enzyme cholinesterase and thus increase the concentration and duration of effect of acetylcholine at its receptors. According to the stability of the complexes formed with cholinesterase, these drugs are divided into two groups: y Reversible y Irreversible In general, reversible anticholinestrases are of more clinical value, whereas the irreversible ones are used as insecticides and war gasses.

Anticholinesterases.
y Reversible.
y Tertiary amines

Physostigmine y Quaternary Ammonium derivatives y Neostigmine y Pyridostigmine y Edrophonium


y

y Irreversible y Organophosphorus compounds y Dyflos(DFP) y Echothiophate y Insecticides y Parathion y Malathion War gases

Acetylcholine
y Pharmacological actions of Acetylcholine:
y Depending on type of receptor, the actions of

acetylcholine are classified into 2 types y Muscarinic y Nicotinic

Receptors location and effects


Receptor s M1 location CNS Gastric glands sympathetic ganglia Some presynaptic sites effects 2nd mesenger effects Not known IP3,DAG leads to Acid secretion inc. ca influx Activation Inhibition of transmitter release

M2

1)Heart SA node Contractility AV node

Inhibition of Dec.rate adenyl Dec. cyclase,opening Dec.in conduction of potassium velocity channel Small decrease

ventricles

M3

1)EYE circular muscle of iris ciliary muscle 2)Bronchiolar smooth muscle 3)GIT smooth muscle of wall Exocrine glands and secretory cells 4)genito-urinary smooth muscle bladder wall sphincters pregnant uterus

IP3,DAG Contraction (miosis) Contraction Contraction

Contraction Inc.secretion

Contraction Relaxation contraction

M3

Relaxation(thru NO) 6)Glands(sweat,salivary,lacrimal,nasopha Inc, secretions yngeal) Post ganglionic neurons, CNS Activation Opening of Na, K channels Opening of Na ,K channels

5)Vascular smooth muscle(Art. Veins)

NN

NM

Skeletal muscle neuromuscular end plate

Skeletal muscle contraction

ACETYLCHOLINE, PHARMACOLOGICAL EFFECTS


y Both muscarinic and nicotinic action y Muscarinic actions 1)Eye:constriction of pupil of

eye(miosis) occur due to contraction of circular fibres of iris y Fall in I/O pressure occur due to better drainage through canal of Schlemm which occurs due to opening up of trabecular meshwork at the base of ciliary muscle

y CVS: Bradycardia and vasodilation occur leads to fall in

blood pressure. Then reflex tachycardia occur. y Negative ionotropy y Negative chronotropy y Negative dromotropy y Produces dilatations of all vascular beds y LUNGS: smooth muscle of bronchi contracts. y Increased secretions of glands of tracheobronchial mucosa. y Dangerous in asthmatics patients

y GIT: Increase in secretory and motor activity of gut y Increased in salivary and gastric secretions y URINARY BLADDER: detrusor muscle

contracts,sphincter relaxed thus promoting micturiton y Exocrine glands: increased secretions of salivary,lacrimal and sweat glands

y NMJ: Causes depolarizations y CNS: In large doses causes central stimulation with

tremors and convulsions. y Therapeutic status of Acetylcholine: Acetylcholine is a quaternary ammonium compound that cannot penetrate membranes. Due to its very brief duration of action, acetylcholine cannot be used clinically. Compounds with better selectivity and longer duration of action are generally used.

y PILOCARPINE:

Pilocarpus microphyllus. y It is a tertiary amine which stimulates mainly muscarinic receptors (weak nicotinic)with a more selective action in stimulating exocrine glands (sweat, salivary, lacrimal, bronchial) and has less effect on other receptors (smooth muscles, CVS) y When applied locally to the eye, it is rapidly absorbed from conjunctiva and causes miosis, reduction of intraocular pressure. y Uses: Pilocarpine is the drug of choice in the emergency treatment of glaucoma. y Adverse effects: Pilocarpine can enter the brain and cause CNS disturbances. It causes sweating and salivation.

y It is an alkaloid obtained from Pilocarpus Jaborandi Or

PHYSOSTIGMINE y It is a tertiary amine. y Physostigmine stimulates muscarinic as well

as nicotinic receptors. y Uses: 1. In paralytic ileus and atony of urinary bladder. 2. To produce miosis and to treat glaucoma. 3. To treat poisoning by the drugs with anticholinergic actions such as atropine y Adverse effects: Higher doses stimulate CNS and may cause convulsions. Bradycardia may also occur.

NEOSTIGMINE
y It is a synthetic quaternary ammonium compound. It

is polar (not lipid soluble), hence less absorbed from GIT or conjunctiva and does not cross the BBB. It does not exert actions on CNS. y Skeletal muscles: y it has a direct action at the motor end-plate in addition to its anticholinesterase action. There is an increase in the strength of muscular contraction. y Other pharmacological effects are same as ACH

Uses:

Post operative paralytic ileus and postoperative retention of urine. Myasthenia gravis
Adverse effects: Salivation, hypotension, abdominal pain, bronchospasm, diarrhoea,nausea,vomiting

Irreversible Anticholinestrases Organophosphorus compounds:


All are highly lipid soluble, except echothiophate which is water soluble. They are rapidly absorbed from intact skin, mucosal surfaces and GIT, and cross BBB. 2. They inhibit AChE.(irreversibly)
1.

Isoflurophate: (Diisopropylflurophosphate, (DFP)


y Mechanism of action: y It is an Organophosphorus compound.It covalently binds to a serine-OH at the esteratic site of the enzyme. The phosphorylated enzyme is very stable and the enzyme is permanently inactivated. Recovery depends on synthesis of new enzyme. y.

y Aging: The phosphorylated enzyme slowly releases

one of its isopropyl groups (alkoxy group, C3H7O). Then, pralidoxime cannot break the bond between the remaining drug and the enzyme. Therefore pralidoxime must be given in less than 24 hrs after poisoning . y DFP ages in 6 8 hrs.

y Pralidoxime (cholinesterase reactivator) due to presence of

a charged group approaches an anionic site on the enzyme and displaces the organophosphate. Actually pralidoxime competes with the organophosphates and is itself phosphorylated, making cholinesterase free. Pralidoxime combines with phosphoryl group to form soluble complex setting esteratic site free and thus reactivating the enzyme

Myasthenia gravis
It is a neuromuscular disorder characterized by rapid muscular fatigue and progressive muscular weakness. It is an autoimmune disease resulting in a reduction of acetylcholine receptors at N.M. junction leading to impairment of N.M transmission. Diagnosis is established by injecting Edrophonium , which causes improvement of muscle strength. Treatment is done by anticholinesterases, which act by prolonging the action of acetylcholine released at N.M junction. Treatment is started by Neostigmine.

Cholinergic Crisis: It is a condition of muscle weakness resulting from overdose of anticholinesterase which causes persistent depolarization of motor end-plate resulting in muscular weakness. Myasthenia Crisis: It is a condition of muscle weakness which is due to insufficient dose of anticholinesterase drug. These two conditions may be differentiated by administration of edrophonium I/V with facilities of respiratory resuscitation. An improvement in strength signifies Myasthenia crisis, whereas a further decrease in strength indicates cholinergic crisis.

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