Transcript Cholinergic - stjpap 2011

1
Cholinergic Receptors
• Nicotinic
– Skeletal muscle
– Ganglia
• Muscarinic
Compliments of Byron Yoburn, Ph.D.
2
Cholinergic Receptors
• Nicotinic:
– Ligand-gated ion
channel
– A pentameric
structure , , , 
– need to occupy 2 
units (binding site)
– Can distinguish the
nAchR in ganglia
and skeletal
muscle
3
Cholinergic Receptors
• Muscarinic: G-protein coupled receptor
Inhibit Adenylyl Cyclase
*(Gi)
Stimulate Phospholipase C
*(Gq)
Regulate K+ channels
*(Gi)
4
Cholinergic Receptors
•Muscarinic: G-protein coupled receptor
Several subtypes
•Nicotinic: Ligand-gated ion channel
Several subtypes
From: Basic and Clinical
Pharmacology 8th edition,
B.G. Katzung; Lange 2001
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Cholinergic Receptors
Details
From: Basic and Clinical
Pharmacology 8th edition,
B.G. Katzung; Lange 2001
6
Cholinergic Systems
Don’t forget:
The Neuromuscular Junction uses ACH and has a nicotinic Receptor
on the Muscle
7
Martini,
Fundamentals of
Anatomy and Physiology, 5th Edition,
Prentice Hall 2001
The Organization of the
Sympathetic Nervous System
8
The
Organization
of the
Sympathetic
Nervous
System
Thoracic
Lumbar
Martinit,
Fundamentals of
Anatomy and Physiology,
5th Edition,
Prentice Hall 2001
9
Sympathetic Synapses
Note location of
synapse
10
The Organization of the Sympathetic Nervous System:
The Adrenal Medulla
11
The Adrenergic
Synapse
12
The
Adrenergic
Synapse
From: Basic and
Clinical Pharmacology
8th edition, B.G.
Katzung; Lange 2001
13
Adrenergic Receptors
It will be important to understand how alpha and beta receptors
From: Basic and
and the subtypes are distinguished:
Clinical Pharmacology
•Originally by relative potency
8th edition, B.G.
Katzung; Lange 2001
•Now by cloning
14
Pharmacologic Demonstration of Adrenoreceptor
Types
• The existence of
alpha and beta
receptors was
originally proposed
by Ahlquist in 1948
• Latter Lands et al
1967, suggested
the beta1 beta2
distinction
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Adrenergic Receptors
16
From: Basic
and Clinical
Pharmacology
8th edition,
B.G. Katzung;
Lange 2001
17
Miscellaneous Autonomic Issues
• Pre versus postsynaptic receptors
• Colocalization/Co-release of peptides and other
transmitters
vesicles in both cholinergic and adrenergic nerves
contain other substances in addition to the primary
transmitter (eg. VIP in cholinergic neurons within
Enteric Nervous System– see Table 6-1 for others).
in some cases, they provide a faster or slower action
to supplement or modulate the effects of the primary
transmitter
these other substances can also participate in
feedback inhibition of the same and nearby nerve
terminals
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Miscellaneous Autonomic Issues
Dopamine receptors and the autonomic System
– There are some DA receptors in cardiovascular system
and the smooth muscle of the renal vasculature that
can can improve renal blood flow
– DA itself at higher doses will act at Beta1 receptors in
the heart
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Cholinergic Agonists
Cholinoceptor activating
Cholinesterase Inhibiting
Chapter 7
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Cholinergic Agonists
Cholinoceptor activating
*acetylcholine
*bethanechol
*carbachol
cevimeline
*pilocarpine
Cholinesterase Inhibiting
ambenonium
demecarium
donepezil
*echothiophate
edrophonium
galantamine
*neostigmine
*physostigmine
pyridostigmine
rivastigmine
tacrine
21
Cholinergic Systems
•
•
•
•
Parasympathetic Nervous system
Skeletal Muscle
Autonomic Ganglia
Some Sympathetic sites (few)
• Classic Agonists
– ACH
– Nicotine (alkaloid)
– Muscarine (alkaloid)
22
Cholinergic Receptors
• Basically 2 types
– Muscarinic: G-protein coupled
– Nicotinic: Ligand gated ion channels
• ACH is the agonist for both types
• Originally distinguished based on sensitivity to
alkaloid agonists
• Were also distinguished using antagonists
– Atropine a classic muscarinic antagonist
– d-tubocurarine a classic nicotinic antagonist
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Nicotinic Receptor subtypes
•
There are at least 2 subtypes
– Ganglionic NN (Neuronal type)
– Skeletal NM (muscle type)
• Easiest way to distinguish is using selective
antagonists
– Hexamethonium = ganglionic blocker
– Decamethonium = skeletal blocker
• They are structurally similar, but can be
separated using selective drugs
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Nicotinic receptors
• Activation requires occupancy of binding site
on both alpha subunits
• Then channel opens and allows flow of Na+
and sometimes Ca++ (cation channel) from
outside the cell into the cytoplasm
• Causes depolarization
Na+
out
ACH
in
Na+
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Muscarinic Receptor Subtypes
• Appear to be at least 5 types
• Are all G-protein coupled
– M1 and M2 are sensitive to atropine, however
the M1 receptor is selectively blocked by the
antagonist pirenzapine (has use as a drug that
reduces gastric acid secretion)
– M1 appears to be found on nerves (CNS and
some sympathetic postganglionic fibers
(vasodilation??))
– M2 found in Heart and smooth muscle
– M3 found in glands, vessels, smooth muscle
– M4 and M5 are found in CNS?? And role is
somewhat unclear
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Muscarinic Receptors
In general, seems to be 2 basic actions
• ACH released from parasympathetic terminals will activate
M receptors
• ACH released from parasympathetic terminals can
interact with presynaptic receptors on the terminals to
reduce further transmitter release,
– This presynaptic inhibition may be on parasympathetic
terminals ( ACH)
– OR on sympathetic terminals ( E / NE)
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Intracellular Events
Muscarinic Receptors
• Various intracellular consequences of receptor
activation
– Activation of vascular M receptors which  NO (EDRF)
which activates Guanylyl cyclase to cGMP
– Inhibition of cAMP formation (M2)
– Activation of K+ channels (M2)
– Activation of the Ca++-Phophoinositide signaling
pathway (IP3-DAG pathway) (M1 and M3)
• Receptor >G-protein>Phospholipase C>Converts PIP2 to
IP3 and DAG
Activates Release
of Ca++
Activates
PKC
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Muscarinic Receptors
Intracellular Messengers
From: Basic Neurochemistry, 6th
Edition, Siegel et al., eds.,
Raven Press 1999
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Cholinergic Drugs
From: Basic and Clinical
Pharmacology 8th edition,
B.G. Katzung; Lange 2001
30
Cholinomimetic Drugs
• Can be direct or indirect
Indirect:
– primarily act via inhibiting the enzyme
acetylcholinesterase which hydolyzes ACH to
choline and acetate
– degradation is rapid and obviously important, so
this leads to enhancement of ACH action
– There appear to be 2 types of inhibitors
• Reversible: Competitive
• Irreversible: include the “nerve gasses” and many
insecticides, form covalent bonds with the
enzyme
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Cholinomimetic Drugs
• Can be direct or indirect
Direct:
– bind to and activate receptors
– in some cases can cause depolarization
blockade (nicotinic)
32 Esters
Directly Acting
• 2 types
– esters including ACH
– alkaloids such as muscarine
and nicotine
• E.g., Pilocarpine,
oxytremorine
– Esters:
• charged, poorly lipid soluble
• poorly absorbed, generally
resistant to hydrolysis
• Have limited uses
– improve gastric tone,
stimulate urination,
ophthalmic (Glaucoma)
• Methacholine, carbamic acid,
carbachol, bethanechol
33 Esters
Directly Acting
Vy rapidly hydrolyzed ;
Large amounts must be infused intravenously to achieve
Concentrations high enough to produce detectable effects
Hydrolyzed less quickly than ACH but more quickly than
Carbamic acid and its derivatives carbachol and
bethanechol
More resistant to hydrolysis by
Acetylcholinesterase than ACH
or methcholine
The -methyl groups on
methacholine and bethanechol
reduces potency of the drugs at
nicotinic receptors.
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Directly Acting
Esters
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Cholinergic Agonists
Directly acting
• Alkaloids and Synthetics
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Cholinergic Agonists
Directly acting
• Alkaloids and Synthetics
–
–
–
–
typically well-absorbed
have similar effects to other ACH agonists
Differ in Muscarinic/Nicotinic specificity
Uses are limited:
• ophthalmic uses
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Cholinergic Agonists
Directly acting
Pharmacodynamics:
• Relatively predictable:
–
–
–
–
–
–
–
–
eye
CV system
Respiratory
GI
Urinary
CNS
Neuromuscular Junction
Glands
Organ
Response
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Cholinergic Agonists
Directly acting
continued
Pharmacodynamics:
• Relatively predictable:
–
–
–
–
–
–
–
–
eye
CV system
Respiratory
GI
Urinary
CNS
Neuromuscular Junction
Glands
Organ
Response
39
Cholinergic Agonists
Direct
Some Pharmacological Properties of Choline Esters
40
Glaucoma
Muscarinic
agonists and
AchE inhibitors
reduce IOP by
contracting the
ciliary body and
enhance fluid
outflow, betaadrenergic
blockers may
also reduce
secretion of
aqueous humor
by the ciliary
epithelium
•
•
Ciliary
body
(ciliary epithelium;
Beta-adrenergic receptors
Stimulate aqueous humor)
The fluid leaves the anterior chamber at the angle where the cornea and iris meet When the
fluid reaches the angle, it flows through a spongy meshwork and leaves the eye.
Open-angle glaucoma= the angle that allows fluid to drain out of the anterior chamber is open.
However the fluid passes too slowly through the meshwork drain. As the fluid builds up, the
pressure inside the eye rises. Unless the pressure at the front of the eye is controlled, it can
damage the optic nerve and cause vision loss. High pressure puts you at risk for glaucoma. It
may not mean that you have the disease.
http://www.nei.nih.gov/health/glaucoma/glaucoma_facts.htm
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Cholinergic Agonists
Indirectly acting
• As a group they block ACH hydrolysis
• Typically act at the enzyme,
– but some compounds may also stimulate the N-Ach R
• An Important group of drugs
– mostly insecticides
– some therapeutic application
• There are pharmacokinetic differences and chemical
structural differences
• Pharmacodymanics are virtually identical
42
Cholinergic Agonists
Indirectly acting
Often classified as
• Reversible:
- Short acting
edrophonium
- Longer-acting
pyridostigmine, neostigmine,
physostigmine
• Irreversible
– The organophosphates:
• Typically forms a covalent bond with the enzyme
• The drug phosphorylates the enzyme
– This phosphorous-enzyme bond is very stable and hydrolyzes
very slowly
• There appears to be a strengthening of the bond over time
(“aging”)
• Can be treated with pralidoxime which can reactivate ACHe
if not AGED
43
Cholinergic Agonists
Indirectly acting
• Chemical groups:
– quartenary ammonium alcohols
– carbamic acid esters with quartenary or tertiary
ammonium (e.g., neostigmine)
– organic derivatives of phosphoric acid = the
organophosphates
44
Cholinergic Agonists
Indirectly acting
•
The therapeutic action of the oxime compounds (eg.
pralidoxime) resides in their capacity to reactivate
acetylcholinesterase without contributing markedly toxic
actions of their own.
Pralidoxime (2-PAM)
O
AChE
R
O
P
R
P
R
R
Pralidoxime (2-PAM)
+
AChE
45
Cholinergic Agonists
Indirectly acting
•
If the R groups on the phosphorylated enzyme are modified by
metabolism, the enzyme has “aged” and now that
phosphorylated enzyme cannot be dephosphorylated!!
Pralidoxime (2-PAM)
O
AChE
O
modifed
P
R
P
modified
R
Pralidoxime (2-PAM)
+
AChE
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Cholinergic Agonists
Indirectly acting
•quartenary ammonium alcohols (e.g., edrophonium)
•carbamic acid esters with quartenary or tertiary ammonium (e.g., neostigmine),
•simple alcohols with a quartenary ammonium group (e.g., edrophonium)
All reversible
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Cholinergic Agonists
Indirectly acting
Organophosphorous Compounds
Mostly
irreversible
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Cholinergic Agonists
Indirectly acting
Absorption issues
– Most of the charged compounds are poorly absorbed (e.g.,
neostigmine
– Thus these drugs are typically not a danger
– The organophosphates are usually well-absorbed making them
dangerous to humans. Absorbed by GI, lung, skin, membranes.
echothiophate is an exception - rather poorly absorbed
• The absorption properties make them effective insecticides
• Some drugs (parathion, malathion) must be activated in vivo.
(converted to oxygen analogs)
– activated malathion is rapidly metabolized in mammals and birds, but
not insects and fish.
– Parathion is NOT deactivated
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Cholinergic Agonists
Indirectly acting
Typical uses
• Insecticides
• glaucoma
increased intraocular pressure which can damage the
retina if untreated
• mysthenia gravis
disease which affects skeletal muscle neuromuscular
junctions
decreased number of functional nicotinic receptors in the
neuromuscular junction. (autoimmune?)
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Cholinergic Agonists
Indirectly acting
Organophosphorous compounds including Insecticides
– DFP=isoflurophate very potent irrevers inhib
– Tabun; extremely toxic nerve gas
– Sarin extremely toxic nerve gas
– Soman extremely toxic nerve gas
– Paraoxon; active metabolite of parathion
– Malaoxon; acitive metabolite of malthion
– Parathion; insecticide to be phased out 10/03
– Diazinon=dimpylate; insecticide for gardening banned for indoor use,
to be phased out 10/05
– Chlopyrifos; insecticide used in consumer products and limited non
residential settings
– Malathion; insecticide, generally safer than other agents
– Echothiophate; extremely potent choline derivative; used in glaucoma
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Insecticide Poisoning
– You should know the signs of poisoning:
– MUSCARINIC EXCESS: miosis, salivation, sweating, bronchial
secretion and constriction, vomiting, diarrhea,
– CNS effects follow: activation, convulsions, coma, respiratory arrest
– Peripheral effects on skeletal N receptors are of especial concern:
depolarizing blockade
– IN short you die because:
• obstruction of airway by secretions, Bronchospasm and laryngospasm
• Neuromuscular blockade
• CNS respiratory failure
– Chronic exposure to organophosphates can cause neurotoxicity which
includes sensory disturbances, ataxia, weakness, fatigue,
– appears to be due to axonal degeneration and demylenation, these are
not due to ACHe effects
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Insecticide Poisoning
• Treatment is typically atropine
• or pralidoxime
– A reactivator
– Seems to “pick-off” the
phosphorous group on ACHe and
thus reactivate it
– Best when given to “fresh”
phosphorylated ACHe
– Seems to work preferentially at
the skeletal N receptor
53
Cholinergic Agonists
Indirectly Acting