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Drugs Affecting the Autonomic Nervous System
Pharmacology 49.222Bill Diehl-Jones RN, PhD
Faculty of Nursing and Department of Zoology
Agenda
• 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:– CV, respiratory systems– Wakefulness
• Clinical Link:– Disturbances in the RAS are
linked to sleep-wake disturbances Reticular Formation
Ascending Sensory Tracts
Thalamus
Radiation Fibres
Visual Inputs
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
Sensory
Motor
Sympathetic
Parasympathetic
Parasympathetic
Preganglionic Nerves
Sympathetic AND Parasympathetic preganglionic fibres release Acetylcholine (ACh)
ACh has two types of 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 Effectors?
• NE from postganglionic sympathetics binds to Adrenergic Receptors
• ACh from postganglionic parasympathetics binds to Muscarinic Receptors
ACh
MuscarinicReceptor
NE
AdrenergicReceptor
Sympathetic Parasympathetic
Cholinergic Neurons
Na+
Choline
Ca++
Receptor
Acetylcholinesterase
Acetylation
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
• 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
• Do not cross blood-brain barrier Na+ ChannelNicotinic Receptor
ACh
CurareNa+
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
Dopamine
Dopa
Dopamine is converted toepinephrine
Word of 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 affinity to
adrenergic agonists• Alpha affinity:
• epinephrine≥norepinephrine>> isoproteranol
• Beta affinity:• Isoproteranol>epinephrine>
norepinephrine
Epinephrine Norepinephrine Isoproteranol
Epinephrine NorepinephrineIsoproteranol
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:• 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 BRAINSherwood, 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 Inhibitory - dopamine
glutamate 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