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PARASYMPATHETIC DRUGS(Cholinomimetic Drugs)

. . . .

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Objectives

1. Cholinoceptor-Activating Drugs

1.1 Direct-acting cholinergic receptor agonists

1.2 Indirect-acting cholinergic receptor agonists

2. Cholinoceptor-Blocking Drugs

2.1 Muscarinic-blocking drugs2.2 Nicotinic-blocking drugs

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1. Cholinoceptor-Activating Drugs

1 2

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Cholinergic NT & Sites of Drug ActionCholinergic NT & Sites of Drug Action

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ACh + NMR Na + influx + EPSP (excitatory postsynaptic potential )

EPSP

depolarizes muscle membrane

action potential+muscle contraction .

Ex: NMJ

Nicotinic agonist

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Na +, K+ depolarizingion channel

Pentamer CNSpostganglioniccell body,dendrites

NN

Na +, K+ depolarizingion channel

Pentamer Neuromuscular junction

NM

-IP 3,-DAG cascade

Seven transmembranesegments,Gq/11 protein-linked

Glands,smooth muscle,endothelium

M3

-Inhibition of cAMPproduction,-Activation of K +

channels

Seven transmembranesegments,G i/o protein-linked

Heart,nerves,smooth muscle

M2

-IP 3,-DAG cascade

Seven transmembranesegments,Gq/11 protein-linked

NervesM1

Postreceptor Mechanism

Structural FeaturesLocationReceptor Type

Cholinoceptor Subtypes and Characteristics

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Drugs that inhibit ChE: edrophonium, neostigmine Drugs that augment effects of ACh: sildenafil (Viagra )

1.1 Direct-acting cholinergic receptor agonists Directly bind to muscarinic and nicotinic receptors

Types1. Choline esters:

- Acetic acid esters: ACh, methacholine

- Carbamic acid esters: carbachol, bethanechol

2. Plant alkaloids: pilocarpine, nicotine, lobeline

1.2 Indirect-acting cholinergic receptor agonist

1. Cholinoceptor-Activating Drugs

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Quaternary NH 4-cpdspoorly absorbed from GI tract & -/-> CNS

ACh & carbachol activate both M & N receptors ,Bethanechol activates only M receptors

Due to non- specificity for M receptor subtypeswide range of effects on many organ systems

ACh: choline ester of acetic acid, rapidly hydrolyzed by AChEextremely short duration

Bethanechol & carbachol , choline ester of carbamic acidresistant to AChE lasting for several hours

1.1.1 Chemistry & Pharmacokinetics:1.1.1.1. Choline esters

1.1 Direct-Acting Cholinergic Receptor Agonists

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found in mushrooms, can cause diarrhea, sweating, salivation & lacrimation, no medical use

1.1.1.2. Plant Alkaloids:

derived from Nicotiana plants &

contains in cigarettes & tobacco products, use for smoking cessation

is tertiary amine well absorbed, use as second-line drug for chronic glaucoma use for xerostomia (dry mouth), low dose,

oral pilocarpine stimulates salivary secretion(high sensitivity of salivary gland)

Nicotine,

Muscarine,

Pilocarpine,

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ANS Effects on Organs

1.1.2 Drugs acting on muscarinic receptors

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Parasympathetic effects Sympathetic effects

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St t f th t i h b f th

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Aqueous humor is secreted by the epithelium of the ciliary body ( ) flows in front of the iris trabecular meshwork-->canal of Schlemm (arrow ).

Blockade of the adrenoceptors: - secretion of aqueous. Blood vessels (not shown) in the sclera are also under autonomic control and

influence aqueous drainage

Structures of the anterior chamber of the eye(Show ANS receptors)

A t i Eff t th E

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Autonomic Effects on the Eye

Suspensoryligament(M) ( )

( ) (M)

Iris; para + constrictor muscle pupil size = miosissym + dilator muscle pupil size = mydriasis

Ciliary muscle constrictrelax suspensory ligament eye accommodation for near visionTrabecular meshwork increase aqueous humour drainage

Effects of pilocarpine and atropine on the eye

Effects of pilocarpine and atropine on the eye

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Effects of pilocarpine and atropine on the eyeEffects of pilocarpine and atropine on the eye

A. Normal eye: Relationshipbetween iris sprincter & ciliary muscle

B. Muscarinic agonist(:pilocarpine)

- iris sprincter contraction->pupil constrict ( miosis)

- ciliary contraction-> relax suspensory ligament-> len thickness

-> focus on close object .C. Muscarinic antagonist

(:atropine)

- iris sprincter relax->pupil dilate (mydriasis )

- ciliary muscle relax

-> suspensory ligament contraction-> len thickness-> blurred vision (cycloplegia).

D g th t l i t l

Drugs that lower intraocular pressure

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Muscarinic agonist Prostaglandins -antagonist & -agonist Carbonic anhydrase inhibitor

Muscarinic agonist (:pilocarpine) ciliary muscle contraction

open trabecular spacedrainage

Drugs that lower intraocular pressureDrugs that lower intraocular pressure

h l l

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Drugs that lower intraocular pressureDrugs that lower intraocular pressure

Can cause ocular pigmentationProstaglandinanalogue

Latanoprost

Used as eye drops2-Adrenoceptoragonist

Clonidine,apraclonidine

Acetazolamide is given systemically.Side effects include diuresis, loss of appetite,tingling, neutropenia.Dorzolamide is used as eye drops.

Side effects include bitter taste and burningsensation.

Carbonic anhydraseinhibitor

Acetazolamide,dorzolamide

Given as eye drops but may still causesystemic side effects: bradycardia,bronchoconstriction.

-Adrenoceptor antagonist

Timolol

Widely used as eye dropsCan cause muscle spasm & systemic effects

AnticholinesteraseEcothiopate

Widely used as eye dropsMuscarinic agonistPilocarpineNotesMechanismDrugs

Effects of Direct Acting Cholinoceptor Stimulants

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19SecretionSweat, salivary,lacrimal, nasopharyngeal

Glands

RelaxationTrigone and sphincter

ContractionDetrusor Urinary bladder

StimulationSecretion

RelaxationSphinctersIncreaseMotilityGI tract

StimulationBronchial glands

Contraction (bronchoconstriction)Bronchial muscleLung

Dilation (via EDRF). Constriction (high-dosedirect effect)

Veins

Dilation (via EDRF). Constriction (high-dosedirect effect)

ArteriesBlood vessels

Small decrease in contractile strengthVentricles

Decrease in conduction velocity (negativedromotropy). Increase in refractory periodAV node

Decrease in contractile strength (negativeinotropy). Decrease in refractory period

Atria

Decrease in rate (negative chronotropy)Sinoatrial nodeHeartContraction for near visionCiliary muscle

Contraction (miosis)Sphincter muscle of irisEye

ResponseOrganEffects of Direct-Acting Cholinoceptor Stimulants

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20Glaucoma ,xerostomia

Topical ocular,oral

NoM > NPilocarpine

Smokingcessation

Oral,transdermal

NoNNicotine

NoneNoMMuscarine

Plant Alkaloids

Glaucoma

Miosis duringophthalmicsurgery

Topical ocular,

Intraocular

NoM & NCarbachol

Stimulate GI &bladder motility

Oral, scNoMBethanechol

Miosis duringophthalmicsurgery

Intraocular YesM & N AcetylcholineCholine esters

Clinicaluse

Route ofadministration

Hydrolyzedby ChE

Receptor specificity

Drug

1 1 3 D A ti Ni ti i R t

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1.1.3.1 Drugs acting on autonomic ganglia: nicotine

Stimulate both sym & parasym ganglia complex effects- tachycardia and- increase of blood pressure;- variable effects on GI motility and secretions;- increased bronchial, salivary and sweat secretions.

Ganglion stimulation may be followed by depolarisation block .

Nicotine also has important CNS effects .

No therapeutic uses,(Except for nicotine to assist giving up smoking)

1.1.3 Drugs Acting on Nicotinic Receptor: Autonomic ganglion & NMJ1.1.3 Drugs Acting on Nicotinic Receptor: Autonomic ganglion & NMJ

1 1 3 2 Drugs acting on neuromuscular junction (NMJ)

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1.1.3.2 Drugs acting on neuromuscular junction (NMJ)

SCh + N MR (postsynaptic site)prolong depolarizationunresponse to subsequent impulse

neuromuscular block= Depolarizing neuromuscular blocking agents

ACh + Receptor (alpha site)

Open Na ion channel

Na + influx

Depolarization

Muscle contraction

Succinylcholine ( SCh or suxamethomium )

Acetylcholine ( ACh)

1 2 Indirect acting cholinergic receptor agonists

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1.2.1 Drugs that Inhibit ChE (Anticholinesterase drugs)1.2.1 Drugs that Inhibit ChE (Anticholinesterase drugs)

2. Butyrylcholinesterase (BuChE or pseudocholinesterase)- occurs in plasma and many tissues (liver),

- non-selective

Cholinesterase : Two main forms of ChE :

1. Acetylcholinesterase (AChE): membrane-bound, specific for AChrapid ACh hydrolysis at cholinergic synapses

1.2.1 Drugs that inhibit ChE1.2.2 Drugs that augment effects of ACh

1.2 Indirect-acting cholinergic receptor agonists

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Reversible antiChE Irreversible antiChE

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(2-PAM)

: Organophosphates(:parathion)

formed covalent bondvery slow hydrolysis

: Carbamates (:neostigmine )formed carbamoylated enzyme

slow hydrolysis

Pharmacologic Effects of antiChE Drugs

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cholinergic transmission at synapses

-CVS: bradycardia, hypotension

-RS: excessive secretions, bronchoconstriction-GI: gastrointestinal hypermotility-Eye: intraocular pressure

Pharmacologic Effects of antiChE Drugs

Autonomic actions:

CNS effects:

-muscle fasciculation and-can produce depolarisation block

Neuromuscular action:

- convulsion: physostigmine, organophosphates(antiChEs that cross BBB)

- AntiChE poisoning may occur from exposureto insecticides or nerve gases

Clinical Uses of Anticholinesterases

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1. Anaesthesia : neostigmine + atropine

Clinical Uses of Anticholinesterases

-to reverse action of non-depolarisingneuromuscular-blocking drugs

:donepezil,galantamine,rivastigmine

-to test : edrophonium-treatment : neostigmine &

pyridostigmine

2. Myasthenia gravis

: ecothiopate

(eye drops)

3. Glaucoma

4. Alzheimers

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Physostigmine, Neostigmine & Pyridostigmine

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Ester of carbamic acid slow hydrolysis, duration 0.5-2 h

Physostigmine-Tertiary amine well absorbed & penetrates BBB- Use in the treatment of anticholinergic drug overdose

(atropine, phenothiazine, tricyclic antidepressant) Neostigmine & Pyridostigmine ,

- Synthetic quaternary amine cpds absorbed -/-> BBB.- Clinical uses:

- treatment of MS,- antidote of nondepolarizing blocking agent- stimulate bladder & GI tract (SC)

Are centrally acting, reversible ChE inhibitors that readily cross BBB &increase brain ACh conc, treat Alzheimers disease

Donepezil, galantamine, rivastigmine

. . rugs a ugmen ec s o: Sildenafil (Viagra ) Used in erectile dysfunction

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Erection requiresrelaxation of thenonvascular smooth

muscle of the corporacavernosa

In response to therelease of NO fromNANC associated withparasympatheticdischarge.

Sildenafil cGMP(- phosphodiesteraseisoform 5)

: Sildenafil (Viagra ), Used in erectile dysfunction

2. Cholinoceptor-Blocking Drugs

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2. Cholinoceptor Blocking Drugs

2.1 Muscarinic-Blocking Drugs- Compete with ACh for M-receptors parasympatholytic drugs- Obtained from:

- Plants (Belladonna alkaloids): atropine, scopolamine, hyoscyamine- Synthesis: ipratropium, dicyclomine, tropicamide, pirenzepine

- Have similar effect, differ in pharmacokinetics & clinical uses

2.2.1 Ganglionic blocking agents2.2.2 Neuromuscular blocking agents

- Nondepolarizing Neuromuscular blocking agents: Tubocurarine

- Depolarizing Neuromuscular blocking agents: Succinylcholine

2.2 Nicotinic-Blocking Drugs

l k

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Pharmacological effects (: atropine )

HR tachycardia

Eye mydriasis, cycloplegia, & intraocular pressure

Relax smooth muscle: bronchial, biliary & urinary tract

CNS : atropine + CNS

GI: GI motility & gastric acid secretion

Secretion dry mouth

2.1 Muscarinic-Blocking Drugs

Dose Dependent Effect of Atropine

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Low dose of atropine inhibits salivation & sweating , The effects are dose-dependent. Higher doses tachycardia, urinary retention & CNS effects

(Brenner 2006 p 66)

Clinical uses of muscarinic antagonists

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-CVS : sinus bradycardia-Eye : dilate pupil

-CNS : motion sickness (scopolamine),parkinsonism (benztropine, biperiden)

-RS : asthma (ipratropium, used in combination with 2 agonists in the management of chronic asthma )

anasethetic premedication (atropine)-GI : antispasmodicpeptic ulcer

Clinical uses of muscarinic antagonists

Muscarinic-Blocking Drugs

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Fewer side effects than othermuscarinic antagonists

Largely superseded by otherantiulcer drugs

Peptic ulcerSelective for M1 receptorsInhibits gastric secretion

by action on ganglion cellsLittle effect on smoothmuscle or CNS

Pirenzepine

As tropicamide (long acting)Similar to tropicamideCyclopentolate

Ophthalmic use to producemydriasis and cycloplegia (as eyedrops)Short acting -

Similar to atropineMay raise intraocularpressure

Tropicamide

Quaternary ammonium compoundTiotropium is similar

By inhalation for asthma ,bronchitis

Similar to atropinemethonitrateDoes not inhibitmucociliary clearance frombronchi

lpratropium

Quaternary ammonium derivativeMainly for GI hypermotilitySimilar to atropine butpoorly absorbed & lacks CNSeffectsSignificant ganglion-blocking activity

Atropinemethonitrate

Belladonna alkaloidCauses sedation;other side effects as atropine

As atropineMotion sickness

Similar to atropineCNS depressant

Hyoscine(Scopolamine )

Belladonna alkaloidMain side effects:

urinaryretention, dry mouth, blurred visionDicycloverine, similar & used mainlyas antispasmodic agent

Adjunct for anaesthesia(reduced secretions, bronchodilatation)AntiChE poisoningBradycardiaGI hypermotility (antispasmodic)

Non-selective antagonistWell absorbed orallyCNS stimulant

Atropine

NotesClinical usesPharmacological propertiesCompound

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2.2.2 Neuromuscular-blocking drugs

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- NMR at postsynaptic site-/-> depolarization

neuromuscular blockflaccid paralysis= Non-depolarizing blocking

drug

Succinylcholine (nChR agonist)

+ N MR (postsynaptic site)prolong depolarizationunresponse to subsequent impulse

neuromuscular blockparalysis

= Depolarizing blocking agents

Tubocurarine (nChR antagonist)

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QuestionsQuestions