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Irreversible Cholinesterase Inhibitors:
• Both AChE and BuChE are inhibited irreversibly by a group of phosphate esters that are highly toxic (LD50 for humans is 0.1–0.001 mg/kg).
• These chemicals are nerve poisons and have been used in warfare, in bioterrorism, and as agricultural insecticides.
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Organophosphorous esters
• A is usually oxygen or sulfur but may also be selenium. When A is other than oxygen, biological activation is required before the compound becomes effective as an inhibitor of cholinesterases.
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Inhibition of AChE
Inhibition of AChE by organophosphorous compounds takes place in two steps:
1. Association of enzyme and inhibitor, and
2. The phosphorylation step,
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Inhibition of AChE
• Insecticides and nerve gases are irreversible inhibitors of cholinesterases by forming a phosphorylated serine at the esteratic site of the enzyme.
• It is possible to reactivate the enzyme if action is taken soon after exposure to these poisons.
• Basically, insecticides must be toxic to insects and safe for humans.
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Phosphorylation and reactivation of cholinesterase. A. Phosphorylation of serine by isofluorphate. B. Phosphorylated serine at esteratic site. C. Nucleophilic attack on phosphorylated residue by 2-PAM. D. free enzyme.
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Cholinesterase reactivators
• pyridine-2-aldoxime methiodide (2-PAM).
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Pralidoxime chloride
• The biological half-life of pralidoxime chloride in humans is about 2 hours, and its effectiveness is a function of its concentration in plasma, which reaches a maximum 2 to 3 hours after oral administration.
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Pralidoxime chloride
Pralidoxime chloride, a quaternary ammonium compound, is most effective by intramuscular, subcutaneous, or intravenous administration. Treatment of poisoning by an anticholinesterase will be most effective if given within a few hours.
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Cholinergic Blocking Agents
• Anticholinergic action by drugs and chemicals apparently depends on their ability to reduce the number of free receptors that can interact with ACh.
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The major chemical types for Cholinergic Blocking Agents
1. Solanaceous alkaloids and synthetic analogs
2. Synthetic aminoalcohol esters
3. Aminoalcohol ethers
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General Notes:
1. The chemical classification of anticholinergics is complicated because some agents act on the ganglia and at the neuromuscular junction in skeletal muscle.
2. Anticholinergics is considered as chemicals having a similarity to ACh but contain additional substituents that enhance their binding to the cholinergic receptor.
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General Notes:
3. Anticholinergic agent may contain a quaternary ammonium function or a tertiary amine that is protonated in the biophase to form a cationic species.
4. The nitrogen is separated from a pivotal carbon atom by a chain.
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Structure–Activity Relationships
The SAR of the chemical groups:
1. The Cationic Head
2. The Hydroxyl Group
3. The Esteratic Group
4. Cyclic Substitution
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The Cationic Head
• Anticholinergics have a point of attachment to cholinergic sites via the cationic head.
• What about tertiary amines?
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The Hydroxyl Group
• Is not essential for activity.
• It enhances antimuscarinic activity.
• Assumption of H-bonding is excist.
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The Esteratic Group
• An esteratic function is not necessary for activity. Explain why?
• Useful for effective binding.
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Cyclic Substitution
• At least one cyclic substituent (phenyl, thienyl, or other) is a common feature in almost all anticholinergic molecules
• Use of aromatic acids leads to low activity of these compounds as anticholinergics but potential activity as local anesthetics.
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Parasympathetic Postganglionic Blocking Agents
• Also known as:
1. Antimuscarinic.
2. Anticholinergic.
3. parasympatholytic, or
4. cholinolytic drugs.
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Therapeutic Actions
• 1. Mydriatic effect: dilation of the pupil of the eye; and cycloplegia, a paralysis of the ciliary structure of the eye, resulting in a paralysis of accommodation for near vision.
• 2. Antispasmodic effect: lowered tone and motility of the GI tract and the genitourinary tract.
• 3. Antisecretory effect: reduced salivation reduced perspiration and reduced acid and gastric secretions.
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References:
• Reference text: Wilson and Gisvold Textbook of Organic Medicinal and Pharmaceutical Chemistry; Delgado JN, Remers WA, (Eds.); 12th ed., 2011.
• https://www.google.iq/search?q=2-PAM+structure&espv=2&biw=1150&bih=556&source=lnms&tbm=isch&sa=X&ei=cQMpVK6XHqbW7gatiYHwDQ&ved=0CAYQ_AUoAQ#facrc=_&imgdii=_&imgrc=2gKvfr-KqjRhwM%253A%3Bdi8bsg-nrlDNaM%3Bhttp%253A%252F%252Fwww.atsdr.cdc.gov%252Fcsem%252Fcholinesterase%252Fimages%252F2pam_action1.png%3Bhttp%253A%252F%252Fwww.atsdr.cdc.gov%252Fcsem%252Fcsem.asp%253Fcsem%253D11%2526po%253D23%3B489%3B368
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