(Cholinergic antagonists) (Anticholinergic ) (Cholinergic Blockers) Parasympathlytic (Cholinergic antagonists) (Anticholinergic ) (Cholinergic Blockers)

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

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.

MUSCARINIC RECEPTOR BLOCKADE ALLOWS SYMPATHETIC DOMINANCE IN DUAL INNERVATED ORGANS X

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 drugs which 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.

Neuromuscular Blockers Na+ Na+ Ca2+ a b ACH Action Potential ACH ACH ACH ACH ACH ACH a b ACH ACH ACH Motor neuron ACH ACH a b ACH ACHEsterase Skeletal Muscle

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

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

Theraputic uses Side effect With anesthesia to relax skeletal muscles In tetanus Fractures. Side effect 1-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).