Transcript Organ System Effects

Introduction to the Autonomic Nervous System
Ed Bilsky, Ph.D.
Department of Pharmacology
University of New England
Phone 283-0170, x2707
E-mail: [email protected]
Autonomic Nervous System
• A largely autonomous system that monitors and controls
internal body functions to maintain homeostasis and
meet the organisms demands
– cardiac output
– blood volume and pressure
– digestive processes
• Contains both afferent and efferent components, along
with integrating centers
• Drugs which modify the function of the autonomic
nervous system can be used therapeutically for many
disease states
Autonomic Nervous System
• There are two efferent divisions that act
antagonistically to each other
– allows for a greater degree of control over various processes
than one system would allow
• Sympathetic branch (fight or flight)
– increased cardiac output
– redirection of blood flow from GI system and skin to skeletal
muscle
• Parasympathetic branch (rest and maintenance)
– decreased cardiac output
– increased GI motility and secretions
Autonomic Nervous System
Divisions of the ANS use a two neuron system:
Preganglionic neuron:
– cell bodies in the spinal cord
– nerves terminate in ganglion
Postganglionic neuron:
– cell bodies in the ganglion
– nerves terminate on effector organs including smooth muscle and
cardiac muscle
Ganglion: aggregation of nerve cells in the
peripheral nervous system
Autonomic Nervous System
Preganglionic Cell Locations
Sympathetic:
– thoracic spinal cord
– lumbar spinal cord
Parasympathetic:
– cranial nerves (CN III, VII, IX, X)
– sacral spinal cord
Neurotransmitters of the ANS
Two primary neurotransmitters in the ANS:
Acetylcholine:
– preganglionic cells of the parasympathetic and
sympathetic branches
– postganglionic cells of the parasympathetic branch
– some postganglionic cells of the sympathetic branch
Norepinephrine:
– most postganglionic cells of the sympathetic branch
Neurotransmitters of the ANS
cranial
parasympathetic
nerves
sympathetic
(thoracolumbar)
nerves
Ach
Ach
visceral
effectors
NE
visceral
effectors
NE
Ach
sacral
parasympathetic
nerves
Ach
Ach
Ach
visceral
effectors
visceral
effector
organs
Neuromodulators of the ANS
• There are numerous other substances found in cholinergic
and noradrenergic neurons, as well as other neurons of the
ANS
• These substances may modulate the actions of the primary
neurotransmitters or have functions of their own
Examples:
–
–
–
–
–
Substance P
CGRP
serotonin
VIP
CCK
Primary Receptors of the ANS
Adrenergic
1 2
1 2 3
Cholinergic
Muscarinic
M1 M2 M3
Nicotinic
NN NM
Cholinergic Receptors
Receptor
Primary Locations
Main Biochemical Effects
M1
sympathetic post-ganglionic neurons,
formation of IP3 and DAG -->
CNS neurons
increased intracellular Ca2+
myocardium, smooth muscle
inhibition of adenylyl cyclase
M2
open K+ channels
M3
NN
vessels (smooth muscle/endothelial),
formation of IP3 and DAG -->
exocrine glands
increased intracellular Ca2+
postganglionic neurons
increased Na+ conductance -->
depolarization of neuron
NM
neuromuscular junction
increased Na+ conductance -->
initiation of muscle contraction
Adrenergic Receptors
Receptor
Primary Locations
Main Biochemical Effects
1
smooth muscle
formation of IP3 and DAG -->
increased intracellular Ca2+
2
presynaptic nerve terminals
platelets, lipocytes, smooth muscle
1
cardiac muscle, lipocytes, CNS
presynaptic ANS nerve terminals
2
smooth muscle, cardiac muscle
inhibition of adenylyl cyclase -->
decreased cAMP
stimulation of adenylyl cyclase -->
increased cAMP
stimulation of adenylyl cyclase -->
increased cAMP
3
lipocytes
stimulation of adenylyl cyclase -->
increased cAMP
Neurotransmission
Four Major Steps:
1. Synthesis and Storage of the neurotransmitter in the
presynaptic neuron
2. Release of the neurotransmitter into the synaptic cleft
3. Interaction of the neurotransmitter with receptors on
the post-synaptic cell
4. Termination of the synaptic actions of the
neurotransmitter
Synthesis and Storage
Acetylcholine example:
• The precursor choline is transported into cholinergic nerve
terminals
– hemicholinums can block the transporter --> decreased synthesis of
ACh
• Once synthesized, acetylcholine is transported into vesicles
for storage
– vesamicol can block the vesicular transporter, decreasing stores of
releasable ACh
• Because of the ubiquitous nature of acetylcholine, these
drugs are not used in clinical pharmacology
Release of Neurotransmitter
Release
Acetycholine example:
• Botulinum toxins are among the most
potent pharmacological agents known
• The various botulinum toxins are
produced by distinct strains of
Clostridium botulinum
• The light chain of the protein exerts
a metalloprotease effect that cleaves
proteins involved in exocytosis
– SNAP-25
– syntaxin
– VAMP-1 and 2
Clinical Correlate
• Intramuscular injections of botulinum
toxin type A are the most effective
treatment for focal dystonia and may be
used in a limited form in patients with
segmental or generalized dystonia
• Treatment is necessary every 3 to 5
months in most patients, and this therapy
has been used safely in some patients for
more than 15 years
– some patients develop resistance to the
clinical response, and antibodies to the A
toxin may develop
– if the dose is limited to less than 300 U
per procedure and the treatment is given
no more frequently than every 3 months,
the risk of immunoresistance is minimized
Interaction of Neurotransmitters with Receptors
Na+
ACh
Ligand-gated
channel
Agonist
G-protein
regulated
Opioid
receptor


G protein
complex
Effector
Termination of Neurotransmitter Effect
Enzymatic breakdown of neurotransmitter:
Acetylcholinesterase
• Acetylcholinesterase (AChE) is one
of only a few enzymes that have
obtained near catalytic perfection
– the rate of hydrolysis is close to the
rate of diffusion to the active site
– a single enzyme can hydrolyze 14,000
ACh molecules/second
• Blockade of acetylcholinesterase
will rapidly increase synaptic levels
of acetylcholine
– neostigmine-reversible inhibitor
– sarin, malathion-irreversible inhibitors
Termination of Neurotransmitter Effect
Reuptake of neurotransmitter:
Reuptake of Catecholamines
• Dopamine and norepinephrine are
inactivated primarily via
reuptake
– specific transporters that
transport the catecholamines back
into the presynaptic terminal
• The effects of cocaine and
amphetamine are mediated in
part through the dopamine
transporter
Cholinomimetic Drugs
Ed Bilsky, Ph.D.
Department of Pharmacology
University of New England
Phone 283-0170, x2707
E-mail: [email protected]
Drugs that Increase Cholinergic Activity
Cholinergic agonists
– muscarinic agonists (pilocarpine)
– nicotinic agonists (nicotine)
Inhibitors of acetylcholinesterase
– reversible inhibitors (neostigmine)
– irreversible inhibitors (nerve gas, insecticides)
Direct Acting Cholinomimetics
Structure:
• Major differences exist between drugs in this class
• The choline esters have quaternary structures that
possess positive charges (e.g., bethanechol)
– water soluble
• Other agents do not have have a charge (e.g., pilocarpine)
• There is a strong stereoselective binding requirement for
the muscarinic receptor
– (S)-bethanechol >> (R)-bethanechol
Direct Acting Cholinomimetics
Pharmacokinetics:
• The quaternary amines are poorly absorbed and poorly
distributed into the CNS compared to the tertiary amines
– bethanechol versus pilocarpine
• Some of these compounds are more resistant to
cholinesterases than others
– bethanechol >> acetylcholine
• Modification of the structure can influence the affinity of
the drug for muscarinic and nicotinic receptors
– bethanechol versus acetylcholine
Direct Acting Cholinomimetics
Pharmacodynamics:
• Muscarinic receptors are coupled to G-proteins that
activate phospholipase C (M1 and M3) or inhibit adenylyl
cylase (M2)
– increased production of IP3 and DAG, decreased levels of cAMP
• These second messengers produce a number of
intracellular effects
– increase intracellular Ca2+ levels and activation of protein kinase C
– opening of K+ channels --> hyperpolarization of the cell
• Activation of nicotinic receptors produces an influx of Na+
ions and depolarization of the cell --> action potential
Organ System Effects
Cardiovascular system:
• Primary effects of muscarinic agonists are a decrease in
peripheral resistance and changes in heart rate
• Direct effects of the heart include:
– increased K+ current in atrial muscle, SA and AV nodes
– decreased Ca2+ current in cardiac cells
– a reduction in hyperpolarization-activated current that underlies
diastolic depolarization
• net effect is to slow the pace maker cells and decrease
atrial contractility
– the ventricles are less densely innervated than the atrial tissue
Organ System Effects
Cardiovascular system (continued):
• The direct effects of muscarinic agonists on the heart are
usually opposed by reflex sympathetic discharge
– elicited by the fall in blood pressure
• Muscarinic agonists can produce marked vasodilation
– generation of EDRF from endothelial cells (NO main contributor)
Respiratory system:
• Muscarinic agonists produce smooth muscle contraction
and stimulate secretion in the bronchial tree
– can aggravate symptoms associated with asthma
Organ System Effects
Genitourinary tract:
• Stimulation of muscarinic receptors increases tone of the
detrusor muscle and relaxes the trigone and sphincter
muscles of the bladder
– promotes voiding of urine
• No major effects on uterine contractility
Organ System Effects
Eye:
• muscarinic stimulation leads to contraction of the smooth
muscle of the iris sphincter and of the cilliary muscle
– responsible for miosis and accomodation, respectively
• Both effects promote the outflow of aqueous humor
– decreases intraoccular pressure
Miscellaneous secretory glands:
• muscarinic agonists stimulate the secretory activity of
sweat, lacrimal and nasopharyngeal glands
Organ System Effects
CNS effects:
• The CNS contains both muscarinic and nicotinic receptors
• Nicotine has important effects on the brainstem and
cortex
– stimulant type effects, addiction liability
– high doses can cause tremor and convulsions
• Muscarinic receptors play a role in movement, cognition,
learning and memory, and vestibular function
– potential therapeutic applications to CNS diseases, though sideeffects limit the clinical use of these agents
Organ System Effects
PNS effects:
• Activation of nicotinic receptors produces action
potentials in post-ganglionic nerves of the ANS
• The activation of both branches of the ANS results in
complex effects on the organism
– cardiovascular effects are primarily sympathomimetic
– GI and genitourinary effects primarily parasympathomimetic
Neuromuscular junction:
• nicotine receptors initiate muscle action potentials
– fasciculations to strong contractions of an entire muscle possible
– can produce depolarization blockade
Indirect Acting Cholinomimetics
Structure:
• Three major classes of compounds
– simple alcohols bearing quaternary ammonium group
– carbamic acid esters of alcohols bearing quaternary or tertiary
ammonium groups
– organic derivatives of phosphoric acid (organophosphates)
Pharmacokinetics:
• The quaternary derivatives are poorly absorbed and poorly
distributed into the CNS compared to the tertiary amines
– physostigmine > neostigmine
• Differences in insecticide absorption and metabolism can affect the
safety of these products
– malathion metabolized quickly in mammals and birds, not insects
Indirect Acting Cholinomimetics
Pharmacodynamics:
• The affinity of the drug to acetycholinesterase
determines the duration of action
– edrophonium and related quaternary alcohols interact weakly
(electrostatic and hydrogen bonds) --> 2-10 min interaction
– carbamate esters (e.g., neostigmine) form covalent bonds --> 30
min to 6 hr interactions
– organophospahtes can form very strong covalent bonds that are
basically irreversible --> hundreds of hours
• An aging process can strengthen the organophosphate
bonds making treatment of nerve gas poisoning very
difficult to manage
Organ System Effects
Cardiovascular system:
• These drugs exert negative chronotropic, inotropic and
dromotropic effects on the heart --> decreased CO
• Limited effects on the vasculature
• Net effect of moderate doses is modest bradycardia and a
fall in CO, with only minimal effects on blood pressure
– higher doses produce marked bradycardia and hypotension
Respiratory, GI and GU systems:
• Similar to effects produced by direct acting agents
Organ System Effects
Neuromuscular junction:
• Low (therapeutic) doses prolong and intensify the effects
of physiologically released acetylcholine
• Higher doses can lead to muscle fibrillation and
fasiculations of an entire motor unit
Therapeutic Applications: Myasthenia Gravis
• Myasthenia gravis is an autoimmune disorder that attacks
the nicotinic ACh receptors at the neuromuscular junction
– leads to profound muscle weakness
• Acetylcholinesterase inhibitors increase the amount of
acetylcholine in the neuromuscular junction
– neostigmine is frequently used for this disorder
• If muscarinic side-effects are prominent, anticholinergics
can be administered (e.g., atropine)
– tolerance usually occurs to the muscarinic side-effects
Why are the direct acting cholinomimetics not used for
myasthenia gravis?
Therapeutic Applications: Reversal of NMB
• By increasing levels of acetylcholine in the NMJ, the
compounds are able to facilitate recovery from
competitive neuromuscular blockade
– restores neuromuscular transmission
• Edrophonium has a more rapid onset of action than
neostigmine, and shorter duration of action
• Neostigmine is preferable to other agents when >90%
twitch depression is to be antagonized
Therapeutic Applications: Glaucoma
• Constriction of the ciliary body promotes
aqueous humor outflow --> decreased
intraoccular pressure
• Direct and indirect cholinomimetics can be used
to treat glaucoma
– pilocarpine is the most commonly used agent
– typically formulated as eye drops
Therapeutic Applications: Atonic GI/GU
• The smooth muscle of the GI and GU systems
can show depressed activity in certain states
– post-operative ileus
– congenital megacolon
• Bethanechol and neostigmine are the most widely
used agents
– increases secretion and motility in the G.I. tract
– can be given orally or by injection
These agents can not be used if there is a mechanical
obstruction of the GI or urinary tract
Therapeutic Applications: Other Uses
• Physostigmine is rarely used for reversing the
effects of anticholinergic poisoning
– has many side-effects of its own that are difficult to
control
• The use of edrophonium for treating
supraventricular tachyarrhythmias has been
discontinued
– newer agents that act at adenosine receptors and
calcium channels have replaced its use in this
condition
Anticholinergics
Neuromuscular receptor antagonists
– Tubocurarine (nicotinic antagonist)
Ganglionic receptor antagonists
– hexamethonium
Muscarinic receptor antagonists
– atropine and scopolamine (belladonna alkaloids)
– pirenzepine
Anticholinergics
Structure:
• Atropine is the prototypic drug in this class
– found in Atropa belladonna (deadly nightshade) and Datura stramonium
(Jimson Weed)
– tertiary amine structure allows passage across the BBB
• Other drug classes possess anticholinergic activity by virtue of their
similar chemical structures
– many antihistamines, antipsychotics and antidepressants
• Anticholinergics that are quaternary amines have been developed for
limiting CNS effects
– ipratropium for asthma
– propantheline for GI use
Anticholinergics
Pharmacokinetics:
• The quaternary amines are poorly absorbed from the GI
tract and poorly distributed into the CNS compared to the
tertiary amines
– atropine >> propantheline
• Metabolism is drug specific
– atropine has a relatively short half-life, with the majority of the
drug being eliminated in the urine unchanged, some metabolism in
the urine (hydrolysis and conjugation)
Anticholinergics
Pharmacodynamics:
• Atropine produces reversible blockade of muscarinic
receptors
– very selective for muscarinic receptors
– does not differentiate between M1, M2 and M3 receptors
• Other anticholinergics possess subtype selective profiles
– pirenzepine M1 > M2 > M3
Organ System Effects
CNS:
• Clinical doses of atropine typically produce minimal CNS effects
– scopolamine has greater CNS effects (sedation, amnesia)
– higher doses of these agents can produce hallucinations
• Blockade of muscarinic receptors has been used to treat tremors
associated with Parkinson’s disease
– newer agents have replaced anticholinergics as a primary treatment,
sometimes used as an adjunct
• Vestibular disturbances, especially motion sickness, appears to be
mediated by CNS muscarinic receptors
– scopolamine can be given orally or by transdermal patch
Organ System Effects
Eye:
• Tertiary anticholinergics produced marked mydriasis due to unopposed
sympathetic activity
• Decreased contraction of the ciliary muscle produces cycloplegia and a
loss of accommodation
• These effects are useful for certain ophthalmology procedures
– contraindicated in patients with glaucoma
Cardiovascular effects:
• Moderate doses have pronounced effects on the SA node to increase
heart rate
– low doses can cause bradycardia due to presynaptic muscarinic receptor
blockade
Organ System Effects
Respiratory system:
• Blockade of muscarinic receptors in the bronchial tree
produces bronchodilation and decreased secretions
• Older class of agents used for treating asthma
– largely replaced in the treatment of asthma by beta-2 agonists
• Ipratropium is sometimes used in asthma and COPD as an
inhalational drug
– decreased systemic distribution compared to atropine
• Anticholinergics can decrease secretions during intubation
procedure and during the delivery of volatile anesthetics
Organ System Effects
GI effects:
•
Decreases secretions and motility in the GI system
•
infrequently used for treating peptic ulcer and diarrhea
•
Decreases spasms of the bladder and ureters is useful in treating some
inflammatory conditions where incontinence is a problem (M3 antagonists)
– dry mouth and constipation are frequent side-effects
– better agents available that have produce less side-effects
– selective M1 blockers are being developed (pirenzepine)
Sweat glands:
• thermoregulatory sweating is inhibited by atropine
– sympathetic nervous system effect
• Large doses of atropine may increase body temperature in adults
– infants and children are much more sensitive to this effect
Cholinergic poisoning
• A number of insecticides and nerve gasses can produce
cholinergic toxicity
• Many of the signs and symptoms can be reversed by
administering atropine
• There are several compounds that can hydrolyze the
phosphoryalted acetylcholinesterase and reverse organic
phosphate poisoning
– need to be administered soon after the exposure
– pralidoxine (PAM) “regenerates” the acetycholinesterase
• Atropine can be used to treat certain types of mushroom
poisoning (Inocybe genus and others)
Anticholinergic poisoning
• High doses of belladonna alkaloids can produce their own
toxic syndrome
– dry as a bone, blind as a bat, red as a beet, mad as a hatter
• Typically associated with accidental poisoning in people
seeking the hallucinogenic actions of the drug
– long-lasting agitation and delerium
• Overdose is typically treated symptomatically due to
problems with the antidotes (physostigmine)
– temperature control and diazepam for seizures
Ganglion Blocking Agents
• The lack of specificity with these agents limits their
clinical use
– hexamethonium and others are used in preclinical research
• The specific response elicited depends on the predominant
ANS innervation
– cycloplegia and loss of accommodation and usually dilation of the
pupil
– cardiovascular effects include significant hypotension
– marked decrease in GI activity and loss of sexual function
• These compounds (e.g., trimethaphan) were once used to
treat malignant hyperthermia
– replaced by other drugs (e.g., nitroprusside)