Organization of the nervous system
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Organization of The Nervous System. Central Nervous System. Peripheral Nervous System. Autonomic Nervous System. Somatic Nervous System. Sympathetic. Parasympathetic. a. b. a. Sympathetic Ganglionic Synapse. Acetylcholinesterase. Ca 2+. Na +. ACH. Action Potential. Nicotinic

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Organization of The Nervous System

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Organization of the nervous system

Organization of The Nervous System

Central Nervous System

Peripheral Nervous System

Autonomic Nervous System

Somatic Nervous System

Sympathetic

Parasympathetic


Organization of the nervous system

a

b

a

Sympathetic Ganglionic Synapse

Acetylcholinesterase

Ca2+

Na+

ACH

Action Potential

Nicotinic

Receptor

Na+

Preganglionic neuron

Postganglionic neuron


Organization of the nervous system

Na+

Sympathetic Organ Synapse

Ca2+

Effector

Organ

G

NE

Action Potential

Adrenergic

Receptor

Postganglionic neuron


Organization of the nervous system

Action Potential

Pharmacologic manipulation of the adrenergic system

Na+

Presynaptic neuron

Tyrosine

Na+

Dopamine

Tyrosine

MAO

H+

DA

NE

NE

Ca2+

Uptake 1

a2

(-)

Na+, Cl-

NE

NE

NE

NE

Uptake 2

a1

b

Effector organ


Synthesis of catecholamines

H

O

C

H

C

H

N

H

2

2

H

O

H

O

C

H

C

H

N

H

2

2

O

H

H

O

H

O

C

H

C

H

N

H

2

O

H

C

H

3

Synthesis of catecholamines

T

Y

R

O

S

I

N

E

C

O

O

H

t

y

r

o

s

i

n

e

h

y

d

r

o

x

y

l

a

s

e

H

O

H

O

C

H

C

H

N

H

D

O

P

A

2

2

C

O

O

H

a

r

o

m

a

t

i

c

L

-

a

m

i

n

o

a

c

i

d

d

e

c

a

r

b

o

x

y

l

a

s

e

H

O

H

O

C

H

D

O

P

A

M

I

N

E

C

H

N

H

2

2

2

b

d

o

p

a

m

i

n

e

-

h

y

d

r

o

x

y

l

a

s

e

N

O

R

E

P

I

N

E

P

H

R

I

N

E

p

h

e

n

y

l

e

t

h

a

n

o

l

a

m

i

n

e

-

N

-

m

e

t

h

y

l

t

r

a

n

s

f

e

r

a

s

e

E

P

I

N

E

P

H

R

I

N

E


Metabolism of norepinephrine

Metabolism of norepinephrine

Monoamine Oxidase (MAO)

3,4-Dihydroxyphenyl-

glycolaldehyde

Norepinephrine

Aldehyde

Reductase

Catechol O-Methyl-

transferase (COMT)

3,4-Dihydroxyphenyl-

ethylene glycol

1) Alcohol Dehydrogenase

2) Aldehyde Dehydrogenase

3-Methoxy-4-hydroxymandelic acid

(Vanilylmandelic acid; VMA)

3-Methoxy-4-hydroxy-

phenylethylene glycol


Metabolism of norepinephrine1

Metabolism of norepinephrine

1) MAO

2) Aldehyde Dehydrogenase

3,4-Dihydroxymandelic Acid

Norepinephrine

COMT

COMT

1) MAO

2) Aldehyde Dehydrogenase

3-Methoxy-4-hydroxymandelic acid

(Vanilylmandelic acid; VMA)

Normetanephrine


Direct acting adrenergic receptor agonists

Direct acting adrenergic receptor agonists

H

O

Dopamine

(Intropin)

H

O

C

H

C

H

N

H

2

2

2

H

O

Norepinephrine

(Levophed)

H

O

C

H

C

H

N

H

2

2

O

H

H

O

Epinephrine

(Adrenalin)

H

O

C

H

C

H

N

H

2

O

H

C

H

3


Receptors and signal transduction in the ans

a1

a2

b

a1B

a1D

a2A

a2B

a2C

b1

b2

Receptors and signal transduction in the ANS

Adrenergic Receptors

a1A

b3


Direct acting adrenergic receptor agonists a 1 receptors

NH

3

COOH

Direct acting adrenergic receptor agonists:a1 receptors

Phospho

-

  • Phenylephrine (Neosynephrine)

  • Methoxamine (Vasoxyl)

  • Oxymetazoline (Visine)

lipase C

(+)

G

q

PIP

2

H

O

IP

Diacylglycerol

3

C

H

C

H

N

H

C

H

2

3

2+

Increase Ca

Activate Protein

Kinase

C

O

H

P

h

e

n

y

l

e

p

h

r

i

n

e

Response


Direct acting adrenergic receptor agonists a 2 receptors

Direct acting adrenergic receptor agonists:a2 receptors

  • Clonidine (Catapres)

  • Methyldopa (Aldomet)

  • Guanabenz (Wytensin)

  • Guanfacine (Tenex)

  • Tizanidine (Zanaflex)

NH

3

Adenylate Cyclase

(-)

G

I

X

K

+

(+)

ATP

cAMP

COOH

Reduce

cAMP

-Dependent

Protein

Kinase

Activity

C

l

o

n

i

d

i

n

e

Response


Direct acting adrenergic receptor agonists b receptors

Direct acting adrenergic receptor agonists:b receptors

Non-selective

  • Isoproterenol (Isuprel)

    b1-selective

  • Dobutamine (Dobutrex)

  • Dopamine (Intropin)

    b2-selective

  • Terbutaline (Brethine, Bricanyl)

  • Metaproterenol (Metaprel, Alupent)

  • Albuterol (Proventil, Ventolin)

  • Salmeterol (Serevent)

  • Ritodrine (Yutopar)

H

O

C

H

3

H

O

C

H

C

H

N

H

C

H

2

C

H

3

O

H

I

s

o

p

r

o

t

e

r

e

n

o

l


Direct acting adrenergic receptor agonists b receptors1

Direct acting adrenergic receptor agonists:b receptors

NH

3

Adenylate Cyclase

(+)

G

S

ATP

cAMP

COOH

Increase

cAMP

-Dependent

Protein

Kinase

Activity

Response


Molecular actions of norepinephrine

Molecular actions of norepinephrine

VI

Phe 290

VII

Ser 207

I

V

Ser 204

II

III

IV

Asp 113


Selectivity of adrenergic receptor agonists

Selectivity of adrenergic receptor agonists

Phenylephrine

Epinephrine

Norepinephrine

Isoproterenol


Cardiovascular effects of sympathomimetics

Cardiovascular effects of sympathomimetics

Isoproterenol

Norepinephrine

Epinephrine

100

PULSE

RATE

(min)

50

180

BLOOD

PRESSURE

(mm Hg)

120

80

PERIPHERAL

RESISTANCE

0

15

0

15

0

15

TIME

(min)


Direct acting adrenergic receptor agonists norepinephrine and epinephrine

Direct acting adrenergic receptor agonists:Norepinephrine and Epinephrine

  • Potent a and b1 receptor agonist

  • Substrate for MAO and COMT

  • Parenteral administration

  • Used as a pressor

  • Sodium bisulfite used in preparations to prevent oxidation

l-Norepinephrine (Levophed)


Direct acting adrenergic receptor agonists norepinephrine and epinephrine1

Direct acting adrenergic receptor agonists:Norepinephrine and Epinephrine

  • Potent a, b1, and b2 receptor agonist

  • Substrate for MAO and COMT

  • Parenteral administration

  • Sodium bisulfite used in preparations to prevent oxidation

  • Available as many salts: hydrochloride, nitrate, bitartrate

  • Uses: Anaphylaxis, glaucoma, in combination with local anesthetics

Epinephrine (Adrenalin)


Direct acting adrenergic receptor agonists a 1 receptor agonists

Direct acting adrenergic receptor agonists:a1 receptor agonists

  • Potent a1 receptor agonist

  • Substrate for MAO

  • Administration: Parenteral, oral, local

  • Uses: Mydriasis without cycloplegia, glaucoma, pressor, nasal decongestant

Phenylephrine (Neo-Synephrine)

  • Potent a1 receptor agonist

  • Potent vasoconstrictor

  • Parenteral administration

  • Use: Pressor agent

Methoxamine (Vasoxyl)


Direct acting adrenergic receptor agonists a 1 receptor agonists 2 aralkylimidazolines

Direct acting adrenergic receptor agonists:a1 receptor agonists: 2-aralkylimidazolines

R = substituted aromatic ring structure

X = methylene or amino

The imidazoline cation is resonance stabilized allowing the + charge to be spread over the entire three atom system. Thus, imidazolines are more basic than simple aliphatic amines.


Direct acting adrenergic receptor agonists a 1 receptor agonists 2 aralkylimidazolines1

Direct acting adrenergic receptor agonists:a1 receptor agonists: 2-aralkylimidazolines

  • Partial agonists at a receptors

  • Administered locally/topically to promote vasoconstriction

  • Basic nature of imidazoline ring causes compounds to exist in ionized form at physiologic pH

  • Tachyphylaxis/Desensitization

  • Uses: Nasal and ophthalmic decongestants

R=

R=

Naphazoline (Privine)

Tetrahydrozoline

(Visine)

R=

Oxymetazoline (Afrin, Visine)


Direct acting adrenergic receptor agonists a 2 receptor agonists

Direct acting adrenergic receptor agonists:a2 receptor agonists

  • (Phenylimino)imidazolidine

  • Selective a2 receptor agonist

  • The basicity of the guanidine group (pKa = 13.6) is decreased (to pKa = 8.0) because of the attachment to the dichlorophenyl ring

  • Clinical effect linked to activation of a2 receptors in the nucleus of the solitary tract (cardiovascular center)

  • Administration: Oral, parenteral, transdermal

  • Uses: Hypertension, opiate withdrawal

Clonidine (Catapres)


A 2 adrenergic agonists reduce blood pressure by reducing sympathetic output from the brain

a2-Adrenergic Agonists Reduce Blood Pressure by Reducing Sympathetic Output from the Brain

Brain

Brain Stem (Cardiovascular Control Center)

a2 Receptors

Sympathetic ganglion

b1 Receptors

Y

Heart

Y

b1 Receptors

Kidney

a1 Receptors

Y


A 2 adrenergic agonists reduce blood pressure by reducing sympathetic output from the brain1

a2-Adrenergic Agonists Reduce Blood Pressure by Reducing Sympathetic Output from the Brain

Brain

Brain Stem (Cardiovascular Control Center)

a2 Receptors

Sympathetic ganglion

b1 Receptors

  • Decreased sympathetic tone

  • Decr. HR

  • Decr. Contractility

  • Decr. Renin release

  • Decr. Vasoconstriction

Y

Heart

Y

b1 Receptors

Kidney

a1 Receptors

Y


Direct acting adrenergic receptor agonists a 2 receptor agonists1

Direct acting adrenergic receptor agonists:a2 receptor agonists

  • “Open-ring” imidazolidines

  • Two atom bridge to the guanidine group decreases the pKa so that the drug is mostly non-ionized at physiological pH

  • Guanabenz has the shortest t-1/2 at ~ 6 hours. Half-life of clonidine and guanfacine is 12-16 hours

  • Administration: oral

  • Uses: Hypertension

Guanabenz (Wytensin)

Guanfacine (Tenex)


Direct acting adrenergic receptor agonists a 2 receptor agonists2

Direct acting adrenergic receptor agonists:a2 receptor agonists

Methyldopate

Esterases

  • Methyldopa (Aldomet)

  • A prodrug metabolized to active a2 receptor agonist, (1R, 2S)-a-methylnorepinephrine

  • Act at CNS a2 receptors to decrease sympathetic outflow

  • Water soluble, ester hydrochloride salt Methyldopate is used for parenteral solutions

  • Administration: Methyldopa, oral; Methyldopate; parenteral

  • Uses: Hypertension

Methyldopa

L-Aromatic Amino

Acid Decarboxylase

a-Methyldopamine

Dopamine

b-Hydroxylase

(1R, 2S)-a-methylnorepinephrine


Clinical pharmacology of a 2 receptor agonists

Clinical pharmacology of a2 receptor agonists

Other Uses:

Apraclonidine (Iopidine): Glaucoma

Tizanidine (Zanaflex): Muscle spasticity

Adverse effects of a2-adrenergic receptor agonists:

Sedation, Na+ and water retention, dry mouth, withdrawal syndrome


Direct acting adrenergic receptor agonists b receptor agonists

Direct acting adrenergic receptor agonists:b receptor agonists

  • Non-selective b receptor agonist

  • Bronchodilation

  • Increased cardiac output

  • Metabolized by conjugation reactions (Phase II) and by COMT

  • Not sensitive to MAO

  • Administration: Oral, parenteral, local (inhaled)

  • Uses: Asthma, Chronic Obstructive Pulmonary Disease (COPD), Cardiostimulant

Isoproterenol (Isuprel)


Direct acting adrenergic receptor agonists b receptor agonists1

Direct acting adrenergic receptor agonists:b receptor agonists

  • Resorcinol derivatives

  • Selective b2 receptor agonists

  • Bronchodilation

  • Cardiac effects observed only at high doses

  • Not metabolized by MAO or COMT

  • Longer duration of action than isoproterenol

  • Administration: Oral, parenteral, local (inhaled)

  • Uses: Asthma, COPD; Terbutaline used as tocolytic (prevent premature labor)

Metaproterenol (Alupent, Metaprel)

Terbutaline (Bricanyl, Brethine)


Direct acting adrenergic receptor agonists b receptor agonists2

Direct acting adrenergic receptor agonists:b receptor agonists

  • Meta hydroxymethyl derivatives

  • Selective b2 receptor agonists

  • Bronchodilation

  • Cardiac effects observed only at high doses

  • Not metabolized by MAO or COMT

  • Longer duration of action than isoproterenol

  • Administration: Oral, local (inhaled); Salmeterol only inhaled

  • Uses: Asthma, COPD

Albuterol (Ventolin, Proventil)

Salmeterol (Serevent)


Direct acting adrenergic receptor agonists long acting b receptor agonists

Direct acting adrenergic receptor agonists:Long acting b receptor agonists

  • Selective b2 receptor agonists

  • Bronchodilation

  • Not metabolized by MAO or COMT

  • Onset of action:

    • Salmeterol 10-20 min

    • Formoterol < 5 min

  • Longer duration of action

  • Administration: inhaled (metered-dose inhaler and powder)

  • Uses: Long-term Asthma, COPD

  • Not recommended for acute treatment of asthma symptoms


Direct acting adrenergic receptor agonists b receptor agonists3

Direct acting adrenergic receptor agonists:b receptor agonists

  • Selective b2 receptor agonists

  • Administration: Oral, parenteral

  • Uses: Tocolytic

Ritodrine (Yutopar)


Direct acting adrenergic receptor agonists b receptor agonists4

Direct acting adrenergic receptor agonists:b receptor agonists

Dobutamine (Dobutrex)

  • Dopamine derivative

  • Available as a racemic mixture

  • (+)-enantiomer: potent b1 receptor agonist

  • (-)-enantiomer: potent a1 receptor agonist, potency for b receptors reduced 10X

  • Net effect is positive inotropic effect on heart with little chronotropic effect

  • Metabolized by COMT and conjugation, not sensitive to MAO

  • Short half-life (~2 min)

  • Administered: Parenteral

  • Use: Acute heart failure, shock


Organization of the nervous system

Action Potential

Indirect-acting sympathomimetics

Na+

Presynaptic neuron

Tyrosine

Na+

Dopamine

Tyrosine

3

MAO

H+

DA

NE

NE

Ca2+

Uptake 1

1

Na+, Cl-

NE

2

NE

NE

NE

a1

b

Effector organ


Indirect acting sympathomimetics amphetamine pseudoephedrine ephedrine phenylpropanolamine tyramine

Indirect-acting sympathomimetics:Amphetamine, pseudoephedrine, ephedrine, phenylpropanolamine, tyramine

Promote release of NE via reverse action of plasma membrane transporter

Clinical uses:

  • Amphetamines: ADHD, narcolepsy, anorexiant

  • Others: Nasal decongestants

Extracellular

AMPH

NET

C

H

C

H

N

H

2

2

NE

C

H

3

A

m

p

h

e

t

a

m

i

n

e

Intracellular


Indirect acting sympathomimetics

Indirect-acting sympathomimetics:

D-(-)-Ephedrine vs. L-(+)-Pseudoephedrine

  • Alkaloid obtained from the stems of Ephedra. Also found in mahuang.

  • D-(-)-Ephedrine has desired (R)-configuration at b-OH and (S)-configuration at the a carbon for direct agonist activity at adrenergic receptors

S

R

D-(-)-Ephedrine

  • L-(+)-Pseudoephedrine is the (S,S)-diastereoisomer; (S)-configuration of b-OH reduces agonist activity-major mechanism is via reversal of the transporter

S

S

L-(+)-Pseudoephedrine


Indirect acting sympathomimetics1

Indirect-acting sympathomimetics:

D-(-)-Ephedrine vs. L-(+)-Pseudoephedrine

D-(-)-Ephedrine

erythro

L-(+)-Pseudoephedrine

threo


Organization of the nervous system

Action Potential

Indirect-acting sympathomimetics: Transporter blockers

Cocaine

Antidepressants

Desipramine

Venlafaxine

Na+

H+

NE

NE

NE

NE

Ca2+

Uptake 1

Na+, Cl-

NE

2

NE

NE

NE

a1

b

Effector organ


Organization of the nervous system

Action Potential

Indirect-acting sympathomimetics:

Cocaine

Antidepressants

Na+

Desipramine

Venlafaxine

H+

NE

NE

NE

Ca2+

Cocaine

NE

NE

2

NE

NE

NE

NE

NE

NE

NE

a1

b

Effector organ


Metabolism of norepinephrine2

Metabolism of norepinephrine

Monoamine Oxidase (MAO)

3,4-Dihydroxyphenyl-

glycolaldehyde

Norepinephrine

Aldehyde

Reductase

Catechol O-Methyl-

transferase (COMT)

3,4-Dihydroxyphenyl-

ethylene glycol

1) Alcohol Dehydrogenase

2) Aldehyde Dehydrogenase

3-Methoxy-4-hydroxymandelic acid

(Vanilylmandelic acid; VMA)

3-Methoxy-4-hydroxy-

phenylethylene glycol


Organization of the nervous system

Action Potential

Indirect-acting sympathomimetics: MAO Inhibitors

Phenelzine

Selegiline

Na+

3

MAO

H+

NE

NE

Ca2+

Na+, Cl-

NE

2

NE

NE

NE

a1

b

Effector organ


Organization of the nervous system

Action Potential

Indirect-acting sympathomimetics: MAO Inhibitors

Phenelzine

Selegiline

Na+

NE

NE

NE

3

MAO

H+

NE

NE

NE

NE

NE

NE

NE

Ca2+

NE

Na+, Cl-

NE

2

NE

NE

NE

NE

NE

NE

a1

b

Effector organ


Organization of the nervous system

Indirect-acting sympathomimetics: MAO Inhibitors

Co-admininstration with other

indirect-acting drugs can lead

to hypertensive crisis

Phenelzine

Selegiline

NE

NE

NE

3

MAO

H+

NE

NE

NE

NE

NE

NE

NE

NE

NE

NE

Amphetamine,

Tyramine

NE

NE

NE

NE

NE

NE

NE

NE

NE

NE

NE

NE

a1

b

Effector organ


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