DRUGS ACTING AT SYNAPTIC AND NEUROEFFECTOR JUNCTION SITES

Cholinergic Receptors and Signal Transduction Muscarinic receptorsG protein-coupled receptors (GPCRs). Responses to muscarinic agonists are slower;

they may be either excitatory or inhibitory, and they are not necessarily linked tochanges in ion permeability.

Nicotinic receptorsigand-gated ion channels whose activation always causes a rapid (millisecond) increase in cellular permeability to Na+ and Ca2+, depolarization, and excitation.

Muscarinic receptorsSelectively stimulated by Muscarine and blocked by atropine

Located primarely on autonomic effector cells in heart, blood vessels, eye,smooth muscles and glands of GIT, respiratory and Urinary tract, sweat glands etc and CNS 5 sbtypes M1, M2, M3, M4 and M5

Characteristics of Muscarinic Acetylcholine Receptor SubtypesRECEPTOR CELLULAR AND TISSUE LOCATION CELLULAR RESPONSE FUNCTIONAL RESPONSE

M1

CNS; Most abundant in cerebral cortex, hippocampus and striatum, Autonomic ganglia, Glands (gastric and salivary), Enteric nerves

Activation of PLC; IP3 and DAG Ca2+ an Depolarization and excitation

Increased cognitive function (learning and memory) Increased seizure activity, Decrease in dopamine release and locomotion, Increase in depolarization of autonomic ganglia Increase in secretions SA node: slowed spontaneous depolarization; hyper AV node: decrease in conduction velocity polarization, HR

M2

Widely expressed in CNS, heart, smooth muscle, autonomic nerve terminals

Inhibition of adenylyl cyclase, Camp, Activation of inwardly rectifying K+ channels, Inhibition of voltagegated Ca2+ channels, Hyperpolarization and inhibition Activation of PLC; IP3 and DAG Ca2+ and PKC Depolarization and excitation

M3

Widely expressed in CNS (< than other mAChRs), Abundant in smooth muscle and glands, Heart

contraction (predominant in some, e.g. bladder) secretion (predominant in salivary gland) Increases food intake, body weight fat deposits

Nicotinic receptorsSelectively stimulated by Nicotine and blocked by tubocurarineThese are pentameric strs which enclose ligand gated cation channels Their activation causes opening of the channel and rapid flow of cations resulting in

depolarization and an action potentialOn the basis of location and selective agonists and antagonists two subtypes NM and NN

NM: Stimulated by phenyltrimethyl ammonium and blocked by tubocurarineThese are present in muscles at neuromuscular junction. They mediate skeletal muscle contraction

NN: Stimulated by dimethyl phenylpiperazinium and blocked by hexamethoniumThese are present on ganglionic cells, adrenal medulla and spinal cord and certain areas of brain. Constitute the primary pathway of transmission in ganglia

Nicotinic receptors

Cholinergic drugsProduce action similar to that of Ach either by directly interacting with cholinergic receptors or by increasing the availability of Ach at receptors on these sites

CHOLINERGIC AGONISTSClassified as 1. Choline esters: Acetylcholine, Methacholine, Carbachol, Bethanecol 2. Alkaloids: Muscarine, Pilocarpine, Arecoline

Cholinergic drugs: ActionsProduce action similar to that of Ach either by directly interacting with cholinergic receptors Ach can be taken as prototype A. Muscarinic actions:

Heart: hyperpolarization of the SA nodal cells, decreases the rate of diastolic depolarization. As aresult rate of impulse generation is reduced- bradycardia or even cardiac arrest may occur Blood vessels: All blood vessels are dilated , thus fall in BP and flushing , specially in the blush area occurs

Smooth muscles: in most organs are contracted, In GIT it may lead to abdominal cramps andevacuation of bowel. In ureter voiding of bladder and in Bronchial muscles perception of an attack of bronchial asthma Glands: secretion is increased-sweating, salivation, lacrimation, tracheobronchial and gastric

secretionEye: contraction of circular muscles of iris- miosis i.e constriction of pupil

Cholinergic drugs: ActionsProduce action similar to that of Ach either by directly interacting with cholinergic receptors Ach can be taken as prototype B. Nicotinic Actions: Autonomic ganglia: Both parasypathetic and sympathetic ganglia are stimulated. High doses of Ach given after atropine causes tachcardia and rise in BP. Skeletal muscles: Application of Ach to muscle end plate causes contraction of the fibre, intraarterial injection of high doses can cause twitching and fasciculations but i.v injection is generally without any effect.

Cholinergic drugs: UsesRarely used for therapeutic purpose. Ach is not used bcz of nonselective action. Methacholine was occasionally used to terminate paroxysmal supraventricular tachycardia Bethanecol has been used in postoperative nonobstructive urinary retention, neurogenic bladder atony. Side effects are prominent: belching, colic, involuntary urination, flushing, sweating, fall in BP, bronchospasm

Cholinergic drugs: AlkaloidsPilocarpine:Obtained from the leaves of Pilocarpus microphyllus and other species.

It has prominent muscarinic actions and also stimulate ganglia mainly through ganglionicmuscarinic receptors. It causes marked sweating, salivation and increases other secretions as well

Small doses generally causes fall in BP but higher doses elicit rise in BP and tachycardiaApplied to the eyes, it penetrates cornea and promptly miosis, ciliary muscle contraction and fall in intraocular tension

Uses: As eye drop (0.5-4%) in open angle glaucoma

ANTICHOLINESTERASES Inhibit cholinesterse

Reversible CarbamatesPhysostigmine Neostigmine Pyridpstigmine Edrophonium Rivastigmine

AcridineTacrine

CarbamatesCarbaryl Propoxur (baygon)

Irreversible OrganophosphatesDyflos Echothiopate Parathion Diazinon Tabun, Sarin, Soman