0
the parasympathetic  nervous system www.freelivedoctor.com
The Parasympathetic Nervous System <ul><li>All information should be reviewed by reading </li></ul><ul><ul><li>Goodman and...
Functions of the Parasympathetic Nervous System <ul><li>Protects the retina from excess light </li></ul><ul><li>Decreases ...
Dual Innervation at Most Sites www.freelivedoctor.com
Concept of Dominance in the Autonomic Nervous System <ul><li>The sympathetic nervous system dominates at some sites </li><...
Parasympathetic Innervation From Brain www.freelivedoctor.com
Parasympathetic Innervation From the Sacral Cord www.freelivedoctor.com
Synthesis of Acetylcholine   Acetylcholine Choline Acetyl CoA + Choline acetylase www.freelivedoctor.com
Cholinergic Fiber www.freelivedoctor.com
Acetylcholine and Its Metabolites Acetylcholine Choline Acetate hydrolysis + AChE www.freelivedoctor.com
Agents Affecting Cholinergic Transmission <ul><li>Hemicholinium </li></ul><ul><li>Latrotoxin </li></ul><ul><li>Vesamicol <...
Uses of Botulinum Toxin Type A <ul><li>Therapeutic Uses </li></ul><ul><ul><li>Blepharospasm </li></ul></ul><ul><ul><li>Str...
General Actions of Acetylcholine  <ul><li>Promotes transmission in postganglionic autonomic fibers </li></ul><ul><li>Promo...
Neuronal Innervation to Organs www.freelivedoctor.com
<ul><li>Autonomic ganglia   </li></ul><ul><ul><li>Nicotinic sites </li></ul></ul><ul><ul><li>Muscarinic sites </li></ul></...
Activities Within Cell Bodies of Autonomic Ganglia Postganglionic neuron, sympathetic or parasympathetic www.freelivedocto...
<ul><li>End plate of skeletal muscle fiber - generation of the EPP </li></ul>Actions Mediated by   N M   Nicotinic Recepto...
Nature of   Nicotinic Receptors <ul><li>Nicotinic receptors are pentameric and ionotropic - the receptor proteins themselv...
Agonists and Antagonists at Nicotinic Receptor Subtypes www.freelivedoctor.com
Response to Doses of Nicotine <ul><li>Low Dose </li></ul><ul><ul><li>Autonomic ganglia </li></ul></ul><ul><ul><li>Adrenal ...
Muscarinic Receptors <ul><li>Muscarinic receptors </li></ul><ul><ul><li>The alkaloid muscarine mimics the actions of acety...
Biochemical Actions Associated With Muscarinic Receptors M 1 , M 3 , and M 5  muscarinic receptors  associate with G q -pr...
G-Protein Coupled Receptors Review biochemistry, physiology, and pharmacology textbooks for the interaction of G-proteins ...
Activation of Phospholipase C   by  Muscarinic Receptor Subtypes <ul><li>M 1 , M 3 , M 5  muscarinic receptors </li></ul>...
Specific Antagonists for Muscarinic Receptor Subtypes *Also blocks the nicotinic receptor www.freelivedoctor.com Darifenac...
ACTIONS OF ACETYLCHOLINE  AT ORGAN SITES www.freelivedoctor.com
Parasympathetic Innervation to the Eye www.freelivedoctor.com
Parasympathetic Control of Accomodation From  The Nurse, Pharmacology, and Drug Therapy Parasympathetic stimulation allows...
Flow   of   Aqueous   From   the   Eye From  Basic and Clinical Pharmacology www.freelivedoctor.com
Parasympathetic Function at Organs Sites (1) <ul><li>Gastrointestinal tract </li></ul><ul><ul><li>Longitudinal muscles </l...
Parasympathetic Function at Organs Sites (2) <ul><li>Lacrimal glands </li></ul><ul><li>Pharyngeal glands </li></ul><ul><li...
Parasympathetic Control of the Cardiovascular System <ul><li>SA Node  </li></ul><ul><li>Atrial muscle </li></ul><ul><li>AV...
Nitric Oxide Mediated Vasodilation www.freelivedoctor.com
Neuronal and Hormonal Control of Blood Pressure www.freelivedoctor.com
Cardiovascular Responses to Low and High Doses of ACh www.freelivedoctor.com
Sites of Dominance in the ANS Adapted from Goodman and Gilman’s  The Pharmacological Basis of Therapeutics 1 The vast majo...
Cholinergic Agents www.freelivedoctor.com
Cholinergic Agents Alkaloids Nicotine Lobeline Arecoline Muscarine Pilocarpine Synthetic Agents Dimethylphenylpiperazinium...
Nicotine   <ul><li>Nicotine mimics the actions of acetylcholine at nicotinic sites </li></ul><ul><ul><li>Cell body of the ...
Muscarine <ul><li>Muscarine mimics the actions of acetylcholine at smooth muscles, cardiac muscles, and glands  </li></ul>...
Pilocarpine <ul><li>Has muscarinic actions </li></ul><ul><li>Used for xerostomia </li></ul><ul><li>Used for glaucoma </li>...
Structure of Acetylcholine and its Derivatives Acetylcholine Methacholine Bethanechol Carbachol www.freelivedoctor.com
Therapeutic Uses of Cholinergic Agonists <ul><li>Dentistry </li></ul><ul><ul><li>Pilocarpine </li></ul></ul><ul><ul><li>Ce...
Contraindications to the Use of Choline Esters <ul><li>Hyperthyroidism </li></ul><ul><li>Asthma </li></ul><ul><li>Coronary...
Toxicity of Choline Esters <ul><li>Flushing </li></ul><ul><li>SWEATING (diaphoresis) </li></ul><ul><li>Abdominal cramps </...
Agents That Inhibit Acetylcholinesterase www.freelivedoctor.com
Acetylcholinesterase (True Cholinesterase) www.freelivedoctor.com
Acetylcholinesterase (1) <ul><li>Sites of location </li></ul><ul><ul><li>Cholinergic neurons </li></ul></ul><ul><ul><li>Ch...
Acetylcholinesterase (2) <ul><li>Esters that are not substrates </li></ul><ul><ul><li>Bethanechol </li></ul></ul><ul><ul><...
Drug Interactions of Choline Esters and Inhibitors of Acetylcholinesterase - Synergism   versus   Additivity <ul><li>Metha...
Butyrylcholinesterase (Plasma esterase, pseudocholinesterase, serum esterase, BuChE, PseudoChE) www.freelivedoctor.com
Butyrylcholinesterase (1) <ul><li>Sites of location </li></ul><ul><ul><li>Plasma, liver, glial cells, other tissues </li><...
Butyrylcholinesterase (2) <ul><li>Esters that are not substrates </li></ul><ul><ul><li>Methacholine, bethanechol, and carb...
Active Site of Acetylcholinesterase  www.freelivedoctor.com
Interaction of AChE and Acetylcholine  www.freelivedoctor.com
Acetylation of AChE and Release of Choline  www.freelivedoctor.com
Hydroxyl Group of Water Attacks the Carbonyl Group of Acetylated-AChE to Liberate AChE www.freelivedoctor.com
Carbamyl Inhibitors of AChE  www.freelivedoctor.com
<ul><li>Their action promoting accumulation of ACh at muscarinic or nicotinic receptors is the basis of their pharmacologi...
<ul><li>Quaternary compounds bind to the ionic binding site of AChE </li></ul><ul><li>Their induce accumulation of AChE at...
<ul><li>High doses produce skeletal muscle weakness due to depolarizing blockade at the end plate of the neuromuscular jun...
<ul><li>Quaternary ammonium compounds do not cross the blood-brain barrier </li></ul><ul><li>For oral administration, high...
Neostigmine Carbamylates Acetylcholinesterase www.freelivedoctor.com
Slow Hydrolysis of Carbamylated-AChE and Enzyme Liberation www.freelivedoctor.com
Organophosphate Inhibitors of  Acetylcholinesterase www.freelivedoctor.com
<ul><li>Chemical characteristics </li></ul><ul><li>Promote accumulation of ACh at </li></ul><ul><ul><li>N M  nicotinic rec...
<ul><li>Their action promoting accumulation of ACh at  the muscarinic receptor of the ciliary muscle is the basis of their...
<ul><li>Inhibition of AChE by these agents is irreversible </li></ul><ul><ul><li>New enzyme synthesis is required for reco...
<ul><li>Enzyme inhibition by these agents can be reversed by cholinesterase reactivators such as pralidoxime if administer...
Diisopropylflurophosphate (DFP) is a Substrate for AChE www.freelivedoctor.com
The Extremely Slow Hydrolysis of Phosphorylated-AChE  New enzyme synthesis is required for recovery of enzyme function www...
Various “States” of Acetylcholinesterase Clockwise: free AChE, acetylated AChE, carbamylated AChE, phosphorylated AChE www...
Acetylated-AChE Is Very Rapdily Hydrolyzed AChE + Acetylcholine    AChE-acetylated + choline AChE-acetylated + H 2 O    ...
Carbamylated-AChE Is Hydrolyzed Slowly AChE + Carbamyl inhibitor    AChE-carbamylated + noncarbamylated metabolite AChE-c...
Phosphorlylated-AChE Is Hydrolyzed Extremely Slowly AChE + organophosphate inhibitor     AChE-phosphorylated  + nonphosph...
AGING OF ACETYLCHOLINESTERASE www.freelivedoctor.com
Loss of An Alkyl Group From Phosphorylated  AChE “Ages” the Enzyme AChE, phosphorylated and inhibited by DFP “ Aged” AChE ...
“ Aging” of Phosphorylated- AChE  www.freelivedoctor.com
Cholinesterase Reactivation www.freelivedoctor.com
Reactivation of  Phosphorylated Acetylcholinesterase <ul><li>Oximes are used to reactivate phosphorylated AChE </li></ul><...
Pralidoxime Reacts Chemically with Phosphorylated-AChE  The oxime group makes a nucleophilic attack upon the phosphorus at...
Oxime Phosphonate and Regenerated AChE  www.freelivedoctor.com
Limitations of Pralidoxime <ul><li>Pralidoxime does not interact with carbamylated-AChE </li></ul><ul><li>Pralidoxime in h...
Other Cholinesterase Reactivators <ul><li>Diacetylmonoxime </li></ul><ul><ul><li>Crosses the blood brain barrier and in ex...
Edrophonium www.freelivedoctor.com
Edrophonium is a Short Acting Inhibitor that Binds  to the Ionic Site but Not to the Esteratic Site of AChE www.freelivedo...
Pharmacology of Acetylcholinesterase Inhibition www.freelivedoctor.com
Inhibition of Acetylcholinesterase Produces  Stimulation of All Cholinergic Sites www.freelivedoctor.com
Carbamyl Inhibitors of AChE <ul><li>Physostigmine </li></ul><ul><li>Neostigmine (N + ) </li></ul><ul><li>Pyridostigmine (N...
Pharmacology of Carbamyl Inhibitors of Acetylcholinesterase <ul><li>Eye </li></ul><ul><li>Exocrine glands </li></ul><ul><l...
Therapeutic Uses of Inhibitors of Acetylcholinesterase <ul><li>Glaucoma (wide angle) </li></ul><ul><li>Atony of the bladde...
Therapeutic Uses of Edrophonium <ul><li>Diagnosis of myasthenia gravis </li></ul><ul><li>In conjunction with chosen therap...
Determining Proper Dose of AChE Inhibitor www.freelivedoctor.com
Inhibitors of AChE Are Used for Therapy of Alzheimer’s Disease <ul><li>Tacrine </li></ul><ul><li>Donepezil </li></ul><ul><...
Organophosphate Inhibitors  of AChE www.freelivedoctor.com
Some Organophosphate Inhibitors of Acetylcholinesterase <ul><li>Tetraethylpyrophosphate </li></ul><ul><li>Echothiophate (N...
Organophosphate Inhibitors - 2 Diisopropylfluorophosphate (DFP) Soman Sarin Tabun www.freelivedoctor.com
Echothiophate Therapeutic use - local application to the eye for wide angle glaucoma  www.freelivedoctor.com
Conversion of Parathion to Paraoxon www.freelivedoctor.com
Conversion of Malathion to Malaoxon www.freelivedoctor.com
Malathion Is Hydrolyzed by Plasma Carboxylases in Birds and Mammals but Not Insects www.freelivedoctor.com
Carboxyl Esterases <ul><li>Preferentially hydrolyzes aliphatic esters </li></ul><ul><li>Malathion is a substrate </li></ul...
Uses of Malathion  <ul><li>Insecticide </li></ul><ul><li>Therapeutics </li></ul><ul><ul><li>Used as a lotion for  Pediculu...
Malathion Metabolism <ul><li>Rapidly metabolized by birds and mammals </li></ul><ul><li>Plasma carboxylases are involved <...
Aryl Esterases <ul><li>Are found in the plasma and liver </li></ul><ul><li>Hydrolyzes organophosphates at the </li></ul><u...
EPA And Organophosphates <ul><li>Diazinon  </li></ul><ul><ul><li>No longer allowed to be manufactured for indoor use in as...
NERVE AGENT VX Chemical name: O-ETHYL-S-(2-DIISOPROPYLAMINOMETHYL)METHYL-PHOSHONOTHIOLATE Trade name: PHOSPHONOTHIOIC ACID...
NERVE AGENT VX Chemical name: O-ETHYL-S-(2-DIISOPROPYLAMINOMETHYL)METHYL-PHOSHONOTHIOLATE Trade name: PHOSPHONOTHIOIC ACID...
Organophosphates as Nerve Gas Agents  in Chemical Warfare (1) <ul><li>Extremely volatile agents such as sarin, tabun, soma...
Organophosphates as Nerve Gas Agents  in Chemical Warfare (2) <ul><li>Irreversible inhibition of acetylcholinesterase by t...
Use of Pyridostigmine During the Gulf War www.freelivedoctor.com
Pharmacology of Muscarinic Receptor Blockade www.freelivedoctor.com
Acetylcholine is an agonist at both muscarinic and nicotinic receptors The nicotinic actions of acetylcholine remain when ...
Muscarinic Receptor Blockade Does Not Affect  Ganglionic Transmission Muscarinic receptor blockade prevents generation of ...
Muscarinic receptor blockade does not interfere with transmission at autonomic ganglionic sites, the adrenal medulla, or s...
In Dual Innervated Organs, Muscarinic Receptor Blockade Allows Sympathetic Dominance X www.freelivedoctor.com
Atropine www.freelivedoctor.com
Characteristics of Atropine <ul><li>Source </li></ul><ul><ul><li>Atropa belladonna </li></ul></ul><ul><ul><li>Datura stram...
Response to ACh in the Presence of Atropine Atropine competitively inhibits muscarinic reponses to ACh www.freelivedoctor....
Actions of Atropine at Tissue Sites <ul><li>Eye  </li></ul><ul><ul><li>Sphincter muscle of the iris: mydriasis </li></ul><...
Changes in Accomodation and Pupillary Diameter after Administration of an Antimuscarinic Agent Reproduced from  Basic and ...
Actions of Atropine At Smooth Muscles And Glands <ul><li>Eye </li></ul><ul><li>Lacrimal glands </li></ul><ul><li>Mucus gla...
Cardiovascular Actions of Atropine  <ul><li>Heart rate </li></ul><ul><ul><li>Low dose </li></ul></ul><ul><ul><li>High dose...
Response to Doses of Atropine Reproduced from  Basic and Clinical Pharmacology www.freelivedoctor.com
M 1 Receptor  Activation  at Parasympathetic Nerve Terminals Exerts A Small Negative Feedback Effect Upon ACh Release in R...
M 1 Receptor  Blockade  Eliminates the Negative Feedback Effect and Increases ACh Release in  Response to Nerve Impulse Fl...
Intravenous infusion of acetylcholine in high doses produces actions at numerous sites. Bradycardia and hypotension are am...
Prior blockade of muscarinic receptors followed by intravenous infusion of a high dose of ACh converts the bradycardiac an...
Effect Of Atropine in Relation to Dosage ... www.freelivedoctor.com
Dose of Atropine DOSE EFFECT 0.5 mg Slight decline in heart rate  Some dryness of mouth Inhibition of sweating www.freeliv...
Dose of Atropine DOSE EFFECT 1.0 mg Definited dryness of mouth  Thirst Inreased heart rate, sometimes    preceded by slowi...
Dose of Atropine DOSE EFFECT 2.0 mg Rapid heart rate   Palpitation Marked dryness of mouth Dilated pupils Some blurring of...
Dose of Atropine DOSE EFFECT 5.0 mg All the previous symptoms are    marked   Difficulty in speaking and swallowing Restle...
Dose of Atropine DOSE EFFECT 10 mg Previous symtoms are more marked and more Pulse, rapid and weak Iris practically oblite...
The previous five slides are reproduced from Goodman and Gilman’s  The Pharmacological Basis of Therapeutics www.freelived...
Scopolamine (1) <ul><li>Source -  Hyoscyamus niger  (henbane) </li></ul><ul><li>Chemical nature of the molecule </li></ul>...
Scopolamine (2) <ul><li>Therapeutic doses of scopolamine normally produce CNS  depression, manifested as drowsiness, amnes...
Therapeutic Uses of Antimuscarinic Agents www.freelivedoctor.com
Therapeutic Uses of Muscarinic Antagonists (1) <ul><li>Cardiovascular System - atropine is generally used for the followin...
Therapeutic Uses of Muscarinic Antagonists (2) <ul><li>Gastrointestinal Tract </li></ul><ul><ul><li>Peptic ulcers </li></u...
Therapeutic Uses of Muscarinic Antagonists (3) <ul><li>Urinary Bladder </li></ul><ul><ul><li>Reverse spasm of the ureteral...
Therapeutic Uses of Muscarinic Antagonists (4) <ul><li>Central Nervous System </li></ul><ul><ul><li>Parkinson’s disease </...
Therapeutic Uses of Muscarinic Antagonists (5) <ul><li>Posioning by inhibitors of acetylcholinesterase </li></ul><ul><li>M...
Toxicity of Atropine www.freelivedoctor.com
Contraindications to the Use Of Antimuscarinic Agents <ul><li>Narrow Angle Glaucoma </li></ul>www.freelivedoctor.com
Flow of Aqueous and Its Escape From the Eye  www.freelivedoctor.com
Contraindications to the Use of Antimuscarinic Agents <ul><li>Narrow angle glaucoma </li></ul><ul><li>Hypertrophy of the p...
Tertiary Muscarinic Antagonists and Their Uses <ul><li>Ophthalmic applications </li></ul><ul><ul><li>Cyclopentolate </li><...
Tertiary Muscarinic Antagonists and Their Uses <ul><li>Used for antispasmodic purposes </li></ul><ul><ul><li>Flavoxate - u...
Tolterodine <ul><li>Therapeutic use - reduce urinary urgency </li></ul><ul><li>Metabolism </li></ul><ul><ul><li>Cytochrome...
Quaternary Ammonium Antagonists (1) <ul><li>General characteristics </li></ul><ul><li>Pharmacology and therapeutic uses </...
Quaternary Ammonium Antagonists (2) <ul><li>Methantheline (N + ) </li></ul><ul><li>Propantheline (N  + ) </li></ul><ul><li...
Quaternary Ammonium Antagonists (3) <ul><li>Anisotropine (N + ) </li></ul><ul><li>Glycopyrrolate (N + ) </li></ul><ul><li>...
Ipratropium <ul><li>Uses  </li></ul><ul><li>Distinctiveness from atropine </li></ul>www.freelivedoctor.com
M 1  Muscarinic Receptor Antagonists <ul><li>Pirenzepine </li></ul><ul><ul><li>Blocks the M 1   and the M 4  receptor </li...
M 2  Muscarinic Receptor Antagonists <ul><li>Tripitamine </li></ul><ul><ul><li>Blocks the M 2  receptor </li></ul></ul><ul...
M 3  Muscarinic Receptor Antagonist <ul><li>Darifenacin </li></ul><ul><ul><li>Blocks the M 3  receptor </li></ul></ul><ul>...
Drugs of Other Classes With Antimuscarinic Activity (1) <ul><li>Tricyclic antidepressants </li></ul><ul><ul><li>Imipramine...
Drugs of Other Classes With Antimuscarinic Activity (2) <ul><li>Phenothiazine Antipsychotic Agents </li></ul><ul><ul><li>C...
Drugs of Other Classes With Antimuscarinic Activity (3) <ul><li>Dibenzodiazepine antipsychotic agents </li></ul><ul><ul><l...
Drugs of Other Classes With Antimuscarinic Activity (4) <ul><li>H 1  Histamine receptor blocking agents </li></ul><ul><ul>...
Upcoming SlideShare
Loading in...5
×

Pharmacology parasympathetic nervous system- in brief

8,672

Published on

0 Comments
9 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
8,672
On Slideshare
0
From Embeds
0
Number of Embeds
2
Actions
Shares
0
Downloads
641
Comments
0
Likes
9
Embeds 0
No embeds

No notes for slide

Transcript of "Pharmacology parasympathetic nervous system- in brief"

  1. 1. the parasympathetic nervous system www.freelivedoctor.com
  2. 2. The Parasympathetic Nervous System <ul><li>All information should be reviewed by reading </li></ul><ul><ul><li>Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th edition </li></ul></ul><ul><ul><li>Basic and Clinical Pharmacology, 9th edition </li></ul></ul>www.freelivedoctor.com
  3. 3. Functions of the Parasympathetic Nervous System <ul><li>Protects the retina from excess light </li></ul><ul><li>Decreases heart rate </li></ul><ul><li>Promotes glandular secretions </li></ul><ul><li>Promotes the emptying of hollow organs </li></ul><ul><li>Promotes the conservation of energy </li></ul><ul><li>Promotes rest and repair </li></ul><ul><li>Physiologically antagonizes the sympathetic nervous system </li></ul>www.freelivedoctor.com
  4. 4. Dual Innervation at Most Sites www.freelivedoctor.com
  5. 5. Concept of Dominance in the Autonomic Nervous System <ul><li>The sympathetic nervous system dominates at some sites </li></ul><ul><li>The parasympathetic nervous system dominates at other sites </li></ul>www.freelivedoctor.com
  6. 6. Parasympathetic Innervation From Brain www.freelivedoctor.com
  7. 7. Parasympathetic Innervation From the Sacral Cord www.freelivedoctor.com
  8. 8. Synthesis of Acetylcholine Acetylcholine Choline Acetyl CoA + Choline acetylase www.freelivedoctor.com
  9. 9. Cholinergic Fiber www.freelivedoctor.com
  10. 10. Acetylcholine and Its Metabolites Acetylcholine Choline Acetate hydrolysis + AChE www.freelivedoctor.com
  11. 11. Agents Affecting Cholinergic Transmission <ul><li>Hemicholinium </li></ul><ul><li>Latrotoxin </li></ul><ul><li>Vesamicol </li></ul><ul><li>Calcium </li></ul><ul><li>Physostigmine </li></ul><ul><li>Atropine </li></ul><ul><li>d-Tubocurarine </li></ul><ul><li>Botulinus Toxin </li></ul>www.freelivedoctor.com
  12. 12. Uses of Botulinum Toxin Type A <ul><li>Therapeutic Uses </li></ul><ul><ul><li>Blepharospasm </li></ul></ul><ul><ul><li>Strabismus </li></ul></ul><ul><ul><li>Cervical dystonia (spasmodic torticollis) </li></ul></ul><ul><ul><li>Spasm of vocal cords </li></ul></ul><ul><ul><li>Achalasia </li></ul></ul><ul><li>Cosmetic Uses </li></ul><ul><ul><li>Eyebrow furrows </li></ul></ul><ul><ul><li>Frontalis muscle hyperactivity </li></ul></ul><ul><ul><li>Lateral canthal wrinkles </li></ul></ul><ul><ul><li>Axillary and palmar hyperhydrosis </li></ul></ul>www.freelivedoctor.com
  13. 13. General Actions of Acetylcholine <ul><li>Promotes transmission in postganglionic autonomic fibers </li></ul><ul><li>Promotes release of epinephrine and norepinephrine from the adrenal medulla </li></ul><ul><li>Promotes transmission in skeletal muscle fibers </li></ul><ul><li>Promotes the functions of the parasympathetic nervous system at cardiac muscle, smooth muscles and glands </li></ul><ul><li>Promotes sympathetic thermoregulatory sweating </li></ul>www.freelivedoctor.com
  14. 14. Neuronal Innervation to Organs www.freelivedoctor.com
  15. 15. <ul><li>Autonomic ganglia </li></ul><ul><ul><li>Nicotinic sites </li></ul></ul><ul><ul><li>Muscarinic sites </li></ul></ul>Actions Mediated by N N Nicotinic Receptor <ul><li>Adrenal medulla </li></ul><ul><ul><li>Nicotinic sites: Release of epinephrine (90%) and norepinephrine (10%) into the circulation . </li></ul></ul>Reproduced from Basic and Clinical Pharmacology www.freelivedoctor.com
  16. 16. Activities Within Cell Bodies of Autonomic Ganglia Postganglionic neuron, sympathetic or parasympathetic www.freelivedoctor.com
  17. 17. <ul><li>End plate of skeletal muscle fiber - generation of the EPP </li></ul>Actions Mediated by N M Nicotinic Receptor www.freelivedoctor.com
  18. 18. Nature of Nicotinic Receptors <ul><li>Nicotinic receptors are pentameric and ionotropic - the receptor proteins themselves form ion channels </li></ul><ul><li>The ion channels are ligand-gated </li></ul><ul><li>Two subtypes </li></ul><ul><ul><li>N N subtype is present on cell body of postganglionic autonomic neuron </li></ul></ul><ul><ul><li>N M subtype is present at the endplate of the neuromuscular junction </li></ul></ul>www.freelivedoctor.com
  19. 19. Agonists and Antagonists at Nicotinic Receptor Subtypes www.freelivedoctor.com
  20. 20. Response to Doses of Nicotine <ul><li>Low Dose </li></ul><ul><ul><li>Autonomic ganglia </li></ul></ul><ul><ul><li>Adrenal medullary cell </li></ul></ul><ul><ul><li>End plate of skeletal muscle </li></ul></ul><ul><li>High Dose </li></ul><ul><ul><li>Autonomic ganglia </li></ul></ul><ul><ul><li>Adrenal medullary cell </li></ul></ul><ul><ul><li>End plate of skeletal muscle </li></ul></ul>www.freelivedoctor.com
  21. 21. Muscarinic Receptors <ul><li>Muscarinic receptors </li></ul><ul><ul><li>The alkaloid muscarine mimics the actions of acetylcholine at these receptor sites </li></ul></ul><ul><ul><li>Metabotropic </li></ul></ul><ul><ul><ul><li>Associated with guanine nucleotide binding proteins (G- proteins) </li></ul></ul></ul><ul><ul><ul><li>Span the cell membrane seven times </li></ul></ul></ul><ul><ul><li>Several subtypes: M 1, M 2, M 3, M 4, M 5 </li></ul></ul><ul><ul><li>Associated with various biochemical and electrophysiological responses </li></ul></ul>www.freelivedoctor.com
  22. 22. Biochemical Actions Associated With Muscarinic Receptors M 1 , M 3 , and M 5 muscarinic receptors associate with G q -protein; result: activation of phospholipase C  M 2 , and M 4 muscarinic receptors associate with G i -protein; result: inhibition of adenyl cyclase phosphatidylinositolbiphosphate (PIP) 2 inositoltriphosphate (IP) 3 diacylglycerol (DAG) www.freelivedoctor.com X
  23. 23. G-Protein Coupled Receptors Review biochemistry, physiology, and pharmacology textbooks for the interaction of G-proteins and receptors. www.freelivedoctor.com
  24. 24. Activation of Phospholipase C  by Muscarinic Receptor Subtypes <ul><li>M 1 , M 3 , M 5 muscarinic receptors </li></ul><ul><li>G q -GTP binding protein involved </li></ul><ul><li>Agonist binds to the receptor </li></ul><ul><li>The receptor associates with G q -protein </li></ul><ul><li>G q -protein exchanges GDP for GTP </li></ul><ul><li>The  subunit of G q -protein dissociates from the  dimer and activates the effector molecule phospholipase C  </li></ul><ul><li>Phospholipase C  hydrolyzes phosphatidylinositolbiphosphate (PIP 2 ) to inositoltriphosphate (IP 3 ) and diacylglycerol (DAG) </li></ul><ul><li>IP 3 releases Ca 2++ from the endoplasmic reticulum and with DAG, activates protein kinase C </li></ul><ul><li>The reaction is terminated by hydrolysis of GTP by the  q monomer; reassociation of  q with the  dimer </li></ul>www.freelivedoctor.com
  25. 25. Specific Antagonists for Muscarinic Receptor Subtypes *Also blocks the nicotinic receptor www.freelivedoctor.com Darifenacin Smooth muscles and glands M 3 Tripitamine Gallamine* Cardiac muscle fiber M 2 Pirenzepine Telenzepine Autonomic ganglia, gastric tissue M 1 SELECTIVE ANTAGONIST(S) TISSUE RECEPTOR
  26. 26. ACTIONS OF ACETYLCHOLINE AT ORGAN SITES www.freelivedoctor.com
  27. 27. Parasympathetic Innervation to the Eye www.freelivedoctor.com
  28. 28. Parasympathetic Control of Accomodation From The Nurse, Pharmacology, and Drug Therapy Parasympathetic stimulation allows contraction of the ciliary muscle. www.freelivedoctor.com
  29. 29. Flow of Aqueous From the Eye From Basic and Clinical Pharmacology www.freelivedoctor.com
  30. 30. Parasympathetic Function at Organs Sites (1) <ul><li>Gastrointestinal tract </li></ul><ul><ul><li>Longitudinal muscles </li></ul></ul><ul><ul><li>Circular muscles </li></ul></ul><ul><ul><li>Sphincter muscles </li></ul></ul><ul><li>Bile duct </li></ul><ul><li>Gall bladder </li></ul><ul><li>Urinary tract </li></ul><ul><ul><li>Ureters </li></ul></ul><ul><ul><li>Detrusor muscle of the bladder </li></ul></ul><ul><ul><li>Trigone </li></ul></ul><ul><ul><li>Sphincter muscle of the bladder </li></ul></ul><ul><li>Bronchial smooth muscles </li></ul>www.freelivedoctor.com
  31. 31. Parasympathetic Function at Organs Sites (2) <ul><li>Lacrimal glands </li></ul><ul><li>Pharyngeal glands </li></ul><ul><li>Salivary glands </li></ul><ul><li>Mucus glands </li></ul><ul><ul><li>Respiratory tract </li></ul></ul><ul><ul><li>Esophagus </li></ul></ul><ul><li>Intestinal glands </li></ul><ul><li>Gastric glands </li></ul><ul><li>Pancreas </li></ul>www.freelivedoctor.com
  32. 32. Parasympathetic Control of the Cardiovascular System <ul><li>SA Node </li></ul><ul><li>Atrial muscle </li></ul><ul><li>AV node </li></ul><ul><li>Purkinje fibers </li></ul><ul><li>Ventricles </li></ul><ul><li>Blood vessels </li></ul>www.freelivedoctor.com
  33. 33. Nitric Oxide Mediated Vasodilation www.freelivedoctor.com
  34. 34. Neuronal and Hormonal Control of Blood Pressure www.freelivedoctor.com
  35. 35. Cardiovascular Responses to Low and High Doses of ACh www.freelivedoctor.com
  36. 36. Sites of Dominance in the ANS Adapted from Goodman and Gilman’s The Pharmacological Basis of Therapeutics 1 The vast majority of blood vessels do not receive parasympathetic innervation www.freelivedoctor.com
  37. 37. Cholinergic Agents www.freelivedoctor.com
  38. 38. Cholinergic Agents Alkaloids Nicotine Lobeline Arecoline Muscarine Pilocarpine Synthetic Agents Dimethylphenylpiperazinium-(DMPP) Oxotremorine Methacholine Bethanechol Carbachol Cevimeline www.freelivedoctor.com
  39. 39. Nicotine <ul><li>Nicotine mimics the actions of acetylcholine at nicotinic sites </li></ul><ul><ul><li>Cell body of the postsynaptic neurons </li></ul></ul><ul><ul><ul><li>sympathetic and parasympathetic divisions </li></ul></ul></ul><ul><ul><li>Chromaffin cells of the adrenal medulla </li></ul></ul><ul><ul><li>End plate of skeletal muscle fiber </li></ul></ul><ul><li>Affinity for N N sites versus N M sites </li></ul><ul><li>Used as an insecticide </li></ul>www.freelivedoctor.com
  40. 40. Muscarine <ul><li>Muscarine mimics the actions of acetylcholine at smooth muscles, cardiac muscles, and glands </li></ul><ul><li>Poisoning by muscarine produces intense effects qualitative to those produced by cholinergic stimulation of smooth muscles, cardiac muscle, and glands </li></ul><ul><li>Muscarine is found in various mushrooms </li></ul><ul><ul><li>Amanita muscaria : content of muscarine is very low </li></ul></ul><ul><ul><li>Inocybe sp : content of muscarine is high </li></ul></ul><ul><ul><li>Clitocybe sp : content of muscarine is high </li></ul></ul>www.freelivedoctor.com
  41. 41. Pilocarpine <ul><li>Has muscarinic actions </li></ul><ul><li>Used for xerostomia </li></ul><ul><li>Used for glaucoma </li></ul>www.freelivedoctor.com
  42. 42. Structure of Acetylcholine and its Derivatives Acetylcholine Methacholine Bethanechol Carbachol www.freelivedoctor.com
  43. 43. Therapeutic Uses of Cholinergic Agonists <ul><li>Dentistry </li></ul><ul><ul><li>Pilocarpine </li></ul></ul><ul><ul><li>Cevimeline </li></ul></ul><ul><li>Ophthalmology </li></ul><ul><ul><li>Pilocarpine </li></ul></ul><ul><ul><li>Carbachol </li></ul></ul><ul><li>Gastrointestinal tract </li></ul><ul><ul><li>Bethanechol </li></ul></ul><ul><li>Urinary bladder </li></ul><ul><ul><li>Bethanechol </li></ul></ul>www.freelivedoctor.com
  44. 44. Contraindications to the Use of Choline Esters <ul><li>Hyperthyroidism </li></ul><ul><li>Asthma </li></ul><ul><li>Coronary insufficiency </li></ul><ul><li>Peptic ulcer </li></ul><ul><li>Organic obstruction in bladder or gastrointestinal tract </li></ul>www.freelivedoctor.com
  45. 45. Toxicity of Choline Esters <ul><li>Flushing </li></ul><ul><li>SWEATING (diaphoresis) </li></ul><ul><li>Abdominal cramps </li></ul><ul><li>Spasm of the urinary bladder </li></ul><ul><li>Spasm of accomodation </li></ul><ul><li>Miosis </li></ul><ul><li>Headache </li></ul><ul><li>Salivation </li></ul><ul><li>Bronchospasm </li></ul><ul><li>Lacrimation </li></ul><ul><li>Hypotension </li></ul><ul><li>Bradycardia </li></ul>www.freelivedoctor.com
  46. 46. Agents That Inhibit Acetylcholinesterase www.freelivedoctor.com
  47. 47. Acetylcholinesterase (True Cholinesterase) www.freelivedoctor.com
  48. 48. Acetylcholinesterase (1) <ul><li>Sites of location </li></ul><ul><ul><li>Cholinergic neurons </li></ul></ul><ul><ul><li>Cholinergic synapses </li></ul></ul><ul><ul><li>Neuromuscular junction </li></ul></ul><ul><ul><li>Red blood cells </li></ul></ul><ul><li>Substrates </li></ul><ul><ul><li>Acetylcholine is the best substrate </li></ul></ul><ul><ul><li>Methacholine is a substrate </li></ul></ul><ul><ul><li>Hydrolyzes ACh at greater velocity than choline esters with acyl groups larger than acetate or proprionate </li></ul></ul>www.freelivedoctor.com
  49. 49. Acetylcholinesterase (2) <ul><li>Esters that are not substrates </li></ul><ul><ul><li>Bethanechol </li></ul></ul><ul><ul><li>Carbachol </li></ul></ul><ul><ul><li>Succinylcholine </li></ul></ul><ul><li>Its inhibition produces synergistic interaction with methacholine and additive actions with bethanechol and carbachol </li></ul><ul><li>Drugs that block its hydrolysis of esters are called cholinesterase inhibitors </li></ul>www.freelivedoctor.com
  50. 50. Drug Interactions of Choline Esters and Inhibitors of Acetylcholinesterase - Synergism versus Additivity <ul><li>Methacholine </li></ul><ul><li>Carbachol </li></ul><ul><li>Bethanechol </li></ul>www.freelivedoctor.com
  51. 51. Butyrylcholinesterase (Plasma esterase, pseudocholinesterase, serum esterase, BuChE, PseudoChE) www.freelivedoctor.com
  52. 52. Butyrylcholinesterase (1) <ul><li>Sites of location </li></ul><ul><ul><li>Plasma, liver, glial cells, other tissues </li></ul></ul><ul><li>Substrates </li></ul><ul><ul><li>Butyrylcholine is the best </li></ul></ul><ul><ul><li>Acetylcholine </li></ul></ul><ul><ul><li>Succinylcholine </li></ul></ul><ul><ul><li>Procaine </li></ul></ul>www.freelivedoctor.com
  53. 53. Butyrylcholinesterase (2) <ul><li>Esters that are not substrates </li></ul><ul><ul><li>Methacholine, bethanechol, and carbachol </li></ul></ul><ul><li>Is inhibited by carbamyl and organophosphate inhibitors of acetylcholinesterase </li></ul>www.freelivedoctor.com
  54. 54. Active Site of Acetylcholinesterase www.freelivedoctor.com
  55. 55. Interaction of AChE and Acetylcholine www.freelivedoctor.com
  56. 56. Acetylation of AChE and Release of Choline www.freelivedoctor.com
  57. 57. Hydroxyl Group of Water Attacks the Carbonyl Group of Acetylated-AChE to Liberate AChE www.freelivedoctor.com
  58. 58. Carbamyl Inhibitors of AChE www.freelivedoctor.com
  59. 59. <ul><li>Their action promoting accumulation of ACh at muscarinic or nicotinic receptors is the basis of their pharmacological, therapeutic, and toxic actions </li></ul><ul><li>Are derivatives of carbamic acid </li></ul><ul><li>Bind covalently to the esteratic site of AChE, resulting in carbamylation of the enzyme </li></ul>Carbamyl Inhibitors of AChE (1) Carbamic acid Carbamic acid ester www.freelivedoctor.com
  60. 60. <ul><li>Quaternary compounds bind to the ionic binding site of AChE </li></ul><ul><li>Their induce accumulation of AChE at nicotinic and muscarinic sites, producing pharmacological responses qualitative to cholinergic stimulation </li></ul><ul><li>Inhibition of AChE is reversible, in the order of hours </li></ul><ul><li>Are metabolized in the plasma by plasma esterases </li></ul>Carbamyl Inhibitors of AChE (2) www.freelivedoctor.com
  61. 61. <ul><li>High doses produce skeletal muscle weakness due to depolarizing blockade at the end plate of the neuromuscular junction </li></ul><ul><li>High doses produce a profound fall in cardiac output and blood pressure </li></ul><ul><li>Their inhibition of AChE is not reversed by pralidoxime </li></ul>Carbamyl Inhibitors of AChE (3) www.freelivedoctor.com
  62. 62. <ul><li>Quaternary ammonium compounds do not cross the blood-brain barrier </li></ul><ul><li>For oral administration, high doses must be given </li></ul>Carbamyl Inhibitors of AChE (4) www.freelivedoctor.com
  63. 63. Neostigmine Carbamylates Acetylcholinesterase www.freelivedoctor.com
  64. 64. Slow Hydrolysis of Carbamylated-AChE and Enzyme Liberation www.freelivedoctor.com
  65. 65. Organophosphate Inhibitors of Acetylcholinesterase www.freelivedoctor.com
  66. 66. <ul><li>Chemical characteristics </li></ul><ul><li>Promote accumulation of ACh at </li></ul><ul><ul><li>N M nicotinic receptor </li></ul></ul><ul><ul><li>N N nicotinic receptor </li></ul></ul><ul><ul><li>Muscarinic receptor </li></ul></ul>Organophosphate Inhibitors of Acetylcholinesterase (1) www.freelivedoctor.com
  67. 67. <ul><li>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 </li></ul><ul><li>Only two of these agents are used for therapeutics </li></ul><ul><ul><li>Echothiophate for glaucoma </li></ul></ul><ul><ul><li>Diisopropylflurophosphate (DFP) for glaucoma (?) </li></ul></ul>Organophosphate Inhibitors of AChE (2) www.freelivedoctor.com
  68. 68. <ul><li>Inhibition of AChE by these agents is irreversible </li></ul><ul><ul><li>New enzyme synthesis is required for recovery of enzyme function </li></ul></ul><ul><li>They also inhibit pseudocholinesterase </li></ul><ul><li>Metabolized by A-esterases (paroxonases) present in plasma and microsomes. They are metabolized by CYP450. </li></ul>Organophosphate Inhibitors of AChE (3) www.freelivedoctor.com
  69. 69. <ul><li>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. </li></ul><ul><li>Except for echothiophate, these agents are extremely lipid soluble, and some are very volatile. </li></ul>Organophosphate Inhibitors of AChE (4) www.freelivedoctor.com
  70. 70. Diisopropylflurophosphate (DFP) is a Substrate for AChE www.freelivedoctor.com
  71. 71. The Extremely Slow Hydrolysis of Phosphorylated-AChE New enzyme synthesis is required for recovery of enzyme function www.freelivedoctor.com
  72. 72. Various “States” of Acetylcholinesterase Clockwise: free AChE, acetylated AChE, carbamylated AChE, phosphorylated AChE www.freelivedoctor.com
  73. 73. Acetylated-AChE Is Very Rapdily Hydrolyzed AChE + Acetylcholine  AChE-acetylated + choline AChE-acetylated + H 2 O  AChE + acetate Hydrolysis of AChE-acetylated is rapid, in the order of microseconds P www.freelivedoctor.com
  74. 74. Carbamylated-AChE Is Hydrolyzed Slowly AChE + Carbamyl inhibitor  AChE-carbamylated + noncarbamylated metabolite AChE-carbamylated + H 2 O  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 www.freelivedoctor.com
  75. 75. Phosphorlylated-AChE Is Hydrolyzed Extremely Slowly AChE + organophosphate inhibitor  AChE-phosphorylated + nonphosphorylated metabolite AChE-phosphorylated + H 2 O  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 www.freelivedoctor.com
  76. 76. AGING OF ACETYLCHOLINESTERASE www.freelivedoctor.com
  77. 77. Loss of An Alkyl Group From Phosphorylated AChE “Ages” the Enzyme AChE, phosphorylated and inhibited by DFP “ Aged” AChE www.freelivedoctor.com
  78. 78. “ Aging” of Phosphorylated- AChE www.freelivedoctor.com
  79. 79. Cholinesterase Reactivation www.freelivedoctor.com
  80. 80. Reactivation of Phosphorylated Acetylcholinesterase <ul><li>Oximes are used to reactivate phosphorylated AChE </li></ul><ul><li>The group (=NOH) has a high affinity for the phosphorus atom </li></ul><ul><li>Pralidoxime has a nucleophilic site that interacts with the phosphorylated site on phosphorylated-AChE </li></ul>www.freelivedoctor.com
  81. 81. Pralidoxime Reacts Chemically with Phosphorylated-AChE The oxime group makes a nucleophilic attack upon the phosphorus atom www.freelivedoctor.com
  82. 82. Oxime Phosphonate and Regenerated AChE www.freelivedoctor.com
  83. 83. Limitations of Pralidoxime <ul><li>Pralidoxime does not interact with carbamylated-AChE </li></ul><ul><li>Pralidoxime in high doses can inhibit AChE </li></ul><ul><li>Its quaternary ammonium group does not allow it to cross the blood brain barrier </li></ul><ul><li>“ Aging” of phosphorylated-AChE reduces the effectiveness of pralidoxime and other oxime reactivators </li></ul>www.freelivedoctor.com
  84. 84. Other Cholinesterase Reactivators <ul><li>Diacetylmonoxime </li></ul><ul><ul><li>Crosses the blood brain barrier and in experimental animals, regenerates some of the CNS cholinesterase </li></ul></ul><ul><li>HI-6 is used in Europe </li></ul><ul><ul><li>Has two oxime centers in its structure </li></ul></ul><ul><ul><li>More potent than pralidoxime </li></ul></ul>www.freelivedoctor.com
  85. 85. Edrophonium www.freelivedoctor.com
  86. 86. Edrophonium is a Short Acting Inhibitor that Binds to the Ionic Site but Not to the Esteratic Site of AChE www.freelivedoctor.com
  87. 87. Pharmacology of Acetylcholinesterase Inhibition www.freelivedoctor.com
  88. 88. Inhibition of Acetylcholinesterase Produces Stimulation of All Cholinergic Sites www.freelivedoctor.com
  89. 89. Carbamyl Inhibitors of AChE <ul><li>Physostigmine </li></ul><ul><li>Neostigmine (N + ) </li></ul><ul><li>Pyridostigmine (N + ) </li></ul><ul><li>Ambenonium (N + ) </li></ul><ul><li>Demecarium (N + ) </li></ul><ul><li>Carbaryl </li></ul>www.freelivedoctor.com
  90. 90. Pharmacology of Carbamyl Inhibitors of Acetylcholinesterase <ul><li>Eye </li></ul><ul><li>Exocrine glands </li></ul><ul><li>Cardiac muscle </li></ul><ul><li>Smooth muscles </li></ul><ul><li>Skeletal muscle </li></ul><ul><li>Toxicity </li></ul>www.freelivedoctor.com
  91. 91. Therapeutic Uses of Inhibitors of Acetylcholinesterase <ul><li>Glaucoma (wide angle) </li></ul><ul><li>Atony of the bladder </li></ul><ul><li>Atony of the gastrointestinal tract </li></ul><ul><li>Intoxication by antimuscarinic agents (use physostigmine) </li></ul><ul><li>Intoxication by tricyclic antidepressants (TCA’s) or phenothiazines (use physostigmine) </li></ul><ul><li>Recovery of neuromuscular function after competitive blockade of N N receptor of skeletal muscle fibers </li></ul><ul><li>Myasthenia gravis </li></ul>www.freelivedoctor.com
  92. 92. Therapeutic Uses of Edrophonium <ul><li>Diagnosis of myasthenia gravis </li></ul><ul><li>In conjunction with chosen therapeutic agent to determine proper dose of agent </li></ul>www.freelivedoctor.com
  93. 93. Determining Proper Dose of AChE Inhibitor www.freelivedoctor.com
  94. 94. Inhibitors of AChE Are Used for Therapy of Alzheimer’s Disease <ul><li>Tacrine </li></ul><ul><li>Donepezil </li></ul><ul><li>Rivastigmine </li></ul><ul><li>Galantamine </li></ul>www.freelivedoctor.com
  95. 95. Organophosphate Inhibitors of AChE www.freelivedoctor.com
  96. 96. Some Organophosphate Inhibitors of Acetylcholinesterase <ul><li>Tetraethylpyrophosphate </li></ul><ul><li>Echothiophate (N + ) </li></ul><ul><li>Diisopropylflurophosphate (DFP) </li></ul><ul><li>Sarin </li></ul><ul><li>Soman </li></ul><ul><li>Tabun </li></ul><ul><li>Malathion </li></ul><ul><li>Parathion </li></ul><ul><li>Diazinon </li></ul><ul><li>Chlorpyrifos </li></ul><ul><li>Many others </li></ul>www.freelivedoctor.com
  97. 97. Organophosphate Inhibitors - 2 Diisopropylfluorophosphate (DFP) Soman Sarin Tabun www.freelivedoctor.com
  98. 98. Echothiophate Therapeutic use - local application to the eye for wide angle glaucoma www.freelivedoctor.com
  99. 99. Conversion of Parathion to Paraoxon www.freelivedoctor.com
  100. 100. Conversion of Malathion to Malaoxon www.freelivedoctor.com
  101. 101. Malathion Is Hydrolyzed by Plasma Carboxylases in Birds and Mammals but Not Insects www.freelivedoctor.com
  102. 102. Carboxyl Esterases <ul><li>Preferentially hydrolyzes aliphatic esters </li></ul><ul><li>Malathion is a substrate </li></ul><ul><li>Are inhibited by organophosphates </li></ul><ul><li>May also be called aliesterases </li></ul>www.freelivedoctor.com
  103. 103. Uses of Malathion <ul><li>Insecticide </li></ul><ul><li>Therapeutics </li></ul><ul><ul><li>Used as a lotion for Pediculus humanus capitis associated with pediculosis </li></ul></ul><ul><ul><li>0.5% solution in 78% isopropranolol is pediculicidal and ovicidal </li></ul></ul><ul><ul><li>Ovide is the brand name </li></ul></ul><ul><ul><li>Primoderm was the former brand name </li></ul></ul>www.freelivedoctor.com
  104. 104. Malathion Metabolism <ul><li>Rapidly metabolized by birds and mammals </li></ul><ul><li>Plasma carboxylases are involved </li></ul><ul><li>Insects do not possess the enzyme </li></ul><ul><li>Organophosphates inhibit malathion metabolism </li></ul><ul><li>Malathion is toxic to fish </li></ul>www.freelivedoctor.com
  105. 105. Aryl Esterases <ul><li>Are found in the plasma and liver </li></ul><ul><li>Hydrolyzes organophosphates at the </li></ul><ul><ul><li>P-F bond </li></ul></ul><ul><ul><li>P-CN bond </li></ul></ul><ul><ul><li>Phosphoester bond </li></ul></ul><ul><ul><li>Anhydride bond </li></ul></ul>www.freelivedoctor.com
  106. 106. EPA And Organophosphates <ul><li>Diazinon </li></ul><ul><ul><li>No longer allowed to be manufactured for indoor use in as of March 1, 2001 or for garden use as of June 3, 2001 </li></ul></ul><ul><ul><li>Found in Real Kill ® , Ortho ® , Spectracide ® </li></ul></ul><ul><ul><li>Limited agricultural use is allowed </li></ul></ul><ul><li>Chlorpyrifos (Dursban) has been phased out </li></ul><ul><li>Parathion has been phased out for agricultural use in the United States </li></ul>www.freelivedoctor.com
  107. 107. NERVE AGENT VX Chemical name: O-ETHYL-S-(2-DIISOPROPYLAMINOMETHYL)METHYL-PHOSHONOTHIOLATE Trade name: PHOSPHONOTHIOIC ACID NERVE AGENT VX www.freelivedoctor.com
  108. 108. NERVE AGENT VX Chemical name: O-ETHYL-S-(2-DIISOPROPYLAMINOMETHYL)METHYL-PHOSHONOTHIOLATE Trade name: PHOSPHONOTHIOIC ACID www.freelivedoctor.com
  109. 109. Organophosphates as Nerve Gas Agents in Chemical Warfare (1) <ul><li>Extremely volatile agents such as sarin, tabun, soman, and agent VX may be used as nerve agents in chemical warfare. </li></ul><ul><li>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. </li></ul><ul><li>Bradycardia and hypotension occur. However, in some cases, tachycardia may be observed, due to intense sympathetic discharge in response severe hypoxemia. </li></ul>www.freelivedoctor.com
  110. 110. Organophosphates as Nerve Gas Agents in Chemical Warfare (2) <ul><li>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 N M nicotinic receptor. Skeletal muscle paralysis occurs. Movement is impossible. The diaphragm is also paralyzed. The individual eventually dies due to respiratory paralysis. </li></ul><ul><li>Pralidoxime, atropine, and removal of the person from the source of exposure are all to be employed in cases of posioning. </li></ul>www.freelivedoctor.com
  111. 111. Use of Pyridostigmine During the Gulf War www.freelivedoctor.com
  112. 112. Pharmacology of Muscarinic Receptor Blockade www.freelivedoctor.com
  113. 113. Acetylcholine is an agonist at both muscarinic and nicotinic receptors The nicotinic actions of acetylcholine remain when muscarinic receptors are blocked www.freelivedoctor.com
  114. 114. Muscarinic Receptor Blockade Does Not Affect Ganglionic Transmission Muscarinic receptor blockade prevents generation of the IPSP and the sEPSP but not the fEPSP www.freelivedoctor.com X
  115. 115. 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. www.freelivedoctor.com X X
  116. 116. In Dual Innervated Organs, Muscarinic Receptor Blockade Allows Sympathetic Dominance X www.freelivedoctor.com
  117. 117. Atropine www.freelivedoctor.com
  118. 118. Characteristics of Atropine <ul><li>Source </li></ul><ul><ul><li>Atropa belladonna </li></ul></ul><ul><ul><li>Datura stramonium </li></ul></ul><ul><ul><ul><li>Known as Jamestown weed or jimsonweed </li></ul></ul></ul><ul><li>Chemical nature </li></ul><ul><ul><li>An alkaloid </li></ul></ul><ul><li>Alternate name is d,l-hyoscyamine </li></ul><ul><li>Nature of blockade </li></ul><ul><ul><li>Competitive </li></ul></ul>www.freelivedoctor.com
  119. 119. Response to ACh in the Presence of Atropine Atropine competitively inhibits muscarinic reponses to ACh www.freelivedoctor.com Log dose of acetylcholine Response control atropine
  120. 120. Actions of Atropine at Tissue Sites <ul><li>Eye </li></ul><ul><ul><li>Sphincter muscle of the iris: mydriasis </li></ul></ul><ul><ul><li>Ciliary muscle: cycloplegia </li></ul></ul>Atropine limits focusing to distant objects Accomodation is blocked by atropine www.freelivedoctor.com
  121. 121. Changes in Accomodation and Pupillary Diameter after Administration of an Antimuscarinic Agent Reproduced from Basic and Clinical Pharmacology www.freelivedoctor.com
  122. 122. Actions of Atropine At Smooth Muscles And Glands <ul><li>Eye </li></ul><ul><li>Lacrimal glands </li></ul><ul><li>Mucus glands of the pharynx and nasal cavity </li></ul><ul><li>Bronchial smooth muscle </li></ul><ul><li>Gastric glands </li></ul><ul><li>Intestinal glands </li></ul><ul><li>Pancreas </li></ul><ul><li>Mucus glands of the respiratory tract </li></ul><ul><li>Lacrimal glands </li></ul><ul><li>Eccrine sweat glands </li></ul>www.freelivedoctor.com
  123. 123. Cardiovascular Actions of Atropine <ul><li>Heart rate </li></ul><ul><ul><li>Low dose </li></ul></ul><ul><ul><li>High dose </li></ul></ul><ul><li>Systemic blood vessels </li></ul><ul><li>Peripheral resistance </li></ul><ul><li>Cutaneous blood vessels </li></ul>www.freelivedoctor.com
  124. 124. Response to Doses of Atropine Reproduced from Basic and Clinical Pharmacology www.freelivedoctor.com
  125. 125. M 1 Receptor 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 www.freelivedoctor.com ACh ACh ACh (----) M1 M2
  126. 126. M 1 Receptor Blockade Eliminates the Negative Feedback Effect and Increases ACh Release in Response to Nerve Impulse Flow postsynaptic fiber cardiac muscle fiber Pirenzepine is an M 1 antagonist www.freelivedoctor.com x ACh ACh ACh ACh M1 M2
  127. 127. 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). www.freelivedoctor.com i.v. infusion
  128. 128. 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. www.freelivedoctor.com x x x i.v. infusion
  129. 129. Effect Of Atropine in Relation to Dosage ... www.freelivedoctor.com
  130. 130. Dose of Atropine DOSE EFFECT 0.5 mg Slight decline in heart rate Some dryness of mouth Inhibition of sweating www.freelivedoctor.com
  131. 131. Dose of Atropine DOSE EFFECT 1.0 mg Definited dryness of mouth Thirst Inreased heart rate, sometimes preceded by slowing Mild dilatation of pupil www.freelivedoctor.com
  132. 132. Dose of Atropine DOSE EFFECT 2.0 mg Rapid heart rate Palpitation Marked dryness of mouth Dilated pupils Some blurring of near vision www.freelivedoctor.com
  133. 133. 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 www.freelivedoctor.com
  134. 134. 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 Coma www.freelivedoctor.com
  135. 135. The previous five slides are reproduced from Goodman and Gilman’s The Pharmacological Basis of Therapeutics www.freelivedoctor.com
  136. 136. Scopolamine (1) <ul><li>Source - Hyoscyamus niger (henbane) </li></ul><ul><li>Chemical nature of the molecule </li></ul><ul><li>Nature of blockade </li></ul><ul><li>Changes in the dose response curve of muscarinic agonists in the presence of scopolamine </li></ul><ul><li>Lower doses of scopolamine (0.1 - 0.2 mg) produce greater cardiac slowing than an equivalent dose of atropine. Higher doses produce tachycardia </li></ul><ul><li>Low doses of scopolamine produce CNS effects that are not seen with equivalent doses of atropine </li></ul>www.freelivedoctor.com
  137. 137. Scopolamine (2) <ul><li>Therapeutic doses of scopolamine normally produce CNS depression, manifested as drowsiness, amnesia, fatigue, dreamless sleep, reduction in REM, euphoria </li></ul><ul><li>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 </li></ul><ul><li>Therapeutic use - prophylaxis of motion sickness; an adhesive preparation, the Transderm scop is used </li></ul>www.freelivedoctor.com
  138. 138. Therapeutic Uses of Antimuscarinic Agents www.freelivedoctor.com
  139. 139. Therapeutic Uses of Muscarinic Antagonists (1) <ul><li>Cardiovascular System - atropine is generally used for the following cases </li></ul><ul><ul><li>Improper use of choline esters </li></ul></ul><ul><ul><li>Sinus or nodal bradycardia in cases of excessive vagal tone associated with myocardial infarct </li></ul></ul><ul><ul><li>Hyperactive carotid sinus (syncope and severe bradycardia) </li></ul></ul><ul><ul><li>Second degree heart block </li></ul></ul>www.freelivedoctor.com
  140. 140. Therapeutic Uses of Muscarinic Antagonists (2) <ul><li>Gastrointestinal Tract </li></ul><ul><ul><li>Peptic ulcers </li></ul></ul><ul><ul><ul><li>In Europe, Japan, and Canada, M 1 muscarinic receptor antagonists such as pirenzepine and telenzepine are used </li></ul></ul></ul><ul><ul><ul><li>In the U.S. H 2 histamine antagonists such as cimetidine are used </li></ul></ul></ul><ul><ul><li>Spasticity of the g.i. tract </li></ul></ul><ul><ul><ul><li>M 3 muscarinic antagonists are being investigated </li></ul></ul></ul><ul><ul><li>Excessive salivation associated with heavy metal poisoning and parkinsonism </li></ul></ul><ul><ul><li>Production of partial blockade of salivation in patients unable to swallow </li></ul></ul>www.freelivedoctor.com
  141. 141. Therapeutic Uses of Muscarinic Antagonists (3) <ul><li>Urinary Bladder </li></ul><ul><ul><li>Reverse spasm of the ureteral smooth muscle (renal colic) </li></ul></ul><ul><ul><li>Increase bladder capacity in cases of enuresis </li></ul></ul><ul><ul><li>Reduce urinary frequency in cases of hypertonic bladder </li></ul></ul>www.freelivedoctor.com
  142. 142. Therapeutic Uses of Muscarinic Antagonists (4) <ul><li>Central Nervous System </li></ul><ul><ul><li>Parkinson’s disease </li></ul></ul><ul><ul><li>Motion sickness </li></ul></ul><ul><ul><li>Produce tranquilization and amnesia prior to surgery and in certain cases such as labor (not a prominent use anymore) </li></ul></ul><ul><ul><li>Anesthesia, to inhibit salivation (not a prominent use anymore) </li></ul></ul><ul><ul><li>Prevent vagal reflexes induced by surgical manipulation of organs </li></ul></ul>www.freelivedoctor.com
  143. 143. Therapeutic Uses of Muscarinic Antagonists (5) <ul><li>Posioning by inhibitors of acetylcholinesterase </li></ul><ul><li>Mushroom poisoning due to muscarine </li></ul><ul><li>In conjunction with inhibitors of acetylcholinesterase when they are used to promote recovery from neuromuscular blockade after surgery </li></ul><ul><li>Injudicious use of choline esters </li></ul><ul><li>Prevent vagal reflexes induced by surgical manipulation of visceral organs </li></ul>Atropine is used for the above www.freelivedoctor.com
  144. 144. Toxicity of Atropine www.freelivedoctor.com
  145. 145. Contraindications to the Use Of Antimuscarinic Agents <ul><li>Narrow Angle Glaucoma </li></ul>www.freelivedoctor.com
  146. 146. Flow of Aqueous and Its Escape From the Eye www.freelivedoctor.com
  147. 147. Contraindications to the Use of Antimuscarinic Agents <ul><li>Narrow angle glaucoma </li></ul><ul><li>Hypertrophy of the prostate gland </li></ul><ul><li>Atony of the bladder </li></ul><ul><li>Atony of the G.I. Tract </li></ul>www.freelivedoctor.com
  148. 148. Tertiary Muscarinic Antagonists and Their Uses <ul><li>Ophthalmic applications </li></ul><ul><ul><li>Cyclopentolate </li></ul></ul><ul><ul><li>Tropicamide </li></ul></ul><ul><ul><li>Homatropine </li></ul></ul><ul><li>Parkinson’s disease </li></ul><ul><ul><li>Benztropine </li></ul></ul><ul><ul><li>Trihexphenidyl </li></ul></ul>www.freelivedoctor.com
  149. 149. Tertiary Muscarinic Antagonists and Their Uses <ul><li>Used for antispasmodic purposes </li></ul><ul><ul><li>Flavoxate - urinary bladder </li></ul></ul><ul><ul><li>Oxybutynin - urinary bladder </li></ul></ul><ul><ul><li>Tolterodine - urinary bladder </li></ul></ul><ul><ul><li>Dicyclomine </li></ul></ul><ul><ul><li>Oxyphencyclimine </li></ul></ul>In general, they are useful for spasms of the g.t. tract, bile duct, ureters, www.freelivedoctor.com
  150. 150. Tolterodine <ul><li>Therapeutic use - reduce urinary urgency </li></ul><ul><li>Metabolism </li></ul><ul><ul><li>Cytochrome P450 </li></ul></ul><ul><ul><li>Active metabolite is DD-01 </li></ul></ul><ul><li>Drug interactions </li></ul><ul><ul><li>Ketoconazole </li></ul></ul><ul><ul><li>Erythromycin </li></ul></ul>www.freelivedoctor.com
  151. 151. Quaternary Ammonium Antagonists (1) <ul><li>General characteristics </li></ul><ul><li>Pharmacology and therapeutic uses </li></ul><ul><li>Distinct side effects with high and sometimes therapeutic doses </li></ul>www.freelivedoctor.com
  152. 152. Quaternary Ammonium Antagonists (2) <ul><li>Methantheline (N + ) </li></ul><ul><li>Propantheline (N + ) </li></ul><ul><li>Methscopolamine (N + ) </li></ul><ul><li>Homatropine methylbromide (N + ) </li></ul><ul><li>Oxyphenonium (N + ) </li></ul>www.freelivedoctor.com
  153. 153. Quaternary Ammonium Antagonists (3) <ul><li>Anisotropine (N + ) </li></ul><ul><li>Glycopyrrolate (N + ) </li></ul><ul><li>Isopropamide (N + ) </li></ul><ul><li>Mepenzolate (N + ) </li></ul><ul><li>Ipratropium (N + ) </li></ul>www.freelivedoctor.com
  154. 154. Ipratropium <ul><li>Uses </li></ul><ul><li>Distinctiveness from atropine </li></ul>www.freelivedoctor.com
  155. 155. M 1 Muscarinic Receptor Antagonists <ul><li>Pirenzepine </li></ul><ul><ul><li>Blocks the M 1 and the M 4 receptor </li></ul></ul><ul><ul><li>Its usefulness for peptic ulcer </li></ul></ul><ul><li>Telenzepine </li></ul><ul><ul><li>Blocks the M 1 receptor </li></ul></ul><ul><ul><li>Its usefulness for peptic ulcer </li></ul></ul>www.freelivedoctor.com
  156. 156. M 2 Muscarinic Receptor Antagonists <ul><li>Tripitamine </li></ul><ul><ul><li>Blocks the M 2 receptor </li></ul></ul><ul><ul><li>Blocks the action of acetylcholine at cardiac muscle fibers </li></ul></ul><ul><li>Gallamine </li></ul><ul><ul><li>Blocks M 2 muscarinic and the N N nicotinic sites </li></ul></ul>www.freelivedoctor.com
  157. 157. M 3 Muscarinic Receptor Antagonist <ul><li>Darifenacin </li></ul><ul><ul><li>Blocks the M 3 receptor </li></ul></ul><ul><ul><li>Blocks the actions of acetylcholine at smooth muscles and glands </li></ul></ul>www.freelivedoctor.com
  158. 158. Drugs of Other Classes With Antimuscarinic Activity (1) <ul><li>Tricyclic antidepressants </li></ul><ul><ul><li>Imipramine </li></ul></ul><ul><ul><li>Amitriptyline </li></ul></ul><ul><ul><li>Protriptyline </li></ul></ul><ul><ul><li>Others </li></ul></ul>.: DEMONSTRATION www.freelivedoctor.com
  159. 159. Drugs of Other Classes With Antimuscarinic Activity (2) <ul><li>Phenothiazine Antipsychotic Agents </li></ul><ul><ul><li>Chlorpromazine </li></ul></ul><ul><ul><li>Thioridazine </li></ul></ul><ul><ul><li>Perphenazine </li></ul></ul><ul><ul><li>Others </li></ul></ul>.: DEMONSTRATION www.freelivedoctor.com
  160. 160. Drugs of Other Classes With Antimuscarinic Activity (3) <ul><li>Dibenzodiazepine antipsychotic agents </li></ul><ul><ul><li>Clozapine </li></ul></ul><ul><ul><li>Olanzepine </li></ul></ul><ul><li>Dibenzoxazepine antipsychotic agents </li></ul><ul><ul><li>Loxapine </li></ul></ul>.: DEMONSTRATION www.freelivedoctor.com
  161. 161. Drugs of Other Classes With Antimuscarinic Activity (4) <ul><li>H 1 Histamine receptor blocking agents </li></ul><ul><ul><li>Diphenhydramine </li></ul></ul><ul><ul><li>Dimenhydrinate </li></ul></ul><ul><ul><li>Promethazine </li></ul></ul><ul><ul><li>Carbinoxamine </li></ul></ul><ul><ul><li>Dimenhydrinate </li></ul></ul><ul><ul><li>Pyrlamine </li></ul></ul><ul><ul><li>Tripelennamine </li></ul></ul><ul><ul><li>Brompheniramine </li></ul></ul><ul><ul><li>Chlorpheniramine </li></ul></ul><ul><ul><li>Cyproheptadine </li></ul></ul>.: DEMONSTRATION www.freelivedoctor.com
  1. A particular slide catching your eye?

    Clipping is a handy way to collect important slides you want to go back to later.

×