Name:______________________________

Silva Lectures (Autonomic Drugs)

I. Cholinergic Agonists:

–Direct Acting:

◦ Pilocarpine:
a) A tertiary amine (can enter CNS).
b) Far less potent than ACh (so it is a partial agonist).
c) Ophthalmologic uses: cholinergic drug of choice for emergency lowering of intraocular
pressure, used alone or in combination with an acetylcholinesterase inhibitor (AChEI).
d) Potent stimulator of secretions (sweat, saliva, tears, etc).
e) Stable to hydrolysis by AChE.

◦ Carbachol:
a) Muscarinic and nicotinic agonist.
b) Poor substrate for AChE.
c) Ophthalmologic uses: Used to lower intraocular pressure in glaucoma by increasing
drainage.

◦ Metacholine:
a) Muscarinic agonist.
b) Increases LES.
c) Ophthalmologic uses: Miotic used in the treatment of glaucoma.
d) Resistant to hydrolysis by AChE.

◦ Bethanechol:
a) Muscarinic agonist.
b) GI uses:
(1.) Reflux (↑LES)
(2.) Esophagitis
(3.) Ileus
(4.) Megacolon
c) GU uses: for urinary retention.
d) Not hydrolyzed by AChE.
e) Side effects: abdominal pain, diarrhea.

◦ Succinylcholine:
a) Nicotinic action on skeletal muscle cells (depolarizing blockade).

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 b) Used for: skeletal muscle relaxant (flaccid paralysis).

–Indirect Acting (the AChEI’s):

◦ As a group: are divided in 3, the alcohols, the carbamates, and the organophosphates.
a) The alcohols and carbamates are reversible.
b) Organophosphates are long acting and “irreversible”. Bound to AChE they actually
undergo “aging”, after which they are truly irreversible, but if an oxime (like
pralidoxime) is administered before that happens the AChE becomes “regenerated” or
“reactivated” because the organophosphate is displaced from the enzyme, making it
again functional.
c) In ophthalmologic use they are cataratogenic chronically.
d) Are often used in insecticides.

◦ Edrophonium:
a) An alcohol.
b) GI uses:
(1.) Reflux (↑LES)
(2.) Esophagitis
(3.) Ileus
(4.) Megacolon
c) CV uses: for arrhythmias (supraventricular and paroxysmal supraventricular
tachycardia).
d) Used for: diagnosis myasthenia gravis by discriminating between MG (patient gets
better after administration) and cholinergic crisis (patient gets worse after
administration). Not for actual treatment of MG.
e) If given in excess it can provoke a cholinergic crisis, in which case atropine (a
muscarinic antagonist) is the antidote.

◦ Ambenomium:
a) A carbamate.
b) Used for: treatment of myasthenia gravis.
c) Long acting.

◦ Physostigmine:
a) A carbamate.
b) Is no longer used.
c) Ophthalmologic use: for glaucoma.

◦ Demecarium:
a) A carbamate.
b) Ophthalmologic use: for glaucoma.
c) Considered ‘irreversible’.

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 ◦ Neostigmine:
a) A carbamate.
b) Does not cross to CNS (has positively charged quaternary nitrogen).
c) GI uses:
(1.) Reflux
(2.) Esophagitis
(3.) Ileus
(4.) Megacolon
d) GU uses: for urinary retention.
e) Used for:
(1.) Diagnosis and treatment of myasthenia gravis.
(2.) In the neuromuscular junction for reversal of non-depolarizing blockade, as
antidote for tubocurarine (and others).

◦ Pyridostigmine:
a) A carbamate.
b) Used for:
(1.) Treatment of myasthenia gravis as drug of choice because its half life is
intermediate between neostigmine and ambenomium.
(2.) Intoxication with atropine.
(3.) Reversal of non-depolarizing blockade as antidote for tubocurarine (and others).

◦ Tacrine, donazepil, rivastigmine, and galantamine:

a) Are carbamates.
b) CNS uses: for senile dementia of the Alzheimer type (mild to moderate).
c) Tacrine was the first but now donazepil is the drug of choice because of diminished
hepatotoxicity and longer half life, which permits one-a-day dosing.
d) Abrupt withdrawal is accompanied by loss in cognitive function.
e) Adverse effects: primarily GI upset.

◦ Echothiophate:
a) An organophosphate.
b) Ophthalmologic uses: for treatment of glaucoma.
c) Highly polar and more stable than other organophosphates, retaining its activity for
weeks.
◦ DFP:
a) An organophosphate.
b) Ophthalmologic uses: for treatment of glaucoma.

II. Cholinergic Antagonists:

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–Muscarinic Antagonists:

◦ Can be tertiary or quaternary amines.

a) Tertiary amines have CNS side effects such as decreased salivation and sweating.
b) Quaternary amines are charged, so they do not readily cross into the CNS and have
much less effects (or side effects) there.

◦ Atropine:
a) A tertiary amine.
b) Ophthalmologic uses:
(1.) Mydriatic
(2.) Cycloplegic
(3.) In intraocular surgery treatment of iritis
(4.) Can precipitate an attack of glaucoma so it is not recommended for patients over
40y/o. Only used when cycloplegia and/or longer lasting effect of mydriasis are
desired.
c) GI uses:
(1.) As anti-spasmodic
(2.) As anti-diarrheal
(3.) Not effective for peptic ulcer
(4.) Often used along with an opioid for GI effects (because they are better acting).
d) GU uses:
(1.) Urinary incontinence
(2.) Bladder inflammation
e) CV uses: for vagal discharge.
f) Respiratory system uses:
(1.) Asthma
(2.) Bronchitis
g) Blocks secretion of saliva, sweat, tears, and respiratory secretions (used before surgery
of that area).
h) Used for: detoxification of mushroom ingestion or insecticide exposure.
i) Systemic side effects:
(1.) Flushing
(2.) Fever
(3.) Tachycardia
(4.) Constipation
(5.) Enuresis
(6.) Delirium
(7.) Confusion

◦ Scopolamine:
a) A tertiary amine.

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 b) CNS uses:
(1.) Has anti-emetic properties. Used for vertigo, motion sickness, post-operative
nausea, and vomiting.
(2.) Blocks short term memory.
c) Ophthalmologic uses:
(1.) Mydriatic
(2.) Cycloplegic
(3.) In intraocular surgery treatment of iritis
d) GI uses:
(1.) As anti-spasmodic
(2.) As anti-diarrheal

◦ Tropicamide:
a) A tertiary amine.
b) Ophthalmologic uses:
(1.) Mydriatic
(2.) Cycloplegic
(3.) In intraocular surgery treatment of iritis
(4.) Also, because it is short acting it is sometimes given with phenylephrine (an α
agonist) as a provocative test for closure angle glaucoma. A positive test reveals an
increased intraocular pressure of 8 mmHg in 1Hr and a gonioscopically closed
angle.

◦ Homatropine:
a) A tertiary amine.
b) Ophthalmologic uses:
(1.) Mydriatic
(2.) Cycloplegic
(3.) In intraocular surgery treatment of iritis

◦ Cyclopentolate:
a) A tertiary amine.
b) Ophthalmologic uses:
(1.) Mydriatic
(2.) Cycloplegic
(3.) In intraocular surgery treatment of iritis
(4.) Along with atropine they are the preferred drugs for producing cycloplegia in
children.

◦ Benztropine, trihexiphenidyl, biperidin:

a) Are tertiary amines.
b) Used for: the treatment of Parkinson’s disease.

◦ Pirenzepine, dicyclomine:

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 a) Are tertiary amines.
b) GI uses:
(1.) Peptic ulcer
(2.) Hypermotility

◦ Ipratropium:
a) A quaternary amine.
b) Respiratory system uses:
(1.) Asthma
(2.) Bronchitis
c) Because of its charge it does not enter systemic circulation or the CNS (remains in the
lungs).

◦ Glycopyrrolate, propantheline:
a) Are quaternary amines.
b) GI uses:
(1.) Peptic ulcer
(2.) Hypermotility
(3.) As anti-spasmodic
(4.) As anti-diarrheal

–Nicotinic Ganglionic Stimulant/Blockers:

◦ Predominant tones in the ANS:

a) Sympathetic in arterioles, veins, heart contractility, and sweat glands.
b) Parasympathetic in heart rate, iris, ciliary muscle, GI tract, and bladder.
c) Nicotinic receptor blockers elicit:
(1.) Hypotension (from vasodilation and venodilation)
(2.) Decreased venous return
(3.) ↓ Cardiac contraction
(4.) ↑ Heart rate (tachycardia)
(5.) Mydriasis
(6.) Cycloplegia
(7.) Decreased GI motility and constipation
(8.) Urine retention
(9.) Anhidrosis

◦ Stimulants:
a) Nicotine (at low doses).
b) AChE inhibitors.
c) Trimethylammonium

◦ Blocking agents (were used in the past to lower blood pressure):

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 a) Nicotine (at high doses).
b) Hexamethonium
c) Mecamylamine
d) Trimethaphan
e) Pentolinium

–Nicotinic Neuromuscular Blockers:

◦ Non-depolarizing:
a) Tubocurarine (curare)
b) Isoquinoline derivatives are more recently used. They are themselves steroid
derivatives.
c) Limitations:
(1.) They cause hypotension because they also block the ganglionic nicotinic receptors.
(2.) Histamine release
(3.) Duration of action

◦ Depolarizing:
a) Succinylcholine

–Other drugs that affect cholinergic transmission:

◦ They are not very useful for systemic for systemic therapy because their effects are not
sufficiently effective.

◦ Hemicholinium:
a) Blocks synthesis of ACh.

◦ Vesamicol:
a) Blocks storage of ACh.

◦ Botulinum toxin:
a) Blocks release of Ach.
b) It is a very large molecule and diffuses very slowly, it can be used by injection for local
effects.

III. Adrenergic Agonists:

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–Direct Acting:

◦ Norepinephrine:
a) A catecholamine.
b) Acts mostly on α but has some β1 receptor activity.
c) Infusion:
(1.) ↑ Systolic pressure
(2.) ↑ Diastolic pressure
(3.) ↑ Mean blood pressure
(4.) ↑ Pulse pressure
(5.) Constriction of vessels
(6.) ↓ Heart rate (reflex bradycardia)
(7.) ↑ Cardiac contractility
(8.) Note: Although it also causes stimulation of the heart’s β 1 receptors, the peripheral
vasoconstriction leads to a “reflex bradycardia” and a ↓ heart rate is thus
observed, yet the ↑ cardiac contractility is maintained.
d) CV uses: in hypotension.

◦ Epinephrine:
a) A catecholamine.
b) Acts on both α and β receptors.
c) Infusion:
(1.) ↑ Systolic pressure
(2.) ↓ Diastolic pressure
(3.) – Mean blood pressure
(4.) ↑ Pulse pressure
(5.) Dilation of vessels
(6.) ↑ Heart rate (tachycardia)
(7.) ↑ Cardiac contractility
(8.) Note: Mean blood pressure remains the same (or somewhat increased) because of
opposing α and β activated functions.
d) Ophthalmologic uses: to increase outflow of aqueous humor in open angle glaucoma.
e) CV uses:
(1.) Hypotension (α1)
(2.) Cardiac arrest/block (β1, β2)
(3.) To decrease blood flow during surgery (α1)
f) Used in anaphylaxis for the various things it can control by activating the several
receptors:
(1.) Angioedema and mucocutaneous congestion (α1)
(2.) CV collapse and mast cell histamine release (β1)
(3.) Bronchospasm (β2)
g) Epinephrine reversal: since after an infusion of epinephrine the α and β effects
oppose each other in their effects on the mean blood pressure which leave it unchanged
(or somewhat increased), when an α blocker is administered before the infusion of

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 epinephrine, the β effects will predominate and a decrease in blood pressure will be
observed.

◦ Isoproterenol:
a) A catecholamine.
b) Acts on β receptors (a non-specific β agonist).
c) Infusion:
(1.) ↑ Systolic pressure
(2.) ↓ Diastolic pressure
(3.) ↓ Mean blood pressure
(4.) ↑ Pulse pressure
(5.) Dilation of vessels
(6.) ↑ Heart rate (tachycardia)
(7.) ↑ Cardiac contractility.
d) CV uses: for AV block (rare).

◦ Dopamine:
a) A catecholamine.
b) Acts on D1 = D2 > β > α.
c) CV uses:
(1.) For heart failure.
(2.) Drug of choice for shock because, unlike norepinephrine, it maintains renal
perfusion.

◦ Dobutamine:
a) A catecholamine.
b) Acts on β1 > β2 (a non-selective β agonist).
c) CV uses:
(1.) For chronic heart failure.
(2.) For cardiogenic shock.

◦ Dipivefrin:
a) A prodrug of epinephrine (so it will have all its properties).
b) Effect reflected on both α and β receptors.
c) Ophthalmologic uses:
(1.) Reduces aqueous humor secretion by contracting ciliary vasculature (α1).
(2.) Improves uveoscleral outflow (β2).
(3.) Activates α2 for decreased aqueous humor secretion.

◦ Phenylephrine:
a) A non-catecholamine.
b) Acts on α1 > α2 (a non-selective α agonist).
c) Ophthalmologic uses:
(1.) As mydriatic.

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 (2.) Along with tropicamide, in the use of angle closure glaucoma test.
d) CV uses: for vasoconstriction.
e) Respiratory system uses: for nasal congestion (by vasoconstriction).

◦ Albuterol, terbutaline, metoprenol:

a) Non-catecholamines.
b) Act on β2 > β1.
c) Respiratory system uses: for bronchial asthma.
d) GU uses: for suppression of premature labor (along with ritadrine), but they must be
used with caution as they increase maternal morbidity.

◦ Amphetamines:
a) Non-catecholamines.
b) Indirect agonists, act by releasing stores of catecholamines.
c) CNS uses:
(1.) Narcolepsy
(2.) Obesity
(3.) Attention deficit disorder (ADD)
d) Ophthalmologic uses:
(1.) Mydriatic
(2.) Hydroxyamphetamine is used to test if Horner’s syndrome is pre or post
ganglionic. If mydriasis is observed then it is pre-ganglionic.

◦ Ephedrine:
a) A non-catecholamine.
b) Indirect agonist, acts by releasing stores of catecholamines, also α1 has activity.
c) Respiratory system uses: along with pseudoephedrine, either can treat nasal congestion.
d) CV uses: for hypotension.
e) GU uses: along with pseudoephedrine, either can treat stress incontinence to ↓ urine
flow.

◦ Cocaine:
a) A non-catecholamine.
b) Indirect agonist, acts by inhibiting reuptake of catecholamines.
c) Used for:
(1.) Vasoconstriction
(2.) Local anesthesia

◦ Clonidine:
a) A non-catecholamine.
b) Acts on α2 > α1 >>> β (a central selective α2 agonist).
c) CV uses: hypertension.
d) CNS uses: to reduce craving in substance abuse cases.

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 e) Ophthalmologic uses: apoclonidine is used to decrease aqueous humor secretion and to
increase outflow.

◦ Brimonidine:
a) A non-catecholamine.
b) Acts on α2 (a selective α2 agonist).
c) Ophthalmologic use:
(1.) ↓ Aqueous humor secretion
(2.) ↑ Outflow

◦ Methylnorepinephrine:
a) Acts on α2 (a selective α2 agonist).

◦ Methoxamine:
a) Acts on α1 (a selective α1 agonist).

◦ Metoproterenol:
a) Acts on β2 (a selective β2 agonist).
b) GU uses: suppression of premature labor.

◦ Phenylpropanolamine, oxymetazaline, xylometazoline:

a) Are α agonists.
b) Respiratory system uses: for nasal congestion.

IV. Adrenergic Antagonists:

–Alpha blockers:

◦ Prazosin, terazosin, dorazosin (-ozin):

a) Block α1 >>> α2 (are selective α1 blockers).
b) CV uses: for hypertension
c) GU uses: for urinary retention in benign prostatic hyperplasia (BPH).
d) Toxicity:
(1.) First dose orthostatic hypertension
(2.) Hypotension
(3.) Dizziness
(4.) Headache

◦ Rauwolscine, yohimbine, tolazoline:

a) Block α2 >> α1 (are selective α2 blockers).

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 b) GU uses: yohimbine is used for impotence (effectiveness is controversial).

◦ Phenoxybenzamine:
a) Irreversibly blocks α1 > α2 (but non-selective α blocker).
b) Used for: pheochromocytoma.
c) Toxicity:
(1.) Orthostatic hypotension
(2.) Reflex tachycardia

◦ Phentolamine:
a) Blocks α1 = α2 (a non-selective α blocker).
b) Used for: pheochromocytoma.
c) GU uses: for erectile dysfunction (with papaverine).
d) Toxicity:
(1.) Orthostatic hypotension
(2.) Reflex tachycardia

–Blockers of both alpha and beta receptors:

◦ Labetalol:
a) Blocks β and α1 receptors.
b) A partial agonist
c) Has local anesthetic action
d) CV uses: for hypertensive emergencies and hypertension.
◦ Carvedilol:
a) Blocks β and α1 receptors.

–Beta blockers (-olol):

◦ Propranolol, etc (carteolol, nadolol, penbutolol, pindolol, timolol, sotalol, metipranolol):

a) Block β receptors.
b) CV uses:
(1.) Ischemia/angina (↓ heat rate and contractility, resulting in ↓ O2 consumption).
(2.) Hypertension (↓ cardiac output, ↓ renin secretion).
(3.) MI (β blockers ↓ mortality).
(4.) Supraventricular tachycardia (↓AV conduction velocity, which prolongs the PR
segment on EKG).
c) Ophthalmologic uses: timolol is used for glaucoma to decrease aqueous humor
secretion.
d) Partial agonistic action observed with: pindolol, penbutolol, and carteolol.
e) Toxicity:
(1.) Impotence

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 (2.) Asthma exacerbation
(3.) Bradycardia
(4.) AV block
(5.) Congestive heart failure
(6.) Sedation
(7.) Sleep alterations

◦ Metoprolol, etc (esmolol, atenolol, acebutolol, betaxolol, alprenolol, etc):

a) Block β1 >>> β2 (selective β1 antagonists).
b) CV uses:
(1.) Ischemia/angina (↓ heat rate and contractility, resulting in ↓ O2 consumption).
(2.) Hypertension (↓ cardiac output, ↓ renin secretion).
(3.) MI (β blockers ↓ mortality).
(4.) Supraventricular tachycardia (esmolol, like propranolol, causes ↓AV conduction
velocity, which prolongs the PR segment on EKG).
c) Ophthalmologic uses: betaxolol is used for glaucoma.
d) Partial agonistic action observed with: acebutolol.
e) Toxicity:
(1.) Impotence
(2.) Asthma exacerbation
(3.) Bradycardia
(4.) AV block
(5.) Congestive heart failure
(6.) Sedation
(7.) Sleep alterations

–Other drugs that affect adrenergic transmission:

◦ Have been used in several diseases like pheochromocytoma and hypertension because they
block sympathetic but not parasympathetic functions.

◦ Metyrosine:
a) Blocks synthesis of norepinephrine.

◦ Reserpine:
a) Blocks catecholamine storage.

◦ Guanethidine:
a) Blocks release of catecholamines.

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