Transcript Lecture 1: Introduction to Pharmacology

Drugs Affecting the Autonomic
Nervous System
Pharmacology 49.222
Bill Diehl-Jones RN, PhD
Faculty of Nursing and Department of Zoology
Agenda
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A Zen Review
Overview of CNS and ANS
Neurotransmitters and 2nd Messengers
Cholinergic Agonists and Antagonists
Adrenergic Agonists and Antagonists
Movement Disorder Drugs
Organization of the Nervous System:
CNS
• 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
Organization of the Nervous System:
Reticular Activating System
• Key Regulatory Functions:
Radiation Fibres
– CV, respiratory systems
– Wakefulness
• Clinical Link:
Thalamus
– Disturbances in the RAS are
linked to sleep-wake Visual Inputs
Reticular Formation
disturbances
Ascending Sensory Tracts
Organization of the Peripheral
Nervous System
• Three major divisions:
– Efferent
• Somatic (motor)
• Autonomic
– Sympathetic and Parasympathetic
– Afferent
• Sensory
Some Basic Plumbing:
The Peripheral Nervous System
Parasympathetic
Sensory
Sympathetic
Motor
Parasympathetic
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
Postganglionic Nerves
Sympathetic
Parasympathetic
• Sympathetics release Norepinephrine
• Parasympathetics release ACh
• Norepinephrine binds to adrenergic
receptors
ACh
• ACh binds to Muscarinic receptors
NE
What Happens at the Effectors?
• NE from postganglionic sympathetics binds to
Adrenergic Receptors
• ACh from postganglionic parasympathetics binds to
Muscarinic Receptors
NE
ACh
Adrenergic
Receptor
Muscarinic
Receptor
Sympathetic
Parasympathetic
Cholinergic Neurons
Na+
Choline
Acetylation
Ca++

Acetylcholinesterase
Receptor
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
Cholinergic Agonists
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Acetylcholine
Bethanechol
Carbachol
Pilocarpine
General Effects of Cholinergic
Agonists
• Decrease heart rate and cardiac output
• Decrease blood pressure
• Increases GI motility and secretion
• Pupillary constriction
Cholinergic Antagonists
• Antimuscarinic agents
– Atropine, ipratropium
• Ganglion blockers
– nicotine
• Neuromuscular
blockers
– Vecuronium,
tubocuarine,
pancuronium
Where are some of these drugs
used?
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?
Scopalamine
(also a cholinergic antagonist)
• Also from Belladonna
• Peripheral effects
similar to atropine
• More CNS effects:
– 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 flavours:
– 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 safety of
anaesthetics
ACh
Curare
• Do not cross bloodNicotinic Receptor
brain barrier
Na+
Na+ Channel
Succinylcholine
• Uses:
– endotracheal intubations
• What is this?
• Why?
Na+
- - -
- - -
+ ++ +
+ + +
Phase I
– electroconvulsive shock
therapy
Na+
• Problem: can cause apnea
++ +
- - -
++ +
- - Phase II
Adrenergic Neurons
Na+
Tyrosine
Dopa
MAO
Ca++
Dopamine

Dopamine is
converted to
epinephrine
Receptor
Word of the Day:
• SYMPATHOMIMETIC
– Adrenergic drug which acts directly on
adrenergic receptor, activating it
Adrenergic Agonists
• Direct
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Albuterol
Dobutamine
Dopamine
Isoproteranol
• Indirect
– Amphetamine
• Mixed
– Ephidrine
Adrenergic Receptors
• Two Families:
– Alpha and Beta
– Based on affinity to
adrenergic agonists
Epinephrine
Norepinephrine
Isoproteranol
Epinephrine
Isoproteranol
• Alpha affinity:
• epinephrine≥norepinephrine>>
isoproteranol
• Beta affinity:
• Isoproteranol>epinephrine>
norepinephrine
Norepinephrine
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 effects (vasodilation)
• High dose: alpha effects (vasoconstriction)
• Therapeutic uses: emerg tmt of asthma, glaucoma,
anaphyslaxis
– (what about terbutaline?)
Adrenergic Agonists
• Indirect:
– Cause NE release only
– Example:
• Amphetamine
– CNS stimulant
– Increases BP by alpha effect on vasculature, beta effect on heart
Mixed-Action
• Causes NE release AND stimulates receptor
• Example:
– Ephedrine:
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What type of 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 “first dose” response (what is this?)
Adrenergic Antagonists
• Beta Blockers
• Example: Propranolol
– Non-selective (blocks beta 1 and beta 2)
– Effects:
• ↓ cardiac output, vasodilation, bronchoconstriction
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
Adrenergic Antagonists
• Eg: Nadolol
– Nonselective beta blocker
– Used for glaucoma
• Eg: Labetolol
– Alpha AND beta blocker
– Used in treating PIH
Drugs that Affect Uptake/Release
• Eg: Cocaine
– Blocks Na+/K+ ATPase
– Prevents reuptake of
epinephrine/norepinephrine
Treatment of Movement
Disorders
What Regulates Movement?
Basal Ganglia 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 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
BASAL GANGLIA SYSTEM
Feedback loops - complex
- form direct & indirect pathways
- balance excitatory & inhibitory
activities
Neurotransimitters:
Excitatory - ACh
glutamate
Inhibitory - dopamine
GABA
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
PATHOPHYSIOLOGY OF PARKINSON’S
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
4. Drug of Choice: LEVODOPA
Why is it used?
- virtually all pt’s with PD show a response to
levodopa
- improves quality of life
- in use since 1960’s
- 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 levodopa’s
peripheral conversion to dopamine)
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
APPROACHES cont’d
• 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