PARASYMPATHOMIMETIC DRUGSPARASYMPATHOMIMETIC DRUGS

OR OR

CHOLINERGIC DRUGSCHOLINERGIC DRUGS

OR OR CHOLINOMIMETIC CHOLINOMIMETIC

DRUGSDRUGS

OROR

CHOLINOCEPTOR ACTIVATING DRUGSCHOLINOCEPTOR ACTIVATING DRUGS

DEFINITIONDEFINITION

These are the group of drugs which produce These are the group of drugs which produce effects resembling those produced by the effects resembling those produced by the stimulation of parasympathetic autonomic stimulation of parasympathetic autonomic

nervous system on the target organsnervous system on the target organs

NeurotransmitterNeurotransmitter Two types of activities Two types of activities

• MuscarinicMuscarinic• Nicotinic Nicotinic

SYNTHESIS, STORAGE, SYNTHESIS, STORAGE,

RELEASE & INACTIVATIONRELEASE & INACTIVATION

MECHANISM OF MECHANISM OF ACTIONACTION

G –protein linked (Muscarinic)G –protein linked (Muscarinic)

Ion channel (Nicotinic)Ion channel (Nicotinic)

PHOSPHO – INOSITOL SYSTEMPHOSPHO – INOSITOL SYSTEM

BINDING OF DRUG WITH RECEPTORBINDING OF DRUG WITH RECEPTOR((ALPHA-1 ADRENDERGIC, MUSCARINIC- CHOLINERGIC)ALPHA-1 ADRENDERGIC, MUSCARINIC- CHOLINERGIC)

ACTIVATION OF PHOSPHOLIPASE-CACTIVATION OF PHOSPHOLIPASE-CPHOSPHATIDYL INOSITOL 4-5 BIPHOSPHATEPHOSPHATIDYL INOSITOL 4-5 BIPHOSPHATE

DIACYL GLYCEROLDIACYL GLYCEROL INOSITOL 1.4.5 TRIPHOSPHATE INOSITOL 1.4.5 TRIPHOSPHATE(CONFINEDTO MEMBRANE)(CONFINEDTO MEMBRANE) (DIFFUSES INTO CYTOSOL) (DIFFUSES INTO CYTOSOL)

ACTIVATION OF PROTEIN KINASECACTIVATION OF PROTEIN KINASEC RELEASE OF Ca++ FROM RELEASE OF Ca++ FROMINTRACELLULARINTRACELLULAR SOURCES SOURCES

ENTRY OF Ca++ THROUGH THE CA++ENTRY OF Ca++ THROUGH THE CA++ FORMATION OF Ca++ CALMODULIN FORMATION OF Ca++ CALMODULIN COMPLEX COMPLEX

CHANNELCHANNEL ALTERATION IN THE ACTIVITY OF Ca++ALTERATION IN THE ACTIVITY OF Ca++ DEPENDENT ENZYMESDEPENDENT ENZYMES

EFFECTEFFECT

CHOLINERGIC RECEPTORSCHOLINERGIC RECEPTORS

MuscarinicMuscarinic

M1 = Nerves, Stomach, BrainM1 = Nerves, Stomach, Brain

Antagonist: PirenzepineAntagonist: Pirenzepine

M2 = Heart, Nerves, Smooth Muscle.M2 = Heart, Nerves, Smooth Muscle.

Antagonist: GallamineAntagonist: Gallamine

M3 = Glands, Endothelium, Smooth Muscle.M3 = Glands, Endothelium, Smooth Muscle.

MM44 and M and M55 newly discovered, role not yet known newly discovered, role not yet known

NicotinicNicotinic

Neuromuscular JunctionNeuromuscular Junction

Agonist: Phenyl Trimethyl AmmoniumAgonist: Phenyl Trimethyl Ammonium

Antagonist: Tubocurarine Antagonist: Tubocurarine

Autonomic Ganglia, Adrenal MedullaAutonomic Ganglia, Adrenal Medulla

Agonist: Dimethyl phenyl piperaziniumAgonist: Dimethyl phenyl piperazinium

Antagonist: HexamethoniumAntagonist: Hexamethonium

CLASSICIFICATIONCLASSICIFICATION

A. Directly ActingA. Directly Acting

B. Indirectly Acting B. Indirectly Acting

A. Directly Acting Cholinergic A. Directly Acting Cholinergic DrugsDrugs : :

I. Choline EstersI. Choline Esters

AcetylcholineAcetylcholine

CarbacholCarbachol

MethacholineMethacholine

BethanecholBethanechol

II. Cholinomimetic AlkaloidsII. Cholinomimetic Alkaloidsa. a. Mainly Muscarinic AgonistsMainly Muscarinic Agonists

Natural Alkaloids:Natural Alkaloids:MuscarineMuscarinePilocarpinePilocarpineArecholineArecholine

Synthetic Alkaloid:Synthetic Alkaloid:OxotramorineOxotramorine

b. b. Mainly Nicotinic AgonistsMainly Nicotinic AgonistsNatural Alkaloids:Natural Alkaloids:

NicotineNicotineLobelineLobeline

Synthetic Alkaloids:Synthetic Alkaloids:Dimethylphenylpiperazinium(DMPP)Dimethylphenylpiperazinium(DMPP)

B. Indirectly Acting Cholinergic DrugsB. Indirectly Acting Cholinergic Drugs (Anticholinesterases)(Anticholinesterases)

I- ReversibleI- Reversible

a. Carbamatesa. Carbamates

b. Alcoholsb. Alcohols

II- IrreversibleII- Irreversible

I- ReversibleI- Reversiblea. Carbamatesa. Carbamates

Tertiary aminesTertiary amines

PhysostigminePhysostigmineQuaternary Ammonium compoundsQuaternary Ammonium compoundsNeostigmineNeostigmine

PyridostigminePyridostigmineDistigmineDistigmineAmbenoniumAmbenoniumDemecariumDemecarium

b. Alcoholsb. AlcoholsEdrophoniumEdrophonium

c. Miscellaneousc. Miscellaneous TacrineTacrineDonepezilDonepezilGalantamineGalantamineRivastigmineRivastigmine

II. II. Irreversible AnticholinesterasesIrreversible Anticholinesterases (Organophosphorus Compounds)(Organophosphorus Compounds)

1)1) Therapeutically usefulTherapeutically useful::EcothiophateEcothiophate

2) War Gases:2) War Gases: SarinSarin

Tuban, Tuban, SomanSoman

3) Insecticides:-3) Insecticides:- Parathion Parathion

MalathionMalathion Diisopropyl Flurophosphate (DFP)Diisopropyl Flurophosphate (DFP)

Tetramethyl Pyrophosphate (TMPP)Tetramethyl Pyrophosphate (TMPP) Octamethyl Pyrophosphotetraamide (OMPA)Octamethyl Pyrophosphotetraamide (OMPA)

ACETYLCHOLINEACETYLCHOLINE

NOT USED AS A DRUGNOT USED AS A DRUG

CHEMISTRYCHEMISTRY

CHEMISTRY

PHARMACOKINETICSPHARMACOKINETICS Acetylcholine & other Choline esters have a Acetylcholine & other Choline esters have a

permanently charged permanently charged quaternary ammonium groupquaternary ammonium group in their structurein their structure

All are All are hydrolysed in the GIThydrolysed in the GIT

The tertiary natural cholinomimetic alkaloids The tertiary natural cholinomimetic alkaloids (pilocarpine, nicotine, lobeline) are well absorbed from (pilocarpine, nicotine, lobeline) are well absorbed from most sites of adm. Muscarine, a quaternary amine is most sites of adm. Muscarine, a quaternary amine is less completely absorbed from the GIT and is toxic too.less completely absorbed from the GIT and is toxic too.

ExcretionExcretion mainly by the kidneys mainly by the kidneys

Pharmacological Actions/ 0rgan Pharmacological Actions/ 0rgan system effects:system effects:

Muscarinic ActionsMuscarinic Actions

Nicotinic ActionsNicotinic Actions

EYE:EYE:• Miosis (constriction of pupil).Miosis (constriction of pupil).• Spasm of accommodationSpasm of accommodation• Decrease in intraocular pressure.Decrease in intraocular pressure.• Conjunctival hyperaemiaConjunctival hyperaemia• LacrimationLacrimation

CVS (Heart & B.V)CVS (Heart & B.V)

Respiratory systemRespiratory system

Gastro intestinal tractGastro intestinal tract

Urinary bladderUrinary bladder

Exocrine glandsExocrine glands

Central Nervous SystemCentral Nervous System

Peripheral nervous systemPeripheral nervous system

N.M .JunctionN.M .Junction

CARBACHOLCARBACHOL Ester of carbamic acidEster of carbamic acid Has both muscarinic and nicotinic actions Has both muscarinic and nicotinic actions Muscarinic actions are prominent on eye, GIT & Muscarinic actions are prominent on eye, GIT &

urinary bladderurinary bladder DOA more than 30 minDOA more than 30 min

Therapeutic uses: Therapeutic uses:

Glaucoma Glaucoma

METHACHOLINEMETHACHOLINE Has methyl group in its structureHas methyl group in its structure Has both muscarinic and nicotinic actions Has both muscarinic and nicotinic actions

(very mild nicotinic actions )(very mild nicotinic actions ) Muscarinic actions are prominent on CVSMuscarinic actions are prominent on CVS Longer DOA as compared to AChLonger DOA as compared to ACh Therapeutic uses: given SC for the relief Therapeutic uses: given SC for the relief

of paroxysmal atrial tachycardiaof paroxysmal atrial tachycardia

BETHANECHOLBETHANECHOL Structure related to Ach, acetate is replaced by Structure related to Ach, acetate is replaced by

carbamate & choline is methylatedcarbamate & choline is methylated Has no nicotinic actionsHas no nicotinic actions Muscarinic actions are prominent on eye, GIT & Muscarinic actions are prominent on eye, GIT &

urinary bladderurinary bladder Prolonged DOAProlonged DOA Therapeutic uses: Therapeutic uses:

• Post operative Gastric distensionPost operative Gastric distension• Paralytic ileusParalytic ileus• Bladder atoniaBladder atonia

MUSCARINEMUSCARINE

Quaternary amine (Quaternary amine (Amanita muscariaAmanita muscaria)) Less complete absorption from the GITLess complete absorption from the GIT Very toxic & can even enter the brainVery toxic & can even enter the brain Rx : AtropineRx : Atropine

PILOCARPINEPILOCARPINE Tertiary amine (Pilocarpus jaborandi leaves)Tertiary amine (Pilocarpus jaborandi leaves) Has muscarinic actionsHas muscarinic actions Therapeutic uses: Therapeutic uses:

• GlaucomaGlaucoma• To reduce the effect of mydriaticsTo reduce the effect of mydriatics• To break adhesionsTo break adhesions

Not used for systemic diseases increased Not used for systemic diseases increased

tracheobronchial secretions leading to tracheobronchial secretions leading to pulmonary oedemapulmonary oedema

NICOTINE & LOBELINENICOTINE & LOBELINE Plant derivativesPlant derivatives Actions are mainly on nicotinic receptors (CNS, Actions are mainly on nicotinic receptors (CNS,

PNS, NMJ)PNS, NMJ) CNS, have important effects on brainstem and CNS, have important effects on brainstem and

cortex. cortex. PNS – autonomic ganglia. PNS – autonomic ganglia. NMJ, immediate depolarization of the end plate NMJ, immediate depolarization of the end plate

– increase in permeability to Na and K ions.– increase in permeability to Na and K ions.