Drugs Affecting the Autonomic Nervous System

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Drugs Affecting the Autonomic Nervous System

• Pharmacology 49.222
• Bill Diehl-Jones RN, PhD
• Faculty of Nursing and Department of Zoology

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Agenda

• A Zen Review
• Overview of CNS and ANS
• Neurotransmitters and 2nd Messengers
• Cholinergic Agonists and Antagonists
• Adrenergic Agonists and Antagonists
• Movement Disorder Drugs

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Organization of the Nervous SystemCNS

• Three divisions of brain
• Forebrain
• cerebral hemispheres
• Midbrain
• Corpora quadrigemini, tegmentum, cerebral
  peduncles
• Hindbrain
• Cerebellum, pons, medulla
• Brainstem
• Midbrain, medulla, pons
• Connects cerebrum, cerebeluum, spinal cord

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Organization of the Nervous SystemReticular
Activating System

• Key Regulatory Functions
• CV, respiratory systems
• Wakefulness
• Clinical Link
• Disturbances in the RAS are linked to sleep-wake
  disturbances

Radiation Fibres
Thalamus
Visual Inputs
Reticular Formation
Ascending Sensory Tracts
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Organization of the Peripheral Nervous System

• Three major divisions
• Efferent
• Somatic (motor)
• Autonomic
• Sympathetic and Parasympathetic
• Afferent
• Sensory

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Some Basic PlumbingThe Peripheral Nervous System
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Preganglionic Nerves
Sympathetic
Parasympathetic

• Sympathetic AND Parasympathetic preganglionic
  fibres release Acetylcholine (ACh)
• ACh has two types of receptors
• Muscarinic and Nicotinic
• Postganglionic nerves have Nicotinic receptors

ACh
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Postganglionic Nerves
Sympathetic
Parasympathetic

• Sympathetics release Norepinephrine
• Parasympathetics release ACh
• Norepinephrine binds to adrenergic receptors
• ACh binds to Muscarinic receptors

ACh
NE
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What Happens at the Effectors?

• NE from postganglionic sympathetics binds to
  Adrenergic Receptors
• ACh from postganglionic parasympathetics binds to
  Muscarinic Receptors

ACh
NE
Muscarinic Receptor
Adrenergic Receptor
Sympathetic
Parasympathetic
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Cholinergic Neurons
Na Choline
Acetylation
Ca
?
Acetylcholinesterase
Receptor
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Cholinergic Receptors

• Muscarinic receptors come in 5 flavours
• M1, M2, M3, M4, M5
• Found in different locations
• Research is on-going to identify specific
  agonists and antagonists
• Nicotinic receptors come in 1 flavour

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Cholinergic Agonists

• Acetylcholine
• Bethanechol
• Carbachol
• Pilocarpine

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General Effects of Cholinergic Agonists

• Decrease heart rate and cardiac output
• Decrease blood pressure
• Increases GI motility and secretion
• Pupillary constriction

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Cholinergic Antagonists

• Antimuscarinic agents
• Atropine, ipratropium
• Ganglion blockers
• nicotine
• Neuromuscular blockers
• Vecuronium, tubocuarine, pancuronium

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Where are some of these drugs used?
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Atropine(a cholinergic antagonist)

• Comes from Belladonna
• High affinity for muscarinic receptors
• Causes mydriasis (dilation of the pupil) and
  cycloplegia
• Useful for eye exams, tmt of organophosphate
  poisoning, antisecretory effects
• Side effects?

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Scopalamine(also a cholinergic antagonist)

• Also from Belladonna
• Peripheral effects similar to atropine
• More CNS effects
• Anti-motion sickness
• amnesiac

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Trimethaphan(yet another cholinergic antagonist)

• Competitive nicotinic ganglion blocker
• Used to lower blood pressure in emergencies

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Neuromuscular Blockers

• Look like acetylcholine
• Either work as antagonists or agonists
• Two flavours
• Non-depolarizing (antagonist)
• Eg tubocurarine
• Block ion channels at motor end plate
• Depolarizing (agonist)
• Eg succinylcholine
• Activates receptor

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Turbocurarine

• Used during surgery to relax muscles
• Increase safety of anaesthetics
• Do not cross blood-brain barrier

ACh
Na
Curare
Nicotinic Receptor
Na Channel
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Succinylcholine

• Uses
• endotracheal intubations
• What is this?
• Why?
• electroconvulsive shock therapy
• Problem can cause apnea

Na
-
-
-
-
-
-







Phase I
Na






-
-
-
-
-
-
Phase II
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Adrenergic Neurons
Na Tyrosine
Dopa
MAO
Ca
Dopamine
?
Dopamine is converted to epinephrine
Receptor
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Word of the Day

• SYMPATHOMIMETIC
• Adrenergic drug which acts directly on adrenergic
  receptor, activating it

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Adrenergic Agonists

• Direct
• Albuterol
• Dobutamine
• Dopamine
• Isoproteranol
• Indirect
• Amphetamine
• Mixed
• Ephidrine

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Adrenergic Receptors

• Two Families
• Alpha and Beta
• Based on affinity to adrenergic agonists
• Alpha affinity
• epinephrinenorepinephrinegtgt isoproteranol
• Beta affinity
• Isoproteranolgtepinephrinegt norepinephrine

Epinephrine
Norepinephrine
Isoproteranol
Epinephrine
Norepinephrine
Isoproteranol
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What do these receptors do?

• Alpha 1
• Vasoconstriction, ? BP, ? tonus sphincter muscles
• Alpha 2
• Inhibit norepinephrine, insulin release
• Beta 1
• Tachycardia, ? lipolysis, ? myocardial
  contractility
• Beta 2
• Vasodilation, bronchodilation, ?insulin release

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Adrenergic Angonists

• Direct acting
• Epinephrine interacts with both alpha and beta
• Low dose mainly beta effects (vasodilation)
• High dose alpha effects (vasoconstriction)
• Therapeutic uses emerg tmt of asthma, glaucoma,
  anaphyslaxis
• (what about terbutaline?)

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Adrenergic Agonists

• Indirect
• Cause NE release only
• Example
• Amphetamine
• CNS stimulant
• Increases BP by alpha effect on vasculature, beta
  effect on heart

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Mixed-Action

• Causes NE release AND stimulates receptor
• Example
• Ephedrine
• What type of drug?
• Alpha and beta stimulant
• Use asthma, nasal sprays
• slower action

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Adrenergic Antagonists

• Alpha blockers
• Eg Prazosin
• Selective alpha 1 blocker
• Tmt hypertension
• relaxes arterial and venous smooth muscle
• Causes first dose response (what is this?)

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Adrenergic Antagonists

• Beta Blockers
• Example Propranolol
• Non-selective (blocks beta 1 and beta 2)
• Effects
• ? cardiac output, vasodilation,
  bronchoconstriction

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Adrenergic Antagonists

• Eg Atenolol, Metoprolol
• Preferentially block beta 1 no beta effects (why
  is this good?)
• Partial Agonists
• Pindolol, acebutolol
• Weakly stimulate beta 1 and beta 2
• Causes less bradycardia

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Adrenergic Antagonists

• Eg Nadolol
• Nonselective beta blocker
• Used for glaucoma
• Eg Labetolol
• Alpha AND beta blocker
• Used in treating PIH

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Drugs that Affect Uptake/Release

• Eg Cocaine
• Blocks Na/K ATPase
• Prevents reuptake of epinephrine/norepinephrine

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Treatment of Movement Disorders
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What Regulates Movement?

• Basal Ganglia are involved

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Example Parkinsonss Disease

• Symptoms ?

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FRONTAL SECTION OF BRAINSherwood, 2001 p 145
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BASAL GANGLIA contd

• Role of basal ganglia
• 1. Inhibit muscle tone throughout the body
• 2. Select maintain purposeful motor activity
• while suppressing useless/unwanted patterns
  of movement
• 3. Coordination of slow, sustained movements
  (especially those related to posture support)
• 4. Help regulate activity of the cerebral cortex

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BASAL GANGLIA SYSTEM

• Feedback loops - complex
• - form direct
  indirect pathways
  - balance
  excitatory inhibitory
  activities
• Neurotransimitters
• Excitatory - ACh Inhibitory - dopamine
• glutamate GABA

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DOPAMINE

• major NT regulating subconscious movements of
  skeletal muscles
• majority located in the terminals of pathway
  stretching from the neuronal cell bodies in SNc
  to the striatum
• generally inhibits the function of striatal
  neurons striatal outputs
• when dopamine production is ?, a chemical
  imbalance occurs affecting movement, balance and
  gait

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PATHOPHYSIOLOGY OF PARKINSONS DISEASE

• Major pathological features
• 1. Death of dopamine producing cells in the SNc
• leads to overactivation of the indirect pathway
• 2. Presence of Lewy bodies small eosinophilic
  inclusions found in the neurons of SNc
• Results in- degeneration of the nigrostriatal
  pathway
• - decreased thalamic excitation of the
  motor cortex

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4. Drug of Choice LEVODOPA

• Why is it used?
• - virtually all pts with PD show
  a response to
  levodopa
• - improves quality of life
• - in use since 1960s
• - easy to administer
  (non-invasive)
• - relatively inexpensive
• - useful in diagnosing PD
• Mechanism of action is a precursor to dopamine
  helps restore the balance of dopamine in striatum
• most effective in combo with Carbidopa (? s
  levodopas peripheral conversion to dopamine)

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5. OTHER APPROACHES TO TREATMENT

• Pharmacological
• Dopamine agonists ie. Bromocriptine or pergolide
  mesylate
• Selective inhibitor of type B monoamine oxidase
  ie.Selegiline
• Antivirals ie. Amantadine
• Anticholinergics ie. Trihexyphenidyl
• COMT inhibitors ie. Entacapone

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APPROACHES contd

• Surgical
• Pallidotomy Thalotomy
• microelectrode destruction of specific site in
  the basal ganglia
• Deep brain stimulation
• electrode implantation with external pacemaker
• Fetal nigral transplantation
• Implantation of embryonic dopaminergic neurons
  into the substantia nigra for growth and supply
  of dopamine