pharmacology parasympathetic nervous system- in brief
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the parasympathetic nervous system
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The Parasympathetic Nervous System
• All information should be reviewed by reading– Goodman and Gilman’s The Pharmacological Basis of
Therapeutics, 10th edition– Basic and Clinical Pharmacology, 9th edition
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Functions of the Parasympathetic Nervous System
• Protects the retina from excess light• Decreases heart rate• Promotes glandular secretions• Promotes the emptying of hollow organs• Promotes the conservation of energy• Promotes rest and repair• Physiologically antagonizes the sympathetic nervous
system
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Dual Innervation at Most Sites
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Concept of Dominance in the Autonomic Nervous System
• The sympathetic nervous system dominates at some sites
• The parasympathetic nervous system dominates at other sites
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Parasympathetic Innervation From Brain
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Parasympathetic Innervation From the Sacral Cord
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Synthesis of Acetylcholine
Acetylcholine
Choline
Acetyl CoA
+
Choline acetylase
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Cholinergic Fiber
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Acetylcholine and Its Metabolites
Acetylcholine
Choline Acetate
hydrolysis
+
AChE
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Agents Affecting Cholinergic Transmission
• Hemicholinium• Latrotoxin• Vesamicol• Calcium• Physostigmine• Atropine• d-Tubocurarine• Botulinus Toxin
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Uses of Botulinum Toxin Type A
Therapeutic Uses– Blepharospasm– Strabismus– Cervical dystonia (spasmodic torticollis)– Spasm of vocal cords– Achalasia
• Cosmetic Uses– Eyebrow furrows– Frontalis muscle hyperactivity– Lateral canthal wrinkles– Axillary and palmar hyperhydrosis
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General Actions of Acetylcholine
• Promotes transmission in postganglionic autonomic fibers• Promotes release of epinephrine and norepinephrine from
the adrenal medulla• Promotes transmission in skeletal muscle fibers• Promotes the functions of the parasympathetic nervous
system at cardiac muscle, smooth muscles and glands• Promotes sympathetic thermoregulatory sweating
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Neuronal Innervation to Organs
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• Autonomic ganglia – Nicotinic sites– Muscarinic sites
• Adrenal medulla
– Nicotinic sites: Release of epinephrine (90%) and norepinephrine
(10%) into the circulation.
Reproduced from Basic and Clinical Pharmacology
Actions Mediated by NN Nicotinic Receptor
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Activities Within Cell Bodies of Autonomic Ganglia
Postganglionic neuron, sympathetic or parasympathetic
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• End plate of skeletal muscle fiber - generation of the EPP
Actions Mediated by NM Nicotinic Receptor
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Nature of Nicotinic Receptors
• Nicotinic receptors are pentameric and ionotropic - the receptor proteins themselves form ion channels
• The ion channels are ligand-gated• Two subtypes
– NN subtype is present on cell body of postganglionic autonomic neuron
– NM subtype is present at the endplate of the
neuromuscular junction
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Agonists and Antagonists at Nicotinic Receptor Subtypes
RECEPTOR TYPE/LOCATION
TISSUE RESPONSE
SPECIFIC AGONISTS SPECIFIC ANTAGONISTS
NN Autonomic ganglia Adrenal medulla
Generation of the fEPSP
1,1-Dimethyl-4-phenylpiperazinium Tetramethylammonium Cytisine Epibatidine
Hexamethonium Trimethaphan
NM End plate of the neuromuscular junction
Generation of the end plate potential
Phenyltrimethylammonium
-Bungarotoxin d-Tubocurarine
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Response to Doses of Nicotine
• Low Dose– Autonomic ganglia– Adrenal medullary cell– End plate of skeletal muscle
• High Dose– Autonomic ganglia– Adrenal medullary cell– End plate of skeletal muscle
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Muscarinic Receptors
• Muscarinic receptors– The alkaloid muscarine mimics the actions of
acetylcholine at these receptor sites– Metabotropic
• Associated with guanine nucleotide binding proteins (G- proteins)
• Span the cell membrane seven times
– Several subtypes: M1, M2, M3, M4, M5
– Associated with various biochemical and electrophysiological responses
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Biochemical Actions Associated With Muscarinic Receptors
M1, M3, and M5 muscarinic receptors associate with Gq-protein; result: activation of phospholipase C
M2, and M4 muscarinic receptors associate with Gi-protein; result: inhibition of adenyl cyclase
X
phosphatidylinositolbiphosphate (PIP)2 inositoltriphosphate (IP)3 diacylglycerol (DAG) www.freelivedoctor.com
G-Protein Coupled Receptors
Review biochemistry, physiology, and pharmacology textbooks for the interaction of G-proteins and receptors.
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Activation of Phospholipase C by Muscarinic Receptor Subtypes
• M1, M3, M5 muscarinic receptors• Gq-GTP binding protein involved• Agonist binds to the receptor• The receptor associates with Gq-protein• Gq-protein exchanges GDP for GTP• The subunit of Gq-protein dissociates from the dimer
and activates the effector molecule phospholipase C • Phospholipase Chydrolyzes
phosphatidylinositolbiphosphate (PIP2) to inositoltriphosphate (IP3) and diacylglycerol (DAG)
• IP3 releases Ca2++ from the endoplasmic reticulum and with DAG, activates protein kinase C
• The reaction is terminated by hydrolysis of GTP by the q monomer; reassociation of q with the dimer www.freelivedoctor.com
Specific Antagonists for Muscarinic Receptor Subtypes
Darifenacin Smooth muscles and glands
M3
Tripitamine
Gallamine*
Cardiac muscle fiber
M2
Pirenzepine
Telenzepine
Autonomic ganglia, gastric tissue
M1
SELECTIVE
ANTAGONIST(S) TISSUE RECEPTOR
*Also blocks the nicotinic receptorwww.freelivedoctor.com
ACTIONS OF ACETYLCHOLINE AT ORGAN SITES
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Parasympathetic Innervation to the Eye
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Parasympathetic Control of Accomodation
From The Nurse, Pharmacology, and Drug Therapy
Parasympathetic stimulation allows contraction of the ciliary muscle.
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Flow of Aqueous From the Eye
From Basic and Clinical Pharmacologywww.freelivedoctor.com
Parasympathetic Function at Organs Sites (1)
• Gastrointestinal tract– Longitudinal muscles– Circular muscles– Sphincter muscles
• Bile duct• Gall bladder• Urinary tract
– Ureters– Detrusor muscle of the bladder– Trigone– Sphincter muscle of the bladder
• Bronchial smooth muscles
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Parasympathetic Function at Organs Sites (2)
• Lacrimal glands• Pharyngeal glands• Salivary glands• Mucus glands
– Respiratory tract– Esophagus
• Intestinal glands• Gastric glands• Pancreas
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Parasympathetic Control of the Cardiovascular System
• SA Node • Atrial muscle• AV node• Purkinje fibers• Ventricles• Blood vessels
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Nitric Oxide Mediated Vasodilation
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Neuronal and Hormonal Control of Blood Pressure
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Cardiovascular Responses to Low and High Doses of ACh
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Sites of Dominance in the ANS
Adapted from Goodman and Gilman’s The Pharmacological Basis of Therapeutics
1The vast majority of blood vessels do not receive parasympathetic innervationwww.freelivedoctor.com
Cholinergic Agents
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Cholinergic Agents
Alkaloids
Nicotine
Lobeline
Arecoline
Muscarine
Pilocarpine
Synthetic Agents
Dimethylphenylpiperazinium-(DMPP)
Oxotremorine
Methacholine
Bethanechol
Carbachol
Cevimeline
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Nicotine
• Nicotine mimics the actions of acetylcholine at nicotinic sites– Cell body of the postsynaptic neurons
• sympathetic and parasympathetic divisions– Chromaffin cells of the adrenal medulla– End plate of skeletal muscle fiber
• Affinity for NN sites versus NM sites• Used as an insecticide
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Muscarine
• Muscarine mimics the actions of acetylcholine at smooth muscles, cardiac muscles, and glands
• Poisoning by muscarine produces intense effects qualitative to those produced by cholinergic stimulation of smooth muscles, cardiac muscle, and glands
• Muscarine is found in various mushrooms– Amanita muscaria: content of muscarine is very
low– Inocybe sp: content of muscarine is high– Clitocybe sp: content of muscarine is high
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Pilocarpine
• Has muscarinic actions• Used for xerostomia• Used for glaucoma
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Structure of Acetylcholine and its Derivatives
Acetylcholine Methacholine
Bethanechol Carbacholwww.freelivedoctor.com
Therapeutic Uses of Cholinergic Agonists
• Dentistry– Pilocarpine– Cevimeline
• Ophthalmology– Pilocarpine– Carbachol
• Gastrointestinal tract – Bethanechol
• Urinary bladder– Bethanechol
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Contraindications to the Use of Choline Esters
• Hyperthyroidism• Asthma• Coronary insufficiency• Peptic ulcer• Organic obstruction in bladder or gastrointestinal tract
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Toxicity of Choline Esters
• Flushing• SWEATING (diaphoresis)• Abdominal cramps• Spasm of the urinary bladder• Spasm of accomodation• Miosis• Headache• Salivation• Bronchospasm• Lacrimation• Hypotension• Bradycardia
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Agents That Inhibit Acetylcholinesterase
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Acetylcholinesterase
(True Cholinesterase)
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Acetylcholinesterase (1)
• Sites of location– Cholinergic neurons– Cholinergic synapses– Neuromuscular junction– Red blood cells
• Substrates– Acetylcholine is the best substrate– Methacholine is a substrate– Hydrolyzes ACh at greater velocity than choline esters with
acyl groups larger than acetate or proprionate
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Acetylcholinesterase (2)
• Esters that are not substrates– Bethanechol– Carbachol– Succinylcholine
• Its inhibition produces synergistic interaction with methacholine and additive actions with bethanechol and carbachol
• Drugs that block its hydrolysis of esters are called cholinesterase inhibitors
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Drug Interactions of Choline Esters and Inhibitors of Acetylcholinesterase - Synergism versus Additivity
• Methacholine
• Carbachol
• Bethanechol
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Butyrylcholinesterase
(Plasma esterase, pseudocholinesterase, serum esterase, BuChE, PseudoChE)
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Butyrylcholinesterase (1)
• Sites of location
– Plasma, liver, glial cells, other tissues
• Substrates
– Butyrylcholine is the best
– Acetylcholine
– Succinylcholine
– Procaine
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Butyrylcholinesterase (2)
• Esters that are not substrates– Methacholine, bethanechol, and carbachol
• Is inhibited by carbamyl and organophosphate inhibitors of acetylcholinesterase
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Active Site of Acetylcholinesterase
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Interaction of AChE and Acetylcholine
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Acetylation of AChE and Release of Choline
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Hydroxyl Group of Water Attacks the Carbonyl Group of Acetylated-AChE to Liberate AChE
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Carbamyl Inhibitors of AChE
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• Their action promoting accumulation of ACh at muscarinic or nicotinic receptors is the basis of their pharmacological, therapeutic, and toxic actions
• Are derivatives of carbamic acid
• Bind covalently to the esteratic site of AChE, resulting in carbamylation of the enzyme
Carbamyl Inhibitors of AChE (1)
Carbamic acid Carbamic acid esterwww.freelivedoctor.com
• Quaternary compounds bind to the ionic binding site of AChE
• Their induce accumulation of AChE at nicotinic and muscarinic sites, producing pharmacological responses qualitative to cholinergic stimulation
• Inhibition of AChE is reversible, in the order of hours
• Are metabolized in the plasma by plasma esterases
Carbamyl Inhibitors of AChE (2)
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• High doses produce skeletal muscle weakness due to depolarizing blockade at the end plate of the neuromuscular junction
• High doses produce a profound fall in cardiac output and blood pressure
• Their inhibition of AChE is not reversed by pralidoxime
Carbamyl Inhibitors of AChE (3)
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• Quaternary ammonium compounds do not cross the blood-brain barrier
• For oral administration, high doses must be given
Carbamyl Inhibitors of AChE (4)
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Neostigmine Carbamylates Acetylcholinesterase
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Slow Hydrolysis of Carbamylated-AChE and Enzyme Liberation
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Organophosphate Inhibitors of Acetylcholinesterase
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• Chemical characteristics
• Promote accumulation of ACh at– NM nicotinic receptor – NN nicotinic receptor– Muscarinic receptor
Organophosphate Inhibitors of Acetylcholinesterase (1)
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• Their action promoting accumulation of ACh at the muscarinic receptor of the ciliary muscle is the basis of their therapeutic effectiveness in open angle glaucoma
• Only two of these agents are used for therapeutics– Echothiophate for glaucoma– Diisopropylflurophosphate (DFP) for glaucoma (?)
Organophosphate Inhibitors of AChE (2)
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• Inhibition of AChE by these agents is irreversible– New enzyme synthesis is required for recovery of
enzyme function
• They also inhibit pseudocholinesterase
• Metabolized by A-esterases (paroxonases) present in plasma and microsomes. They are metabolized by CYP450.
Organophosphate Inhibitors of AChE (3)
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• Enzyme inhibition by these agents can be reversed by cholinesterase reactivators such as pralidoxime if administered before “aging” of AChE has occurred. Inhibition by agents that undergo rapid “aging” is not reversed.
• Except for echothiophate, these agents are extremely lipid soluble, and some are very volatile.
Organophosphate Inhibitors of AChE (4)
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Diisopropylflurophosphate (DFP) is a Substrate for AChE
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The Extremely Slow Hydrolysis of Phosphorylated-AChE
New enzyme synthesis is required for recovery of enzyme function
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Various “States” of Acetylcholinesterase
Clockwise: free AChE, acetylated AChE, carbamylated AChE, phosphorylated AChEwww.freelivedoctor.com
Acetylated-AChE Is Very Rapdily Hydrolyzed
AChE + Acetylcholine AChE-acetylated + choline
AChE-acetylated + H2O AChE + acetate
Hydrolysis of AChE-acetylated is rapid, in the order of microseconds
P
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Carbamylated-AChE Is Hydrolyzed Slowly
AChE + Carbamyl inhibitor AChE-carbamylated + noncarbamylated metabolite
AChE-carbamylated + H2O AChE + carbamic acid derivative
Hydrolysis of the AChE-carbamylated is slow, in the order of hours. The carbamylated enzyme is reversibly inhibited, and recovery of function is in the order of hours
Enzyme after phosphorylation by neostigmine
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Phosphorlylated-AChE Is Hydrolyzed Extremely Slowly
AChE + organophosphate inhibitor AChE-phosphorylated + nonphosphorylated metabolite
AChE-phosphorylated + H2O AChE + phosphorylated derivative
Hydrolysis of the AChE-phosphorylated is extremely slow, in the order of days. The phosphorylated enzyme is considered to be irreversibly inhibited, and recovery of function is in the order of days. Pralidoxime, a reactivating agent, may be adminstered to a subject before the enzyme has “aged.”
Enzyme after phosphorylation by DFP
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AGING OF ACETYLCHOLINESTERASE
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Loss of An Alkyl Group From Phosphorylated AChE “Ages” the Enzyme
AChE, phosphorylated and inhibited by DFP
“Aged” AChE
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“Aging” of Phosphorylated- AChE
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Cholinesterase Reactivation
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Reactivation of Phosphorylated Acetylcholinesterase
• Oximes are used to reactivate phosphorylated AChE• The group (=NOH) has a high affinity for the phosphorus
atom• Pralidoxime has a nucleophilic site that interacts with the
phosphorylated site on phosphorylated-AChE
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Pralidoxime Reacts Chemically with Phosphorylated-AChE
The oxime group makes a nucleophilic attack upon the phosphorus atomwww.freelivedoctor.com
Oxime Phosphonate and Regenerated AChE
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Limitations of Pralidoxime
• Pralidoxime does not interact with carbamylated-AChE
• Pralidoxime in high doses can inhibit AChE
• Its quaternary ammonium group does not allow it to cross the blood brain barrier
• “Aging” of phosphorylated-AChE reduces the effectiveness of pralidoxime and other oxime reactivators
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Other Cholinesterase Reactivators
• Diacetylmonoxime– Crosses the blood brain barrier and in
experimental animals, regenerates some of the CNS cholinesterase
• HI-6 is used in Europe– Has two oxime centers in its structure– More potent than pralidoxime
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Edrophonium
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Edrophonium is a Short Acting Inhibitor that Binds to the Ionic Site but Not to the Esteratic Site of AChE
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Pharmacology of Acetylcholinesterase Inhibition
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Inhibition of Acetylcholinesterase Produces Stimulation of All Cholinergic Sites
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Carbamyl Inhibitors of AChE
• Physostigmine• Neostigmine (N+)• Pyridostigmine (N+)• Ambenonium (N+)• Demecarium (N+)• Carbaryl
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Pharmacology of Carbamyl Inhibitors of Acetylcholinesterase
• Eye• Exocrine glands• Cardiac muscle• Smooth muscles• Skeletal muscle• Toxicity
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Therapeutic Uses of Inhibitors of Acetylcholinesterase
• Glaucoma (wide angle)• Atony of the bladder• Atony of the gastrointestinal tract
• Intoxication by antimuscarinic agents (use physostigmine)
• Intoxication by tricyclic antidepressants (TCA’s) or
phenothiazines (use physostigmine)
• Recovery of neuromuscular function after competitive blockade of NN receptor of skeletal muscle fibers
• Myasthenia gravis
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Therapeutic Uses of Edrophonium
• Diagnosis of myasthenia gravis
• In conjunction with chosen therapeutic agent to determine proper dose of agent
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Determining Proper Dose of AChE Inhibitor
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Inhibitors of AChE Are Used for Therapy of Alzheimer’s Disease
• Tacrine
• Donepezil
• Rivastigmine
• Galantamine
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Organophosphate Inhibitors of AChE
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Some Organophosphate Inhibitors of Acetylcholinesterase
• Tetraethylpyrophosphate• Echothiophate (N+)• Diisopropylflurophosphate (DFP)• Sarin• Soman• Tabun• Malathion• Parathion• Diazinon• Chlorpyrifos• Many others
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Organophosphate Inhibitors - 2
Diisopropylfluorophosphate (DFP)
Soman
SarinTabunwww.freelivedoctor.com
Echothiophate
Therapeutic use - local application to the eye for wide angle glaucoma
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Conversion of Parathion to Paraoxon
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Conversion of Malathion to Malaoxon
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Malathion Is Hydrolyzed by Plasma Carboxylases in Birds and Mammals but Not Insects
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Carboxyl Esterases
• Preferentially hydrolyzes aliphatic esters
• Malathion is a substrate
• Are inhibited by organophosphates
• May also be called aliesterases
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Uses of Malathion
• Insecticide
• Therapeutics– Used as a lotion for Pediculus humanus capitis
associated with pediculosis– 0.5% solution in 78% isopropranolol is
pediculicidal and ovicidal– Ovide is the brand name– Primoderm was the former brand name
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Malathion Metabolism
• Rapidly metabolized by birds and mammals
• Plasma carboxylases are involved
• Insects do not possess the enzyme
• Organophosphates inhibit malathion metabolism
• Malathion is toxic to fish
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Aryl Esterases
• Are found in the plasma and liver
• Hydrolyzes organophosphates at the– P-F bond– P-CN bond– Phosphoester bond– Anhydride bond
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EPA And Organophosphates
• Diazinon – No longer allowed to be manufactured for indoor
use in as of March 1, 2001 or for garden use as of June 3, 2001
– Found in Real Kill®, Ortho®, Spectracide®
– Limited agricultural use is allowed
• Chlorpyrifos (Dursban) has been phased out
• Parathion has been phased out for agricultural use in the United States
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NERVE AGENT VXChemical name:
O-ETHYL-S-(2-DIISOPROPYLAMINOMETHYL)METHYL-PHOSHONOTHIOLATE
Trade name: PHOSPHONOTHIOIC ACID
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NERVE AGENT VXNERVE AGENT VX
Chemical name:
O-ETHYL-S-(2-DIISOPROPYLAMINOMETHYL)METHYL-PHOSHONOTHIOLATE
Trade name: PHOSPHONOTHIOIC ACID
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Organophosphates as Nerve Gas Agents in Chemical Warfare (1)
• Extremely volatile agents such as sarin, tabun, soman, and agent VX may be used as nerve agents in chemical warfare.
• Accumulation of ACh at cholinergic receptors produces effects reflecting stimulation of cardiac muscle, smooth muscles and glands. Such effects would be identical to those caused by muscarine poisoning.
• Bradycardia and hypotension occur. However, in some cases, tachycardia may be observed, due to intense sympathetic discharge in response severe hypoxemia.
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Organophosphates as Nerve Gas Agents in Chemical Warfare (2)
• Irreversible inhibition of acetylcholinesterase by these agents produces accumulation of ACh at the end plate of skeletal muscle fibers. This in turn leads to depolarizing blockade of the NM nicotinic receptor. Skeletal muscle paralysis occurs. Movement is impossible. The diaphragm is also paralyzed. The individual eventually dies due to respiratory paralysis.
• Pralidoxime, atropine, and removal of the person from the source of exposure are all to be employed in cases of posioning.
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Use of Pyridostigmine During the Gulf War
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Pharmacology of Muscarinic Receptor Blockade
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Acetylcholine is an agonist at both muscarinic and nicotinic receptors
The nicotinic actions of acetylcholine remain when muscarinic receptors are blocked
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Muscarinic Receptor Blockade Does Not Affect Ganglionic Transmission
X
Muscarinic receptor blockade prevents generation of the IPSP and the sEPSP but not the fEPSP
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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.
XX
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In Dual Innervated Organs, Muscarinic Receptor Blockade Allows Sympathetic Dominance
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Atropine
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Characteristics of Atropine
• Source– Atropa belladonna– Datura stramonium
• Known as Jamestown weed or jimsonweed
• Chemical nature– An alkaloid
• Alternate name is d,l-hyoscyamine• Nature of blockade
– Competitive
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Response to ACh in the Presence of Atropine
Log dose of acetylcholine
Res
po
nse
con
tro
l
atro
pin
e
Atropine competitively inhibits muscarinic reponses to ACh
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Actions of Atropine at Tissue Sites
• Eye – Sphincter muscle of the iris: mydriasis– Ciliary muscle: cycloplegia
Atropine limits focusing to distant objects
Accomodation is blocked by atropine
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Changes in Accomodation and Pupillary Diameter after Administration of an Antimuscarinic Agent
Changes in Accomodation and PupillaryDiameter after Administration of a Drug
0 1 5 3 0 4 5 6 0 7 5 9 00
2
4
6
8
1 0
pup il diameter
a cco modation
Time (minutes)
Acc
omod
atio
n (d
iopt
ers)
Pup
il di
amet
er (
mm
)
Reproduced from Basic and Clinical Pharmacologywww.freelivedoctor.com
Actions of Atropine At Smooth Muscles And Glands
• Eye• Lacrimal glands• Mucus glands of the pharynx and nasal cavity• Bronchial smooth muscle• Gastric glands• Intestinal glands• Pancreas• Mucus glands of the respiratory tract• Lacrimal glands• Eccrine sweat glands
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Cardiovascular Actions of Atropine
• Heart rate– Low dose– High dose
• Systemic blood vessels• Peripheral resistance• Cutaneous blood vessels
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Response to Doses of Atropine
Reproduced from Basic and Clinical Pharmacologywww.freelivedoctor.com
M1Receptor Activation at Parasympathetic Nerve Terminals Exerts A Small Negative Feedback Effect Upon ACh Release in Response to
Nerve Impulse Flow
postsynaptic fiber
cardiac muscle fiber
ACh
ACh
ACh
(----)
M1
M2
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M1Receptor Blockade Eliminates the Negative Feedback Effect and Increases ACh Release in Response to Nerve Impulse Flow
postsynaptic fiber
cardiac muscle fiber
Pirenzepine is an M1 antagonist
x ACh ACh
ACh ACh
M1
M2
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Intravenous infusion of acetylcholine in high doses produces actions at numerous sites. Bradycardia and hypotension are among the results. Such actions are accentuated in the presence of inhibitors of AChE (they also block plasma pseudocholinesterase).
i.v. infusion
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Prior blockade of muscarinic receptors followed by intravenous infusion of a high dose of ACh converts the bradycardiac and hypotensive responses to tachycardia and hypertension, mediated through the nicotinic receptors.
x
x
x
i.v. infusion
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Effect Of Atropine in Relation to Dosage ...
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Dose of Atropine
DOSE EFFECT
0.5 mg Slight decline in heart rate
Some dryness of mouth
Inhibition of sweating
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Dose of Atropine
DOSE EFFECT
1.0 mg Definited dryness of mouth
Thirst
Inreased heart rate, sometimes preceded by slowing
Mild dilatation of pupil
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Dose of Atropine
DOSE EFFECT
2.0 mg Rapid heart rate
Palpitation
Marked dryness of mouth
Dilated pupils
Some blurring of near vision
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Dose of Atropine
DOSE EFFECT
5.0 mg All the previous symptoms are marked
Difficulty in speaking and swallowing
Restlessness and fatigue
Headache
Dry hot skin
Difficulty in micturition
Reduced intestinal peristalsis
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Dose of Atropine
DOSE EFFECT
10 mg Previous symtoms are more marked
and more Pulse, rapid and weak
Iris practically obliterated
Vision very blurred
Skin flushed, hot, dry, and scarlet
Ataxia
Restlessness and excitement
Hallucinations and delirium
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The previous five slides are reproduced fromGoodman and Gilman’s
The Pharmacological Basis of Therapeutics
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Scopolamine (1)
• Source - Hyoscyamus niger (henbane)• Chemical nature of the molecule• Nature of blockade• Changes in the dose response curve of muscarinic
agonists in the presence of scopolamine• Lower doses of scopolamine (0.1 - 0.2 mg) produce
greater cardiac slowing than an equivalent dose of atropine. Higher doses produce tachycardia
• Low doses of scopolamine produce CNS effects that are not seen with equivalent doses of atropine
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Scopolamine (2)
• Therapeutic doses of scopolamine normally produce CNS depression, manifested as drowsiness, amnesia, fatigue, dreamless sleep, reduction in REM, euphoria
• In the presence of pain, the same therapeutic dose occasionally cause excitement, restlessness, hallucinations, or delirium. Such excitement is always seen with large doses, as is also seen with large doses of atropine
• Therapeutic use - prophylaxis of motion sickness; an adhesive preparation, the Transderm scop is used
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Therapeutic Uses of Antimuscarinic Agents
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Therapeutic Uses of Muscarinic Antagonists (1)
• Cardiovascular System - atropine is generally used for the following cases– Improper use of choline esters
– Sinus or nodal bradycardia in cases of excessive vagal tone associated with myocardial infarct
– Hyperactive carotid sinus (syncope and severe bradycardia)
– Second degree heart block
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Therapeutic Uses of Muscarinic Antagonists (2)
• Gastrointestinal Tract
– Peptic ulcers
• In Europe, Japan, and Canada, M1 muscarinic receptor antagonists such as pirenzepine and telenzepine are used
• In the U.S. H2 histamine antagonists such as cimetidine are used
– Spasticity of the g.i. tract
• M3 muscarinic antagonists are being investigated
– Excessive salivation associated with heavy metal poisoning and parkinsonism
– Production of partial blockade of salivation in patients unable to swallow
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Therapeutic Uses of Muscarinic Antagonists (3)
• Urinary Bladder
– Reverse spasm of the ureteral smooth muscle (renal colic)
– Increase bladder capacity in cases of enuresis
– Reduce urinary frequency in cases of hypertonic bladder
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Therapeutic Uses of Muscarinic Antagonists (4)
• Central Nervous System– Parkinson’s disease– Motion sickness– Produce tranquilization and amnesia prior to
surgery and in certain cases such as labor (not a prominent use anymore)
– Anesthesia, to inhibit salivation (not a prominent use anymore)
– Prevent vagal reflexes induced by surgical manipulation of organs
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Therapeutic Uses of Muscarinic Antagonists (5)
• Posioning by inhibitors of acetylcholinesterase• Mushroom poisoning due to muscarine• In conjunction with inhibitors of acetylcholinesterase
when they are used to promote recovery from neuromuscular blockade after surgery
• Injudicious use of choline esters• Prevent vagal reflexes induced by surgical
manipulation of visceral organs
Atropine is used for the above
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Toxicity of Atropine
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Contraindications to the Use Of Antimuscarinic Agents
• Narrow Angle Glaucoma
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Flow of Aqueous and Its Escape From the Eye
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Contraindications to the Use of Antimuscarinic Agents
• Narrow angle glaucoma• Hypertrophy of the prostate gland• Atony of the bladder• Atony of the G.I. Tract
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Tertiary Muscarinic Antagonists and Their Uses
• Ophthalmic applications– Cyclopentolate– Tropicamide– Homatropine
• Parkinson’s disease– Benztropine– Trihexphenidyl
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Tertiary Muscarinic Antagonists and Their Uses
• Used for antispasmodic purposes– Flavoxate - urinary bladder– Oxybutynin - urinary bladder– Tolterodine - urinary bladder– Dicyclomine– Oxyphencyclimine
In general, they are useful for spasms of the g.t. tract, bile duct, ureters,
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Tolterodine
• Therapeutic use - reduce urinary urgency• Metabolism
– Cytochrome P450– Active metabolite is DD-01
• Drug interactions– Ketoconazole– Erythromycin
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Quaternary Ammonium Antagonists (1)
• General characteristics• Pharmacology and therapeutic uses• Distinct side effects with high and sometimes
therapeutic doses
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Quaternary Ammonium Antagonists (2)
• Methantheline (N+)• Propantheline (N +)• Methscopolamine (N +) • Homatropine methylbromide (N +)• Oxyphenonium (N +)
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Quaternary Ammonium Antagonists (3)
• Anisotropine (N+)• Glycopyrrolate (N+)• Isopropamide (N+)• Mepenzolate (N+)• Ipratropium (N+)
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Ipratropium
• Uses • Distinctiveness from atropine
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M1 Muscarinic Receptor Antagonists
• Pirenzepine
– Blocks the M1 and the M4 receptor
– Its usefulness for peptic ulcer• Telenzepine
– Blocks the M1 receptor– Its usefulness for peptic ulcer
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M2 Muscarinic Receptor Antagonists
• Tripitamine
– Blocks the M2 receptor
– Blocks the action of acetylcholine at cardiac muscle fibers
• Gallamine
– Blocks M2 muscarinic and the NN nicotinic sites
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M3 Muscarinic Receptor Antagonist
• Darifenacin
– Blocks the M3 receptor
– Blocks the actions of acetylcholine at smooth muscles and glands
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Drugs of Other Classes With Antimuscarinic Activity (1)
• Tricyclic antidepressants– Imipramine– Amitriptyline– Protriptyline– Others
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Drugs of Other Classes With Antimuscarinic Activity (2)
• Phenothiazine Antipsychotic Agents– Chlorpromazine– Thioridazine– Perphenazine– Others
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Drugs of Other Classes With Antimuscarinic Activity (3)
• Dibenzodiazepine antipsychotic agents– Clozapine– Olanzepine
• Dibenzoxazepine antipsychotic agents– Loxapine
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Drugs of Other Classes With Antimuscarinic Activity (4)
• H1 Histamine receptor blocking agents
– Diphenhydramine– Dimenhydrinate
– Promethazine
– Carbinoxamine
– Dimenhydrinate
– Pyrlamine
– Tripelennamine
– Brompheniramine
– Chlorpheniramine
– Cyproheptadine
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