Drugs Affecting the Autonomic
Nervous System

Pharmacology 49.222
Bill Diehl-Jones RN, PhD
Faculty of Nursing and Departme...
Agenda
•
•
•
•
•
•

A Zen Review
Overview of CNS and ANS
Neurotransmitters and 2nd Messengers
Cholinergic Agonists and Ant...
Organization of the Nervous System:
CNS
• Three divisions of brain:
– Forebrain
• cerebral hemispheres

– Midbrain
• Corpo...
Organization of the Nervous System:
Reticular Activating System
• Key Regulatory Functions:

Radiation Fibres

– CV, respi...
Organization of the Peripheral
Nervous System
• Three major divisions:
– Efferent
• Somatic (motor)
• Autonomic
– Sympathe...
Some Basic Plumbing:
The Peripheral Nervous System

Parasympathetic
Sensory

Sympathetic
Motor

Parasympathetic
Preganglionic Nerves
Sympathetic

Parasympathetic

Sympathetic AND Parasympathetic
preganglionic fibres release
Acetylchol...
Postganglionic Nerves
Sympathetic

Parasympathetic

• Sympathetics release Norepinephrine
• Parasympathetics release ACh
•...
What Happens at the Effectors?
• NE from postganglionic sympathetics binds to
Adrenergic Receptors
• ACh from postganglion...
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
– Rese...
Cholinergic Agonists
•
•
•
•

Acetylcholine
Bethanechol
Carbachol
Pilocarpine
General Effects of Cholinergic
Agonists
• Decrease heart rate and cardiac output
• Decrease blood pressure
• Increases GI ...
Cholinergic Antagonists
• Antimuscarinic agents
– Atropine, ipratropium

• Ganglion blockers
– nicotine

• Neuromuscular
b...
Where are some of these drugs
used?
Atropine
(a cholinergic antagonist)
• Comes from Belladonna
– High affinity for muscarinic
receptors
– Causes “mydriasis” ...
Scopalamine
(also a cholinergic antagonist)

• Also from Belladonna
• Peripheral effects
similar to atropine
• More CNS ef...
Trimethaphan
(yet another cholinergic antagonist)

• Competitive nicotinic
ganglion blocker
• Used to lower blood
pressure...
Neuromuscular Blockers
• Look like acetylcholine
• Either work as antagonists or agonists
• Two flavours:
– Non-depolarizi...
Turbocurarine
• Used during surgery to
relax muscles
– Increase safety of
anaesthetics

ACh
Curare

• Do not cross bloodNi...
Succinylcholine
• Uses:
– endotracheal intubations
• What is this?
• Why?

Na+
- - -

- - -

+ ++ +

+ + +

Phase I

– ele...
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
–
–
–
–

Albuterol
Dobutamine
Dopamine
Isoproteranol

• Indirect
– Amphetamine

• Mixed
– Eph...
Adrenergic Receptors
• Two Families:
– Alpha and Beta
– Based on affinity to
adrenergic agonists

Epinephrine

Norepinephr...
What do these receptors do?
• Alpha 1
– Vasoconstriction, ↑ BP, ↑ tonus sphincter muscles

• Alpha 2
– Inhibit norepinephr...
Adrenergic Angonists
• Direct acting:
– Epinephrine: interacts with both alpha and beta
• Low dose: mainly beta effects (v...
Adrenergic Agonists
• Indirect:
– Cause NE release only
– Example:
• Amphetamine
– CNS stimulant
– Increases BP by alpha e...
Mixed-Action
• Causes NE release AND stimulates receptor
• Example:
– Ephedrine:
•
•
•
•

What type of drug?
Alpha and bet...
Adrenergic Antagonists
• Alpha blockers
– Eg: Prazosin
• Selective alpha 1 blocker
• Tmt: hypertension
– relaxes arterial ...
Adrenergic Antagonists
• Beta Blockers
• Example: Propranolol
– Non-selective (blocks beta 1 and beta 2)
– Effects:
• ↓ ca...
Adrenergic Antagonists
• Eg: Atenolol, Metoprolol
– Preferentially block beta 1; no beta effects (why
is this good?)

• Pa...
Adrenergic Antagonists
• Eg: Nadolol
– Nonselective beta blocker
– Used for glaucoma

• Eg: Labetolol
– Alpha AND beta blo...
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 ...
BASAL GANGLIA SYSTEM

Feedback loops - complex
- form direct & indirect pathways
- balance excitatory & inhibitory
activit...
DOPAMINE
• major NT regulating subconscious movements of skeletal
muscles
• majority located in the terminals of pathway s...
PATHOPHYSIOLOGY OF PARKINSON’S
DISEASE
• Major pathological features:
1. Death of dopamine producing cells in the SNc
lead...
4. Drug of Choice: LEVODOPA
Why is it used?
- virtually all pt’s with PD show a response to
levodopa
- improves quality of...
5. OTHER APPROACHES TO TREATMENT

• Pharmacological:
– Dopamine agonists: ie. Bromocriptine or pergolide
mesylate

– Selec...
APPROACHES cont’d

• Surgical:
• Pallidotomy & Thalotomy:
– microelectrode destruction of specific site in the basal
gangl...
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Pharm ans

  1. 1. Drugs Affecting the Autonomic Nervous System Pharmacology 49.222 Bill Diehl-Jones RN, PhD Faculty of Nursing and Department of Zoology
  2. 2. Agenda • • • • • • A Zen Review Overview of CNS and ANS Neurotransmitters and 2nd Messengers Cholinergic Agonists and Antagonists Adrenergic Agonists and Antagonists Movement Disorder Drugs
  3. 3. 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
  4. 4. 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
  5. 5. Organization of the Peripheral Nervous System • Three major divisions: – Efferent • Somatic (motor) • Autonomic – Sympathetic and Parasympathetic – Afferent • Sensory
  6. 6. Some Basic Plumbing: The Peripheral Nervous System Parasympathetic Sensory Sympathetic Motor Parasympathetic
  7. 7. 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
  8. 8. Postganglionic Nerves Sympathetic Parasympathetic • Sympathetics release Norepinephrine • Parasympathetics release ACh • Norepinephrine binds to adrenergic receptors ACh • ACh binds to Muscarinic receptors NE
  9. 9. 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
  10. 10. Cholinergic Neurons Na+ Choline Acetylation Ca++  Acetylcholinesterase Receptor
  11. 11. 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
  12. 12. Cholinergic Agonists • • • • Acetylcholine Bethanechol Carbachol Pilocarpine
  13. 13. General Effects of Cholinergic Agonists • Decrease heart rate and cardiac output • Decrease blood pressure • Increases GI motility and secretion • Pupillary constriction
  14. 14. Cholinergic Antagonists • Antimuscarinic agents – Atropine, ipratropium • Ganglion blockers – nicotine • Neuromuscular blockers – Vecuronium, tubocuarine, pancuronium
  15. 15. Where are some of these drugs used?
  16. 16. 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?
  17. 17. Scopalamine (also a cholinergic antagonist) • Also from Belladonna • Peripheral effects similar to atropine • More CNS effects: – Anti-motion sickness – amnesiac
  18. 18. Trimethaphan (yet another cholinergic antagonist) • Competitive nicotinic ganglion blocker • Used to lower blood pressure in emergencies
  19. 19. 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
  20. 20. Turbocurarine • Used during surgery to relax muscles – Increase safety of anaesthetics ACh Curare • Do not cross bloodNicotinic Receptor brain barrier Na+ Na+ Channel
  21. 21. Succinylcholine • Uses: – endotracheal intubations • What is this? • Why? Na+ - - - - - - + ++ + + + + Phase I – electroconvulsive shock therapy Na+ • Problem: can cause apnea ++ + ++ + - - - - - Phase II
  22. 22. Adrenergic Neurons Na+ Tyrosine Dopa MAO Ca++ Dopamine  Dopamine is converted to epinephrine Receptor
  23. 23. Word of the Day: • SYMPATHOMIMETIC – Adrenergic drug which acts directly on adrenergic receptor, activating it
  24. 24. Adrenergic Agonists • Direct – – – – Albuterol Dobutamine Dopamine Isoproteranol • Indirect – Amphetamine • Mixed – Ephidrine
  25. 25. 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
  26. 26. 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
  27. 27. 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?)
  28. 28. Adrenergic Agonists • Indirect: – Cause NE release only – Example: • Amphetamine – CNS stimulant – Increases BP by alpha effect on vasculature, beta effect on heart
  29. 29. Mixed-Action • Causes NE release AND stimulates receptor • Example: – Ephedrine: • • • • What type of drug? Alpha and beta stimulant Use: asthma, nasal sprays slower action
  30. 30. 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?)
  31. 31. Adrenergic Antagonists • Beta Blockers • Example: Propranolol – Non-selective (blocks beta 1 and beta 2) – Effects: • ↓ cardiac output, vasodilation, bronchoconstriction
  32. 32. 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
  33. 33. Adrenergic Antagonists • Eg: Nadolol – Nonselective beta blocker – Used for glaucoma • Eg: Labetolol – Alpha AND beta blocker – Used in treating PIH
  34. 34. Drugs that Affect Uptake/Release • Eg: Cocaine – Blocks Na+/K+ ATPase – Prevents reuptake of epinephrine/norepinephrine
  35. 35. Treatment of Movement Disorders
  36. 36. What Regulates Movement? Basal Ganglia are involved
  37. 37. Example: Parkinsons’s Disease • Symptoms ?
  38. 38. FRONTAL SECTION OF BRAIN Sherwood, 2001 p 145
  39. 39. 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
  40. 40. BASAL GANGLIA SYSTEM Feedback loops - complex - form direct & indirect pathways - balance excitatory & inhibitory activities Neurotransimitters: Excitatory - ACh glutamate Inhibitory - dopamine GABA
  41. 41. 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
  42. 42. 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
  43. 43. 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)
  44. 44. 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
  45. 45. 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

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