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Cholinergic neurons and

receptors

Cholinergic neurons and
receptors

Adrenergic neurons and
receptors

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Most organs receive dual sympathetic
and parasympathetic innervation

However, some organs only receive
sympathetic innervation:

Spleen
Sweat Glands
Piloerector Muscles
Most Blood Vessels
Vascular smooth muscle is a prime example of a target organ that
does not have dual innervation
Blood pressure and peripheral resistance are controlled by the
sympathetic nervous system
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Mydriasis & Miosis
Mydriasis
Dilatation of pupil




Miosis
Constriction of pupil
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Sympathetic: Contraction of radial muscle produces dilation (mydriasis)
Parasympathetic: Contraction of circular muscle produces constriction (miosis)
Sympathomimetic drugs
Adrenomimetic drugs
Adrenergic agonists
Adrenoceptor agonists

1

2
and
1

2

1
and
2

1
and
2

EPINEPHRINE
NOREPINEPHRINE
DOPAMINE
IBOPAMINE
AMPHETAMINE
METHAMPHETAMINE
EPHEDRINE
PSEUDOEPHEDRINE
DOBUTAMINE
ISOPROTERENOL

1

2
and
1

2

1
and
2

1
and
2


PHENYLEPHRINE
METHOXAMINE
MEPHENTERMINE
METARAMINOL
MITODRINE

2
and
1

2

1
and
2

1
and
2


METHYLDOPA
CLONIDINE
GUANABENZ
GUANFACINE

2
and
1

2

1
and
2

1
and
2


NAPHAZOLINE
TETRAHYDROZOLINE
OXYMETAZOLINE
XYLOMETAZOLINE

2
and
1

2

1
and
2

1
and
2

METAPROTERENOL
TERBUTALINE, ALBUTEROL
RITODRINE
ISOETHARINE, PILBUTEROL
BITOLTEROL, FENOTEROL
FORMOTEROL, SALMETEROL
PROCATEROL
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Signal Transduction by 1 - Adrenergic Receptors
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Signal Transduction by
2
- and - Adrenergic Receptors


27
Adrenergic (Sympathomimetic):
Drugs
1. Cathecholamines
Cannot cross Blood Brain Barrier
Endogenous: Epinephrine, NE, Dopamine
Exogenous (synthetic): Dobutamine (post-heart
failure) and Isoproterenol (Bronchodilators)

2. Non-Cathecholamines
Cross the Blood Brain Barrier
Ephedrine (Metabolife diet pills), albuterol
(anti-asthma), and phenylephrine
(decongestant)
28
Adrenergic (Sympathomimetic):
Uses
Primarily used for emergency drugs
1. Cardiac arrest stimulates the heart
2. Hypotension increase BP
3. CHF increase force and contraction of heart
4. Asthma bronchodilator
5. URT Congestion decongestant
6. Allergic reaction vasoconstriction and decongestant
7. Hypoglycemia glycogenolysis
8. Local bleeding vasoconstriction
9. Obstetrics uterine relaxant
10. Eye disorder vasoconstriction
29
Adrenergic (Sympathomimetic): Adverse
Effects
1. Cathecholamines
Nervousness and
restlessness
Angina
Hypertension
Tachycardia
Hyperglycemia
Nausea and vomiting
2. Non-Cathecholamines
Severe anxiety and
insonmia
Tachycardia and
palpitations
Dysrhythmias
Muscular weakness
and cramps
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Adrenergic (Sympathomimetic):
Contraindications
Cardiac dysrythmia
Angina
Hypertension
Glaucoma
Pregnant women
32
Adrenergic (Sympathomimetic): Cathecholamine Drugs
Epinephrine hydrochloride
(Adrenalin Chloride)
Drug of choice for
Anaphylaxis
Active ingredient in OTC
(over-the-counter) asthma
preparation
Effects: (+) Alpha and Beta
recepts
BP and HR
blood flow to brain,
heart, and skeletal muscle
Peripheral
vasoconstriction
(-) GIT motility
33
Adrenergic (Sympathomimetic): Cathecholamine
Drugs
Norepinephrine
(Levophed)
Strong vasoconstrictor
Used for Hypotension
and Cardiac Arrest

Dopamine Hydrochloride
(Intropin)
Precursor to NE
Dosage effects:
Low dose causes
renal perfusion
Low to moderate dose
causes increased
CO
Higher doses
increased peripheral
resistance and BP
34
Adrenergic (Sympathomimetic): Cathecholamine Drugs
Dobutamine hydrochloride
(Dobutrex)
Synthetic cathecholamine
Acts directly on heart
muscle to increase the
contraction

Isoproterenol hydrochloride
(Isuprel)
Synthetic cathecholamine
Bronchodilator
(+) Beta1 and Beta2
receptors
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Adrenergic (Sympathomimetic): Anti-Cathecholamine
Drugs
Ephedrine and
Pseudoephedrine (Sudafed)
Less potent but longer acting
than epinephrine
Bronchodilator and Nasal
decongestant (allergic
reaction)

Phenylephrine hydrochloride
(Neo-Synephrine)
(+) Alpha receptor
Vasoconstrictor,
decongestant, and
bronchodilator

Albuterol (Proventil)
Bronchodilator
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Clonidine (Catapres

)
Centrally acting alpha 2 receptor agonist

Effects Reduces blood pressure and
produces inhibition of sympathetic
vasomotor centers

Indications Hypertension
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Amphetamine
Actions - CNS stimulant and cardiovascular
stimulant (increased BP and heart rate and
contraction)
Mechanism of action Releases catecholamines
from presynaptic storage vesicles.
Indications - narcolepsy, appetite control
Adverse effects Restlessness, tremor, irritability,
insomnia, tachycardia, hypertension

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Anti-Adrenergic (Sympatholytic)
Block the effect of sympathetic nervous
system

Treatment goal is to reduce pathologic
response to activity, stress, and other
stimuli

Two major types:
1. Alpha-adrenergic blocking agent
2. Beta-adrenergic blocking agent
Selective
1
-blockers
Selectively block
1
receptors
Ie. Alfuzosin, doxazosin, prazosin, terazosin,
tamsulosin
Used in the treatment of chronic hypertension
Also used to treat urinary retention in men
with benign prostatic hyperplasia
Non-selective -blockers
Block both
1
and
2
receptors
phentolamine and phenoxybenzamine
Competitive
inhibitor
Non-competitive
inhibitor
Chemical sympathectomy
Hypertensive Episodes
- decreases vascular
resistance
- lowers BP
- smooth muscle
relaxation in the bladder
Used to treat
hypertensive episodes of
Pheochromocytoma
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Anti-Adrenergic (Alpha-adrenergic
blocker): Uses
1. Mild to moderate hypertension
2. Benign prostatic hypertrophy (BPH)
3. Migraine headaches
4. Pheochromocytoma tumor of the
adrenal glands
Increased secretion of Epinephrine and NE
5. CHF with diuretics
6. Peripheral vascular disorders (frostbites)
43
Anti-Adrenergic (Alpha-adrenergic
blocker): Adverse Effects
Nasal congestion
Nausea
Vomiting
Postural hypotension
44
Anti-Adrenergic (Alpha-adrenergic
blocker): Contraindications
Hypersensitivity
Sepsis
Hepatic or renal disease
Atherosclerosis (alpha 2 blocker)
Hypertension (alpha 2 blocker)
Anemia
Pregnancy and lactating
Caution to children and elderly
45
Anti-Adrenergic (Alpha-adrenergic
blocker): Important Drugs
Phentolamine mesylate (Regitine)
Prevents tissue necrosis after extravasation of IV NE
Prevents and controls hypertension caused by
Pheochromocytoma

Doxazosin (Cardura), Prozosin (Minipress), and
Terazosin (Hytrin)
Acts on the periphery
Treats hypertension or BPH

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Anti-Adrenergic (Beta-blockers)

-Nonselective blocker:
propranolol*, timolol, nadolol
-Combined - and - blocking:
Carvedilol, labetalol
-
1
selective blocker: metoprolol,
atenolol
-
2
selective blocker: butoxamine
47
Anti-Adrenergic (Beta-
Adrenergic)
Block the effect of Adrenergic stimulation of Beta1
or Beta2

Competes with NE receptor site

Beta blockers
Decrease in BP, heart contraction, and CO
Beta2 blockers causes vasodilation in skeletal
muscles

Treatment for Angina pectoris and decrease BP
48
Anti-Adrenergic (Beta-Adrenergic):
Uses
Angina decrease in O2 demand, heart
contraction, HR, BP
Dysrhythmias slow sinus node, prolongs AV
conduction
Hypertension lowers BP
MI to decrease Cathecholamin-induced
dysrhythmias
Glaucoma decreases IOP
Migraine unclear
Palpitation and Tremor unapproved anti-
anxiety
49
Anti-Adrenergic (Beta-Adrenergic):
Adverse Effects
Bradycardia
Shortness of breath
Edema
Reduced tolerance to
exercise
Hypoglycemia
CHF
Orthostatic hypotension
Fatigue
Nausea
Vomiting
Bronchospasm
Impotence
Depression
Sleep disorders
50
Anti-Adrenergic (Beta-Adrenergic):
Contraindication
Diabetes with insulin
Kidney and liver disease (metabolism
and excretion)
Alcohol, CNS depressant, and OTC
decongestant
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Anti-Adrenergic (Beta-Adrenergic):
Important Drugs
Propranolol hydrochloride
(Inderal)
Treats hypertrophic subaortic
stenosis, hypertension,
angina, dysrythmias, and MI

Metoprolol tartrate
(Lopressor)
Treats hypertension and
dysrythmias

Atenolol (Tenormin)
Treats hypertension, angina,
and MI

Timolol maleate (Timoptic)
Eye drop for treatment of
Glaucoma
Drugs for Glaucoma
Multiple medication classes used to treat glaucoma-
several are autonomic drugs

Alpha 2 adrenergic agonists (Apraclonidine) [Iopidine];
(Bromonidine) [AlphaganP]

Topical carbonic anhydrase inhibitors (Dorzolamide)
[Trusopt]

Beta blockers (Betaxolol, Timolol)

Prostaglandin analogs (Latanoprost) [Xalatan]

Cholinergic agonists - Direct (Pilocarpine)

Sympathomimetics (Dipivefrin)
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PARASYMPATHOMIMETIC DRUGS
PARASYMPATHOLITIC DRUGS
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Cholinergic receptors
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Amanita muscaria L.
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Cholinoceptor-activating drugs
Para sympathomimetics Cholinomimetics

Cholinoceptor stimulants
Direct-acting
(receptor agonists)
Indirect-acting
(cholinesterase inhibitors)
Muscarinic Nicotinic
Choline esters
Alkaloids
Ganglionic
Neuromuscular
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Direct Cholinergic Agonists
Choline Esters
Acetylcholine
Methacholine
Carbachol
Bethanechol

Alkaloids
Muscarine
Pilocarpine
Alkaloids are not
metabolized by
cholinesterases
Properties of choline esters
Choline Ester Susceptibility to
Cholinesterase
Muscarinic
Action
Nicotinic
Action
Acetylcholine ++++ +++ +++
Methacholine + ++++ None
Carbachol Negligible ++ +++
Bethanechol Negligible ++ None
Acetylcholinesterase inhibitors
Three chemical groups:
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Alcohols Esters Organophosphates
1- Edrophonium 1- Neostigmine
2- Physostigmine
1- Echothiophate
2- Isoflurophate
Neostigmine is not
absorbed and does not
enter CNS
Physostigmine is absorbed
from all sites including
conjunctiva and enters
CNS
All organophosphorous
compounds are well
absorbed from all sites of
administration and enter
the CNS except
echothiophate
Reversible inhibition after
2-10 min.
Reversible inhibition after
30 min to 6 hours
Irreversible inhibition (can
be reversed by
pralidoxime)
Therapeutic uses of cholinoceptor
stimulants
Disease Mechanism of action Drug
1- Glaucoma Contraction of the ciliary
muscle and increasing the
outflow of the aqueous
humor
Pilocarpine
Physostigmine
echothiophate
2- Postoperative ileus
Bethanechol or
neostigmine
3- Reflux esophagitis
4- Urinary retention
5- Myasthenia gravis neostigmine,
pyridostigmine, or
ambenonium.
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Cholinergic (Direct-acting): Drugs
Bethanechol chloride
(Urecholine)
Treats urinary retention and
glaucoma

Pilocarpine hydrochloride
(Pilocar)
Decreases IOP in Glaucoma

Carbachol intraocular (Miostat)
Treats Glaucoma

Metoclopramide hydrochloride
(Reglan)
Prevents chemotherapy-
induced nausea and vomiting
Treats Acid-reflux disease
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Cholinergic (Indirect-acting): Important
drugs
Neostigmine bromide
(Prostigmin)
Treats urinary retention

Edrophonium chloride
(Tensilon)
Diagnoses Myasthenia
gravis

Pyridostigmine bromide
(mestinon)
Drug of choice for
Myasthenia gravis
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Edrophonium (Tensilon

)
Clinical indication diagnosis of
myasthenia gravis

More rapidly absorbed and shorter
duration of action than neostigmine
Toxicity of cholinoceptor stimulants
Direct acting muscarinic
stimulants (ex. Pilocarpine)
meiosis, nausea, vomiting, diarrhea, salivation,
sweating, cutaneous vasodilation, and bronchial
constriction. These effects are all blocked by
atropine.
Cholinesterase inhibitors Acute toxicity: Treated by atropine and
pralidoxime)
1- meiosis, nausea, vomiting, diarrhea, salivation,
sweating, cutaneous vasodilation, and bronchial
constriction
2- These manifestations are followed by:
(1) central stimulation, which cause convulsions and
may progress to coma and respiratory arrest;
(2) skeletal muscle paralysis
(3) hypertension and cardiac arrhythmias.

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CHOLINOCEPTOR-BLOCKING DRUGS
PARASYMPHATOLITIC DRUGS

ANTICHOLINERGIC DRUGS


Antimuscarinic Antinicotinic


M
1
-selective Nonselective Ganglion Neuromuscular
(Pirenzepin) blockers blockers
Muscarinic receptor blockers
(antimuscarinic or parasympatholytic because they block
the effects of parasympathetic autonomic discharge)
I- Natural:
1. Atropine
2. Scopolamine (hyoscine)

II- Synthetic Substitutes
a) Tertiary amines :
1. Propantheline
2. Pirenzepine
3. Dicyclomine
4. Tropicamide
5. Benztropin
6. Oxybutynin
b) Quaternary amines
1. Ipratropium
2.Trospium

Antimuscarinic drugs used in
ophtalmology
Drug Duration of
Effects (days)
Usual Concentration
(%)
Atropine 7-10 0.5-1
Scopolamine 3-7 0.25
Homatropine 1-3 2-5
Cyclopentolate 1 0.5-2
Tropicamide 0.25 0.5-1
Atropine & Scopolamine
plant origin
atropine - Atropa belladonna
scopolamine - Hyoscyamus niger
well absorbed from mucous
membranes or skin
competes with Ach for muscarinic
receptors
organs differ in sensitivity to these
drugs
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Atropa belladonna
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Hyoscyamus niger
Atropine
most sensitive
salivary glands
bronchial glands
sweat glands
intermediate sensitivity - heart
tissues
least sensitive - parietal cells
highly selective for muscarinic
receptors
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Atropine Sulfate
General Pharmacological Effects - A belladonna
alkaloid competitively blocks muscarinic receptors
from acetylcholine - ability to cross the CNS

Indications
Eye - Diagnostic use only - Causes mydriasis (pupil dilation)
and cycloplegia (inability to focus). Increases intraocular
pressure in patients with glaucoma
GI - Antispasmodic agent for GI tract and bladder - Reduces
motility and slightly reduces hydrochloric acid secretion.
Antidote for cholinergic agonists - organophosphate
overdoses
Cardiovascular applications

Adverse Reactions - (autonomic)- dry mouth, blurred
vision, dry eyes, tachycardia, and constipation; (CNS)
- confusion, and hallucinations
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Anticholinergic Contraindications
Contraindications - Narrow angle glaucoma,
Tachycardia, GI or GU Obstructive disease,
Myasthenia gravis, Asthma (Atropine only)

Myasthenia gravis - Anticholinergics contraindicated
however (Atropine and propantheline) may be used
in conjunction with Anticholinesterase medications
to reduce GI side effects

Atropine in asthma - Systemic absorption and CNS
penetration results in side effects and toxicity
Therapeutic uses of atropine
1- Preanesthetic mediction:
Given half an hour before general anesthesia to:
a) Decrease salivary and bronchial secretion
b) Protect the heart from excessive vagal tone which may occur
during anesthesia
c) Counteract the depressant effect of morphine on the respiratory
center
2- Antispasmodic
3- Treatment of severe bradycardia
4- Antidote to parasympathomimetics
5- Hyperhidrosis
6- Treatment of poisoning with cholinoceptor stimulants (as
cholinesterase inhibitors)
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Scopolamine
Belladonna alkaloid with similar peripheral effects
and greater CNS effects compared to atropine
Indications
Motion Sickness
Surgery; block short-term memory, reduce the
flow of saliva (antisialagogue).
Adverse Reactions - Similar to atropine: drowsiness
(17%), dry mouth (67%), blurred vision, pupil dilation.

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Ipratropium (Atrovent

)
Indication Bronchospasm

Available as an inhaler, solution for nebulization, and
nasal spray (for rhinorrhea)

Bronchodilation - caused by inhibiting cyclic guanosine
monophosphate in the lungs