DRUGS acting on the PARASYMPATHATIC NERVOUS SYSTEM

Dr. Naila Abrar

Parasympathetic Nervous System

Muscarinic Nicotinic

Autonomic neuroeffector Ganglia & NMJ junctions

Acetylcholine

GPCRIon

Channels

CHOLINOCEPTORS

NicotinicIon channel

Muscarinic GPCR

Receptor Type

Other Names Location Structural Features

Postreceptor Mechanism

M1

   Nerves Seven

transmembrane segments, Gq/11 protein-linked

IP3, DAG cascade 

M2 Cardiac M2

 Heart, nerves, smooth muscle

Seven transmembrane segments, Gi/o protein-linked

Inhibition of cAMP production, activation of K+ channels

M3

   Glands, smooth

muscle, endothelium

Seven transmembrane segments, Gq/11 protein-linked

IP3, DAG cascade 

M4   CNS Seven transmembrane segments, Gi/o protein-linked

Inhibition of cAMP production

M5

   CNS Seven

transmembrane segments, Gq/11 protein-linked

IP3, DAG cascade 

Receptor Type

Other Names Location Structural Features

Postreceptor Mechanism

NM

 Muscle type, end plate receptor

Skeletal muscle neuromuscular junction

Pentamer [(1)21)] 

Na+, K+ depolarizing ion channel 

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- GPCRInhibitory effects (M2 & M4)

Inhibition of adenylyl cyclase- decrease of cAMP (GPCR-Gi/Go)

Excitatory effects (M1,M3,M5)

Increase activity of IP3 & DAG (GPCR-Gq/11)

MECHANISM OF ACTION of directly acting cholinomimetics

Nicotinic – pentameric ion channelNa+ & K+ move down conc. gradient DepolarizationSkeletal muscle-Action potential

propagation-contractionProlonged agonist occupancy-

depolarizing blockade

ACETYLCHOLINE

CHEMISTRYAn ester of acetic acid and choline

SYNTHESIS, STORAGE, RELEASE & INACTIVATION

Pharmacological actions/ Organ system effects:

Muscarinic Actions

Nicotinic Actions

EYE:M3

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 M2

-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

M3

Bronchial muscle contraction

Bronchial gland stimulation-

increase tracheobronchial secretions

GIT

M3

Increase motility

Relaxation of sphincters

Increase tone of LES

URINARY BLADDER

M3

Detrusor muscle contraction

Relaxation of sphincters

Promote micturition

Exocrine glands- M3

- Increase in salivation, sweat, lacrimation

Central Nervous System - M1

- 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 effectsTherapeutic uses• Glaucoma (other options available)• Reverse effects of mydriatics• Xerostomia • Break adhesions