1. Drugs Affecting the Autonomic Nervous System
Pharmacology
Bill Diehl-Jones RN, PhD
Faculty of Nursing and Department of Zoology

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. 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. 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
Radiation Fibres
Thalamus
Visual Inputs
Reticular Formation
Ascending Sensory Tracts

5. Organization of the Peripheral Nervous System
Three major divisions:
Efferent
Somatic (motor)
Autonomic
Sympathetic and Parasympathetic
Afferent
Sensory

6. Some Basic Plumbing: The Peripheral Nervous System
Sensory
Motor
Sympathetic
Parasympathetic

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. Postganglionic Nerves
Sympathetic
Parasympathetic
Sympathetics release Norepinephrine
Parasympathetics release ACh
Norepinephrine binds to adrenergic receptors
ACh binds to Muscarinic receptors
ACh NE

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. Cholinergic Neurons Na+ Choline Ca++  Receptor Acetylation
Acetylcholinesterase
Receptor

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. Cholinergic Agonists
Acetylcholine
Bethanechol
Carbachol
Pilocarpine

13. General Effects of Cholinergic Agonists
Decrease heart rate and cardiac output
Decrease blood pressure
Increases GI motility and secretion
Pupillary constriction

14. Cholinergic Antagonists
Antimuscarinic agents
Atropine, ipratropium
Ganglion blockers
nicotine
Neuromuscular blockers
Vecuronium, tubocuarine, pancuronium

15. Where are some of these drugs used?

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. Scopalamine (also a cholinergic antagonist)
Also from Belladonna
Peripheral effects similar to atropine
More CNS effects:
Anti-motion sickness
amnesiac

18. Trimethaphan (yet another cholinergic antagonist)
Competitive nicotinic ganglion blocker
Used to lower blood pressure in emergencies

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. Turbocurarine Used during surgery to relax muscles
Increase safety of anaesthetics
Do not cross blood-brain barrier
ACh
Na+
Curare
Nicotinic Receptor
Na+ Channel

21. Succinylcholine Uses: Problem: can cause apnea
endotracheal intubations
What is this?
Why?
electroconvulsive shock therapy
Problem: can cause apnea
Na+ - - - - - - + + + + + + +
Phase I
Na+ + + + + + + - - - - - -
Phase II

22. Adrenergic Neurons Na+ Tyrosine Ca++  Receptor Dopa MAO Dopamine
Dopamine is
converted to
epinephrine
Receptor

23. Word of the Day: SYMPATHOMIMETIC
Adrenergic drug which acts directly on adrenergic receptor, activating it

24. Adrenergic Agonists Direct Indirect Mixed Albuterol Dobutamine
Dopamine
Isoproteranol
Indirect
Amphetamine
Mixed
Ephidrine

25. Adrenergic Receptors Two Families: Alpha affinity: Beta affinity:
Alpha and Beta
Based on affinity to adrenergic agonists
Alpha affinity:
epinephrine≥norepinephrine>> isoproteranol
Beta affinity:
Isoproteranol>epinephrine> norepinephrine
Epinephrine
Norepinephrine
Isoproteranol
Isoproteranol
Epinephrine
Norepinephrine

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. 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. Adrenergic Agonists Indirect: Cause NE release only Example:
Amphetamine
CNS stimulant
Increases BP by alpha effect on vasculature, beta effect on heart

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. 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. Adrenergic Antagonists
Beta Blockers
Example: Propranolol
Non-selective (blocks beta 1 and beta 2)
Effects:
↓ cardiac output, vasodilation, bronchoconstriction

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. Adrenergic Antagonists
Eg: Nadolol
Nonselective beta blocker
Used for glaucoma
Eg: Labetolol
Alpha AND beta blocker
Used in treating PIH

34. Drugs that Affect Uptake/Release
Eg: Cocaine
Blocks Na+/K+ ATPase
Prevents reuptake of epinephrine/norepinephrine

35. Treatment of Movement Disorders

36. What Regulates Movement?
Basal Ganglia are involved

37. Example: Parkinsons’s Disease
Symptoms ?

38. FRONTAL SECTION OF BRAIN Sherwood, 2001 p 145
Refer to enlargement in notes
CEREBRUM –is the largest portion of the brain, divided into 2 halves R & L hemispheres, which are connected to each other by the corpus calosum – which allows a constant exchange of info b/w the 2 halves. Each hemisphere is composed of a thin outer shell of gray matter which is the cerebral cortex which covers a thick central core of white matter. It is deep within this white matter that the basal nuclei are located.
Gray matter = computers to the CNS
White matter= wires that connect the computers to each other
BASAL GANGLIA- are the deep nuclei comprised of gray matter structures, that lie beneath the cerebral cortex, surrounding the thalamus and hypothalamus
SUBCORTICAL STRUCTURES- include Basal nuclei in the cerebrum, thalamus, and hypothalamus
- form a complex relationship with the cortex in higher brain function

39. Role of basal ganglia: BASAL GANGLIA cont’d
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
– system doesn’t influence movement thru spinal cord pathways but rather acts as part of FB loops to all areas of cortex with primary input to motor areas.
-A balance b/w excitatory & inhibitory NTs is required for smooth, purposeful movement
-The BG do not directly influence the efferent motor neurons that bring about muscle contraction, but instead act by modifying ongoing activity in motor pathways. They accomplish this task by receiving and sending out information, as seen by the numerous fibers that link them to other regions of the brain.
BG play a complex role in the control of movement.
May have other nonmotor functions that are less understood.

40. Feedback loops - complex
BASAL GANGLIA SYSTEM
Feedback loops - complex
- form direct & indirect pathways balance excitatory & inhibitory activities
Neurotransimitters:
Excitatory - ACh Inhibitory - dopamine
glutamate GABA
Summary of the key features involved in BG system

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
The dopaminergic system appears to have an underlying influence on motor activity
excites the direct pathway, inhibits the indirect pathway
Each dopaminergic neuron makes thousands of synaptic contacts with the striatum and therefore modulates the activity of a large number of cells

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
1. Loss of projection in the striatum, decreased D1 receptors
Why they die ? Is unkown possible causes next slide
2 Lewy bodies ? Mechanism leading to their formation, but their presence always signifies neuronal degeneration and nerve cell loss, PD can’t occur without them being present in some of the degenerating nerve cells (Gibb,’92)
-80% of dopaminergic neurons are lost before clinical S&S appear (Conely & Kirchner, ’99)
-Normal BG Fxn requires a balance B/W E and inhib acitivity, symptoms occur d/t imbalance
-The lack of Dopamine in BG and excess of ACh lead to hypertonia, tremor, rigidity
If the thalamus is inhibited too much, the cortical motor system is supressed

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)
Despite > 25 yr in use, Action still not fully understood, believed to be decarboxylated… is a dopamine precursor
Levodopa is the only example in clinical neurology of a successful correlation of a Nerotransmitter effect via po replacement therapy
_ Debate re: timing of initiation of TX ? Wait until Sx are worse to delay use
Disadvantages:
-occur with long term use – motor complications, dyskinesia in 30 % of pts after 2 yr tx – may be as high as 50 –90% after 5 – 10 yrs tx Why? – one theory – as PD progresses, remaining dop neurons develop a decreased ability to store dop, & thus, rely more on exogenous dopa
ON/OFF syndrome
Side effects: CNS-nightmares, aggression, invol movemt, body jerks, GI dry mouth, constipation,EENT blurred vision, excessv salivation
= a narrow therapeutic window

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
TX often determined according to age
stimulates dop receptors, longer acting, ? Neuro protective thru antioxidant effects, ? Slow progression of PD, may be used as monotherapy of adjunctive
antivirals – most effective with more prominent akinesia or ridgidity, often used in early PD
most effective with prominent tremor
COMT – inhibits the COMT enzyme that breaks down levodopa, may increase CNS delivery of dopamine, may also provide a more controlled concentraion of levodopa, decreases pulsativity
Further research re: meds is needed

45. Pallidotomy & Thalotomy:
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
Surgical TX has been around since the 1930’s
Main goal: suppress sympt, by modifying the pathophsiological process behind the sympt, or restoring N physio at least in part, does not provide a cure. , may compliment drug TX
Effects depend on the method used and target chosen in the brain
Controversy re: timing ; usually reserved for those whose symptoms are severe, & meds no longer effective
Usually uses a thermalcoagulation method of destruction, usu unilateral,( bilat – risk speech/cognitive prob) may have a 50% in rigidity, bradyinesia off time, dyskinesia, & tremor – may last 6 mos – 4 yrs (Lyons&Keller, 01)
Thalotomy – lesion at thalamus- helps regulate tremor
2. Inhibits activity in brain area being stimulated, applies a technique that was developed for cardiac pts, provides continual stimulation, is adjustable, reversible, FDA approved for the thalamus only, most effectv with tremor, dykinesia symptoms from 50 –90%, effects may last > 10 yrs Adv: little tissue destrution
3.Around since the 1980’s, + results seen up to 10 yrs post, problem ++ ethical concerns – uses fetal tissue from aborted fetuses, need 3-5 donars / hemisphere – studies being done on the use of porcine neurons
? Stem cell research
Problems with surgery: only 100 surgeon worldwide able to perform these procedures (Harshaw,00), ++$$$, availabitlity, risk