lecture 1: introduction to pharmacology

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

MotorSympathetic

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 body2. Select & maintain purposeful motor activity while suppressing useless/unwanted patterns

of movement3. 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 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

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