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Drugs AIIecting the Autonomic

Nervous System
Pharmacology 49.222
Bill Diehl-Jones RN, PhD
Faculty oI Nursing and Department oI Zoology
Agenda
A Zen Review
Overview oI CNS and ANS
Neurotransmitters and 2
nd
Messengers
Cholinergic Agonists and Antagonists
Adrenergic Agonists and Antagonists
Movement Disorder Drugs
Organization oI the Nervous System:
CNS
Three divisions oI brain:
Forebrain
cerebral hemispheres
Midbrain
Corpora quadrigemini, tegmentum, cerebral
peduncles
Hindbrain
Cerebellum, pons, medulla
Brainstem:
Midbrain, medulla, pons
Connects cerebrum, cerebeluum, spinal
cord
Organization oI the Nervous System:
Reticular Activating System
Key Regulatory Functions:
CV, respiratory systems
WakeIulness
Clinical Link:
Disturbances in the RAS are
linked to sleep-wake
disturbances
ReticuIar Formation
Ascending Sensory Tracts
ThaIamus
Radiation Fibres
VisuaI Inputs
Organization oI the Peripheral
Nervous System
Three major divisions:
EIIerent
Somatic (motor)
Autonomic
Sympathetic and Parasympathetic
AIIerent
Sensory
Some Basic Plumbing:
The Peripheral Nervous System
Sensory
Motor
Sympathetic
Parasympathetic
Parasympathetic
Preganglionic Nerves
Sympathetic AND Parasympathetic
preganglionic Iibres release
Acetylcholine (ACh)
ACh has two types oI receptors:
Muscarinic and Nicotinic
Postganglionic nerves have Nicotinic
receptors
Sympathetic Parasympathetic
ACh
Postganglionic Nerves
Sympathetics release Norepinephrine
Parasympathetics release ACh
Norepinephrine binds to adrenergic
receptors
ACh binds to Muscarinic receptors
Sympathetic Parasympathetic
ACh
NE
What Happens at the EIIectors?
NE Irom postganglionic sympathetics binds to
Adrenergic Receptors
ACh Irom postganglionic parasympathetics binds to
Muscarinic Receptors
ACh
Muscarinic
Receptor
NE
Adrenergic
Receptor
Sympathetic
Parasympathetic
Cholinergic Neurons
Na

Choline
Ca

Receptor
Acetylcholinesterase
Acetylation
W
Cholinergic Receptors
Muscarinic receptors come in 5 Ilavours
M1, M2, M3, M4, M5
Found in diIIerent locations
Research is on-going to identiIy speciIic
agonists and antagonists
Nicotinic receptors come in 1 Ilavour
Cholinergic Agonists
Acetylcholine
Bethanechol
Carbachol
Pilocarpine
eneral EIIects oI Cholinergic
Agonists
Decrease heart rate and cardiac output
Decrease blood pressure
Increases I motility and secretion
Pupillary constriction
Cholinergic Antagonists
Antimuscarinic agents
Atropine, ipratropium
anglion blockers
nicotine
Neuromuscular
blockers
Vecuronium,
tubocuarine,
pancuronium
Where are some oI these drugs
used?
Atropine
(a cholinergic antagonist)
Comes Irom Belladonna
High aIIinity Ior muscarinic
receptors
Causes 'mydriasis (dilation oI
the pupil) and 'cycloplegia
UseIul Ior eye exams, tmt oI
organophosphate poisoning,
antisecretory eIIects
Side eIIects?
Scopalamine
(also a cholinergic antagonist)
Also Irom Belladonna
Peripheral eIIects
similar to atropine
More CNS eIIects:
Anti-motion sickness
amnesiac
Trimethaphan
(yet another cholinergic antagonist)
Competitive nicotinic
ganglion blocker
Used to lower blood
pressure in emergencies
Neuromuscular Blockers
Look like acetylcholine
Either work as antagonists or agonists
Two Ilavours:
Non-depolarizing (antagonist)
Eg: tubocurarine
Block ion channels at motor end plate
Depolarizing (agonist)
Eg: succinylcholine
Activates receptor
Turbocurarine
Used during surgery to
relax muscles
Increase saIety oI
anaesthetics
Do not cross blood-
brain barrier Na

Channel
Nicotinic Receptor
ACh
Curare
Na

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

- - - - - -

- - - - - -
Na

Na

Phase I
Phase II
Adrenergic Neurons
Na

Tyrosine
Ca

Receptor
MAO
W
Dopamine
Dopa
Dopamine is
converted to
epinephrine
Word oI the Day:
SYMPATHOMIMETIC
Adrenergic drug which acts directly on
adrenergic receptor, activating it
Adrenergic Agonists
Direct
Albuterol
Dobutamine
Dopamine
Isoproteranol
Indirect
Amphetamine
Mixed
Ephidrine
Adrenergic Receptors
Two Families:
Alpha and Beta
Based on aIIinity to
adrenergic agonists
Alpha aIIinity:
epinephrine_norepinephrine~~
isoproteranol
Beta aIIinity:
Isoproteranol~epinephrine~
norepinephrine
Epinephrine Norepinephrine Isoproteranol
Epinephrine Norepinephrine Isoproteranol
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
Adrenergic Angonists
Direct acting:
Epinephrine: interacts with both alpha and beta
Low dose: mainly beta eIIects (vasodilation)
High dose: alpha eIIects (vasoconstriction)
Therapeutic uses: emerg tmt oI asthma, glaucoma,
anaphyslaxis
(what about terbutaline?)
Adrenergic Agonists
Indirect:
Cause NE release only
Example:
Amphetamine
CNS stimulant
Increases BP by alpha eIIect on vasculature, beta eIIect on heart
Mixed-Action
Causes NE release AND stimulates receptor
Example:
Ephedrine:
What type oI drug?
Alpha and beta stimulant
Use: asthma, nasal sprays
slower action
Adrenergic Antagonists
Alpha blockers
Eg: Prazosin
Selective alpha 1 blocker
Tmt: hypertension
relaxes arterial and venous smooth muscle
Causes 'Iirst dose response (what is this?)
Adrenergic Antagonists
Beta Blockers
Example: Propranolol
Non-selective (blocks beta 1 and beta 2)
EIIects:
cardiac output, vasodilation, bronchoconstriction
Adrenergic Antagonists
Eg: Atenolol, Metoprolol
PreIerentially block beta 1; no beta eIIects (why
is this good?)
Partial Agonists:
Pindolol, acebutolol
Weakly stimulate beta 1 and beta 2
Causes less bradycardia
Adrenergic Antagonists
Eg: Nadolol
Nonselective beta blocker
Used Ior glaucoma
Eg: Labetolol
Alpha AND beta blocker
Used in treating PIH
Drugs that AIIect Uptake/Release
Eg: Cocaine
Blocks Na/K ATPase
Prevents reuptake oI
epinephrine/norepinephrine
Treatment oI Movement
Disorders
What Regulates Movement?
Basal anglia are involved
Example:
Parkinsons`s Disease
Symptoms ?
FRONTAL SECTION OF BRAIN
Sherwood, 2001 p 145
BASAL GANGLIA cont'd
Role of basal ganglia:
1. Inhibit muscle tone throughout the body
2. Select & maintain purposeIul motor activity
while suppressing useless/unwanted patterns
oI movement
3. Coordination oI slow, sustained movements
(especially those related to posture & support)
4. Help regulate activity oI the cerebral cortex
BASAL GANGLIA SYSTEM
Feedback loops - complex
- Iorm direct & indirect pathways
- balance excitatory & inhibitory
activities
Neurotransimitters:
citatory - ACh Inhibitory - dopamine
glutamate ABA
OPAMINE
major NT regulating subconscious movements oI skeletal
muscles
majority located in the terminals oI pathway stretching
Irom the neuronal cell bodies in SNc to the striatum
generally inhibits the Iunction oI striatal neurons & striatal
outputs
when dopamine production is , a chemical imbalance
occurs aIIecting movement, balance and gait
PATHOPHYSIOLOGY OF PARKINSON`S
ISEASE
Major pathological features:
1. 0ath of dopamin0 producing c08 in th0 SAc
leads to overactivation oI the indirect pathway
2. Pr080nc0 of L0y bodi08 small eosinophilic
inclusions Iound in the neurons oI SNc
Results in:- degeneration oI the nigrostriatal
pathway
- decreased thalamic excitation oI the
motor cortex
rug of Choice: LEVOOPA
Why is it used?
- virtually all pt`s with PD show a response to
levodopa
- improves quality oI liIe
- in use since 1960`s
- easy to administer (non-invasive)
- relatively inexpensive
- useIul in diagnosing PD
0chani8m of action: is a precursor to dopamine helps
restore the balance oI dopamine in striatum
most eIIective in combo with Carbidopa ( `s levodopa`s
peripheral conversion to dopamine)
OTHER APPROACHES TO TREATMENT
Pharmacological:
opamin0 agoni8t8: ie. Bromocriptine or pergolide
mesylate
S00ctiv0 inhibitor of typ0 B monoamin0
oida80: ie.Selegiline
Antivira8: ie. Amantadine
Antichoin0rgic8: ie. Trihexyphenidyl
CO% inhibitor8: ie. Entacapone
APPROACHES cont'd
Surgical:
Paidotomy & %haotomy:
microelectrode destruction oI speciIic site in the basal
ganglia
00p brain 8timuation:
electrode implantation with external pacemaker
F0ta nigra tran8pantation:
Implantation oI embryonic dopaminergic neurons into
the substantia nigra Ior growth and supply oI dopamine