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The Autonomic Nervous System. Organization of The Nervous System. Central Nervous System. Peripheral Nervous System. Autonomic Nervous System. Somatic Nervous System. Sympathetic. Parasympathetic. How do we define neuron types in the ANS?. Parasympathetic. Sympathetic. Acetylcholine.

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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

how do we define neuron types in the ans
How do we define neuron types in the ANS?

Parasympathetic

Sympathetic

Acetylcholine

Norepinephrine

(Noradrenaline)

Muscarine

Epinephrine

(Adrenaline)

Nicotine

slide4

a

b

a

Parasympathetic Ganglionic Synapse

Acetylcholinesterase

Ca2+

Na+

ACH

Action Potential

Nicotinic

Receptor

Na+

Preganglionic neuron

Postganglionic neuron

slide5

Na+

Parasympathetic Organ Synapse

Acetylcholinesterase

Ca2+

Effector

Organ

K+

G

Action Potential

ACH

Muscarinic

Receptor

Postganglionic neuron

summary of parasympathetic neurons and synapses
Summary of parasympathetic neurons and synapses

Preganglionic neurons

  • Long
  • Synapse with postganglionic neurons at or near organ
  • Release acetylcholine (ACH) to activate nicotinic receptors on postganglionic neurons

Postganglionic neurons

  • Short
  • Synapse on the target organ
  • Release acetylcholine (ACH) to activate muscarinic receptors on the target organ
slide7

a

b

a

Sympathetic Ganglionic Synapse

Acetylcholinesterase

Ca2+

Na+

ACH

Action Potential

Nicotinic

Receptor

Na+

Preganglionic neuron

Postganglionic neuron

slide8

Na+

Sympathetic Organ Synapse

Ca2+

Effector

Organ

G

NE

Action Potential

Adrenergic

Receptor

Postganglionic neuron

summary of sympathetic neurons and synapses
Summary of sympathetic neurons and synapses

Preganglionic neurons

  • Short
  • Synapse with postganglionic neurons near spinal cord
  • Release acetylcholine (ACH) to activate nicotinic receptors on postganglionic neurons

Postganglionic neurons

  • Long
  • Synapse on the target organ
  • Release norepinephrine to activate adrenergic receptors on target organs
exceptions in the sympathetic nervous system
Exceptions in the sympathetic nervous system:
  • Sweat glands:
    • Postganglionic neurons involved with stress-related excretion release norepinephrine (“sweaty palms”)
    • Postganglionic neurons involved with thermoregulation release acetylcholine
exceptions in the sympathetic nervous system1
Exceptions in the sympathetic nervous system:
  • Kidneys:
    • Postganglionic neurons to the smooth muscle of the renal vascular bed release dopamine
  • Adrenal gland:
    • Preganglionic neurons do not synapse in the paraverterbral sympathetic ganglion
    • Preganglionic neurons synapse directly on the adrenal gland, release acetylcholine, and activate nicotinic receptors on the adrenal gland
    • Adrenal glands release epinephrine into systemic circulation

Most postganglionic sympathetic

neurons release what

neurotransmitter?

how do drugs influence the ans
How do drugs influence the ANS?
  • Mimic or block the effects of the two primary neurotransmitters, Acetylcholine and Norepinephrine/Epinephrine
  • Drugs that mimic neurotransmitters are referred to as “receptor agonists”
    • These drugs activate receptors
  • Drugs that block neurotransmitters are referred to as “receptor antagonists”
    • These drugs block the endogenous neurotransmitters from activating receptors
classification of drugs affecting the ans
Classification of drugs affecting the ANS
  • Parasympathetic nervous system

Mimic acetylcholine = cholinergic = muscarinic agonists = parasympathomimetic

Block acetylcholine = anticholinergic = muscarinic antagonist = parasympatholytic

  • Sympathetic nervous system

Mimic norepinephrine = adrenergic = adrenergic agonist = sympathomimetic

Block norepinephrine = antiadrenergic = adrenergic antagonist = sympatholytic

receptors and signal transduction in the ans
Receptors and signal transduction in the ANS

Cholinergic Receptors

Nicotinic

Muscarinic

Ganglionic

Skeletal

Muscle

Neuronal

CNS

receptors and signal transduction in the ans1
Receptors and signal transduction in the ANS

Cholinergic Receptors

Nicotinic

Muscarinic

M1

M3

M5

M2

M4

slide18
Receptors and signal transduction in the ANS: Muscarinic receptors are 7 transmembrane domain, G-protein coupled receptors
receptors and signal transduction in the ans muscarinic receptors m 1 m 3 m 5
Receptors and signal transduction in the ANS: Muscarinic receptors(M1, M3, M5)

NH

3

Phospho

-

(+)

G

lipase C

q

PIP

2

IP

Diacylglycerol

COOH

3

2+

Increase Ca

Activate Protein

Kinase

C

Response

receptors and signal transduction in the ans2

a1

a2

b

a1B

a1D

a2A

a2B

a2C

b1

b2

Receptors and signal transduction in the ANS

Adrenergic Receptors

a1A

b3

slide26

b

1

b

1,

Functional Responses Mediated by the ANS

Adrenergic

Cholinergic

Effector Organ

Response

Receptor

Response

Receptor

Heart

Rate of Contraction

Increase

Decrease

M

2

Force of Contraction

Increase

Decrease

M

2

functional responses mediated by the ans
Functional Responses Mediated by the ANS

Adrenergic

Cholinergic

Effector Organ

Response

Receptor

Response

Receptor

a

Arteries (most)

Vasoconstriction

----------

--

1

a

Veins

Vasoconstriction

----------

--

2

b

Skeletal Muscle

Vasodilation

----------

--

2

Endothelium

----------

--

Release EDRF

M

3

functional responses mediated by the ans1

b

2

Functional Responses Mediated by the ANS

Adrenergic

Cholinergic

Effector Organ

Response

Receptor

Response

Receptor

Lung

Bronchiolar

smooth muscle

Bronchodilation

Bronchoconstriction

M3

functional responses mediated by the ans2

a

a

1

1

Functional Responses Mediated by the ANS

Adrenergic

Cholinergic

Effector Organ

Response

Receptor

Response

Receptor

Genitourinary, smooth muscle

b2

Bladder wall

Relaxation

Contraction

M3

a

Ureter

Contraction

Relaxation

M3

1

a

Sphincter

Contraction

Relaxation

M3

1

Uterus (pregnant)

Relaxation

b2

Variable

Contraction

M

3

Erection

Penis/vas deferens

Ejaculation

M3

functional responses mediated by the ans3

a

1

M

M

3

3

Functional Responses Mediated by the ANS

Adrenergic

Cholinergic

Effector Organ

Response

Receptor

Response

Receptor

Gastrointestinal Tract

Salivary Glands

Increase secretion

Increase secretion

Smooth Muscle:

a

b

Walls

Contraction

Relaxation

M3

,

2

2

a

Sphincters

Contraction

Relaxation

M3

1

Secretion

----------

--

Increase secretion

functional responses mediated by the ans4
Functional Responses Mediated by the ANS

Adrenergic

Cholinergic

Effector Organ

Response

Receptor

Response

Receptor

Skin

a1

Hair follicles,

Smooth muscle

Contraction,

Piloerection

--------------

--

Sweat glands

--------------

M3

Thermoregulation

Increase secretion

--

--------------

a1

Apocrine (stress)

Increase secretion

--

functional responses mediated by the ans5
Functional Responses Mediated by the ANS

Adrenergic

Cholinergic

Effector Organ

Response

Receptor

Response

Receptor

Eye

Iris

--------------

a1

Radial muscle

Contraction

--

Contraction

--

Circular muscle

-------------

M3

Contraction

b2]

[Relaxation

Ciliary muscle

M3

--------------

b2

Increase secretion

of aqueous humor

Ciliary epithelium

--

functional responses mediated by the ans6
Functional Responses Mediated by the ANS

Adrenergic

Cholinergic

Effector Organ

Response

Receptor

Response

Receptor

Metabolic functions

a1,b2

Liver

Glycogenolysis

--------------

--

Gluconeogenesis

b1,b3

Fat cells

Lipolysis

--------------

--

b

Kidney

--------------

--

Increase renin

secretion

1

--------------

Pancreas

a2

Decrease insulin

release

--

slide35

a

b

a

Action Potential

Pharmacologic manipulation of the cholinergic system

Ca2+

Na+

Muscarinic

Receptor

ACH

Choline

Acetyltransferase

Acetylcholinesterase

Acetyl CoA

+

Acetylcholine

Choline

Na+

H+

Nicotinic

Receptor

ACH

Choline

Acetate

Choline

Presynaptic neuron

Postsynaptic target

receptor agonists activate signal transduction pathways

NH

3

Phospho

-

(+)

G

lipase C

q

PIP

2

IP

Diacylglycerol

COOH

3

2+

Increase Ca

Activate Protein

Kinase

C

Response

Receptor agonists activate signal transduction pathways

O

C

H

3

C

C

H

C

H

N

C

H

2

2

3

C

H

O

3

C

H

Acetylcholine

3

M3 muscarinic

receptor

slide37

Cholinergic agonist for treatment of Sjogren’s Syndrome—autoimmune destruction of moisture-producing glands

  • Use Increase saliva production
  • Warnings/precautions: heart disease, night driving, urinary tract obstruction, GI tract obstruction
  • Contraindicated: uncontrolled asthma, when miosis is undesirable (narrow-angle glaucoma)
clinical pharmacology of cholinergic receptor agonists
Clinical pharmacology of cholinergic receptor agonists

Cholinesterase

Drug

Receptor

Sensitivity

Clinical Use

Acetylcholine

M, N

Yes

Intraocular use for miosis during surgery

Carbachol

M, N

No

Intraocular use for miosis during surgery,

glaucoma

Pilocarpine

M

No

Glaucoma

Bethanechol

M

No

Urinary retention, post-operative ileus

Varenicline

N

No

Smoking cessation

M=Muscarinic

N=Nicotinic

slide39

Action Potential

Pharmacologic manipulation of AChE: No inhibition

Ca2+

Na+

Muscarinic

Receptor

ACH

ACH

Acetylcholinesterase

ACH

ACH

ACH

ACH

ACH

ACH

ACH

ACH

ACH

Choline

Acetate

Presynaptic neuron

Postsynaptic target

slide40

Action Potential

Pharmacologic manipulation of AChE: Inhibition by drugs

Ca2+

ACH

ACH

Na+

ACH

Muscarinic

Receptor

ACH

ACH

Acetylcholinesterase

ACH

ACH

ACH

ACH

ACH

ACH

ACH

ACH

ACH

ACH

ACH

ACH

Presynaptic neuron

Postsynaptic target

clinical pharmacology of acetylcholinesterase inhibitors
Clinical pharmacology of acetylcholinesterase inhibitors

Type of

Route of

Drug

inhibition

administration

Clinical Use

Edrophonium

Rev

IM or IV

Diagnostic for Myasthenia Gravis

Neostigmine

Rev

IM, IV, or oral

Myasthenia Gravis, post-operative ileus and

bladder distention, surgical adjunct

Physostigmine

Rev

IM, IV, or local

Glaucoma, Alzheimer’s disease, antidote to

anticholinergic overdose

Tacrine

Rev

Oral

Alzheimer’s disease

Donepezil

Rev

Oral

Alzheimer’s disease

Isofluorophate

Irrev

Local

Glaucoma

Echothiophate

Irrev

Local

Glaucoma

contraindications to the use of parasympathomimetic drugs
Contraindications to the use of parasympathomimetic drugs
  • Asthma
  • COPD
  • Peptic ulcer
  • Obstruction of the urinary or GI tract
cholinergic agent side effects and toxicity
Cholinergic agent side effects and toxicity

SLUD

  • Salivation
  • Lacrimation
  • Urination
  • Defecation

Also:

  • Increased sweating
  • Decreased heart rate
  • Pupils constricted
  • CNS activation
  • Treatment:
  • Cholinergic receptor antagonist (Atropine)
  • If irreversible AChE inhibitor, 2-PAM (Pralidoxime)
clinical correlation alzheimer s disease
Clinical Correlation:Alzheimer’s Disease
  • Most common cause of dementia after age 50
  • Atrophy of brain
  • Widening of sulci and thinning of gyri
  • Improper processing of b-amyloid precursor protein (b-APP) leads to toxic form (b-A42) that promotes apoptosis
  • On pathological exam:
    • Senile plaques: b-amyloid
    • Neurofibrillary tangles
  • Loss of cholinergic neurons in brain
treatment of alzheimer s disease
Treatment of Alzheimer’s Disease
  • Bind to anionic site and block ACh binding
  • Reversible
  • Non-covalent
  • Enhances cognitive ability
  • Does not slow progression of disease
  • Newer agent: Donepezil (Aricept)
treatment of alzheimer s disease1
Treatment of Alzheimer’s Disease
  • Reversible carbamate AChE inhibitor
  • Enhances cognitive ability by increasing cholinergic function
  • Loses effectiveness as disease progresses
  • Side Effects: Nausea, vomiting, anorexia, and weight loss
  • Newer long-acting carbamate: Eptastigmine
treatment of alzheimer s disease2
Treatment of Alzheimer’s Disease
  • Reversible competitive AChE inhibitor
  • Extract from daffodil (Narcissus pseudonarcissus) bulbs
  • Loses effectiveness as disease progresses
  • May be a nicotinic receptor agonist
  • Inhibitors of P450 enzymes (3A4, 2D6) will increase galantamine bioavailability
treatment of alzheimer s disease3
Treatment of Alzheimer’s Disease
  • N-methyl-D-aspartate (NMDA) receptor antagonist
  • NMDA receptors are activated by glutamate in the CNS in areas associated with cognition and memory
  • Neuronal loss in Alzheimer’s may be related to increased activity of glutamate
  • May slow progression of the disease
  • Favorable adverse effect profile
organization of the nervous system1
Organization of The Nervous System

Central Nervous System

Peripheral Nervous System

Autonomic Nervous System

Somatic Nervous System

Sympathetic

Parasympathetic

slide51

a

b

a

Sympathetic Ganglionic Synapse

Acetylcholinesterase

Ca2+

Na+

ACH

Action Potential

Nicotinic

Receptor

Na+

Preganglionic neuron

Postganglionic neuron

slide52

Na+

Sympathetic Organ Synapse

Ca2+

Effector

Organ

G

NE

Action Potential

Adrenergic

Receptor

Postganglionic neuron

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

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 ans3

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
  • Phenylephrine (Neosynephrine)
  • Methoxamine (Vasoxyl)
  • Oxymetazoline (Visine)

Phospho

-

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

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
  • 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 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
slide74

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

slide76

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

slide77

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 norepinephrine1
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

slide79

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

slide80

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

slide81

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

sympatholytic pharmacology
Sympatholytic pharmacology
  • Selective vs. Non-selective
  • Antagonist vs. Partial Agonist
  • Reversible vs. Irreversible
receptor agonists activate signal transduction pathways1

NH

H

O

3

H

O

C

H

C

H

N

H

2

2

O

H

Norepinephrine

Phospho

-

(+)

G

lipase C

q

PIP

2

IP

Diacylglycerol

COOH

3

2+

Increase Ca

Activate Protein

Kinase

C

Response

Receptor agonists activate signal transduction pathways

a1 adrenergic

receptor

receptor antagonists block agonist binding to the receptor

H

O

H

O

C

H

C

H

N

H

2

2

O

H

Norepinephrine

Receptor antagonists block agonist binding to the receptor

Antagonist

NH

3

Phospho

-

G

lipase C

q

What effect would an antagonist alone have on receptor activation?

COOH

clinical pharmacology of a adrenergic receptor antagonists
Clinical pharmacology of a-adrenergic receptor antagonists

Route of

Drug

Receptor

admin.

Clinical uses

a

, a

Phenoxybenzamine

Oral

Pheochromocytoma, hypertensive crisis

1

2

a

, a

Phentolamine

Parenteral

Pheochromocytoma, hypertensive crisis,

1

2

male impotence

a

Prazosin

Oral

Hypertension, benign prostatic

1

hypertrophy

a

Terazosin

Oral

Hypertension, benign prostatic

1

hypertrophy

a

Doxazosin

Oral

Hypertension, benign prostatic

1

hypertrophy

Side effects of a1 receptor antagonists:

Orthostatic hypotension, inhibition of ejaculation, nasal stuffiness, tachycardia

non selective adrenergic receptor antagonists
Non-selective adrenergic receptor antagonists

b-Haloalkylamines

  • Non-selective a receptor antagonist
  • Also blocks acetylcholine, histamine, and serotonin receptors
  • Irreversible antagonist resulting from covalent modification of receptor

Phenoxybenzamine (Dibenzyline)

non selective adrenergic receptor antagonists1
Non-selective adrenergic receptor antagonists

Imidazolines

  • Non-selective a receptor antagonist
  • Competitive (reversible) blocker
  • Potent vasodilator, but induces pronouced reflex tachycardia
  • Block of presynaptic a2 receptors may promote release of NE
  • Also blocks 5-HT receptors, and is a muscarinic and histamine receptor agonist

Phentolamine (Regitine)

reversible vs irreversible receptor blockade
Reversible vs. Irreversible receptor blockade

1 M Phent

1 M Phenox

10 M Phenox

10 M Phent

+ Phenoxybenzamine

+ Phentolamine

a1 adrenergic receptor antagonists
a1-adrenergic receptor antagonists
  • “Quinazolines”
  • Vary in half-life:
    • Prazosin 3 hrs
    • Terazosin 12 hrs
    • Doxazosin 20 hrs
  • Undergo extensive metabolism, excreted mainly in the bile
  • Vasodilators
  • Relaxation of smooth muscle in enlarged prostate and in bladder base
  • “First-dose” effect
a2 adrenergic receptor antagonists
a2-adrenergic receptor antagonists
  • Indole alkaloid
  • Found in Rubaceae and related trees. Also in Rauwolfia Serpentina.
  • Blockade of a2 receptors increases sympathetic discharge
  • Folklore suggests use in the treatment of male impotence

Yohimbine (Yocon)

b adrenergic receptor antagonists
b-adrenergic receptor antagonists

Pharmacological effects

  • Decreased cardiac output and heart rate
  • Reduced renin release
  • Increase VLDL, Decrease HDL
  • Inhibit lipolysis
  • Inhibit compensatory glycogenolysis and glucose release in response to hypoglycemia
  • Increase bronchial airway resistance

P

r

o

p

r

a

n

o

l

o

l

(

I

n

d

e

r

a

l

)

Therapeutic uses for b-adrenergic receptor antagonists:

Hypertension, angina, cardiac arrhythmias, migraine, stage fright, thyrotoxicosis, glaucoma, congestive heart failure (types II and III)

non selective b adrenergic receptor antagonists

Timolol (Timoptic, Blocadren)

Non-selective b-adrenergic receptor antagonists
  • Less lipophilic than propranolol
  • Long half-life: ~20 hours
  • Mostly excreted unchanged in urine
  • Administered: Oral
  • Uses: Hypertension, angina, migraine
  • Thiadiazole nucleus with morpholine ring
  • Administered: Oral, Ophthalmic
  • Uses: Hypertension, angina, migraine, glaucoma

Nadolol (Corgard)

non selective b adrenergic receptor antagonists1
Non-selective b-adrenergic receptor antagonists
  • Possesses “Intrinsic sympathomimetic activity (ISA)
  • Partial agonist
  • Less likely to cause bradycardia and lipid abnormalities
  • Administered: Oral
  • Uses: Hypertension, angina, migraine

Pindolol (Visken)

What would a pindolol dose-response curve look like?

dose response curves and partial agonists
Dose-Response Curves and Partial Agonists

NE

NE +

Pindolol

Pindolol

NE +

Propranolol

%

non selective b adrenergic receptor antagonists2
Non-selective b-adrenergic receptor antagonists
  • Possesses “Intrinsic sympathomimetic activity (ISA)
  • Partial agonist
  • Less likely to cause bradycardia and lipid abnormalities
  • Administered: Oral, Opththalmic
  • Uses: Hypertension, glaucoma
selective b1 adrenergic receptor antagonists
Selective b1-adrenergic receptor antagonists
  • “Cardioselective”
  • Less bronchconstriction
  • Moderate lipophilicity
  • Half-life: 3-4 hours
  • Significant first-pass metabolism
  • Administered: Oral, parenteral
  • Uses: Hypertension, angina, antiarrhythmic, congestive heart failure
selective b1 adrenergic receptor antagonists1
Selective b1-adrenergic receptor antagonists
  • “Cardioselective”
  • Less bronchconstriction
  • Low lipophilicity
  • Half-life: 6-9 hours
  • Administered: Oral, parenteral
  • Uses: Hypertension, angina

Atenolol (Tenormin)

selective b1 adrenergic receptor antagonists2
Selective b1-adrenergic receptor antagonists
  • Very short acting
  • Half-life: 9 minutes
  • Rapid hydrolysis by esterases found in red blood cells
  • Administered: Parenteral Note: incompatible with sodium bicarbonate
  • Uses: Supraventricular tachycardia, atrial fibrillation/flutter, perioperative hypertension

Esmolol (Brevibloc)

slide99

Side effects of b-blockers:

  • Bradycardia, AV block, sedation, mask symptoms of hypoglycemia, withdrawal syndrome
slide100

Action Potential

Effect of chronic b-receptor blockade

Na+

Presynaptic neuron

Tyrosine

Na+

Dopamine

Tyrosine

MAO

H+

DA

NE

NE

Ca2+

Uptake 1

Na+, Cl-

NE

NE

NE

NE

Effector organ

slide101

Action Potential

Effect of chronic b-receptor blockade:

Receptor up-regulation

Na+

Tyrosine

Na+

Dopamine

Tyrosine

MAO

H+

DA

NE

NE

Ca2+

Uptake 1

Na+, Cl-

NE

NE

NE

NE

Effector organ

slide102

Side effects of b-blockers:

  • Bradycardia, AV block, sedation, mask symptoms of hypoglycemia, withdrawal syndrome

Contraindications:

  • Asthma, COPD, congestive heart failure (Type IV)
mixed adrenergic receptor antagonists
Mixed adrenergic receptor antagonists
  • Non-selective b receptor antagonist
  • a1 receptor antagonist
  • Two asymmetric carbons (1 and 1’)
  • (1R, 1’R)-isomer possesses b-blocking activity
  • (1S, 1’R)-isomer possesses greatest a1 receptor blocking activity
  • b-blocking activity prevents reflex tachycardia normally associated with a1 receptor antagonists
  • Administered: Oral, parenteral
  • Uses: Hypertension, hypertensive crisis

Labetalol (Normodyne, Trandate)

mixed adrenergic receptor antagonists1
Mixed adrenergic receptor antagonists

Carvedilol (Coreg)

  • Non-selective b receptor antagonist
  • a1 receptor antagonist
  • Both enantiomers antagonize a1 receptors
  • Only (S)-enantiomer possesses b-blocking activity
  • b-blocking activity prevents reflex tachycardia normally associated with a1 receptor antagonists
  • Administered: Oral
  • Uses: Hypertension, congestive heart failure (Types II and III)
slide105

Action Potential

Pharmacologic manipulation of the adrenergic system

Na+

Presynaptic neuron

Tyrosine

Na+

1

Dopamine

Tyrosine

2

MAO

H+

DA

NE

NE

Ca2+

Uptake 1

3

Na+, Cl-

NE

NE

NE

NE

b

Effector organ

inhibition of norepinephrine synthesis

X

Metyrosine

Inhibition of norepinephrine synthesis

H

O

C

H

C

H

N

H

T

Y

R

O

S

I

N

E

2

2

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

H

O

H

O

C

H

C

H

N

H

N

O

R

E

P

I

N

E

P

H

R

I

N

E

2

2

O

H

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

H

O

H

O

C

H

C

H

E

P

I

N

E

P

H

R

I

N

E

N

H

2

O

H

C

H

3

slide107

Action Potential

Drugs that reduce storage or release of NE

Na+

Tyrosine

Na+

Dopamine

Tyrosine

Reserpine

Guanethidine

MAO

H+

NE

NE

Ca2+

NE

Guanethidine,

Bretylium

Guanethidine

b

Effector organ

catecholamine depleters
Catecholamine depleters
  • Slow onset of action
  • Sustained effect (weeks)
  • Used in the treatment of hypertension
  • May precipitate depression

Reserpine (Serpasil)

  • Indole alkaloid obtained from the root of Rauwolfia serpentina
  • Block vesicular monoamine transporters
  • Deplete vesicular pool of NE
drugs that reduce storage or release of ne
Drugs that reduce storage or release of NE
  • Possess guanidino moiety (pKa > 12)
  • Resonance stabilization of cation “spreads” positive charge over the entire four atom system
  • Almost completely protonated at physiological pH
  • “Pharmacologic sympathectomy”
  • Effects can be blocked by transport blockers
  • Uses: Hypertension

Guanethidine (Ismelin)

slide110

Action Potential

Drugs that reduce storage or release of NE

Na+

Tyrosine

Na+

Dopamine

Guanethidine

Tyrosine

MAO

H+

NE

NE

Ca2+

NE

Guanethidine,

Guanethidine

b

Effector organ

sample reflexes
Sample Reflexes
  • CV effects of parasympathomimetic drugs
  • CV effects of sympathomimetic drugs
  • CV effects of vasodilators
    • Nitroglycerin
  • CV Effects of vasoconstrictors
    • Phenylephrine (NEO-SYNEPHRINE)
source
Source

American Society for Pharmacology and Experimental Therapeutics Website

http://www.aspet.org/Neuropharmacology/Teaching_Resources/