1) Cholinergics and anticholinesterases act on the nervous system by interacting with acetylcholine, a neurotransmitter that utilizes both muscarinic and nicotinic receptors.
2) Specific drugs have been developed that act as muscarinic agonists by mimicking acetylcholine's action at muscarinic receptors. These include methacholine, carbachol, bethanecol, and pilocarpine.
3) Anticholinesterases inhibit the acetylcholinesterase enzyme, preventing the breakdown of acetylcholine in the synapse. This indirectly increases acetylcholine concentrations and promotes its effects.
Neurohumoral transmission in CNS-
The term neurohumoral transmission designates the transfer of a nerve impulse from a presynaptic to a postsynaptic neuron by means of a humoral agent e.g. a biogenic amine, an amino acid or a peptide.
UNIT III_cholinergic neurotransmitter agonistSONALI PAWAR
The document discusses cholinergic neurotransmitters and parasympathomimetic agents. It begins by providing an overview of acetylcholine as the principal neurotransmitter of the parasympathetic nervous system. It then discusses the classification of parasympathomimetic agents into direct-acting agents like acetylcholine and indirect-acting agents like cholinesterase inhibitors. The document also covers the structure and mechanisms of several parasympathomimetic drugs including carbachol, bethanechol, methacholine, pilocarpine, physostigmine, and neostigmine. It concludes by describing the cholinergic receptors, muscarinic and nicotinic, and their distributions in the body.
This ppt covers the classification, structures and IUPAC names, Mechanism of action and uses of individual drugs...under anticonvulsants topic..Side effects/metabolism are also given for few
This document summarizes the structure-activity relationships of phenothiazine drugs. It notes that substitution at the 2-position and N-10 position is important for activity. The best substituents are electron-withdrawing groups at the 2-position, which increase antipsychotic effects. A three-carbon chain between the 10-position and amine nitrogen is critical for neuroleptic activity. The amine must be tertiary. Phenothiazines are thought to act as antagonists at dopamine receptors in the limbic system to treat thought disorders like schizophrenia.
General anesthetic and pre anestheticsGourav Singh
The document discusses different aspects of anesthesia including:
1. Anesthesia refers to reversible loss of sensation and consciousness and is achieved through anesthetic agents that induce loss of pain and sensation along with loss of reflexes.
2. There are two main types of anesthesia - local anesthesia and general anesthesia. General anesthesia involves drug-induced absence of all sensation allowing surgery.
3. Anesthesia works through several stages from initial analgesia to eventual respiratory paralysis if overdosed. Proper pre-anesthesia medications are used to make the anesthesia safer and more comfortable for the patient.
Part II: UNIT cholinergic neurotransmitter - Antagonist DrugsSONALI PAWAR
This document discusses cholinergic neurotransmitters and cholinergic blocking agents. It begins by describing various cholinergic blocking agents including solanaceous alkaloids like atropine, scopolamine, and hyoscyamine as well as synthetic agents like tropicamide, cyclopentolate, dicyclomine, glycopyrrolate, and propantheline. It then discusses the mechanisms of action and medical uses of these drugs, which work by antagonizing acetylcholine at nicotinic or muscarinic receptors. The document also covers structural activity relationships of parasympatholytic agents and their use in treating conditions like smooth muscle spasms, ulcers, overactive bladder, and Parkinson
This document outlines a lecture on medicinal chemistry related to the cholinergic system. It will review concepts of acetylcholine mimetics and acetylcholinesterase inhibitors. For muscarinic agonists, it will discuss biosynthesis and metabolism of acetylcholine, structure activity relationship studies of various muscarinic agonists. For acetylcholinesterase inhibitors, it will cover the mechanism of acetylcholine hydrolysis, reversible and irreversible inhibitors, and the antidote for irreversible inhibitors. Learning objectives and resources are also provided.
Neurohumoral transmission in CNS-
The term neurohumoral transmission designates the transfer of a nerve impulse from a presynaptic to a postsynaptic neuron by means of a humoral agent e.g. a biogenic amine, an amino acid or a peptide.
UNIT III_cholinergic neurotransmitter agonistSONALI PAWAR
The document discusses cholinergic neurotransmitters and parasympathomimetic agents. It begins by providing an overview of acetylcholine as the principal neurotransmitter of the parasympathetic nervous system. It then discusses the classification of parasympathomimetic agents into direct-acting agents like acetylcholine and indirect-acting agents like cholinesterase inhibitors. The document also covers the structure and mechanisms of several parasympathomimetic drugs including carbachol, bethanechol, methacholine, pilocarpine, physostigmine, and neostigmine. It concludes by describing the cholinergic receptors, muscarinic and nicotinic, and their distributions in the body.
This ppt covers the classification, structures and IUPAC names, Mechanism of action and uses of individual drugs...under anticonvulsants topic..Side effects/metabolism are also given for few
This document summarizes the structure-activity relationships of phenothiazine drugs. It notes that substitution at the 2-position and N-10 position is important for activity. The best substituents are electron-withdrawing groups at the 2-position, which increase antipsychotic effects. A three-carbon chain between the 10-position and amine nitrogen is critical for neuroleptic activity. The amine must be tertiary. Phenothiazines are thought to act as antagonists at dopamine receptors in the limbic system to treat thought disorders like schizophrenia.
General anesthetic and pre anestheticsGourav Singh
The document discusses different aspects of anesthesia including:
1. Anesthesia refers to reversible loss of sensation and consciousness and is achieved through anesthetic agents that induce loss of pain and sensation along with loss of reflexes.
2. There are two main types of anesthesia - local anesthesia and general anesthesia. General anesthesia involves drug-induced absence of all sensation allowing surgery.
3. Anesthesia works through several stages from initial analgesia to eventual respiratory paralysis if overdosed. Proper pre-anesthesia medications are used to make the anesthesia safer and more comfortable for the patient.
Part II: UNIT cholinergic neurotransmitter - Antagonist DrugsSONALI PAWAR
This document discusses cholinergic neurotransmitters and cholinergic blocking agents. It begins by describing various cholinergic blocking agents including solanaceous alkaloids like atropine, scopolamine, and hyoscyamine as well as synthetic agents like tropicamide, cyclopentolate, dicyclomine, glycopyrrolate, and propantheline. It then discusses the mechanisms of action and medical uses of these drugs, which work by antagonizing acetylcholine at nicotinic or muscarinic receptors. The document also covers structural activity relationships of parasympatholytic agents and their use in treating conditions like smooth muscle spasms, ulcers, overactive bladder, and Parkinson
This document outlines a lecture on medicinal chemistry related to the cholinergic system. It will review concepts of acetylcholine mimetics and acetylcholinesterase inhibitors. For muscarinic agonists, it will discuss biosynthesis and metabolism of acetylcholine, structure activity relationship studies of various muscarinic agonists. For acetylcholinesterase inhibitors, it will cover the mechanism of acetylcholine hydrolysis, reversible and irreversible inhibitors, and the antidote for irreversible inhibitors. Learning objectives and resources are also provided.
BIOSYNTHESIS OF ACETYLCHOLINE IN CNS AND CHOLINERGIC TRANSMISSIONWasiu Adeseji
Acetylcholine (ACh) is a neurotransmitter synthesized locally within cholinergic neurons from choline and acetyl-CoA. During neurotransmission, an action potential causes calcium influx and vesicle fusion, releasing ACh into the synaptic cleft. ACh then binds post-synaptic nicotinic or muscarinic receptors, opening ion channels and continuing the action potential in the next neuron. In the central nervous system, ACh is involved in processes like learning, memory, and sleep regulation. Deficiencies in central cholinergic systems are implicated in Alzheimer's disease.
This document discusses antipsychotic agents used to treat schizophrenia. It begins with an introduction that explains the positive and negative symptoms of schizophrenia and how antipsychotics work by decreasing dopaminergic neurotransmission. The document then covers the classification of typical and atypical antipsychotics, including examples from different drug classes. It discusses the mechanism of action of phenothiazine derivatives and provides structure-activity relationships. Specific phenothiazine derivatives are highlighted, including chlorpromazine. The document also briefly discusses thioxanthene derivatives as bioisosteres of phenothiazines. In summary, the document provides an overview of antipsychotic agents used to treat schizophrenia, focusing on phenothiazine derivatives and structure-activity relationships
Learn the nor adrenergic transmission in ANS. Synthesis, storage ,release, uptake,metabolism of nor-adrenaline. Types of adrenoceptors. Agonist and antagonist of adrenoceptors.
it's our aim to provide notes for pharmacy student without any charge.so that we make pharmacy education easier.
किसी भी शुल्क के बिना फार्मेसी छात्र के लिए नोट्स प्रदान करना हमारा लक्ष्य है।ताकि हम फार्मेसी शिक्षा को आसान बना दें।
Classification and mechanism of action of alzheimers drugs SajalChowdhury4
This document discusses Alzheimer's disease and the drugs used to treat it. It begins by defining Alzheimer's as a neurodegenerative disease that causes brain cell deterioration and memory loss. It then outlines the symptoms of Alzheimer's. The document categorizes the approved drugs for Alzheimer's into two classes: cholinesterase inhibitors like donepezil, rivastigmine, and galantamine, and the NMDA antagonist memantine. It provides details on the mechanisms of action of memantine, tacrine, and galantamine, explaining how they work to increase acetylcholine levels in the brain and inhibit acetylcholinesterase.
Biosynthesis and catabolism of acetylcholine by Dheeraj gargDheeraj Aggarwal
Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (and humans) as a neurotransmitter—a chemical message released by nerve cells to send signals to other cells, such as neurons, muscle cells and gland cells.
Unit 3 Drugs Affecting PNS (As per PCI syllabus)Mirza Anwar Baig
This document provides an overview of a lecture on drugs acting on the autonomic nervous system. It discusses the autonomic neurotransmission and classification of drugs into parasympathomimetics, parasympatholytics, sympathomimetics, and sympatholytics. Specific drugs discussed in detail include direct-acting cholinergic agonists like acetylcholine and indirect-acting cholinergic agonists like anticholinesterase agents. Anticholinergic drugs like atropine are also summarized in terms of their mechanisms and therapeutic uses.
This document provides information about sympathomimetic agents. It discusses direct-acting, indirect-acting, and mixed-acting agents and how they work. Specific agents are described, including their properties, mechanisms of action, uses, and storage requirements. Sympathomimetic drugs act on adrenergic receptors to increase heart rate and blood pressure. Structure-activity relationships are also covered, explaining how chemical modifications impact receptor selectivity and duration of action.
This document discusses drug metabolism, which occurs in two phases: Phase I and Phase II reactions. Phase I reactions introduce functional groups like hydroxyl groups and involve oxidation, reduction, and hydrolysis. This is done primarily by cytochrome P450 enzymes in the liver. Phase II reactions conjugate these metabolites to make them more polar and water soluble, through glucuronidation, sulfation, methylation, acetylation, and conjugation with amino acids like glycine. Together, these two phases of metabolism convert lipophilic drugs into more hydrophilic forms that can be more readily excreted from the body. The rate and pathway of a drug's metabolism can be affected by its physicochemical properties as well as environmental and
Chemistry of Anti Anginal Drugs by Professor BeubenzProfessor Beubenz
This document discusses the chemistry of anti-anginal agents. It begins by defining angina pectoris as chest pain due to reduced blood flow to the heart muscle. It then describes the four main types of angina and various tests used to diagnose it. Treatment includes lifestyle changes, medications, procedures, and cardiac rehabilitation. The document focuses on the classes of medications used to treat angina, including vasodilators like nitrates; calcium channel blockers; antihypertensives; and diuretics. It provides examples of drugs in each class and explains their mechanisms of action, with a focus on how they work to relax blood vessels and reduce blood pressure. Structures are shown for representative drugs from each class.
UNIT I: DRUG METABOLISM: S.Y. B. PHARMACY IV SEMESTERSONALI PAWAR
This document provides an overview of drug metabolism. It discusses the phases of metabolism including phase I reactions like oxidation mediated by cytochrome P450 enzymes and phase II conjugation reactions. It describes the key cytochrome P450 enzyme families and their role in drug metabolism. First pass metabolism and factors that influence it are also summarized.
This document provides information on anticonvulsant/antiepileptic drugs. It begins by defining epilepsy and describing the main types. It then discusses the classification and mechanisms of action of various anticonvulsant classes, including barbiturates, hydantoins, oxazolidinediones, succinimides, ureas, benzodiazepines, and newer agents. For several examples within each class, it provides details on their chemistry, pharmacology, clinical uses, and adverse effects. The document aims to give an overview of the treatment of epilepsy through the use of anticonvulsant medications.
This document summarizes parasympatholytic drugs, also known as anticholinergic or antimuscarinic drugs. It discusses the pharmacological properties and uses of atropine and scopolamine, which are belladonna alkaloids that act as competitive inhibitors at muscarinic receptors in the parasympathetic nervous system. It also describes newer anticholinergic drugs that have more selective actions, such as ipratropium bromide and tiotropium bromide for bronchodilation in respiratory disorders, and oxybutynin for urinary incontinence.
The document discusses cholinergic blockers, also known as cholinolytics, which are drugs that reduce the effects of acetylcholine by blocking muscarinic and nicotinic receptors. It covers the mechanism of action, classification, and examples of important cholinergic blockers like atropine, hyoscine, and ipratropium. The summary also mentions side effects of cholinergic blockers and provides syntheses of selected compounds like ipratropium bromide and dicyclomine.
Serotonin (5-HT) is an important neurotransmitter that is synthesized from tryptophan. It acts through 14 different receptor subtypes located throughout the body. 5-HT is involved in many physiological functions like mood, vomiting, smooth muscle contraction, and platelet aggregation. Drugs that modulate 5-HT receptors or reuptake can be used to treat conditions like migraine, anxiety, vomiting, and gastrointestinal disorders. Specifically, triptans like sumatriptan are effective acute treatments for migraine while methysergide and propranolol can be used preventatively due to 5-HT's role in trigeminal nerve activation and neurogenic inflammation during migraine attacks.
Sex hormones include androgens like testosterone and estrogens like estradiol. Testosterone is the primary male sex hormone and is used to treat symptoms of sexual dysfunction in men. It can cause side effects like acne, swelling, and breast enlargement. Nandrolone is an anabolic steroid used to treat conditions like anemias and osteoporosis. Progesterone prepares the uterus for pregnancy and can cause side effects like headaches. Estriol is produced during pregnancy and used in menopausal hormone therapy. Estradiol is the major female sex hormone and used to treat menopause symptoms and low estrogen levels.
The document outlines the units and topics covered in a course on Medicinal Chemistry-I. Unit II discusses the synthesis of drugs acting on the autonomic nervous system including Tolazoline, Salbutamol, Phenylephrine, and Propranolol. Unit III covers drugs acting on the cholinergic nervous system such as Neostigmine, Dicyclomine Hydrochloride, Carbachol, and Ipratropium bromide. Units IV and V address drugs acting on the central nervous system, listing substances like Diazepam, Chlorpromazine, Ethosuximide, and others.
The document discusses the cholinergic system and cholinergic drugs. It describes how acetylcholine is the major neurotransmitter at sites of cholinergic transmission in both the central and peripheral nervous systems. It acts on two types of receptors: muscarinic and nicotinic receptors. Cholinergic drugs, also called cholinomimetics, mimic the actions of acetylcholine and can be direct-acting receptor agonists or indirect-acting cholinesterase inhibitors. The document then outlines structure-activity relationships for cholinergic drugs, noting features important for receptor binding and agonist activity.
The document provides an overview of the autonomic nervous system (ANS), including its distribution and differences between the sympathetic and parasympathetic nervous systems. It discusses neurohumoral transmission in the ANS and the main neurotransmitters for each division. The sympathetic nervous system uses norepinephrine and epinephrine as neurotransmitters, while the parasympathetic nervous system uses acetylcholine. It also briefly describes the synthesis of acetylcholine and catecholamines.
BIOSYNTHESIS OF ACETYLCHOLINE IN CNS AND CHOLINERGIC TRANSMISSIONWasiu Adeseji
Acetylcholine (ACh) is a neurotransmitter synthesized locally within cholinergic neurons from choline and acetyl-CoA. During neurotransmission, an action potential causes calcium influx and vesicle fusion, releasing ACh into the synaptic cleft. ACh then binds post-synaptic nicotinic or muscarinic receptors, opening ion channels and continuing the action potential in the next neuron. In the central nervous system, ACh is involved in processes like learning, memory, and sleep regulation. Deficiencies in central cholinergic systems are implicated in Alzheimer's disease.
This document discusses antipsychotic agents used to treat schizophrenia. It begins with an introduction that explains the positive and negative symptoms of schizophrenia and how antipsychotics work by decreasing dopaminergic neurotransmission. The document then covers the classification of typical and atypical antipsychotics, including examples from different drug classes. It discusses the mechanism of action of phenothiazine derivatives and provides structure-activity relationships. Specific phenothiazine derivatives are highlighted, including chlorpromazine. The document also briefly discusses thioxanthene derivatives as bioisosteres of phenothiazines. In summary, the document provides an overview of antipsychotic agents used to treat schizophrenia, focusing on phenothiazine derivatives and structure-activity relationships
Learn the nor adrenergic transmission in ANS. Synthesis, storage ,release, uptake,metabolism of nor-adrenaline. Types of adrenoceptors. Agonist and antagonist of adrenoceptors.
it's our aim to provide notes for pharmacy student without any charge.so that we make pharmacy education easier.
किसी भी शुल्क के बिना फार्मेसी छात्र के लिए नोट्स प्रदान करना हमारा लक्ष्य है।ताकि हम फार्मेसी शिक्षा को आसान बना दें।
Classification and mechanism of action of alzheimers drugs SajalChowdhury4
This document discusses Alzheimer's disease and the drugs used to treat it. It begins by defining Alzheimer's as a neurodegenerative disease that causes brain cell deterioration and memory loss. It then outlines the symptoms of Alzheimer's. The document categorizes the approved drugs for Alzheimer's into two classes: cholinesterase inhibitors like donepezil, rivastigmine, and galantamine, and the NMDA antagonist memantine. It provides details on the mechanisms of action of memantine, tacrine, and galantamine, explaining how they work to increase acetylcholine levels in the brain and inhibit acetylcholinesterase.
Biosynthesis and catabolism of acetylcholine by Dheeraj gargDheeraj Aggarwal
Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (and humans) as a neurotransmitter—a chemical message released by nerve cells to send signals to other cells, such as neurons, muscle cells and gland cells.
Unit 3 Drugs Affecting PNS (As per PCI syllabus)Mirza Anwar Baig
This document provides an overview of a lecture on drugs acting on the autonomic nervous system. It discusses the autonomic neurotransmission and classification of drugs into parasympathomimetics, parasympatholytics, sympathomimetics, and sympatholytics. Specific drugs discussed in detail include direct-acting cholinergic agonists like acetylcholine and indirect-acting cholinergic agonists like anticholinesterase agents. Anticholinergic drugs like atropine are also summarized in terms of their mechanisms and therapeutic uses.
This document provides information about sympathomimetic agents. It discusses direct-acting, indirect-acting, and mixed-acting agents and how they work. Specific agents are described, including their properties, mechanisms of action, uses, and storage requirements. Sympathomimetic drugs act on adrenergic receptors to increase heart rate and blood pressure. Structure-activity relationships are also covered, explaining how chemical modifications impact receptor selectivity and duration of action.
This document discusses drug metabolism, which occurs in two phases: Phase I and Phase II reactions. Phase I reactions introduce functional groups like hydroxyl groups and involve oxidation, reduction, and hydrolysis. This is done primarily by cytochrome P450 enzymes in the liver. Phase II reactions conjugate these metabolites to make them more polar and water soluble, through glucuronidation, sulfation, methylation, acetylation, and conjugation with amino acids like glycine. Together, these two phases of metabolism convert lipophilic drugs into more hydrophilic forms that can be more readily excreted from the body. The rate and pathway of a drug's metabolism can be affected by its physicochemical properties as well as environmental and
Chemistry of Anti Anginal Drugs by Professor BeubenzProfessor Beubenz
This document discusses the chemistry of anti-anginal agents. It begins by defining angina pectoris as chest pain due to reduced blood flow to the heart muscle. It then describes the four main types of angina and various tests used to diagnose it. Treatment includes lifestyle changes, medications, procedures, and cardiac rehabilitation. The document focuses on the classes of medications used to treat angina, including vasodilators like nitrates; calcium channel blockers; antihypertensives; and diuretics. It provides examples of drugs in each class and explains their mechanisms of action, with a focus on how they work to relax blood vessels and reduce blood pressure. Structures are shown for representative drugs from each class.
UNIT I: DRUG METABOLISM: S.Y. B. PHARMACY IV SEMESTERSONALI PAWAR
This document provides an overview of drug metabolism. It discusses the phases of metabolism including phase I reactions like oxidation mediated by cytochrome P450 enzymes and phase II conjugation reactions. It describes the key cytochrome P450 enzyme families and their role in drug metabolism. First pass metabolism and factors that influence it are also summarized.
This document provides information on anticonvulsant/antiepileptic drugs. It begins by defining epilepsy and describing the main types. It then discusses the classification and mechanisms of action of various anticonvulsant classes, including barbiturates, hydantoins, oxazolidinediones, succinimides, ureas, benzodiazepines, and newer agents. For several examples within each class, it provides details on their chemistry, pharmacology, clinical uses, and adverse effects. The document aims to give an overview of the treatment of epilepsy through the use of anticonvulsant medications.
This document summarizes parasympatholytic drugs, also known as anticholinergic or antimuscarinic drugs. It discusses the pharmacological properties and uses of atropine and scopolamine, which are belladonna alkaloids that act as competitive inhibitors at muscarinic receptors in the parasympathetic nervous system. It also describes newer anticholinergic drugs that have more selective actions, such as ipratropium bromide and tiotropium bromide for bronchodilation in respiratory disorders, and oxybutynin for urinary incontinence.
The document discusses cholinergic blockers, also known as cholinolytics, which are drugs that reduce the effects of acetylcholine by blocking muscarinic and nicotinic receptors. It covers the mechanism of action, classification, and examples of important cholinergic blockers like atropine, hyoscine, and ipratropium. The summary also mentions side effects of cholinergic blockers and provides syntheses of selected compounds like ipratropium bromide and dicyclomine.
Serotonin (5-HT) is an important neurotransmitter that is synthesized from tryptophan. It acts through 14 different receptor subtypes located throughout the body. 5-HT is involved in many physiological functions like mood, vomiting, smooth muscle contraction, and platelet aggregation. Drugs that modulate 5-HT receptors or reuptake can be used to treat conditions like migraine, anxiety, vomiting, and gastrointestinal disorders. Specifically, triptans like sumatriptan are effective acute treatments for migraine while methysergide and propranolol can be used preventatively due to 5-HT's role in trigeminal nerve activation and neurogenic inflammation during migraine attacks.
Sex hormones include androgens like testosterone and estrogens like estradiol. Testosterone is the primary male sex hormone and is used to treat symptoms of sexual dysfunction in men. It can cause side effects like acne, swelling, and breast enlargement. Nandrolone is an anabolic steroid used to treat conditions like anemias and osteoporosis. Progesterone prepares the uterus for pregnancy and can cause side effects like headaches. Estriol is produced during pregnancy and used in menopausal hormone therapy. Estradiol is the major female sex hormone and used to treat menopause symptoms and low estrogen levels.
The document outlines the units and topics covered in a course on Medicinal Chemistry-I. Unit II discusses the synthesis of drugs acting on the autonomic nervous system including Tolazoline, Salbutamol, Phenylephrine, and Propranolol. Unit III covers drugs acting on the cholinergic nervous system such as Neostigmine, Dicyclomine Hydrochloride, Carbachol, and Ipratropium bromide. Units IV and V address drugs acting on the central nervous system, listing substances like Diazepam, Chlorpromazine, Ethosuximide, and others.
The document discusses the cholinergic system and cholinergic drugs. It describes how acetylcholine is the major neurotransmitter at sites of cholinergic transmission in both the central and peripheral nervous systems. It acts on two types of receptors: muscarinic and nicotinic receptors. Cholinergic drugs, also called cholinomimetics, mimic the actions of acetylcholine and can be direct-acting receptor agonists or indirect-acting cholinesterase inhibitors. The document then outlines structure-activity relationships for cholinergic drugs, noting features important for receptor binding and agonist activity.
The document provides an overview of the autonomic nervous system (ANS), including its distribution and differences between the sympathetic and parasympathetic nervous systems. It discusses neurohumoral transmission in the ANS and the main neurotransmitters for each division. The sympathetic nervous system uses norepinephrine and epinephrine as neurotransmitters, while the parasympathetic nervous system uses acetylcholine. It also briefly describes the synthesis of acetylcholine and catecholamines.
Introduction to Autonomic Nervous systemNaser Tadvi
The document provides an overview of the autonomic nervous system (ANS), including its distribution and differences between the sympathetic and parasympathetic nervous systems. It discusses that the ANS is divided into the sympathetic and parasympathetic nervous systems. The sympathetic nervous system uses norepinephrine as its neurotransmitter and is involved in the body's fight or flight response. The parasympathetic nervous system uses acetylcholine as its neurotransmitter and is involved in rest and digest functions. Neurotransmission in the ANS occurs through the release and binding of neurotransmitters to receptors on target organs.
This document provides information about the parasympathetic nervous system and cholinergic agents. It begins by outlining learning objectives about defining the biochemistry of the parasympathetic system, classifying agonists and antagonists, and explaining the structure-activity relationship of acetylcholine. It then discusses the anatomy and functions of the motor nerves, including the roles of acetylcholine. The document outlines the SAR of acetylcholine and binding interactions. It describes cholinergic agonists and antagonists, including clinical uses. Muscarinic and nicotinic receptors and their subtypes are defined. The actions and uses of cholinergic drugs like atropine and tubocurarine are summarized.
The document discusses the autonomic nervous system (ANS) and drugs that act on it. It begins by describing the organization of the nervous system into the central and peripheral divisions. It then focuses on the ANS, which controls involuntary functions and has two divisions - the sympathetic ("fight or flight") and parasympathetic ("rest and digest"). The document goes on to describe the anatomy and functions of the sympathetic and parasympathetic systems, as well as their neurotransmitters (epinephrine/norepinephrine and acetylcholine). It then discusses different types of drugs that act on the cholinergic and adrenergic systems, including direct-acting cholinergic drugs, anticholinesterases, antimuscar
Adrenergic and cholinergic agents pptx.pptxPurushothamKN1
This document discusses adrenergic and cholinergic agents that act on the autonomic nervous system. It begins by introducing the autonomic nervous system and its divisions - the sympathetic and parasympathetic nervous systems. Acetylcholine is described as the neurotransmitter of the parasympathetic system. Cholinergic agonists and antagonists are then discussed, including bethanicol and anticholinesterases. Next, adrenergic drugs acting directly on receptors or indirectly by inhibiting norepinephrine storage are covered. Specific drugs like propranolol, prazosin, and methyldopa are explained in terms of their mechanisms and structure-activity relationships.
Types of drugs that act on Autonomic Nervous System and there is a link about loosing body Weight in a faster way , you must try it . The offer is limited
Anticholinergics are drugs that inhibit the pharmacological response of acetylcholine (Ach) by competitively binding to and blocking muscarinic receptors. Their general structure consists of two carbocyclic or heterocyclic rings (R1 and R2) connected by a chain with an ester or ether group (X) and a basic nitrogen substituent. The R3 group can be hydrogen, hydroxyl, or hydroxymethyl. Maximum potency is seen with 2 carbon units between the ring and nitrogen. Older anticholinergics like atropine and scopolamine are non-selective for muscarinic receptor subtypes, while newer drugs show selectivity. Anticholinergics are used to treat
Presentation on Parasympathetic Nervous SystemPrerana Jadhav
Autonomic Nervous system is a part of nervous system that controls and regulate the internal organs.
Sympathetic Nervous System: Release Adrenaline
Parasympathetic Nervous System: Release Acetylcholine
Pre & post ganglionic fibres of parasympathetic nerves liberate Ach.
Important Responses of Ach
Contraction of Smooth muscles
Cardiac Inhibition
Peripheral Vasodilation
Henry Dale, a British physiologist working in London in 1914, found that two foreign substances, nicotine and muscarine, could each mimic some, but not all, of the parasympathetic effects of acetylcholine.
1. The document discusses the autonomic nervous system and drugs that act on it. It covers the classification of the nervous system, the actions of the sympathetic and parasympathetic systems, and neurotransmitters.
2. Drugs are classified as agonists that mimic neurotransmitters or antagonists that block neurotransmitter actions. Cholinergic drugs act at acetylcholine receptors and adrenergic drugs act at norepinephrine receptors.
3. The main cholinergic drugs discussed are acetylcholine, nicotine, and muscarine agonists as well as acetylcholinesterase inhibitor antagonists like neostigmine and organophosphates. Anticholinergic antagonists like atrop
PARASYMPATHOMIMETIC DRUGS Classification and SAR.pptxJasmine Chaudhary
This document discusses parasympathomimetic drugs, also known as cholinergic drugs, which mimic the action of acetylcholine in the body. It describes two types of cholinergic drugs: direct-acting drugs that stimulate cholinergic receptors, and indirect-acting drugs that inhibit the acetylcholinesterase enzyme and increase acetylcholine levels. The document provides details on the classification, structure-activity relationships, mechanisms of action, effects, and examples of both types of cholinergic drugs.
cholingeric and Anticholinesterase drug in detail .this ppt contains introduction ,mechanism of action ,pharmacological action ,uses and adverse effect of the drug
Pharmacology Lecture Slides on Autonomic Nervous System Introduction by Sanjaya Mani Dixit Assistant Professor of Pharmacology at Kathmandu Medical College
2 Pharmacology I, intro ANS cholinergic drugs.pptxAhmad Kharousheh
The document provides an overview of the autonomic nervous system, describing the two divisions of the sympathetic and parasympathetic nervous systems. It explains the neurotransmitters involved, including acetylcholine and norepinephrine, and the receptors they act on. The document also discusses the classes of drugs that act on the autonomic nervous system, including direct-acting cholinergic agonists, indirect-acting cholinergic agonists that inhibit acetylcholinesterase, and antimuscarinic drugs that block muscarinic receptors.
This document discusses the autonomic nervous system (ANS) and its sympathetic and parasympathetic divisions. It describes the roles and functions of the sympathetic and parasympathetic systems, including that the sympathetic system prepares the body for "fight or flight" while the parasympathetic system maintains essential functions at rest. Key neurotransmitters of each system are acetylcholine and norepinephrine. The document also examines cholinergic and adrenergic transmission in detail, including the receptors, synthesis and actions of acetylcholine and catecholamines.
015 cholinesterase inhibitors and anticholinergic drugs bothyshiri
Acetylcholine is a major neurotransmitter in both the central and peripheral nervous systems. It acts on nicotinic and muscarinic receptors. Acetylcholinesterase inhibitors such as neostigmine prolong the action of acetylcholine by inhibiting its breakdown, allowing rebinding to nicotinic receptors and reversal of neuromuscular blockade. The choice of inhibitor, dosage, muscle relaxant being antagonized, and depth of blockade all impact the speed and completeness of reversal. Anticholinergics are given to prevent muscarinic side effects from excess acetylcholine.
The document discusses the pharmacology of autonomic drugs and the nervous system. It describes the organization of the central and peripheral nervous systems, including the autonomic nervous system which has sympathetic and parasympathetic divisions. It then focuses on cholinergic and adrenergic transmission in depth, covering the synthesis, release, receptors, and destruction of acetylcholine. For cholinergic transmission, it discusses the muscarinic and nicotinic receptors in detail. For adrenergic transmission, it notes catecholamines like norepinephrine and epinephrine are synthesized and stored. The document concludes by briefly mentioning some cholinergic drugs like pilocarpine and adrenergic drugs.
Otto Loewi discovered the first neurotransmitter, acetylcholine, in 1921 through an experiment using two frog hearts. He found that electrical stimulation of the vagus nerve of one heart caused it to slow down, and the same effect was seen in the second heart, showing that a chemical was being transmitted. Neurotransmitters meet four criteria: they are synthesized and stored in neurons, released at synapses, mimic the action of natural transmitters as drugs, and are removed from synapses. There are two main classes of neurotransmitters - small molecules like acetylcholine, dopamine, serotonin; and peptides. Small molecules are synthesized in axon terminals while peptides are made in cell bodies.
The document discusses different types of cholinergic and adrenergic receptors in the body. It describes how cholinergic receptors are classified into nicotinic and muscarinic receptors. Nicotinic receptors are further divided into NM and NN receptors located at neuromuscular junctions and autonomic ganglia. The five subtypes of muscarinic receptors are described along with their locations and functions. Adrenergic receptors are classified into alpha-1, alpha-2, beta-1, beta-2, and beta-3 receptors, with details provided on their locations and responses. The mechanisms of action of these various receptor types are also summarized.
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2. Our Nervous System
Because of its wide and important involvement,
understanding Nervous system is important to treat
many diseases
Functions –
• To transmit signals to and from
body organs or cells to carry out
o Heartbeat, Respiration
o Digestion, Hormone secretion
o Movement, body pressure
• To process sensory information
• Logic, Decision and Memory
3. Drugs based on Nervous System treat
various clinical conditions
Cholinergic NS NS based on other
Neurotransmitters
Impaired or excessive
gastric/secretion
Epilepsy – irregular neuronal
activity leading to muscle spasm
Glaucoma – increased
pressure on eye
Bradycardia – slow heart beat
Anxiety – feeling irrational fear
Relief from pain
Alzheimer’s and –loss of
memory
Parkinson disease – loss of
movement control
Myasthenia gravis – muscle
weakness
Cause unconsciousness during
surgery
4. First lesson in Medicinal chemistry
• Medicinal Chemistry aims to cure diseases. But
to do that we need to know what biological
factor is causing disease. Then we create drugs
that interact with that particular factor to either
suppress it or stimulate it.
• These biological factors arise from alteration in
the process of normal body functioning. Thus to
find and understand what goes wrong during
illness, we must first study the normal
functioning of body. This allows us to recognize
a central biological factor that is most involved
in causing disease. Then we make drugs to act
on it.
5. Neurons
• Neurons are individual cells of the Nervous
System that process and transmit signals by
electrical and chemical process.
• Adjacent neurons are physically separated by
the each other. The gap region is called
synapse.
6. Fig: Neurotransmitters moving through
Synapse between two neurons
Pre-synaptic
Neuron
(sends signal)
Post-synaptic
Neuron
(receives signal)
7. • Neurotransmitters (NT) are endogenous
(produced by body) chemicals that transmit
signals across a synapse from sending presynaptic
neuron to the target postsynaptic neuron
• They are synthesized and stored in neuron itself
• There are many NTs eg Acetylcholine, Adrenaline,
serotonin, dopamine, GABA
• The process of transmission of signal along a
neuron and over the synapse is called
neurotransmission. Signal can pass over the
synapse by either chemically or electrically
• One neurons interacts with many other neurons
in all possible directions.
9. Types of peripheral NS
• Somatic NS-
– controls voluntary muscle Movement
– Transmits sensory information to brain
• Autonomic NS
– Controls involuntary body functions such as Heart
beat, secretion (GI acid/insulin), fight or flight
responses
10. Two types of Autonomic NS
Parasympathetic NS
Uses Acetylcholine
Sympathetic NS
Uses Adrenaline
Makes body
ready for fight
or flight
Makes body
ready for rest
11. Did you note the mono-directionality ?
• Instead of a single light switch that you can
turn on/off or a single volume knob you can
turn high/low…..
• In this case you have two independent control
system for doing opposing things, eg
sympathetic increases heart beat while
parasympathetic is required to slow heart
beat, there is no way neither NS can reverse or
undo it’s action by itself.
12. Introduction
• Cholinergics refer to the part of Nervous
system that utilize Acetylchlonine (Ach) as a
neurotransmitter. It is key NT in the
parasympathetic NS
• A unique feature of Ach is that the same
molecule can bind with two different
receptors (muscarinic and nicotinic receptor)
using different conformation.
Acetylcholine
Acetyl Choline
13. Physio-Chemical property of Ach
• It is ester of acetic acid and choline
• It is soluble in water due to salt form at Nitrogen
• In solid form it is stable but in solution, the ester group gets
hydrolyzed (ie ester group turns into acid and alcohol).
• If acid or base is present, as in stomach, then rate of hydrolysis is so
fast that it prevents oral dosing of Ach
• Even if we prepare it’s solution in neutral water and inject in blood
so as to bypass the acidic stomach, an ester hydrolyzing enzyme
called butrylcholinesterase significantly degrades it s that the
pharmacological response is very weak
• Even if it was administered in stable form, It’s ionic ammonium
group prevents good penetration across the lipophillic cell wall
• This chemical property makes it a weak agonist plus since it is non-
selective agonist of Muscarinic and Nicotinic
• (Thus having no ester group and no ionic amine is an approach tp
making more stable and strong Ach agonist. However selectivity is a
different issue)
14. Based on above info we can make simple
changes to Ach hopefully design derivatives to
improve stability and cell penetration.
Ach
Conceptual Agonist drugs
Drug design is a conceptual thing. We don’t really know if drug will really work as
expected until we synthesize and test them. To improve chances of success the design part
should not be random but have some rational
15. Muscarinic receptor
• They are agonized by a poisonous mushroom
derived compound called muscarine
• They occur primarily in the CNS and in Autonomic
NS, and are part of a large family of G-protein-
coupled receptors
• Physiological functions include heart rate and
force, contraction of smooth muscles and the
release of other neurotransmitters.
• There are five subtypes of muscarinic AChRs
based on pharmacological activity: M1-M5
16. Nicotinic receptor
• They are agonized by nicotine
• They also occur in the CNS and Autonomic NS plus are
exclusive in neuromuscular junction, and are part of a
ligand gated ion channel receptors
• Physiological functions depend upon muscle-type or
neuronal-type
• Muscle-type nicotinic AChRs are localized at
neuromuscular junctions and allow muscle contraction
and maintain muscle tone; (thus these are targets for
muscle relaxants)
• Neuronal type are involved in cognitive function,
learning and memory, arousal, reward, motor control
and analgesia.
17. H3C O
O
CH2 CH2 N(CH3)3
Quaternary
Ammonum group
Ethylene
group
Acyloxy
group
SAR of cholinergics as Muscarinic agonist
• Cholinergic drugs mimic action of Ach on
Muscarinic or nicotinic receptors and produce
the same effect as Ach but in greater
magnitude
• A general strategy of making an agonist is to
use the original compound, in this case Ach,
as a framework
18. 1) Modification of quaternary Ammonium group
a) Presence of nitrogen in quaternary ionic form is
important for agonist activity. Replacement of
Nitrogen with other elements such as Sulphur,
Arsenic and Phosphorous reduces activity
b) Presence of three methyl group is needed for
agonist activity. Changing the three methyl
group by higher alkanes or Hydrogen also causes
loss of activity
H3C O
O
CH2 CH2 N(CH3)3
Quaternary
Ammonum group
Ethylene
group
Acyloxy
group
19. Replacement with Arsenic or Phosphorous maintains + charge but still
reduces activity
Replacement with sulphur removes the + charge and causes
reduced activity
Only this has good potency
Conclusion
1) positive charge needed 2) Positive charge should be on Nitrogen only
3) Charge on Nitrogen only possible when it bonded to 4 atoms ie quaternary form needed
Valency
S = 4
P = 3
Ar = 3
N =3
20. • If R = methyl,(CH3) --> active
• If R = ethyl (C2H5) --> antagonist!
• If R = propyl (C3H9) and higher alkyls --> inactive
• If only one of the R = ethyl or propyl active
but less potent than Ach
• If any or all R = H activity goes on decreasing
21. 2) Change in the ethylene group
c) A “rule of five” idea states that there should
be no more than 5 atoms between the
Nitrogen and the terminal Hydrogen
As the chain length increased from two, activity
is rapidly lost.
C O
N
O
H
H
H
1
2
3
4
5
This tells us
about the
relative size of
binding site
22. d) Inclusion of methyl group in the ethylene
carbons can alter selectivity
Methyl inclusion in β carbon relative to N
retains potency of Ach and more selective to
muscarinic receptor. This compound is called
methacholine and used clinically
Methyl inclusion in α carbon relative to N
reduces potency but makes more selective to
nicotinic receptor. This is not used clinically
23. •Methyl group in Beta carbon
•As potent as Ach
•Selective to Muscarinic receptor
•Used clinically
•Methyl group in alpha carbon
•Not As potent as Ach
•Selective to Nicotinic receptor
•Not Used clinically
Methacholine
H3C O
O
CH2 CH N(CH3)3
CH3
H3C O
O
CH CH2 N(CH3)3
CH3
24. 3) Modifications to the Acetoxy group
e) Substituting the Acetyl with higher
homologous group such as propionyl or butyryl
Reduces activity.
R O
O
CH2 CH2 N(CH3)3
If R = propionyl (C3H7), butyrl (C4H9) or
higher than activity is reduced
25. f) The ester group isn’t mandatory as
quanternary amine group but an oxygen
atom is required in this region
g) Since ester group makes it liable to hydrolysis,
alternate groups were included and found that
replacing the ester with carbamate, ether or
ketone function resists hydrolysis while
maintaining activity
26. H3C O CH2 CH2 N(CH3)3
H3C CH2 CH2 N(CH3)3
O
H2N O
O
CH2 CH2 N(CH3)3
carbamates
Ethers
Ketone
(Carbamates are resistant enough
to Gastric acid to be given orally)
Modification to
reduce hydrolysis
27. SAR of
cholinergics/Muscarinic
agonist
1. Presence of nitrogen in quaternary ionic form is
important for agonist activity
2. Presence of three methyl group in Nitrogen is needed for
agonist activity
3. A “rule of five” idea states that there should be no more
than 5 atoms between the Nitrogen and the terminal
Hydrogen
4. Inclusion of methyl group in beta carbon to N makes
muscarinic selective in alpha carbon to N makes nicotinic
seelctive
5. The ester group isn’t mandatory as quanternary amine
group but an oxygen atom is required in this region
6. Replacing the ester with carbamate, ether or ketone
function resists hydrolysis while maintaining activity
H3C O
O
CH2 CH2 N(CH3)3
Quaternary
Ammonum group
Ethylene
group
Acyloxy
group
28. Designing a better drug by using SAR
• Problem with Ach was it’s instability and
unselective activity
• Combine point 4 and point 6 into a new
structure and see what you get?
• How does it compare with Ach?
29. Pharmacological action of Ach
A) Through the muscarinic receptor
Cardiac effects
• Bradycardia,
• decrease of atrioventricular conduction.
• decrease of the strength of atrium
contractions.
Blood vessels
• Acetylcholine injection causes release of nitric
oxide (NO) which dilates blood veins
30. • Effects on smooth muscles
• intestine: an increase in tone with sometimes an
increase in the peristaltic contractions. This can lead to
Nausea and vomiting.
• ureters: increase in tone.
• bronchi: bronchoconstriction. (An aerosol of
acetylcholine can cause an attack of asthma)
• Effects on secretions
• Acetylcholine increases digestive (abundant saliva),
bronchial, cutaneous (sweat) and lacrimal (tears)
secretions.
• Effects on the eye
• Acetylcholine induces a decrease of iris diameter or
miosis which can lower the intra-ocular pressure
31. • Through the nicotinic receptor
• In Autonomic NS, Ach allows nerve transmission
• In neuromuscular junctions
– At low dose Ach allow skeletal muscle movement
(important for breathing)
– At high does, it causes muscle paralysis!
• In Brain, cholinergic deficiency causes Alzheimer
disease
33. Specific Muscarinic agonist
Drugs other than Ach that produce the same effects
As Ach at Muscarinic receptor but for longer time
and greater intensity
– Methacholone Chloride
– Carbachol Chloride
– Bethanecol Chloride
– Pilocarpine Hydrochloride
Mechanism of Action (MOA) : They act directly by
binding to muscarinic receptor as a agonist and
produce the same effects as Ach
34. Methacholone
Chloride
• It is a muscarinic selective cholinergic agonist.
• It’s S enantiomer is 240 times more potent than R
enantiomer. Howeever, R iosmer is a weak
inhibitor of Ach degrading enzyme called
Acetylcholinesterases.
• Thus this is given as a racemic mixture
• Use – It is used to induce bronchospam in asthma
patients for purpose of verifying the diagnosing
asthma
• MOA
35. Carbachol
Chloride
• It is carbamate analog of Ach. This feature
makes it very resistant to hydrolysis by both GI
acid and Acetylcholinesterase such that it can
be given orally. But it is not selective to
muscarinic or nicotinic receptor.
• Uses: It’s use is limited to treatment of
glaucoma and constrict the pupils during eye
surgery.
• MOA
36. Bethanecol
Chloride
• It is an carbamate derivative of Ach which
contains a methyl group in beta carbon to
Nitrogen. This makes the molecule very stable to
hydrolysis and selective to muscarine too.
• Uses:
– treat urinary retention resulting from general
anesthetic
– treat gastrointestinal atony (muscles lose their
peristalic ability)
• MOA
37. Pilocarpine
Chloride
• It is a plant derived alkaloid whose structure does not
match the established SAR but still acts like an
cholinomimetic
• It is not selective to muscarine. Unlike other muscarine
agonists, it can penetrate the eye well following topical
application
• Uses:
– Treat dryness of mouth caused by radiation therapy in the
head or neck
– Glaucoma
– constrict the pupils during cataract surgery
• MOA
39. Anticholinesterase
• Acetylcholinesterase (AchE) is a enzyme that
hydrolyzes Ach into Acetic acid and Choline
• MOA: Anticholinesterase drugs work by inhibiting the
enzyme Acetylcholinesterase which prevents hydrolysis
of Ach thus increasing their concentration in the
synapse which promotes more Ach action. Since they
promote Ach activity without binding to any receptor
they are also called indirectly acting cholinergic
agonists
• Note: There is enough Acetylcholinesterase in the
synapse to hydrolyze 3 X 108 molecules of Ach in 1
millisecond (10-3sec). Normally only 3 X 106 Ach are
released into synapse
40. Applications
• Improve muscle strength in Myasthenia gravis
• Glaucoma
• Alzheimer's
• Insecticides
• Chemical weapon (serine gas)
• There are two types: Reversible and Irreversible
41. Theory of AchE inhibitors
If instead of acetyl group there is carbamate group then
hydrolysis will be resisted. The AchE which is not
hydrolyzed cannot be used again. Thus goal of AchE
inhibitor is to provide such hydrolysis resistant functional
group such as carbamates or phosphate ester
During hydrolysis of Ach, the AchE gets acylated. It needs to
be hydrolyzed by water to be regenerated in free from or
else it can’t function again.
42. Reversible Anticholinesterase
• These are compounds can act by two ways:
• A) They bind but don’t react with AchE with
greater affinity than Ach like Ach does or
• B)these compounds that bind and react with
AchE to form acylate AchE which is mores table
form but still capable of being easily hydrolyzed
• Reversible means that they inhibit AchE for short
time (only few mins)
• These compounds have more therapeutic uses
than irreversible ones eg Physostigmine and
Neostigmine
43. Physostigmine
• It is an alkaloid type anticholinesterase obtained from
the seeds of calabar beans
• It has no charged amine and is more lippohillic and can
thus penetrate the blood brain barrier
• It has very great affinity for AchE but that can only in
charged form. Thus there is pH limitation in it’s activity.
• Uses
– Glaucoma
– Counter CNS poisoning by atropine and tricyclic
depressents
• MOA – It inhibits AchE by binding and reacting to it and
carbamylating it. This carbamylated enzyme is slow to
hydrolysis
44. Neostigmine
• It is a synthetic anticholinesterase based on Physostigmine.
• It resembles the aromatic features of physostigmine and
also the distance between the ester and ammonium is
same
• But since it has charge on Nitrogen, it cannot cross the CNS
like physostigmine does
• Also its half life is shorter than physostigmine
• Uses
– Myasthenia gravis
– To counter Urinary retention
• MOA – It inhibits AchE by binding and reacting to it and
carbamylating it. This carbamylated enzyme is slow to
hydrolysis
45. Irreversible Anticholinesterase
• These compounds act by only one way: that bind and
react with AchE to AchE with greater affinity than Ach
to form acylated enzyme which strongly resist
hydrolysis
• Irreversible means that they inhibit AchE for very long
time(many hours)
• These compounds have less therapeutic uses than
reversible ones.
• Serine gas and organophosphate insecticides are based
on this concept.
• They cause cholinergic crisis
• Their common structural feature is the presence of
Phosphate ester bond which strongly resist hydrolysis
46. Cholinergic crisis
• A cholinergic crisis is an over-stimulation at a
neuromuscular junction due to an excess of
acetylcholine (ACh). This happens due to
inactivity (perhaps even inhibition) of the AChE
enzyme, which normally breaks down
acetylcholine. This is a consequence of some
types of nerve gas, (e.g. sarin gas) or insecticides.
• It causes muscle paralysis and respiratory failure
47. Aging
Irreversible Anticholinesterase containing Phosphate ester
resist hydrolysis very strongly. They also undergo a feature
called aging which increases this resistance even more.
When AchE becomes acylated for a long time with, one of
the ester bond is broken. This creates a negative charge that
oppose nucleophillic attack on phosphorous and in this
state it resists hydrolysis even more. At this stage antidotes
against Irreversible anticholinesterase such as PAM doesn’t work.
Thus regeneration of AchE is blocked for even longer periods
leading to cholinergic crisis
48. Organophosphate poisoning
Most insecticides use concept of irreversible AchE
inhibition to kill pesticides. These compounds
contain Phosphate ester bond that strongly resist
hydrolysis. They are very lipophillic and volatile
also. They can quickly enter the blood stream and
inhibit AchE for a many hours. This promotes Ach
activity in the synapse which leads to ‘cholinergic
crisis’. When this happens muscles stop responding
to Ach causing paralysis and respiratory failure
(death)
49. Antidote to insecticides
Because insecticides can lead to chloinergic
crisis, antidotes were designed to hydrolyze the
acylated AchE. A successful antidote was PAM
It has a quaternary ammonium and a very
strong nucleophile called oxime group and both
work together to free AchE from the phosphate
ester compounds
Pralidoxime
(PAM)
50. How PAM reverses poisoning by
organophosphate or serine gas ?
There are two sites in the binding pocket of AchE. One is a anionic site
which is empty and other is the Esteric site where the phosphate
compound sits. 3 event follows
• First the charged ammonium of PAM binds to the anionic site.
• From there PAM’s strong nucleophillic oxime group can be in close
distance to attack the ester bond between Phosphorous and serine
amino acid of AchE
• This form free AchE and phosphorylated PAM
Limitation: For PAM to work, it must be used immediately following
exposure to insecticides or serine gas or no more than 36 hrs of
exposure or else aging will occur and it wont be able to dislocate the
phosphate form the receptor
The search is on for stronger nucleophilic molecules that effectively displaces phosphate even
in aged form. This is a problem entirely of pure chemistry. No receptor/enzyme consideration
But enzymes are very powerful in catalyzing any reaction. What if we could engineer a protein
to specifically cleave this bond? Protein engineering is a established science!
57. Muscarinic receptor Nicotinic receptor
Named after it’s agonist Muscarine Named after it’s agonist Nicotine
It is a GPCR It is a Ligand gated ion channel
Subtypes : M1-M5 Muscle type or neuronal type
Location CNS, Autonomic NS Location : CNS, Autonomic,
Neuromuscular junctions
Allow Smooth Muscle contraction Allow Skeletal muscle contraction
58. Acetylcholine
2 problems prevent it from being a good drug
– Unselective
– Unstable (Easy to hydrolyze)
Solution
– Ethylene group control selectivity
– Acyloxy group controls stability
H3C O
O
CH2 CH2 N(CH3)3
Quaternary
Ammonum group
Ethylene
group
Acyloxy
group
(maintains
activity)
(controls
selectivity)
(modify
stability)
59. 2 ways of promoting Ach activity
• 1) Directly: Agonize muscarinic receptor
• 2) Indirectly : Inhibit Acetylcholinesterase
(AchE) ---> Ach not hydrolyzed ---> more Ach
to bind to receptors for longer time
(But This also promotes nicotinic activity!)
60. • During AchE mediated hydrolysis of Ach, AchE
gets gets attached with acyl group
• This acylated AchE needs to be hydrolyzed by
water to be free and function again
• Anticholinesterase inhibitor, both reversible
and irrversible contain functional groups
which makes this step very difficult for water
since water is not a strong nucloephile
61. • Order of Resistance to hydrolysis
• AchE-Phosphate ester>>>>>> AchE-carbamate
>> AchE-ester
• Reversivle Anticholinesterase block AchE for
few min----> thus have therapeutic value
• Irreversivle Anticholinesterase block AchE for
many hours---> thus have toxic effect -->
cholinergic crisis --> respiratory failure
62. Q) How Ach gives only specific Muc or Nic
response if it can bind to both of them?
63. Design criteria of good AchE inhibitor
• All AchE inhibitor based insecticide below
Phosphorylate the enzyme and have a peculiar
group in the right side of compound. Figure out
the organic chemistry.
• Remember: Rational drug design is not limited by
not having software to look at binding site or do
any fancy docking, QSAR. In this case the fact that
acylated AchE needs to be hydrolyzed and and
hydrolysis is a nucleophilic attack that is affected
by leaving group is all that you need
64.
65. • But there is no rationality for making an
irreversible AchE inhibitor unless you are
making a chemical weapon.
• Our focus should be on making a better PAM
alternative. All existing drugs are based on
oximes because it is a powerful nucleophile.
Do you know any stronger nucleophilies? How
about sulphur based compounds?
66. All these are useless in aging and the charge on Nitrogen
makes it difficult to reverse poisoning in CNS.
We need a antidote that
• Has stronger nucleophilic group than oxime
• Enough lipophilicity to penetrate into brain
•You will later see that charge in nitrogen isn’t mandatory
67. First lesson in Drug design
• When we say a drug or endogenous ligand interacts
with its target receptor or enzymes we mean that there
is formation of chemical bond such as
– H-Bond
– Dipole bond
– Ionic bond
– Covalent bond
– Van der wall bond
– Hydrophobic
– Pi-pi bond, pi-cation bond (you won’t find this in books but
this is important too as you will see in next slide)
68. Introduction to Structure based drug design (SBDD)
Implementation of knowledge of chemical bonding and
binding site to design drugs
69. Notice how enzmye catalysis works.
1) In AchE binding site, Hydrogen from a Histidine
protonates O of Ach and OH of erine attacks as a
nucleophile, just like what happens in lab: first C=O
protonation by some acidic catalyst then OH of
water attacks as a nucleophillic. Difference is in
enzyme both functionality is built in by various
amino acids, one acidic type (Histidine – it is basic
in neutral form but because of it’s basicity it mostly
remains in conjugated acid form) and other
nucleophilic type (Serine)
71. 2) The charged Nitrogen is used to anchor Ach into
binding site, where it forms not the expected
ionic bond (cation of Ach and anion in enzyme)
but cation-pi bond. The pi refers to aromatic rings
provided by tryptophan and phenylalanine of the
enzyme.
What this implies is that positive charge on PAM,
which makes brain penetration difficult, is not
really required. Instead we can include functional
groups that do pi-pi bonding with the enzyme ie
aromatic rings. This increases lipophilicity too!
72. Thus, In theory………
N
OH
this should also work
N
OH
this should also work and
penetrate brain more
We made specific changes in PAM in response to knowledge of how
Ach chemically binds to AchE. This change has advantage of
penetration brain better. Because we used the binding site as a
reference, this is called Structure based Drug Design and is one of
the principle of Rational drug design.
Assignment: Watch this video and learn about the Structure based
Drug Design of the first Anti-influenza drug, Zamanavir and bring
written report
Youtube/How protein crystallography changed drug design
N
N
OH
instead of this
73. How chemical interaction dictates conformation?
Ach When bound to nicotine
receptor Ach When in aqueous solution
trans form Gauche form
Ref : Conformation of acetylcholine bound to the nicotinic acetylcholine
receptor. Proc. Natl. Acad. Sci. USA 85 (1988)
Q)Normally, gauche is more stable than trans form in solution. However when bound to nicotine
Ach readily adopts such Trans conformation. Why?
Ans) At this trans form the total entropy ie chemical interaction with receptor overcomes
any entropy loss to finally result a large change in gibbs free energy ie thermodynamics of
binding matters