Pharmacology of the

Autonomic Nervous System

Dr. Ahmed Atia

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Peripheral Nervous System
Somatic Nervous Autonomic Nervous
System System

Parasympathetic Sympathetic
Nervous System Nervous System

Discrete Diffuse
Activation Activation
Skeletal
Muscle
Glands, Smooth Muscle
& Cardiac Muscle 2
3
4
5
 Cholinergic
Neurotransmission
• Synthesis
Choline Acetyl Transferase
• Storage
Vesicles
• Release – Na+ / Ca2+
• Receptor Activation
Musc / Nic
• Termination of Action
Acetyl cholinesterase

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 Adrenergic Neurotransmission

•Synthesis
Tyrosine Hydroxylase**
Dopadecarboxylase
• Storage
Dopamine- hydroxylase
• Release – Na+ / Ca2+
• Receptor Activation:
1,,1
• Autoreceptor Activation
2 ,
• Termination of Action:
Diffusion / COMT / MAO
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 Autonomic Receptors:
• Cholinoceptor (acetylcholine)
Nicotinic – ionotropic (n, m)
Muscarinic – G-protein coupled (M1-5)
• Adrenoceptor (epinephrine, norepinephrine)
Alpha (α1ABD, α2ABC): G-protein coupled
Beta (β1-3): G-protein coupled
Dopaminergic receptors (dopamine)
D1-5 (2S, 2L): G-protein coupled
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ANS – CHOLINERGIC
PHARMACOLOGY

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 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
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 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, Glaucoma

• Adverse effects –
– Muscarinic (M): salivation, flushing, bronchospasm,
sweating, nausea, abdominal pain, GI cramping, diarrhea,
and possibly, decreased blood pressure.
– Nicotinic (N)- Fasciculations, respiratory arrest
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 Direct Acting Cholinergic
Nicotinic Agonists
• Nicotine
– MOA**- Low doses – ganglionic stimulation causing
euphoria. CNS effects cause relaxation and improves
attention (Acute)
– Indications – None
– Adverse effects – Vomiting, convulsions, hypertension,
cardiac arrhythmias, Respiratory arrest.
• Succinylcholine *:
– MOA - Overstimulation results in depolarizing blockade
– Indications – muscle relaxation/paralysis associated
with intubation, other procedures
– Adverse effects – Fasciculations, respiratory arrest,
malignant hyperthermia 12
 Indirect Acting Cholinergic
Agonists - Reversible
• Edrophonium - Neostigmine – Pyridostigmine -
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
respiratory arrest (N).
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 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
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 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).
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 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) 16
 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
– CNS - restlessness, confusion, and hallucinations

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 Parasympatholytics
Muscarinic receptor antagonists
• Atropine Sulfate – Cholinesterase poisoning,
– ACLS: Bradycardia, Pulseless Electrical Activity and Asystole
• Benztropine (Cogentin) – Parkinsonism (improving muscle control and
reducing stiffness)
• 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 (prevent nausea)

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 Parasympatholytics
Nicotinic receptor antagonists-
Ganglionic Blockers (NN)
• 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
– Hypotension, Orthostatic Hypotension, atony of bladder and GI Tract,
cycloplegia, xerostomia, sexual dysfunction, hyperthermia
• Rarely used therapeutically

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 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.
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ANS – ADRENERGIC
PHARMACOLOGY

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

• “Beta receptors are inhibitory everywhere

but the heart”

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 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
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 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

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 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
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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- Serotonin and norepinephrine
reuptake inhibitors)
• 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

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 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)
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 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
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 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.
– Glaucoma a
• Adverse effects – Bradycardia, Hypotension,
Headaches, Sedation, Depression.
• Caution for Withdrawal Supersensitivity with
Chronic use
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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.
Can increase ventricular rate in atrial fibrillation

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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 hyperglycemia
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 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). 33
 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)
2) Depression
3) Agitation*
4) Cardiac Arrhythmias
5) Seizures*
* 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
• 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. 37

 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,
nasal stuffiness.
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 Alpha-1 Selective Adrenergic
Blocking Agents
• Prazosin (Minipress) - Prototype
• Doxazosin (Cardura)
• Terazosin (Hytrin)
• Tamsulosin (Flomax) – Selective for Alpha 1Aa

• Indications:
– Hypertension
– Benign Prostatic Hypertrophya - relaxes bladder neck
and prostate smooth muscle
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 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)
– reflex tachycardia
– sodium and water retention (prazosin) (limits use in
high blood pressure)
– nasal stuffiness
– ejaculatory dysfunction

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 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
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 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, Vivid dreams, depression, Bronchoconstriction in
asthmatics/COPD, Sexual dysfunction, Decreased
glycogenolysis and glucagon secretion
• Caution for Withdrawal Supersensitivity with Chronic use
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 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
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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 44