Transcript the parasympathetic nervous system

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
Bethanechol
Methacholine
Carbachol
Therapeutic Uses of Cholinergic Agonists
• Dentistry
– Pilocarpine
– Cevimeline
• Ophthalmology
– Pilocarpine
– Carbachol
• Gastrointestinal tract
– Bethanechol
• Urinary bladder
– Bethanechol
Contraindications to the Use of Choline Esters
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Hyperthyroidism
Asthma
Coronary insufficiency
Peptic ulcer
Organic obstruction in bladder or gastrointestinal tract
Toxicity of Choline Esters
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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
Carbamyl Inhibitors of AChE (1)
• 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
Carbamic acid
Carbamic acid ester
Carbamyl Inhibitors of AChE (2)
• 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 (3)
• 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 (4)
• 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
Organophosphate Inhibitors of Acetylcholinesterase (1)
• Chemical characteristics
• Promote accumulation of ACh at
– NM nicotinic receptor
– NN nicotinic receptor
– Muscarinic receptor
Organophosphate Inhibitors of AChE (2)
• 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 (3)
• 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 (4)
• 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 AChE
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 atom
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
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Physostigmine
Neostigmine (N+)
Pyridostigmine (N+)
Ambenonium (N+)
Demecarium (N+)
Carbaryl
Pharmacology of Carbamyl Inhibitors of
Acetylcholinesterase
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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
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Tetraethylpyrophosphate
Echothiophate (N+)
Diisopropylflurophosphate (DFP)
Sarin
Soman
Tabun
Malathion
Parathion
Diazinon
Chlorpyrifos
Many others
Organophosphate Inhibitors - 2
Diisopropylfluorophosphate
(DFP)
Sarin
Soman
Tabun
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
R(CH2)CO-OR'
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
Chemical name:
O-ETHYL-S-(2-DIISOPROPYLAMINOMETHYL)METHYLPHOSHONOTHIOLATE
Trade name: PHOSPHONOTHIOIC ACID
NERVE AGENT VX
NERVE AGENT VX
Chemical name:
O-ETHYL-S-(2-DIISOPROPYLAMINOMETHYL)METHYLPHOSHONOTHIOLATE
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