Drugs Affecting the Autonomic Nervous System - PowerPoint Presentation

Slide1

Drugs Affecting the Autonomic Nervous System

Pharmacology 49.222

Bill Diehl-Jones RN, PhD

Faculty of Nursing and Department of ZoologySlide2

Agenda

A Zen Review

Overview of CNS and ANS

Neurotransmitters and 2

nd

Messengers

Cholinergic Agonists and Antagonists

Adrenergic Agonists and Antagonists

Movement Disorder DrugsSlide3

Organization of the Nervous System:CNS

Three divisions of brain:

Forebrain

cerebral hemispheres

Midbrain

Corpora quadrigemini, tegmentum, cerebral pedunclesHindbrainCerebellum, pons, medullaBrainstem:Midbrain, medulla, ponsConnects cerebrum, cerebeluum, spinal cordSlide4

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 InputsSlide5

Organization of the Peripheral Nervous System

Three major divisions:

Efferent

Somatic (motor)

Autonomic

Sympathetic and ParasympatheticAfferentSensorySlide6

Some Basic Plumbing:

The Peripheral Nervous System

Sensory

Motor

Sympathetic

Parasympathetic

ParasympatheticSlide7

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

AChSlide8

Postganglionic Nerves

Sympathetics release Norepinephrine

Parasympathetics release ACh

Norepinephrine binds to adrenergic receptors

ACh binds to Muscarinic receptors

Sympathetic

Parasympathetic

ACh

NESlide9

What Happens at the Effectors?

NE from postganglionic sympathetics binds to Adrenergic Receptors

ACh from postganglionic parasympathetics binds to Muscarinic Receptors

ACh

Muscarinic

Receptor

NE

Adrenergic

Receptor

Sympathetic

ParasympatheticSlide10

Cholinergic Neurons

Na

+

Choline

Ca

++

Receptor

Acetylcholinesterase

Acetylation

Slide11

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 flavourSlide12

Cholinergic Agonists

Acetylcholine

Bethanechol

Carbachol

PilocarpineSlide13

General Effects of Cholinergic Agonists

Decrease heart rate and cardiac output

Decrease blood pressure

Increases GI motility and secretion

Pupillary constrictionSlide14

Cholinergic Antagonists

Antimuscarinic agents

Atropine, ipratropium

Ganglion blockers

nicotine

Neuromuscular blockersVecuronium, tubocuarine, pancuroniumSlide15

Where are some of these drugs used?Slide16

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?Slide17

Scopalamine(also a cholinergic antagonist)

Also from Belladonna

Peripheral effects similar to atropine

More CNS effects:

Anti-motion sickness

amnesiacSlide18

Trimethaphan(yet another cholinergic antagonist)

Competitive nicotinic ganglion blocker

Used to lower blood pressure in emergenciesSlide19

Neuromuscular Blockers

Look like acetylcholine

Either work as antagonists or agonists

Two flavours:

Non-depolarizing (antagonist)

Eg: tubocurarineBlock ion channels at motor end plateDepolarizing (agonist)Eg: succinylcholineActivates receptorSlide20

Turbocurarine

Used during surgery to relax muscles

Increase safety of anaesthetics

Do not cross blood-brain barrier

Na

+

Channel

Nicotinic Receptor

ACh

Curare

Na

+Slide21

Succinylcholine

Uses:

endotracheal intubations

What is this?

Why?

electroconvulsive shock therapyProblem: can cause apnea

+

+

+

+

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+

+

-

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-

-

+

+

+

+

+

+

-

-

-

-

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-

Na

+

Na

+

Phase I

Phase IISlide22

Adrenergic Neurons

Na

+

Tyrosine

Ca

++

Receptor

MAO



Dopamine

Dopa

Dopamine is

converted to

epinephrineSlide23

Word of the Day:

SYMPATHOMIMETIC

Adrenergic drug which acts directly on adrenergic receptor, activating itSlide24

Adrenergic Agonists

Direct

Albuterol

Dobutamine

Dopamine

IsoproteranolIndirectAmphetamineMixed EphidrineSlide25

Adrenergic Receptors

Two Families:

Alpha and Beta

Based on affinity to adrenergic agonists

Alpha affinity:

epinephrine≥norepinephrine>> isoproteranolBeta affinity:Isoproteranol>epinephrine> norepinephrine

Epinephrine

Norepinephrine

Isoproteranol

Epinephrine

Norepinephrine

IsoproteranolSlide26

What do these receptors do?

Alpha 1

Vasoconstriction,

↑

BP,

↑ tonus sphincter musclesAlpha 2Inhibit norepinephrine, insulin releaseBeta 1Tachycardia, ↑ lipolysis, ↑ myocardial contractilityBeta 2

Vasodilation, bronchodilation, ↓insulin releaseSlide27

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?)Slide28

Adrenergic Agonists

Indirect:

Cause NE release only

Example:

Amphetamine

CNS stimulantIncreases BP by alpha effect on vasculature, beta effect on heartSlide29

Mixed-Action

Causes NE release AND stimulates receptor

Example:

Ephedrine:

What type of drug?

Alpha and beta stimulantUse: asthma, nasal spraysslower actionSlide30

Adrenergic Antagonists

Alpha blockers

Eg: Prazosin

Selective alpha 1 blocker

Tmt: hypertension

relaxes arterial and venous smooth muscleCauses “first dose” response (what is this?)Slide31

Adrenergic Antagonists

Beta Blockers

Example: Propranolol

Non-selective (blocks beta 1 and beta 2)

Effects:

↓ cardiac output, vasodilation, bronchoconstrictionSlide32

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 2Causes less bradycardiaSlide33

Adrenergic Antagonists

Eg: Nadolol

Nonselective beta blocker

Used for glaucoma

Eg: Labetolol

Alpha AND beta blockerUsed in treating PIHSlide34

Drugs that Affect Uptake/Release

Eg: Cocaine

Blocks Na+/K+ ATPase

Prevents reuptake of epinephrine/norepinephrineSlide35

Treatment of Movement DisordersSlide36

What Regulates Movement?

Basal Ganglia are involvedSlide37

Example: Parkinsons’s Disease

Symptoms ?Slide38

FRONTAL SECTION OF BRAIN

Sherwood, 2001 p 145Slide39

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 cortexSlide40

BASAL GANGLIA SYSTEM

Feedback loops

-

complex

- form direct & indirect pathways - balance excitatory & inhibitory

activitiesNeurotransimitters: Excitatory - ACh Inhibitory - dopamine glutamate GABASlide41

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 gaitSlide42

PATHOPHYSIOLOGY OF PARKINSON’S DISEASE

Major pathological features:

1.

Death of dopamine producing cells in the SNc

leads to overactivation of the indirect pathway2. Presence of Lewy bodies –small eosinophilic inclusions found in the neurons of SNcResults in:- degeneration of the nigrostriatal pathway

- decreased thalamic excitation of the motor cortex Slide43

4. Drug of Choice: LEVODOPA

Why is it used?

-

v

irtually 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)Slide44

5. OTHER APPROACHES TO TREATMENT

Pharmacological:

Dopamine agonists:

ie. Bromocriptine or pergolide mesylate

Selective inhibitor of type B monoamine oxidase: ie.SelegilineAntivirals: ie. AmantadineAnticholinergics: ie. TrihexyphenidylCOMT inhibitors: ie. EntacaponeSlide45

APPROACHES cont’d

Surgical

:

Pallidotomy & Thalotomy:

m

icroelectrode destruction of specific site in the basal ganglia Deep brain stimulation: electrode implantation with external pacemakerFetal nigral transplantation:Implantation of embryonic dopaminergic neurons into the substantia nigra for growth and supply of dopamine