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