(Cholinergic antagonists) (Anticholinergic ) (Cholinergic ...cden.tu.edu.iq/images/New/2016/Lectures/Dr.Ghadeer/3-2017/3.pdfB- anti nicotinic agent "Nicotinic Antagonists: Agents that

Parasympathlytic

(Cholinergic antagonists) (Anticholinergic )

(Cholinergic Blockers)

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

● Competitive (reversible) antagonists of ACh ● Antagonistic responses include: decreased contraction of GI and urinary tract smooth

muscles, dilation of pupils, reduced gastric secretion, decreased saliva secretion.

A- antimuscarinic agents (Muscarinic Antagonists):

A- antimuscarinic agents (Muscarinic Antagonists):

1-Atropine (belladonna alkaloid) ● (Competitive inhibitors) . -bind to muscarinic receptors and prevent Ach binding. ● reversible blockade of ACh at muscarinic receptors by competitive binding -reversal effect of atropine by increasing ACh or agonist ----> decreased blockade

-atropine is central & peripheral muscarinic blocker.

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

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MUSCARINIC RECEPTOR BLOCKADE ALLOWS SYMPATHETIC DOMINANCE IN DUAL INNERVATED ORGANS

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Atropine actions●Eye: *mydriasis *unresponsiveness to light *cycloplegia *increase IOP

● GIT: reduce activity of GIT.● Urinary system: reduce hyper motility.● Cardiovascular system: at low dose bradycardia at high dose tachycardia● Secretions: reduce secretions

Therapeutic uses of atropine

1-Ophthalmic: Ophthalmologic examinations. mydriatic & cycloplegic effects. 2-antispasmotic agent : relax GIT & bladder (Treatment of smooth muscle spasms).

3-antidot for cholinergic agonists: Rx of over dose of organophosphate 4-antisecretory agent: reduce secretions of respiratory tract and

salivary gland . (Reduction of nasal and upper respiratory

tract secretions in cold and flu)

Pharmacokinetics of atropine● Absorbed & metabolized by liver.● Eliminated by urine.● Half life/4hr.● Parenteral preparations (derivatives)

are more potent than the parent compounds.

Adverse effects of atropine

● Dryness of mouth ● Blurred vision● Increase in IOP● Attack of glaucoma● Tachycardia● Constipation● CNS effects● Collapse of circulatory & respiratory systems● Urine retention

Treatment of atropine poisoning ● Ventilation ● Cold spongy● Diazepam● physostigmin

Antimuscarinic agents

2-scopolamine:● greater actions on CNS (than atropine) Low doses of scopolamine produce CNS effects

that are not seen with equivalent doses of atropine.

● (longer duration of action than atropine) *actions & uses: prophylaxis of motion sickness drug side effects : sedation , amnesic action

Antimuscarinic agents

3-ipratropium useful in Rx of asthma & chronic obstructive

pulmonary disease ● Administration: by inhalation as aerosol (to provide maximal

concentration at the site of action)

Synthetic amtimuscarinic agent

1- Probanthine 2- Methanthelin bromide ● uses : treatment of peptic ulcer ●C/I●Glaucoma●Stomach obstruction ●Old patient●Cardiac disturbance

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

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

Antinicotinic include :

1- Ganglion blockers

2- Neuromuscular blockers 1-ganglionic blockers 1-Hexamthonim 2-Pentamethanium 3-Trimethaphan.

Pharmacological effects of ganglionic blockers:

● Eye: mydriasis , paralysis of accommodation ● Respiratory tract: reduce secretions ● Salivary glands: xerstomia ● GIT: reduce secretions & motility ● Cardiovascular: decrease blood pressure ● Urinary tract : urinary retention ● Sweat glands: decrease sweating ● CNS: no direct effects

Uses ● Operation of neurosurgery ● Hypertension with phochromocytoma

2- Neuromuscular blocking drugswhich block Ach at N-M-J(neuromuscular

junction), classified as:

A- Non-Depolarizing Agent:- Tubocurarine Gallamine Pancuronium B- Depolarizing Agent:- Suxamethonium Decamethonium succinylcholine

Neuromuscular blockers:●Neuromuscular blockers: Drugs used during

surgical procedures and in intensive care units to cause paralysis.

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

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

Action PotentialCa 2+

Motor neuron

Na+

ACH

ACHACH

ACH

ACHACH

ACH

ACHACH

αα β

αα β

ααβ

ACH

ACH

ACH

ACH

Na+

Skeletal Muscle

ACHEsterase

Neuromuscular Blockers

A-non depolarizing: First drug is curarine(d- tubocurarine)(Plant alkaloid). ●They act as competitive antagonists at the

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

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

Tubocurarine

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

procedures.

Mechanism of action

1- at low dose :combine with nicotinic receptors & prevent

the binding of Ach(competitive blockers)2-at high dose:block the ion channels of the end plate.

Actions● Paralysis of :muscle of face & eye,

fingers, limbs , neck, trunk & diaphragm muscles.

Theraputic uses

● With anesthesia to relax skeletal muscles

● In tetanus ● Fractures.●Side effect1-hypotention .2- bronchospasm

Drugs interactions

1- cholinestrase inhibitors e.g neostigmine, physostigmine &

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

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

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

nerve terminal. ● Produces flaccid paralysis of skeletal muscle

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

● Immuno resistance may develop with continued use.

Botulinum toxin

• The acetylcholine vesicle release process is blocked by botulinum toxin

Therapeutic use botulinum toxin• 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).