ParasympathlyticParasympathlytic

(Cholinergic antagonists) (Cholinergic antagonists)

(Anticholinergic )(Anticholinergic )

(Cholinergic Blockers)(Cholinergic Blockers)

فاضل محمد ثامر حسانالمالح

Group – B-

Agents with high binding affinity for muscarinic Agents with high binding affinity for muscarinic receptors but receptors but no intrinsic activityno intrinsic activity. Pharmacologic . Pharmacologic effects opposite of the muscarinic agonists.effects opposite of the muscarinic agonists.

Competitive (reversible) antagonists of AChCompetitive (reversible) antagonists of ACh Antagonistic responses include:Antagonistic responses include:

decreased contraction decreased contraction of GI and urinary tract smooth muscles, of GI and urinary tract smooth muscles,

dilation of pupils, dilation of pupils,

reduced gastric secretion, reduced gastric secretion,

decreased saliva secretion.decreased saliva secretion.

A- antimuscarinic agentsA- antimuscarinic agents(Muscarinic Antagonists)(Muscarinic Antagonists)::

A- antimuscarinic agentsA- antimuscarinic agents(Muscarinic Antagonists):(Muscarinic Antagonists):

1-Atropine (belladonna alkaloid) 1-Atropine (belladonna alkaloid) (Competitive inhibitors) .(Competitive inhibitors) .

-bind to muscarinic receptors and prevent Ach -bind to muscarinic receptors and prevent Ach binding. binding.

reversible blockade of ACh at muscarinic receptors by competitive binding-reversal effect of atropine by increasing ACh or agonist ----> decreased blockade

..

Muscarinic receptor blockade Muscarinic receptor blockade does not interfere with does not interfere with transmission at autonomic transmission at autonomic ganglionic sites, the adrenal ganglionic sites, the adrenal medulla, or skeletal muscle medulla, or skeletal muscle fibers. fibers. Sympathetic adrenergic Sympathetic adrenergic functions are not affectedfunctions are not affected..

MUSCARINIC RECEPTOR BLOCKADE MUSCARINIC RECEPTOR BLOCKADE ALLOWS ALLOWS SYMPATHETICSYMPATHETIC DOMINANCE DOMINANCE IN DUAL INNERVATED ORGANSIN DUAL INNERVATED ORGANS

X

Atropine actionsAtropine actions

Eye:Eye:

*mydriasis*mydriasis

*unresponsiveness to light*unresponsiveness to light

*cycloplegia*cycloplegia

*increase IOP*increase IOP

GIT:GIT:

reduce activity of GIT.reduce activity of GIT. Urinary system:Urinary system:

reduce hyper motility.reduce hyper motility. Cardiovascular system:Cardiovascular system:

at low dose bradycardia at low dose bradycardia

at high dose tachycardiaat high dose tachycardia Secretions:Secretions:

reduce secretionsreduce secretions

Therapeutic uses of Therapeutic uses of atropineatropine

1-Ophthalmic:1-Ophthalmic: Ophthalmologic examinations..

mydriatic & cycloplegic effects.mydriatic & cycloplegic effects.

2-antispasmotic agent 2-antispasmotic agent : relax GIT & bladder: relax GIT & bladder

((Treatment of smooth muscle spasms).

3-antidot for cholinergic agonists:3-antidot for cholinergic agonists:

Rx of over dose of organophosphateRx of over dose of organophosphate

4-antisecretory agent:4-antisecretory agent:

reduce secretions of respiratory tract and reduce secretions of respiratory tract and salivary gland .salivary gland .

((Reduction of nasal and upper respiratory tract secretions in cold and flu)secretions in cold and flu)

Pharmacokinetics of Pharmacokinetics of atropineatropine Absorbed & metabolized by liver.Absorbed & metabolized by liver. Eliminated by urine.Eliminated by urine. Half life/4hr.Half life/4hr. Parenteral preparations Parenteral preparations

(derivatives) are more potent (derivatives) are more potent than the parent compounds.than the parent compounds.

Adverse effects of Adverse effects of atropineatropine

Dryness of mouth Dryness of mouth Blurred visionBlurred vision Increase in IOPIncrease in IOP Attack of glaucomaAttack of glaucoma TachycardiaTachycardia ConstipationConstipation CNS effectsCNS effects Collapse of circulatory & respiratory systemsCollapse of circulatory & respiratory systems Urine retentionUrine retention

Treatment of atropine Treatment of atropine poisoningpoisoning

Ventilation Ventilation Cold spongyCold spongy DiazepamDiazepam physostigminphysostigmin

Antimuscarinic agentsAntimuscarinic agents

2-scopolamine:2-scopolamine: greater actions on CNSgreater actions on CNS (than atropine) (than atropine)

Low doses of scopolamine produce CNS effects that are not seen with equivalent doses of atropine.

(longer duration of action than atropine)(longer duration of action than atropine)

**actions & uses: actions & uses:

prophylaxis of motion sickness drug motion sickness drug

side effects : side effects : sedation , amnesic action sedation , amnesic action

Antimuscarinic agentsAntimuscarinic agents

3-ipratropium3-ipratropium useful in Rx of asthma & chronic obstructive useful in Rx of asthma & chronic obstructive

pulmonary diseasepulmonary disease Administration:

by inhalation as aerosol (to provide maximal concentration at the site of action)

Synthetic Synthetic amtimuscarinic agent amtimuscarinic agent

1- Probanthine 1- Probanthine

2- Methanthelin bromide2- Methanthelin bromide uses : treatment of peptic ulcer uses : treatment of peptic ulcer C/IC/IGlaucomaGlaucomaStomach obstruction Stomach obstruction Old patientOld patientCardiac disturbanceCardiac disturbance

B- anti nicotinic agentB- anti nicotinic agent Nicotinic Antagonists:Nicotinic Antagonists: Agents that bind to Agents that bind to

cholinergic nicotinic receptors but do not have cholinergic nicotinic receptors but do not have efficacy.(Competitive antagonists).efficacy.(Competitive antagonists).

Antinicotinic include :

1- Ganglion blockers

2- Neuromuscular blockers

1-ganglionic blockers1-ganglionic blockers 1-Hexamthonim1-Hexamthonim

2-Pentamethanium2-Pentamethanium

3-Trimethaphan.3-Trimethaphan.

Pharmacological effects of Pharmacological effects of ganglionic blockersganglionic blockers::

EyeEye: mydriasis , paralysis of accommodation: mydriasis , paralysis of accommodation Respiratory tractRespiratory tract: reduce secretions: reduce secretions Salivary glands: Salivary glands: xerstomiaxerstomia GIT:GIT: reduce secretions & motility reduce secretions & motility Cardiovascular: Cardiovascular: decrease blood pressuredecrease blood pressure Urinary tract Urinary tract : urinary retention: urinary retention Sweat glandsSweat glands: decrease sweating: decrease sweating CNS: CNS: no direct effectsno direct effects

UsesUses

Operation of neurosurgery Operation of neurosurgery Hypertension with Hypertension with

phochromocytomaphochromocytoma

22 - -Neuromuscular blocking Neuromuscular blocking drugsdrugs

which block Ach at N-M-J(neuromuscular junction), classified as:

A- Non-Depolarizing Agent:-TubocurarineGallaminePancuroniumB- Depolarizing Agent:-SuxamethoniumDecamethoniumsuccinylcholine

Neuromuscular blockers: Neuromuscular blockers: Drugs used during Neuromuscular blockers: Drugs used during

surgical procedures and in intensive care surgical procedures and in intensive care units to units to cause paralysis.cause paralysis.

Since skeletal muscle Since skeletal muscle contraction is elicited contraction is elicited by nicotinic (NM) cholinergic mechanisms.by nicotinic (NM) cholinergic mechanisms.

Neuromuscular Neuromuscular blockers blockers interfere with interfere with transmission at the neuromusculartransmission at the neuromuscular end end plate and lack CNS activity.plate and lack CNS activity.

Action PotentialC

a2+

Motor neuron

Na +

ACH

ACHACH

ACH

ACHACH

ACH

ACHACH

ACH

ACH

ACH

ACH

Na+

SkeletalMuscle

ACHEsterase

Neuromuscular Blockers

A-non depolarizing:A-non depolarizing:

First drug is curarine(d- tubocurarine)First drug is curarine(d- tubocurarine)(Plant alkaloid).(Plant alkaloid). They act as They act as competitive antagonists competitive antagonists at the at the

ACh receptors of the endplate(ACh receptors of the endplate(act by blocking nAChR).

Blockade by these agents (such as Blockade by these agents (such as tubocurarine and pancuronium) can be tubocurarine and pancuronium) can be reversed by reversed by increasing the amount of ACh in increasing the amount of ACh in the synaptic cleft, the synaptic cleft, for example, by the for example, by the administration of a cholinesterase inhibitor.administration of a cholinesterase inhibitor.

TubocurarineTubocurarine

Causes muscle paralysis .Causes muscle paralysis . Rapid onset of action.Rapid onset of action. Therapeutic Use: Therapeutic Use: As a muscle relaxant in various As a muscle relaxant in various

surgical procedures.surgical procedures.

Mechanism of actionMechanism of action

::

combine with nicotinic receptors & combine with nicotinic receptors & prevent the binding of prevent the binding of Ach(competitive blockers)Ach(competitive blockers)

..

ActionsActions

Paralysis of :muscle of face & eye, Paralysis of :muscle of face & eye, fingers, limbs , neck, trunk & fingers, limbs , neck, trunk & diaphragm muscles.diaphragm muscles.

Theraputic usesTheraputic uses

With anesthesia to relax skeletal With anesthesia to relax skeletal muscles muscles

In tetanus In tetanus Fractures.Fractures.

Side effectSide effect1-hypotention .1-hypotention .

2- bronchospasm 2- bronchospasm

Drugs interactionsDrugs interactions

1- cholinestrase inhibitors1- cholinestrase inhibitors e.g neostigmine, physostigmine & e.g neostigmine, physostigmine &

edrophonium. edrophonium. (produce antagonist effect)(produce antagonist effect)2-halogenated hydrocarbon anesthetics2-halogenated hydrocarbon anesthetics e.g halothane e.g halothane (increased muscle relaxant )(increased muscle relaxant )3-aminoglycoside antibiotics3-aminoglycoside antibiotics e.g gentamicin e.g gentamicin (increased muscle relaxant )(increased muscle relaxant )

Botulinum Toxin (Botox):Botulinum Toxin (Botox): Toxin Toxin produced by the bacterium produced by the bacterium Clostridium Clostridium

Botulinum.Botulinum. purified & highly diluted for therapeutic usepurified & highly diluted for therapeutic use Prevents Acetylcholine release from the Prevents Acetylcholine release from the

nerve terminal. nerve terminal. Produces Produces flaccid paralysis flaccid paralysis of skeletal muscle of skeletal muscle

, Inhibition lasts from several weeks to 3 to 4 , Inhibition lasts from several weeks to 3 to 4 months. months.

Immuno resistance may develop with Immuno resistance may develop with continued use.continued use.

Botulinum toxinBotulinum toxin

• The acetylcholine vesicle release process is blocked by botulinum toxin

Therapeutic use botulinum toxinTherapeutic use botulinum toxin• Dermatological / Cosmetic Uses:Dermatological / Cosmetic Uses:• Local facial injections of botulinum toxin are widely used

for the short-term treatment (1–3 months per treatment) of wrinkles associated with aging around the eyes; neck and mouth to control muscle spasms and to facilitate muscle relaxation .

• Local injection of botulinum toxin has also become a useful treatment for generalized spastic disorders (eg, cerebral palsy).

• Most studies have used type A botulinum toxin, but type B is also available.

• Prevent excessive sweating (palm).