pharmacology parasympathetic nervous system- in brief

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


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


Dual Innervation at Most Sites


Concept of Dominance in the Autonomic Nervous System

• The sympathetic nervous system dominates at some sites

• The parasympathetic nervous system dominates at other sites


Parasympathetic Innervation From Brain


Parasympathetic Innervation From the Sacral Cord


Synthesis of Acetylcholine

Acetylcholine

Choline

Acetyl CoA

+

Choline acetylase


Cholinergic Fiber


Acetylcholine and Its Metabolites

Acetylcholine

Choline Acetate

hydrolysis

+

AChE


Agents Affecting Cholinergic Transmission

• Hemicholinium• Latrotoxin• Vesamicol• Calcium• Physostigmine• Atropine• d-Tubocurarine• Botulinus Toxin


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


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


Neuronal Innervation to Organs


• 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


Activities Within Cell Bodies of Autonomic Ganglia

Postganglionic neuron, sympathetic or parasympathetic


• End plate of skeletal muscle fiber - generation of the EPP

Actions Mediated by NM Nicotinic Receptor


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


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


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


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


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.


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


Parasympathetic Innervation to the Eye


Parasympathetic Control of Accomodation

From The Nurse, Pharmacology, and Drug Therapy

Parasympathetic stimulation allows contraction of the ciliary muscle.


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


Parasympathetic Function at Organs Sites (2)

• Lacrimal glands• Pharyngeal glands• Salivary glands• Mucus glands

– Respiratory tract– Esophagus

• Intestinal glands• Gastric glands• Pancreas


Parasympathetic Control of the Cardiovascular System

• SA Node • Atrial muscle• AV node• Purkinje fibers• Ventricles• Blood vessels


Nitric Oxide Mediated Vasodilation


Neuronal and Hormonal Control of Blood Pressure


Cardiovascular Responses to Low and High Doses of ACh


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


Cholinergic Agents

Alkaloids

Nicotine

Lobeline

Arecoline

Muscarine

Pilocarpine

Synthetic Agents

Dimethylphenylpiperazinium-(DMPP)

Oxotremorine

Methacholine

Bethanechol

Carbachol

Cevimeline


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


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


Pilocarpine

• Has muscarinic actions• Used for xerostomia• Used for glaucoma


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


Contraindications to the Use of Choline Esters

• Hyperthyroidism• Asthma• Coronary insufficiency• Peptic ulcer• Organic obstruction in bladder or gastrointestinal tract


Toxicity of Choline Esters

• Flushing• SWEATING (diaphoresis)• Abdominal cramps• Spasm of the urinary bladder• Spasm of accomodation• Miosis• Headache• Salivation• Bronchospasm• Lacrimation• Hypotension• Bradycardia


Agents That Inhibit Acetylcholinesterase


Acetylcholinesterase

(True Cholinesterase)


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


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


Drug Interactions of Choline Esters and Inhibitors of Acetylcholinesterase - Synergism versus Additivity

• Methacholine

• Carbachol

• Bethanechol


Butyrylcholinesterase

(Plasma esterase, pseudocholinesterase, serum esterase, BuChE, PseudoChE)


Butyrylcholinesterase (1)

• Sites of location

– Plasma, liver, glial cells, other tissues

• Substrates

– Butyrylcholine is the best

– Acetylcholine

– Succinylcholine

– Procaine


Butyrylcholinesterase (2)

• Esters that are not substrates– Methacholine, bethanechol, and carbachol

• Is inhibited by carbamyl and organophosphate inhibitors of acetylcholinesterase


Active Site of Acetylcholinesterase


Interaction of AChE and Acetylcholine


Acetylation of AChE and Release of Choline


Hydroxyl Group of Water Attacks the Carbonyl Group of Acetylated-AChE to Liberate AChE


Carbamyl Inhibitors of AChE


• 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



• 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



• Quaternary ammonium compounds do not cross the blood-brain barrier

• For oral administration, high doses must be given



Neostigmine Carbamylates Acetylcholinesterase


Slow Hydrolysis of Carbamylated-AChE and Enzyme Liberation


Organophosphate Inhibitors of Acetylcholinesterase


• Chemical characteristics

• Promote accumulation of ACh at– NM nicotinic receptor – NN nicotinic receptor– Muscarinic receptor

Organophosphate Inhibitors of Acetylcholinesterase (1)


• 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)


• 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.



• 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.



Diisopropylflurophosphate (DFP) is a Substrate for AChE


The Extremely Slow Hydrolysis of Phosphorylated-AChE

New enzyme synthesis is required for recovery of enzyme function


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


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


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


AGING OF ACETYLCHOLINESTERASE


Loss of An Alkyl Group From Phosphorylated AChE “Ages” the Enzyme

AChE, phosphorylated and inhibited by DFP

“Aged” AChE


“Aging” of Phosphorylated- AChE


Cholinesterase Reactivation


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


Pralidoxime Reacts Chemically with Phosphorylated-AChE

The oxime group makes a nucleophilic attack upon the phosphorus atomwww.freelivedoctor.com

Oxime Phosphonate and Regenerated AChE


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


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


Edrophonium


Edrophonium is a Short Acting Inhibitor that Binds to the Ionic Site but Not to the Esteratic Site of AChE


Pharmacology of Acetylcholinesterase Inhibition


Inhibition of Acetylcholinesterase Produces Stimulation of All Cholinergic Sites


Carbamyl Inhibitors of AChE

• Physostigmine• Neostigmine (N+)• Pyridostigmine (N+)• Ambenonium (N+)• Demecarium (N+)• Carbaryl


Pharmacology of Carbamyl Inhibitors of Acetylcholinesterase

• Eye• Exocrine glands• Cardiac muscle• Smooth muscles• Skeletal muscle• Toxicity


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


Therapeutic Uses of Edrophonium

• Diagnosis of myasthenia gravis

• In conjunction with chosen therapeutic agent to determine proper dose of agent


Determining Proper Dose of AChE Inhibitor


Inhibitors of AChE Are Used for Therapy of Alzheimer’s Disease

• Tacrine

• Donepezil

• Rivastigmine

• Galantamine


Organophosphate Inhibitors of AChE


Some Organophosphate Inhibitors of Acetylcholinesterase

• Tetraethylpyrophosphate• Echothiophate (N+)• Diisopropylflurophosphate (DFP)• Sarin• Soman• Tabun• Malathion• Parathion• Diazinon• Chlorpyrifos• Many others


Organophosphate Inhibitors - 2

Diisopropylfluorophosphate (DFP)

Soman

SarinTabunwww.freelivedoctor.com

Echothiophate

Therapeutic use - local application to the eye for wide angle glaucoma


Conversion of Parathion to Paraoxon


Conversion of Malathion to Malaoxon


Malathion Is Hydrolyzed by Plasma Carboxylases in Birds and Mammals but Not Insects


Carboxyl Esterases

• Preferentially hydrolyzes aliphatic esters

• Malathion is a substrate

• Are inhibited by organophosphates

• May also be called aliesterases


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


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


Aryl Esterases

• Are found in the plasma and liver

• Hydrolyzes organophosphates at the– P-F bond– P-CN bond– Phosphoester bond– Anhydride bond


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


NERVE AGENT VXChemical name:

O-ETHYL-S-(2-DIISOPROPYLAMINOMETHYL)METHYL-PHOSHONOTHIOLATE

Trade name: PHOSPHONOTHIOIC ACID


NERVE AGENT VXNERVE AGENT VX

Chemical name:

O-ETHYL-S-(2-DIISOPROPYLAMINOMETHYL)METHYL-PHOSHONOTHIOLATE

Trade name: PHOSPHONOTHIOIC ACID


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.


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.


Use of Pyridostigmine During the Gulf War


Pharmacology of Muscarinic Receptor Blockade


Acetylcholine is an agonist at both muscarinic and nicotinic receptors

The nicotinic actions of acetylcholine remain when muscarinic receptors are blocked


Muscarinic Receptor Blockade Does Not Affect Ganglionic Transmission

X

Muscarinic receptor blockade prevents generation of the IPSP and the sEPSP but not the fEPSP


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


In Dual Innervated Organs, Muscarinic Receptor Blockade Allows Sympathetic Dominance

Xwww.freelivedoctor.com

Atropine


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


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


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


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


Cardiovascular Actions of Atropine

• Heart rate– Low dose– High dose

• Systemic blood vessels• Peripheral resistance• Cutaneous blood vessels


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


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


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


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


Effect Of Atropine in Relation to Dosage ...


Dose of Atropine

DOSE EFFECT

0.5 mg Slight decline in heart rate

Some dryness of mouth

Inhibition of sweating


Dose of Atropine

DOSE EFFECT

1.0 mg Definited dryness of mouth

Thirst

Inreased heart rate, sometimes preceded by slowing

Mild dilatation of pupil


Dose of Atropine

DOSE EFFECT

2.0 mg Rapid heart rate

Palpitation

Marked dryness of mouth

Dilated pupils

Some blurring of near vision


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


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

Comawww.freelivedoctor.com

The previous five slides are reproduced fromGoodman and Gilman’s

The Pharmacological Basis of Therapeutics


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


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


Therapeutic Uses of Antimuscarinic Agents


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



• 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



• 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



• 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



• 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


Toxicity of Atropine


Contraindications to the Use Of Antimuscarinic Agents

• Narrow Angle Glaucoma


Flow of Aqueous and Its Escape From the Eye


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


Tertiary Muscarinic Antagonists and Their Uses

• Ophthalmic applications– Cyclopentolate– Tropicamide– Homatropine

• Parkinson’s disease– Benztropine– Trihexphenidyl


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,


Tolterodine

• Therapeutic use - reduce urinary urgency• Metabolism

– Cytochrome P450– Active metabolite is DD-01

• Drug interactions– Ketoconazole– Erythromycin


Quaternary Ammonium Antagonists (1)

• General characteristics• Pharmacology and therapeutic uses• Distinct side effects with high and sometimes

therapeutic doses



• Methantheline (N+)• Propantheline (N +)• Methscopolamine (N +) • Homatropine methylbromide (N +)• Oxyphenonium (N +)



• Anisotropine (N+)• Glycopyrrolate (N+)• Isopropamide (N+)• Mepenzolate (N+)• Ipratropium (N+)


Ipratropium

• Uses • Distinctiveness from atropine


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


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


M3 Muscarinic Receptor Antagonist

• Darifenacin

– Blocks the M3 receptor

– Blocks the actions of acetylcholine at smooth muscles and glands


Drugs of Other Classes With Antimuscarinic Activity (1)

• Tricyclic antidepressants– Imipramine– Amitriptyline– Protriptyline– Others

.:

DEMONSTRATION

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DEMONSTRATIONwww.freelivedoctor.com


• Phenothiazine Antipsychotic Agents– Chlorpromazine– Thioridazine– Perphenazine– Others

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• Dibenzodiazepine antipsychotic agents– Clozapine– Olanzepine

• Dibenzoxazepine antipsychotic agents– Loxapine

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• H1 Histamine receptor blocking agents

– Diphenhydramine– Dimenhydrinate

– Promethazine

– Carbinoxamine

– Dimenhydrinate

– Pyrlamine

– Tripelennamine

– Brompheniramine

– Chlorpheniramine

– Cyproheptadine

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pharmacology parasympathetic nervous system- in brief

Documents

autonomic nervous system

nicotinic receptor subtypes

parasympathetic nervous

receptor proteins

g q protein result

receptor associates

parasympathetic innervation

gtp thesubunit of g