Pharmacology of the

Autonomic Nervous System

Part 2

Thomas E. Tenner, Jr., Ph.D.

Dept. of Medical Education
Dept. Pharmacology & Neuroscience
tom.tenner@ttuhsc.edu
743-7169

1
Recommended Background Reading :
 

Chapters 7, 8, 9, and 10
Basic and Clinical Pharmacology
Bertram Katzung
(13th Edition)

2
 Learning Objectives:
1) List and describe the mechanism of action, therapeutic
indications, and adverse effects of cholinergic agonists and
cholinesterase inhibitors.
2) List and describe the mechanism of action, therapeutic
indications, and adverse effects of muscarinic and nicotinic
receptor antagonists.
3) List and describe the mechanism of action, therapeutic
indications, and adverse effects of direct, indirect, and
mixed acting adrenergic agonists.
4) List and describe the mechanism of action, therapeutic
indications, and adverse effects of  adrenergic and  -
adrenergic blocking agents.

3
ANS – CHOLINERGIC
PHARMACOLOGY

4
 PARASYMPATHOMIMETICS
(CHOLINOMIMETICS):
Drugs that facilitate or mimic some or all of the actions of
the parasympathetic nervous system.

Direct Acting Indirect Acting

Muscarinic Nicotinic Anticholinesterases

receptor receptor
agonists agonists
Reversible Irreversible
5
 Direct Acting Cholinergic
Agonists
• Acetylcholine *not used therapeutically – N/M
• Carbachol * (Miostat) – N/M
• Bethanechol * (Urecholine) – M
• Pilocarpine (Pilocar, Ocusert) – M

• Indications – Urinary retention after surgery or postpartum,

Glaucoma
• Adverse effects –
– Muscarinic (M): salivation, flushing, bronchospasm,
sweating, nausea, abdominal pain – acid indigestion and GI
cramping, diarrhea, and possibly, decreased blood
pressure.
6
– Nicotinic (N)- Fasciculations, respiratory arrest
 Direct Acting Cholinergic
Nicotinic Agonists
• Nicotine
– MOA**- Low doses – ganglionic stimulation causing
euphoria and arousal. CNS effects cause relaxation and
improves attention (Acute)
– Indications – None
– Adverse effects – Vomiting, convulsions, hypertension,
cardiac arrhythmias, Respiratory arrest – (depolarizing
blockade), Muscarinic effects - PNS ganglia stimulation.
• Succinylcholine *:
– MOA - Overstimulation results in depolarizing blockade
– Indications – muscle relaxation/paralysis associated
with intubation, other procedures
– Adverse effects – Fasciculations, respiratory arrest,
7
malignant hyperthermia
 Indirect Acting Cholinergic
Agonists - Reversible
• Edrophonium *(Tensilon)
• Neostigmine *
• Pyridostigmine* (Mestinon,)
• Physostigmine
• MOA - Prolongs duration of acetylcholine by binding with
and blocking acetylcholinesterase.
• Therefore both Nicotinic(N) and Muscarinic(M) effects!
• Indications – Myasthenia Gravis, Glaucoma, Atropine
Poisoning
• Adverse effects –salivation, flushing, bradycardia,
bronchospasm, sweating, nausea, abdominal pain, diarrhea,
decreased blood pressure, muscle fasciculations (N), and
8
respiratory arrest (N).
 Indirect Acting Cholinergic
Agonists – Reversible - CNS
• Used in Alzheimer’s :

• Donepezil (Aricept, Aricept ODT)

• Galantamine (Razadyne, Razadyne ER)
• Rivastigmine (Exelon) – tertiary amine

• Mechanism of action – Increase cerebral

concentrations of acetylcholine by inhibiting
acetylcholinesterase
• Adverse effects –Same as other reversible
ACHase Inhibitors
9
 Indirect Acting Cholinergic
Agonists - Irreversible
• Echothiophate* (Phospholine)

• MOA- Prolongs duration of acetylcholine by permanently

inactivating acetylcholinesterase.
• Therefore both Nicotinic(N) and Muscarinic(M) effects!
• Indications – Glaucoma
• Adverse effects –salivation, flushing, bradycardia,
bronchospasm, sweating, nausea, abdominal pain, diarrhea,
decreased blood pressure, muscle fasciculations (N), and
respiratory arrest (N).
10
 “SLUDWARMF”
• Sweating
• Lacrimation
• Urination
• Diarrhea
Muscarinic
• Wheezing
• Accommodation
• Rhinorrhea
• Miosis
• Fasciculations Nicotinic 11
 PARASYMPATHOLYTICS
(ANTICHOLINERGICS):
Drugs that reduce or inhibit some or all of the actions of
the parasympathetic nervous system.

Muscarinic Nicotinic
receptor receptor
antagonists antagonists

Ganglionic Neuromuscular
blocking drugs blocking drugs
(Nn) (Nm) 12
 Parasympatholytics
Muscarinic receptor antagonists
• MOA- Block muscarinic receptors on the effector organs
of the parasympathetic nervous system and on the
sweat glands
• Indications – Varied - specificity for muscarinic
receptors is a key reason behind their usefulness.
• Adverse effects –
– Autonomic
• PNS - dry mouth, blurred vision, tachycardia,
urinary retention, and constipation
• SAS - Inhibition of sweating
– CNS - restlessness, confusion, and hallucinations
• Common mnemonic : “hot as a hare, blind as a bat, dry
as a bone, red as a beet, and mad as a hatter"
13
 Parasympatholytics
Muscarinic receptor antagonists
• Atropine Sulfate – Cholinesterase poisoning,
– ACLS: Bradycardia, Pulseless Electrical Activity
and Asystole
• Benztropine (Cogentin) – Parkinsonism
• Dicyclomine (Bentyl) – Irritable Bowel Syndrome
• Ipratropium *(Atrovent) – COPD, Rhinorrhea
• Tiotropium * (Spiriva) – COPD, Rhinorrhea
• Oxybutynin (Ditropan) – Overactive bladder
• Tolterodine (Detrol) – Overactive bladder
• Tropicamide (Mydriacyl) - Mydriasis (short duration)
• Scopolamine - Motion Sickness, Amnesia 14
 Parasympatholytics
Nicotinic receptor antagonists-
Ganglionic Blockers (NN)
• Mecamylamine – Non-depolarizing, competitive
blocker
• Nicotine – Depolarizing blocker
– High doses – ganglionic blockade causing
respiratory paralysis and hypotension
• No selectivity - block receptors on both the
parasympathetic and sympathetic ganglia
• Adverse Effects – Intolerable
– Hypotension, Orthostatic Hypotension, atony of bladder
and GI Tract, cycloplegia, xerostomia, sexual dysfunction,
hyperthermia
15
• Rarely used therapeutically
 Parasympatholytics
Nicotinic receptor antagonists-
Neuromuscular Blockers (NM)
• Tubocurarine* - Prototype
• Atracurium*
• Pancuronium *
• Rocuronium*
• Vecuronium*
• Indications – muscle relaxation/paralysis
associated with intubation, other procedures
• MOA - Competitive blocker - action can be
reversed by increasing concentration of Ach**
• Adverse Effects – Respiratory arrest. 16
ANS – ADRENERGIC
PHARMACOLOGY

17
 Raymond Ahlquist (1948) on
Adrenergic receptor function
• “Alpha receptors are excitatory
everywhere but the gut”

• “Beta receptors are inhibitory everywhere

but the heart”

18
 Adrenergic Agonists
• Catecholamines - Name is based on their
chemical structure (hydroxyl groups at the 3 and
4 position of a benzene ring):

– High potency - activate both alpha and beta receptors

– Rapid inactivation - Destroyed by COMT (Catechol O-
methyltransferase) and by MAO (Monoamine oxidase)
which are both located at the neuron and in the gut
wall. Catecholamines are not effective when given
orally
– Poor CNS penetration - They are polar but they still
may cause some CNS effects
– 5 catecholamines - epinephrine, norepinephrine,
dopamine, dobutamine, and isoproterenol
19
 Epinephrine:
Basic Catecholamine Structure

 
H
HO 3 1 CH CH2 N
CH3
HO 4
OH

20
 Adrenergic agonists Cont.
• Non-catecholamines -
– Not destroyed by COMT and MAO
deactivation is limited, so they have longer
half lives
– Better CNS penetration due to increased lipid
solubility

25
 SYMPATHOMIMETICS:
Drugs that facilitate or mimic some or all of the
actions of the sympathetic nervous system.

Direct Acting Indirect Acting Mixed Acting

α-adrenergic Drugs that Drugs that Both Direct

agonists block NE facilitate NE and Indirect
uptake release Actions
β-adrenergic
agonists Drugs that inhibit
enzymatic breakdown
26
of NE
 Mechanism of action of adrenergic
agonists
• Direct-Acting Agonists - Mimic NE and EPI. They bind to the
adrenergic receptors without interacting with the prejunctional
neuron.
• (EPI, NE, ISO and Phenylephrine)
• Indirect-Acting Agonists:
• Displace norepinephrine from storage sites
(Amphetamine, hydroxyamphetamine, and tyramine)
• Block the uptake of norepinephrine at storage sites
(Cocaine, Tricylic Antidepressants, SNRI)
• Inhibit enzymatic breakdown of norepinephrine
(Monoamine Oxidase Inhibitors, i.e., phenelzine)
• Mixed-action agonists - Both stimulate receptors and
displace NE from storage sites.
• (Ephedrine, pseudoephedrine)
 Catecholamines:
Rank Order of Potency

– Isoproterenol: β 1 = β 2 = β 3 >>>> α1 = α2

– Norepinephrine : α1 = α2 = β 1 = β 3 >>>> β 2

– Epinephrine: α1 = α2 = β 1 = β 2 = β 3

– Dopamine : DA 1> β 1> α1

28
 Adrenergic Receptor Subtypes

α-adrenergic receptors β-adrenergic receptors

(Epinephrinea> Isoproterenol) (Isoproterenol > Epinephrine)

α 1-adrenergic
receptors β 1-adrenergic
(Phenylephrine > Clonidine) receptors
(EPI = NE)

β 2-adrenergic
receptors
(EPI>NE)

α 2-adrenergic β 3-adrenergic
receptors receptors
(Clonidine > Phenylephrine) (NE>EPI)
29
 Direct Acting Alpha1 -
Adrenergic Agonists
• Phenylephrine (Neo-Synephrine)
• Oxymetazoline ( Afrin, Visine L.R.)

• Indications – Nasal decongestant, mydriatic,

and systemically as a vasopressor for
hypotension to raise BP.

• Adverse effects – Hypertension, Nervousness,

Headaches
30
 Direct Acting Alpha 2 -
Adrenergic Agonists
• Clonidine (Catapres)
• Apraclonidine a (Lopidine)
• Brimonidine a (Alphagan P)
• Indications :
– Hypertension - produces inhibition of sympathetic
vasomotor centers, reducing blood pressure.
– ADHD and impulsive behavior
– Glaucoma a
• Adverse effects – Bradycardia, Hypotension,
Headaches, Sedation, Depression,
• Caution for Withdrawal Supersensitivity with
31
Chronic use
Direct Acting Beta 1- Adrenergic
Agonists
• Dobutamine (Dobutrex)

• Mechanism of Action – Primarily a beta 1

agonist. Increases cardiac output with few heart
rate or vascular effects
• Indication - Congestive heart failure
• Adverse actions – tachycardia, palpitations,
severe hypotension (alpha antagonist effect).
Can increase ventricular rate in atrial fibrillation

32
Direct Acting Beta 2- Adrenergic
Agonists
• Albuterol (Proventil, Ventolin)
• Terbutaline (Brethine, Bricanyl)
• Metaproterenol (Alupent)
• Long Acting Beta Agonists (LABA)
– Salmeterol (Serevent)
– Formoterol (Perforomist)
• Indications : Bronchodilator, Asthma; LABA only
in COPD.
• Adverse effects – Nervousness, muscle
tremors, tachycardia.
• Systemic route: Hypokalemia and hyperglycemia33
 Indirect Acting Adrenergic
Agonists
• Amphetaminea
• Hydroxyamphetamine
• Cocaine
• TCA’s, SNRI’sb
• MAOI’sb
• Indications :
– Attention Deficit Disorder (ADD) a
– Narcolepsya
– Depressioni/Neuropathic painb
• Adverse effects – Similar to direct acting
Adrenomimetic drugs. (See next slides). 34
 Amphetamines
- Adverse Effects:
• CNS •CVS
palpitations
confusion
arrhythmias
insomnia
hypertension
irritability angina
weakness circulatory collapse
vertigo/dizziness headache
tremor chills
hyperactive reflexes sweating
delirium •GI
panic anorexia
suicide nausea, vomitinmg &
amphetamine psychosis diarrhea
abdominal cramping
 Cocaine
Adverse Effects:
1) Anxiety* reaction (hypertension,
tachycardia, sweating & paranoia)
2) Depression
3) Agitation*
4) Cardiac Arrhythmias
5) Seizures*
6) Incidence of MI unrelated to dose, duration
of use or route of administration (no marker)
* Can be treated with Benzodiazepines-Diazepam
 SYMPATHOLYTICS:
Drugs that reduce or inhibit some or all of the
actions of the sympathetic nervous system.

Ganglionic α-adrenergic β-adrenergic

blocking drugs antagonists antagonists

Adrenergic
neuronal
blocking drugs
 Adrenergic Neuronal Blocking
Drug
• Reserpine – Discontinued in US
• MOA: Prevents uptake of biogenic amines (DA,
NE, EPI, 5HT) in both central and peripheral
neurons (also adrenal chromaffin granules)
Results in Biogenic amine depletion - denervation
• Indications : Hypertension .
• Adverse effects – Diarrhea, cramps, GI acid
secretion, postural hypotension, bradycardia,
sexual dysfunction, sedation, depression (suicide).

• Caution for Supersensitivity with Chronic use. 38

 Nonselective Alpha Adrenergic
Blocking Agents
• Phentolaminea (Regitine)
– reversible and competitive
• Phenoxybenzamineb (Dibenzyline)
– irreversible and non-competitive
• MOA – block both Alpha1 and Alpha2
• Indications : Diagnosisa and Treatmentb of
Pheochromocytoma
• Adverse effects – Orthostatic hypotension,
exaggerated reflex tachycardia (why), nasal
stuffiness, ejaculatory dysfunction 39
 Alpha-1 Selective Adrenergic
Blocking Agents
• Prazosin (Minipress) - Prototype
• Doxazosin (Cardura)
• Terazosin (Hytrin)
• Tamsulosin (Flomax) – Selective for Alpha 1Aa

• Indications:
– Hypertension – not monotherapy
– Benign Prostatic Hypertrophya - relaxes bladder neck
and prostate smooth muscle
40
 Alpha-1 Selective Adrenergic
Blocking Agents
• Adverse effects :
• First Dose Effect - Exaggerated hypotension
that can lead to syncope especially when
patient stands after sitting or lying down
(orthostatic hypotension)
– less reflex tachycardia (why)
– sodium and water retention (prazosin) (limits
use in high blood pressure)
– nasal stuffiness
– ejaculatory dysfunction 41
 Beta Adrenergic Blocking
Agents
• Propranolol a (Inderal)
• Timolol a (Timoptic)
• Nadolol a (Corgard)
• Atenolol b (Tenormin)
• Metoprolol b (Lopressor)
• Esmolol b (Brevibloc)

• MOA :
a
Nonselective - both beta-1 and 2
b
“Cardioselective” Beta-1 specific
42
 Beta Blockers Indications cont.
• Indications :
– Prevention of migraines - May prevent catecholamine
vasodilation in the brain vasculature (Beta-2?)
– Hyperthyroidism – Thyroid storm
– Glaucoma – (Timolol)
– Arrhythmias, Angina pectoris, Myocardial Infarction, Heart
failure – Protective effect against sympathetic
overstimulation – improved survival !!
• Adverse reactions – Bradycardia, Heart block, Heart
failure, Raynaud’s (peripheral vasospasm), Vivid dreams,
depression, Bronchoconstriction in asthmatics/COPD, Sexual
dysfunction, Decreased glycogenolysis and glucagon
secretion
43
• Caution for Withdrawal Supersensitivity with Chronic use
 Alpha and Beta Adrenergic
Blocking Agents
• Labetalol a(Trandate, Normodyne)
• Carvedilol b(Coreg)

• MOA – block both Alpha1 and Beta Adrenoceptors.

– Result in peripheral vasodilation that lowers
blood pressure with reduced cardiac rate and
contraction
• Indications : Hypertension a and Congestive heart
failure b
• Adverse effects – Combines BOTH Alpha and
44
Beta adrenoceptor blocker adverse effects.
Process Affected Drug Example Site Action
Receptor Activation Bethanechol, Muscarinic Receptor Parasympatho-
or Blockade Pilocarpine Activation mimetic,
Atropine Muscarinic Receptor Parasympatholytic
Blockade
Nicotine Nicotinic Receptor Skeletal muscle
Activation activation
Tubocurarine Nicotinic Receptor Muscle paralysis,
Blockade respiratory arrest
Epinephrine α1, α2, β1, β2, β3 Sympathomimetic
Receptor Activation
Norepinephrine α1, α2, β1, Receptor Sympathomimetic
Activation
Phenylephrine α1 Receptor Activation Sympathomimetic
Phentolamine α1, α2, Receptor Sympatholytic
Blockade
Prazosin α1 Receptor Blockade Sympatholytic
Isoproterenol β1, β2, β3 Receptor Sympathomimetic
Activation
Propranolol β1, β2, β3 Receptor Sympatholytic
Blockade 45
 Target Organ Responses
Adrenergic and Cholinergic Receptors

Adrenergic Cholinergic
Subtype: 1 2 1 2 M N
Agonist
Antagonist
Location
Importance
46
 Prototype Drugs
Adrenergic Cholinergic
Synthesis/storage
Release
Receptor
Agonist
Antagonist
Removal
47
 Control of Blood Pressure

Arterial - Afterload
mABP = CO x TPR

Cardiac - HR SV
Chronotropy

Cardiac - Inotropy CF VR 48
Venous – Preload