Sheet 5 Cholinergic antagonists.pptx

Cholinergic Antagonists Lecture 4 Pharmacology Lecture 5, Cholinergic Antagonists 1 Dr Salem Abukres  Cholinergic Antagonists Also called cholinergic blockers, parasympatholytic, or anticholinergic drugs Bind...

Cholinergic Antagonists Lecture 4 Pharmacology Lecture 5, Cholinergic Antagonists 1 Dr Salem Abukres  Cholinergic Antagonists Also called cholinergic blockers, parasympatholytic, or anticholinergic drugs Bind to cholinoceptors, but they do not trigger the usual effects. The most useful of these agents selectively block muscarinic receptors of the parasympathetic nerves A second group of drugs, the ganglionic blockers, show a preference for the nicotinic receptors of the sympathetic and parasympathetic ganglia A third family of compounds, the neuromuscular-blocking agents, interfere with transmission of efferent impulses to skeletal muscles Pharmacology Lecture 5, Cholinergic Antagonists 2 Dr Salem Abukres Pharmacology Lecture 5, Cholinergic Antagonists 3 Dr Salem Abukres II. ANTIMUSCARINIC AGENTS Atropine and scopolamine Block muscarinic receptors causing inhibition of all muscarinic functions Block the few exceptional sympathetic neurons that are cholinergic, such as those innervating salivary and sweat glands have little or no action at skeletal neuromuscular junctions (NMJs) or autonomic ganglia Note: A number of antihistaminic and antidepressant drugs also have antimuscarinic activity. Pharmacology Lecture 5, Cholinergic Antagonists Dr Salem Abukres 4 A. Atropine High affinity for muscarinic receptors Binds competitively Action may last for days The greatest inhibitory effects are on bronchial tissue and the secretion of sweat and saliva Pharmacology Lecture 5, Cholinergic Antagonists 5 Dr Salem Abukres  1. Actions: a. Eye: persistent mydriasis b. Gastrointestinal (GI): (dilation of the pupil)- antispasmodic to reduce ophthalmic examinations. activity of the GI tract In patients with narrow- Not effective in promoting angle glaucoma, healing of peptic intraocular pressure ulcer ;hydrochloric acid production is not significantly may rise dangerously. affected. Shorter-acting agents, such reduce saliva secretion, as the antimuscarinic ocular accommodation, and tropicamide, or an a - micturition (urination). adrenergic drug, such as Pharmacology Lecture 5, Cholinergic Antagonists phenylephrine Dr Salem Abukres 6  d. c. Urinary Cardiovascula system: r:. e.Secretions: reduce depending on salivary glands, hypermotility producing a the dose states of the drying oral mucous urinary membranes (xerostomia). bladder Sweat and lacrimal enuresis glands are similarly (involuntary affected. [Note: voiding of urine) Inhibition of secretions but a-adrenergic by sweat glands can agonists with cause elevated body fewer side effects temperature, may be more which can be effective dangerous in children and the elderly.] Pharmacology Lecture 5, Cholinergic Antagonists 7 Dr Salem Abukres 2. Therapeutic uses: a. Ophthalmic: b. Antispasmodic: measurement of refractive errors Atropine (as the active isomer, Atropine may induce an acute l-hyoscyamine) attack of eye pain due to sudden increases in eye pressure in is used as an individuals with narrow-angle antispasmodic agent to glaucoma. Shorter-acting antimuscarinics relax the GI tract and (cyclopentolate and tropicamide) bladder have largely replaced atropine due to the prolonged mydriasis observed with atropine Pharmacology Lecture 5, Cholinergic Antagonists 8 Dr Salem Abukres c. Antidote for cholinergic agonists: d. Antisecretory overdoses of cholinesterase : The drug is sometimes inhibitor insecticides used as an antisecretory mushroom poisoning (certain mushrooms contain cholinergic agent to block secretions substances that block in the upper and lower cholinesterases respiratory tracts prior to The drug also blocks the surgery. effects of excess ACh resulting from acetylcholinesterase (AChE) inhibitors such as physostigmine. Pharmacology Lecture 5, Cholinergic Antagonists 9 Dr Salem Abukres 4. Adverse effects: Depending on the dose, atropine may cause dry mouth, blurred vision, “sandy eyes,” tachycardia, urinary retention, and constipation. Effects on the CNS include restlessness, confusion, hallucinations, collapse of the circulatory and respiratory systems, and death. In older individuals, the use of atropine is too risky, because it may exacerbate an attack of glaucoma due to an increase in intraocular pressure It may also induce troublesome urinary retention in this population Atropine may be dangerous in children, because they are sensitive to its effects, particularly to the rapid increases in body temperature that it may elicit Pharmacology Lecture 5, Cholinergic Antagonists 10 Dr Salem Abukres Pharmacology Lecture 5, Cholinergic Antagonists 11 Dr Salem Abukres B. Scopolamine produces peripheral effects similar to those of atropine. However, scopolamine has greater action on the CNS (unlike with atropine, CNS effects are observed at therapeutic doses) and a longer duration of action in comparison to those of atropine. has some special actions as: anti–motion sickness has the unusual effect of blocking short-term memory In contrast to atropine, scopolamine produces sedation, but at higher doses it can produce excitement instead. Scopolamine may produce euphoria and is susceptible to abuse. Pharmacology Lecture 5, Cholinergic Antagonists 12 Dr Salem Abukres 2. Therapeutic uses: is limited to prevention of motion sickness (for which it is particularly effective) and to blocking short-term memory prevents communication between the nerves of the vestibule and the vomiting center in the brain by blocking the action of acetylcholine. Scopolamine also may work directly on the vomiting center is much more effective prophylactically than for treating motion sickness once it occurs. The amnesic action of scopolamine makes it an important adjunct drug in anesthetic procedures.] ensuring that patients don't remember traumatic events during surgery. Pharmacology Lecture 5, Cholinergic Antagonists 13 Dr Salem Abukres C. Ipratropium and tiotropium These agents are approved as bronchodilators for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), Both are delivered via inhalation Pharmacology Lecture 5, Cholinergic Antagonists 14 Dr Salem Abukres D. Tropicamide and E. Benztropine and cyclopentolate trihexyphenidyl as ophthalmic solutions for These agents are mydriasis and cycloplegia. Their duration of action is shorter than that centrally acting of atropine. antimuscarinic agents Cycloplegia is the paralysis of the ciliary muscle of the eye resulting in treatment of Parkinson dilatation of the pupil and paralysis of disease accommodation (lens can no longer be adjusted to focus on nearby objects). ciliary muscles are important for moving the eyes get maximum resolution. Pharmacology Lecture 5, Cholinergic Antagonists 15 Dr Salem Abukres Pharmacology Lecture 5, Cholinergic Antagonists 16 Dr Salem Abukres Pharmacology Lecture 5, Cholinergic Antagonists 17 Dr Salem Abukres These muscles are important for moving the eyes get maximum resolution. Pharmacology Lecture 5, Cholinergic Antagonists 18 Dr Salem Abukres Pharmacology Lecture 5, Cholinergic Antagonists 19 Dr Salem Abukres oxybutynin By blocking muscarinic Oxybutynin is available as a receptors in the bladder, transdermal system intra vesicular pressure is (topical patch), which is lowered, bladder better tolerated because it capacity is increased, causes less dry mouth and the frequency of than do oral formulation bladder contractions is reduced. Pharmacology Lecture 5, Cholinergic Antagonists 20 Dr Salem Abukres III. GANGLIONIC BLOCKERS These drugs show no selectivity toward the parasympathetic or sympathetic ganglia and are not effective as neuromuscular antagonists. Thus, these drugs block the entire output of the autonomic nervous system at the nicotinic receptor Therefore, ganglionic blockade is rarely used therapeutically, but often serves as a tool in experimental pharmacology. Pharmacology Lecture 5, Cholinergic Antagonists 21 Dr Salem Abukres A. Nicotine The stimulatory effects are complex and result from increased release of neurotransmitter For example, enhanced release of dopamine and norepinephrine may be associated with pleasure as well as appetite suppression B. Mecamylamine Mecamylamine [mek-a-MILL-a-meen] produces a competitive nicotinic blockade of the ganglia. Mecamylamine has been supplanted by superior agents with fewer side effects. Pharmacology Lecture 5, Cholinergic Antagonists 22 Dr Salem Abukres  IV. NEUROMUSCULAR-BLOCKING DRUGS These drugs block cholinergic transmission between motor nerve endings and the nicotinic receptors on the neuromuscular endplate of skeletal muscle These neuromuscular blockers are structural analogs of ACh, and they act either as antagonists (nondepolarizing type) or agonists (depolarizing type) at the receptors on the endplate of the NMJ. Neuromuscular blockers are clinically useful during surgery for producing complete muscle relaxation, without having to use higher anesthetic doses to achieve comparable muscular relaxation Pharmacology Lecture 5, Cholinergic Antagonists 23 Dr Salem Abukres A. Nondepolarizing (competitive) blockers Eg. Tubocurarine (less used nowadays) The neuromuscular-blocking agents have significantly increased the safety of anesthesia, because less anesthetic is required to produce muscle relaxation, allowing patients to recover quickly and completely after surgery Pharmacology Lecture 5, Cholinergic Antagonists 24 Dr Salem Abukres 1. Mechanism of action: a. At low doses: Nondepolarizing neuromuscular-blocking drugs interact with the nicotinic receptors to prevent the binding of Ach. Thus, these drugs prevent depolarization of the muscle cell membrane and inhibit muscular contraction. Because these agents compete with ACh at the receptor without stimulating it, they are called competitive blockers. Their action can be overcome by increasing the concentration of ACh in the synaptic gap, for example, by administration of cholinesterase inhibitors as neostigmine Anesthesiologists often employ this strategy to shorten the duration of the neuromuscular blockade. Pharmacology Lecture 5, Cholinergic Antagonists 25 Dr Salem Abukres Pharmacology Lecture 5, Cholinergic Antagonists 26 Dr Salem Abukres 1. Mechanism of action: b. At high doses: Nondepolarizing blockers can block the ion channels of the endplate. This leads to further weakening of neuromuscular transmission, thereby reducing the ability of AChE inhibitors to reverse the actions of the non depolarizing muscle relaxants. With complete blockade, no direct electrical stimulation is seen. Pharmacology Lecture 5, Cholinergic Antagonists 27 Dr Salem Abukres B. Depolarizing agents Depolarizing blocking agents work by depolarizing the plasma membrane of the muscle fiber, similar to the action of ACh. However, these agents are more resistant to degradation by AChE, and can thus more persistently depolarize the muscle fibers. Succinylcholine is the only depolarizing muscle relaxant in use today. Therapeutic uses: Because of its rapid onset and short duration of action, succinylcholine is useful when rapid endotracheal intubation is required during the induction of anesthesia. It is also used during electroconvulsive shock treatment. Pharmacology Lecture 5, Cholinergic Antagonists 28 Dr Salem Abukres Pharmacology Lecture 5, Cholinergic Antagonists 29 Dr Salem Abukres Pharmacology Lecture 5, Cholinergic Antagonists 30 Dr Salem Abukres Pharmacology Lecture 5, Cholinergic Antagonists 31 Dr Salem Abukres