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 .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
XAtropine actions
Eye: *mydriasis *unresponsiveness to light *cycloplegia *increase IOPGIT: 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 retentionTreatment of atropine poisoning
Ventilation Cold spongy Diazepam physostigminAntimuscarinic 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 actionAntimuscarinic 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 disturbanceB- 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 effectsUses
Operation of neurosurgery Hypertension with phochromocytoma2- 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 succinylcholineNeuromuscular 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 Potential
Ca2+Motor neuron
Na+
ACH
ACH
ACH
ACH
ACH
ACH
ACH
ACH
ACH
a
a
b
a
a
b
a
a
b
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
: 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
With anesthesia to relax skeletal muscles In tetanus Fractures. Side effect 1-hypotention . 2- bronchospasmDrugs 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.