DRUGS acting on the PARASYMPATHATIC NERVOUS SYSTEM Dr. Naila Abrar

Parasympathetic Nervous System Muscarinic Nicotinic Autonomic neuroeffector Ganglia & NMJ junctions Acetylcholine GPCR Ion Channels

CHOLINOCEPTORS Nicotinic Ion channel Muscarinic GPCR

Receptor Type Other NamesLocationStructural FeaturesPostreceptor Mechanism M1 M1 NervesSeven transmembrane segments, G q/11 protein-linked IP 3, DAG cascade M2M2 Cardiac M 2 Heart, nerves, smooth muscle Seven transmembrane segments, G i/o protein-linked Inhibition of cAMP production, activation of K + channels M3 M3 Glands, smooth muscle, endothelium Seven transmembrane segments, G q/11 protein-linked IP 3, DAG cascade M4M4 CNSSeven transmembrane segments, G i/o protein-linked Inhibition of cAMP production M5 M5 CNSSeven transmembrane segments, G q/11 protein-linked IP 3, DAG cascade

Receptor TypeOther NamesLocationStructural Features Postreceptor Mechanism NM NM Muscle type, end plate receptor Skeletal muscle neuromuscular junction Pentamer [(1) 2 1)] Na +, K + depolarizing ion channel NN NN Neuronal type, ganglion receptor CNS postganglionic cell body, dendrites Pentamer with and subunits only, eg, (4) 2 (2) 3 (CNS) or 3 5(2) 3 (ganglia) Na +, K + depolarizing ion channel

PARASYMPATHOMIMETIC DRUGS or CHOLINERGIC DRUGS or CHOLINOMIMETIC DRUGS

CLASSICIFICATION A.Directly Acting B.Indirectly Acting

A. Directly Acting Cholinergic Drugs I.CHOLINE ESTERS II.CHOLINOMIMETIC ALKALOIDS

I.CHOLINE ESTERS - Acetylcholine - Methacholine - Carbachol - Bethanechol

II. CHOLINOMIMETIC ALKALOIDS a. Mainly Muscarinic Agonists  Natural Alkaloids: - Muscarine - Pilocarpine - Arecholine  Synthetic Alkaloid: - Oxotremorine b.Mainly Nicotinic Agonists  Natural Alkaloids: - Nicotine - Lobeline  Synthetic Alkaloids: - Dimethylphenyl- piperazinium(DMPP)

B. Indirectly Acting Cholinergic Drugs (Anticholinesterases) I- REVERSIBLE  Carbamates  Tertiary amines- physostigmine  Quaternary ammonium compounds- neostigmine, pyridostigmine, tacrine, ambenonium, demecarium  Alcohols- edrophonium  Miscellaneous- tacrine, galantamine, rivastigmine, donepezil II- IRREVERSIBLE  Organophosphates  Therapeutically useful -ecothiopate  War gases -sarin, tuban, soman  Insecticides -parathion, malathion, DFP, TEPP, OMPA

PHARMACOKINETICS Esters-Quaternary ammonium gp Choline esters are poorly absorbed and poorly distributed into CNS Methacholine is resistant to hydrolysis by cholinesterase Carbamic acid esters carbachol and bethanechol- most resistant-longer duration of action

Pharmacokinetic (contd.) Pilocarpine, nicotine, lobeline-tertiary natural compounds- well absorbed Muscarine, quaternary amine is toxic when ingested present in certain mushrooms Excretion chiefly through kidneys

MECHANISM OF ACTION of directly acting cholinomimetics 1.Activation of muscarinic receptors on effector cells directly to alter organ function 2.Interaction with muscarinic receptors on nerve terminals to inhibit release of their neurotransmitter

MECHANISM OF ACTION of directly acting cholinomimetics Muscarinic- GPCR  Inhibitory effects (M 2 & M 4 )  Inhibition of adenylyl cyclase- decrease of cAMP (GPCR-G i /G o )  Excitatory effects (M 1,M 3,M 5 )  Increase activity of IP 3 & DAG (GPCR- G q/11 )

MECHANISM OF ACTION of directly acting cholinomimetics Nicotinic – pentameric ion channel  Na + & K + move down conc. gradient  Depolarization  Skeletal muscle-Action potential propagation-contraction  Prolonged agonist occupancy- depolarizing blockade

ACETYLCHOLINE CHEMISTRY An ester of acetic acid and choline

SYNTHESIS, STORAGE, RELEASE & INACTIVATION

Pharmacological actions/ Organ system effects:  Muscarinic Actions  Nicotinic Actions

EYE:  M 3  Miosis (constriction of pupil)- contraction of papillary sphincter ms.  Spasm of accommodation (contraction of ciliary muscle)- eye fixed for near vision Decrease in intraocular pressure Conjunctival hyperemia Lacrimation

CVS (Heart & Blood Vessels)  Negative chronotropic effect- bradycardia M 2 -Decreases rate of spontaneous depolarization  Negative dromotropic effect- decrease in conduction velocity in AV node- (inhibiting Ca channels)  Negative inotropic effect- decreased cardiac output ( hyperpolarization, decrease cAMP & epinephrine release)  Vasodilation- fall in blood pressure- NO

RESPIRATORY SYSTEM  M 3  Bronchial muscle contraction  Bronchial gland stimulation- increase tracheobronchial secretions

GIT  M 3  Increase motility  Relaxation of sphincters  Increase tone of LES

URINARY BLADDER  M 3  Detrusor muscle contraction  Relaxation of sphincters  Promote micturition

 Exocrine glands- M 3 - Increase in salivation, sweat, lacrimation  Central Nervous System - M 1 - Cortical arousal, or activation  Peripheral nervous system - Stimulation of ganglia both the systems are activated

 Neuromuscular junction - Na + and K + entry into cell- depolarization - Skeletal muscle contraction

THERAPEUTIC USES Glaucoma (pilocarpine) Accommodative estropia Induction of miosis (Ach, carbachol) Postoperative ileus (bethanechol) Congenital megacolon (bethanechol) Atony of urinary bladder – post op, diabetic autonomic neuropathy (bethanechol)

THERAPEUTIC USES (contd.) Dry mouth with Sjogren’s syndrome (pilocarpine, cevimeline) Diagnosis of bronchial airway hyperreactivity (methacholine)

ADVERSE EFFECTS Signs of muscarinic excess. Salivation, sweating Difficulty in visual accommodation NVD, abd. cramps Urinary urgency Cutaneous vasodilatation Bronchoconstriction Hypotension

CONTRAINDICATIONS Bronchial asthma GI or urinary tract obstruction Peptic ulcer Recent myocardial infarction Coronary insufficiency Hyperthyroidism

MUSHROOM POISONING Signs of muscarinic excess-salivation, sweating, NVD, visual disturbances, headache, abd. Colic,urinary urgency, bradycardia, bronchospasm, hypotension, shock Atropine (1-2mg I/M every 30mins)

ACUTE NICOTINE TOXICITY A.CNS stimulation, cause convulsions, coma and respiratory arrest. B.Skeletal muscle depolarization and respiratory paralysis. C.Hypertension and cardiac arrhythmia.

CHRONIC TOBACCO USE Increased risk of vascular disease. Sudden coronary death. Aggravation of peptic ulcer in smokers.

Other Choline Esters Methacholine Carbachol Bethanechol

METHACHOLINE Both muscarinic and nicotinic actions. Muscarinic actions are more prominent on CVS than on GIT and urinary bladder. Duration of action 30 min. Paroxymal atrial tachycardia.

CARBACHOL Not destroyed by cholinesterase. Longer duration of action and potent than methacholine. Therapeutic uses Post operative abdominal distention, paralytic ileus, urinary retention and glaucoma.

BETHANECHOL Weak but prolonged effect Therapeutic uses Difficulty in micturition, gastric distention following surgery.

PILOCARPINE Pilocarpus microphyllus (jaborandi) Tertiary amine-enters CNS More muscarinic effects Therapeutic uses Glaucoma (other options available) Reverse effects of mydriatics Xerostomia Break adhesions