PHARMACOLOGY OF THE AUTONOMIC

NERVOUS SYSTEM

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Introduction

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 Autonomic Neurotransmitters
• Acetylcholine, epinephrine and norepinephrine
(noradrenaline) are the major autonomic
neurotransmitters.

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 Norepinephrine (NE) and epinephrine (Epi)
– NE is the neurotransmitter at sympathetic postsynaptic
neurons except those innervating sweat glands.
– Adrenergic neurons:- that release NE and/or Epi
– Adrenoceptors: are defined as those receptors that
mediate responses to noradrenaline and adrenaline.
– Adrenomimetic (sympathomimetic):- drugs that mimic
NE/Epi on interaction with adrenoceptors
– Adrenoceptor antagonists:- are drugs that antagonize
the effect of NE/Epi

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 Steps in Neurohumoral transmission

 Synthesis of the transmitter

 Storage of the transmitter
 AP triggered release of the transmitter
 Interaction of the released transmitter with
receptors on the effector cell membrane and the
associated change in the effector cell
 Rapid removal of the transmitter from the vicinity of
the receptors
 Recovery of the effector cell to the state that
preceded transmitter action 5
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 Over view of ANS Functions
The ANS has three principal functions:
1. Regulation of the heart
2. Regulation of the secretory glands
 salivary, gastric, sweat and bronchial glands
3. Regulation of smooth muscles,
- muscles of bronchi
- muscles of blood vessels
- muscles of urogenital
- muscles of GIT 7
 Principal Functions of the PsNs
• Specifically, stimulation of appropriate PsN will
cause:
 slowing of the heart
 increased gastric secretion
 emptying of the bladder
 emptying of the bowel
 focusing of the eye for near vision
 constriction of the pupil

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 Principal functions of the SNS

The main functions of the sympathetic nervous system

are:
A. Regulation of the CVS
B. Regulation of body temperature
C. Implementation of the "fight" or "flight"
reaction.
Characteristic features are:
a) Shunting of blood away from the skin and
visceral into skeletal muscles.
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b) Dilation of the bronchi to improve
oxygenation
c) Dilation of the pupil (promote visual
acuity)
d) Mobilization of stored energy

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Locations of cholinergic and adrenergic
receptor subtypes

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 Locations of cholinergic receptor subtypes
Receptor type Location
M1 brain, exocrine GIT glands,
and autonomic ganglia
M2 heart, brain, autonomic
ganglia, and smooth
muscle
M3 smooth muscle, exocrine
glands, brain, and
endothelial cells
Nm Skeletal muscle NMJ

Nn Post ganglionic cell body,

dendrites 12
 Locations of adrenergic receptor subtypes
Type Tissue Actions
Most vascular smooth muscles Contraction
Alpha1
Pupillary dilator muscle Mydriasis
Heart Increase force of
contraction
Adrenergic nerve terminals Inhibition of transmitter
Alpha2 (presynaptic) release
Platelets Aggregation
Heart Increased rate and force
Beta1 of contraction
Respiratory, uterine, and Relaxation
Beta2 vascular smooth muscle
Human liver Glycogenolysis
Fat cells Lipolysis
Beta3
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 Drugs affecting specific processes
in ACh life cycle
Synthesis of Ach Hemicholinium

Release of Ach Botulinum toxin(inhibition)

Combination of Ach Atropine (muscarinic

with receptor receptors) , d-Tubocurarine
(nicotinic receptors)
Destruction or removal of Ach Physostigmine
from site of action (cholinesterase inhibitor)

Recovery of postsynaptic cell from Succinylcholine

the effects of Ach
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 Drugs affecting specific processes
in NE life cycle
Synthesis of NE alpha-Methyldopa

Storage of NE reserpine

Release of transmitter Guanethidine

Combination of NE Prazosin (alpha-receptors),

with receptor Propranolol (beta-receptors)

Destruction or removal of NE Tolcapone (COMT inhibitor),

from site of action Phenelzine (MAO inhibitor),
Tricyclic antidepressants (inhibit
neuronal transport
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. Drugs acting on the parasympathetic nervous
system
a. Parasympathomimetics or cholinergic drugs: are
drugs which mimic acetylcholine or the effects of
parasympathetic nerve stimulation.
b. Parasympatholytics: are drugs that inhibit
parasympathetic nervous system activity or that
of cholinergic drugs

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 CHOLINERGIC DRUGS
 also called parasympathomimetics
 There are two groups of cholinergic drugs: direct
acting and indirect acting
1) Direct-acting
 bind to and activate muscarinic or nicotinic
receptors (mostly both)
 the direct-acting agonists show little specificity in
their actions, which limits their clinical usefulness.

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• Different groups of direct acting cholinimimetics
exist
Esters of choline: acetylcholine, methacholine,
carbachol, betanechol
Cholinergic alkaloids:
 Those with chiefly nicotinic actions include
nicotinetc.
 Those with chiefly muscarinic actions
include muscarine, pilocarpine, etc.

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2) Indirect-acting: inhibit the action of
acetylcholinesterase enzyme
a. Reversible inhibitors: neostigmine,
physostigmine, edrophonium
b. Irreversible inhibitors : Organophosphate
compounds eg: echothiophate

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Acetylcholine
is the prototypical cholinergic agent
because of its unique pharmacokinetic
properties, it has never been used in medical
therapeutics:
»poorly absorbed from the gastric mucosa,
Hence it should be given parenterally.
»duration of action very short and unreliable
for therapeutic purpose
»lack of selectivity as an agonist for different
types of cholinoreceptors

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Pharmacodynamics of acetylcholine:
 ACh has both muscarinic and nicotinic activity
 Muscarinic: mediated by cAMP, IP3, DAG
 Nicotinic: opening of ion channels
Cardiovascular system:
Heart- slow heart rate, and decrease cardiac
output
Blood vessels- vasodilation
Blood pressure- falls because of the effect on the
heart and blood vessels
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Gastrointestinal tract:
It stimulates the tone and motility of the GlT but
the sphincters will be relaxed
Urinary tract:
It stimulates the detrusor muscle and relaxes the
internal urethral sphincter resulting in evacuation
of bladder
Bronchioles:
»It increase bronchial secretion and brings
about bronchoconstriction
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Eye:
»It has two effects- miosis and
accommodation for near objects because
of stimulation of the constrictor pupillae
and ciliary muscles respectively
Exocrine glands:
» it stimulates salivary, gastric, bronchial,
lachrymal and sweat gland secretions
Skeletal muscle: contraction

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• Indication of acetylcholine
acetylcholine (1% solution) to cause miosis (of
short duration) during cataract surgery
– carbachol is used during eye surgery necessitating
miosis of a longer duration

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 Choline - ester derivatives of ACh:
• methacholine, carbachol, bethanechol
methacoline and bethanechol
Compared to ACh, these are more selective to M
than N receptors
Longer duration of action
Carbachol used in:
Glaucoma
Retention of urine (postoperative)
Paralytic ileus

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 Contra indications to the use of cholinomimetics
Bronchial asthma:- because they may induce
bronchial constriction and increase bronchial
secretions
Hyperthyroidism:- b/c of the danger of inducing
atrial fibrillation
Peptic ulcer disease:- b/c of the increase in gastric
acid secretion
Coronary insufficiency:- b/c the hypotension
produced will further compromise coronary blood
flow
Mechanical intestinal and urinary outlet obstruction
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 Cholinergic alkaloids
Pilocarpine
 Pharmacodynamics
– a pure muscarinic receptor agonist
– longer duration of action

 Indications :
 Glaucoma
 Xerostomia

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Indirect-acting cholinomimetics
 are inhibitors of cholinesterase enzyme
 ChE is located both pre- and postsynaptically in the
nerve terminal, where it is membrane bound
 provoke a response at all cholinoceptors (M and N)
in the body
a. Reversible ChEIs:
» eg. neostigmine, physostigmine,
pyridostigmine , edrophonium
b. Irreversible ChEIs :
» eg. organophosphate compounds eg.
echothiophate

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• Effects of poisoning by organophosphates
 the first signs are muscarinic stimulation, followed by
nicotinic receptor stimulation and then desensitization
of nicotinic receptors.
 Excessive enzyme inhibition can ultimately lead to a
cholinergic crisis that includes:
gastrointestinal distress (nausea, vomiting, diarrhea,
excessive salivation)
respiratory distress (bronchospasm and increased
bronchial secretions)
cardiovascular distress (bradycardia or tachycardia,A-
V block, hypotension)
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 visual disturbance (miosis, blurred vision)
 sweating
loss of skeletal motor function (progressing
through incoordination, muscle cramps,
weakness, fasciculation, and paralysis)
CNS symptoms include agitation, dizziness, and
mental confusion
• Death usually results from paralysis of skeletal
muscles required for respiration but may also result
from cardiac arrest

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• Treatment of the Poisoning due to cholinesterase
inhibitors
 atropine
 injection of increasing doses of atropine
sulfate to block all adverse effects resulting
from stimulation of muscarinic receptors.
 mechanical respiratory support
 This may be required since atropine will not
alleviate skeletal and respiratory muscle
paralysis

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• When the poisoning is due to an organophosphate
 Pralidoxime
 reactivate cholinesterases in the periphery and a
decrease in the degree of the blockade at the
skeletal neuromuscular junction
» Pralidoxime has a greater effect at the
skeletal neuromuscular junction than at
autonomic effector sites.

– NB: after sometime, the enzyme-organophosphate

complex will undergo aging. After this time the
interaction is irreversible b/c of some structural
changes
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 Anticholinergics
 block the effects of Ach and other cholinergic drugs at
cholinergic receptors of effector cells.
 fall into two major families:
1. Antimuscarinics: - antagonists of M receptors
– tertiary amines such as atropine, scopolamine,
tropicamide.
– quaternary amines such as ipratropium,
propantheline.
2. Antinicotinics:- antagonists of N receptors
 ganglion blockers such as hexamethonium,
trimethaphan.
 neuromuscular blockers such as gallamine,
tubocurarine, pancuronium, etc.
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Antimuscarinics
– produce effects only by blocking the activation of
muscarinic receptors by muscarinic agonists or by
neuronally released Ach
– Clinical use:
• Antispasmodics and antisecretory
• Mydriasis
• Asthma
• PUD
• Parkinson’s disease
• Cholinergic poisoning
• Motion sickness
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Atropine
the prototype of muscarinic antagonists
 Pharmacodynamics
–antagonizes the effect of ACh by competing for
the muscarinic receptors peripherally and in the
CNS
–has effects opposite to the acetylcholine
CNS:
lower doses produce sedation
higher doses produce excitation, agitation and
hallucination
Eyes:
relaxation of constrictor pupillae (mydriasis)
relaxation or weakening of ciliary muscle
(cycloplegia-loss of the ability to accommodate)
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 CVS:
bradycardia at low dose
tachycardia at higher dose
 Respiratory:
bronchodilation and reduction of secretion
 GIT:
decreased motility and secretions
 GUS:
Relaxes smooth muscle of ureter and bladder wall;
voiding is slowed.
 Sweat Glands:
suppresses sweating

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 Pharmacokinetics
is tertiary amine and well absorbed from the GIT,
conjunctiva and can cross the BBB
 Clinical Indications
Pre anesthetic
As antispasmodic in cases of intestinal, biliary,
and renal colic
Heart block
Eye
Hyperhidrosis (too much sweating)
Antidote for cholinergic agonists eg.
organophosphate poisonings , and overdose of
phystostigmine

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 Side effects
dryness of the mouth, tachycardia and blurred
vision, retention of urine
Photophobia
Hyperthermia
almost no detectable effect on the CNS in doses
that are used clinically
low doses of cholinesterase inhibitors such as
physostigmine may be used to overcome atropine
toxicity
 Contraindications
Glaucoma, Prostatic hyperplasia
Bladder outlet obstruction
 D/Is: TCAs, phenothiazines, antihistamines: Anti
cholinergics 38
 Hyoscine (scopolamine)
 scopolamine has certain advantages over atropine.
These include:
can be used for short- travel motion sickness
– similar to atropine in pharmacokinetics and adverse
effects
ipratropium
 Clinical indications
asthma given via inhalation route
chronic obstructive pulmonary disease
tropicamide and cyclopentolate
like atropine to bring about mydriasis and
cyclopegia but preferred b/c of very short
duration of effect than atropine
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 Neuromuscular Blocking Agents
 Either by acting presynaptically to inhibit ACh
synthesis or release, or by acting postsynaptically
 clinically, neuromuscular blockade is used only as an
adjunct to anaesthesia
the drugs that are used all work by interfering
with the postsynaptic action of Ach (on
nicotinic receptors of skeletal muscle)
 clinically used drugs are structural analogs of
acetylcholine and cause muscle relaxation

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1. non-depolarizing blockers eg. tubocurarine
– act as antagonists of cholinoreceptors on the end
plate of the neuromuscular junction
»blocking ACh receptors (and, in some cases, also
by blocking ion channels)
2. depolarizing blockers eg. succinylcholine
– act as agonists at the above mentioned receptors
»eventually block cholinergic receptors
(Nm)on skeletal muscles and thereby cause
muscle relaxation
 major use neuromuscular blockers:-
to produce muscle relaxation during surgery
without a need for high dose of anesthetics
also for tracheal intubation
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Non- depolarizing NM blockers:- tubocurarine, mivacurium, and
atracurium
 Mechanism of action
a) At low doses
interact with the nicotinic receptors to prevent
competitively the binding of ACh
With no significant effect on ion channels of the end
plate
– Action can be reversed by increasing the concentration of
ACh in the synaptic gap. eg by administration of ChEIs such
as neostigmine
» this strategy often used to shorten the duration
of the neuromuscular blockade in anesthesia

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b) At high doses
– block cholinoreceptors at motor end plate
– can block the ion channels of the end plate further
weakening muscles
» this reduces the ability of AChEIs to
reverse the actions of non depolarizing
muscle relaxants

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 Pharmacokinetics:
all neuromuscular blocking agents are injected
intravenously, because their uptake via oral
absorption is minimal
Many of the drugs are not metabolized; their
actions are terminated by redistribution
 Adverse effects:
in general, agents are safe with minimal side effects
(tubocurarine, mivacurium, and atracurium), which
release histamine, can produce a fall in blood
pressure, flushing, and bronchoconstriction.

 D/Is- aminogylcosides, AChEIs, CaCB

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 Depolarizing neuromuscular blocking agents
succinylcholine
 Mechanism of action
attaches to the nicotinic receptor and acts like
acetylcholine to depolarize the junction but
eventually blocking it
Unlike acetylcholine which is instantly
destroyed by AChE, the depolarizing agent
persists at high concentrations in the synaptic
cleft remaining attached to the receptor for a
relatively longer time and providing a constant
stimulation of the receptor
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 – initially produces short-lasting muscle
fasciculations, followed within a few minutes by
paralysis
– normally, the duration of action of succinylcholine
is extremely short, because this drug is rapidly
broken down by plasma cholinesterase (when it
enters the blood).
 Pharmacokinetics:
 succinylcholine is injected intravenously
 Its brief duration of action (several minutes)
results from redistribution and rapid hydrolysis by
plasma cholinesterase

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 Therapeutic use
endotracheal intubation
also employed during electroconvulsive shock
treatment
 Adverse effects
hyperthermia
–occasionally caused malignant hyperthermia in
genetically susceptible people
Treated by administration of dantrolene
apnea
–in a patient who is genetically deficient in
plasma cholinesterase or has an atypical form of
the enzyme
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hyperkalemia

–due to increased potassium release from

intracellular stores

»dangerous in burn patients or patients

with massive tissue damage in which
postassium is been rapidly lost from
within cells.

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Drugs acting on the sympathetic nervous system

a. Sympathomimetics or adrenergic drugs: - are

drugs that mimic the effects of sympathetic
nerve stimulation.
b. Sympatholytics: - are drugs that inhibit the
activity of sympathetic nerve or that of
sympathomimetics.

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 Adrenergic drugs are divided into two groups on the
basis of their chemical structure
Non
Catecholamine catecholamines
Drug Receptor Drug Receptor
stimulated stimulated

Adrenaline α1, α2, β1, β2 Ephedrine α1, α2, β1, β2

Noradrenaline α1, α2, β1 Phenylephrine α1

Isoprenaline β1, β2 Terbutaline β2

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Dopamine β1, DA
• can be grouped by mode of action
Direct acting: directly interact with and activate
adrenoreceptors, e.g., adrenaline and noradrenaline
–many adrenomimetic drugs produce responses
by interacting with the adrenoceptors on
sympathetic effector cells
Indirect acting : their actions are dependent on the
release of endogenous catecholamines.
i. Induction of release, e.g., amphetamine,
tyramine
ii. inhibition of reuptake , e.g. cocaine, tricyclic
antidepressants

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 Clinical consequences of Alpha 1 Stimulation
• Stimulation of  1 receptors produces two responses
that can be of therapeutic use:
i. vasoconstriction (in the vessels of the skin,
viscera and mucous membranes)
ii. mydriasis
• But vasoconstriction is the one for which  1
stimulation is most often employed including:-
a) Hemostasis: arrest of bleeding.
b) Nasal decongestion: Drugs can relieve this
congestion by causing alpha 1 mediated
vasoconstriction.

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 c) Adjunct to local anaesthetics : frequently
combined with local anaesthetic to delay
anaesthetic absorption.
» It prolongs anaesthesia
» It allows reduction in anaesthetic
dosage and
» It reduces the systemic effects that a
local anaesthetic might produce.
d) Elevation of blood pressure
e) Mydriasis
 Adverse effects of Alpha1 Stimulation
1. Hypertension
2. Necrosis
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 Clinical consequences of Beta 1 Stimulation

 Therapeutic applications of Beta1 stimulation

a. treatment of cardiac arrest
b. treatment of heart failure
c. treatment of shock
 Adverse effects of Beta1 Stimulation
a) effects on heart rate and rhythm. tachycardia
or even arrhythmia
b) angina pectoris

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 Clinical Consequences of Beta2 stimulation
 Therapeutic application of Beta2 Stimulation
1. asthma- since stimulation of beta2
receptors in the lung causes
bronchodilation
2. delay of premature labour
 Adverse effects of beta2 stimulation
 hyperglycemia only in patients with diabetes

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 Adrenergic agonists
Adrenaline
 receptor specificity: alpha1, alpha2, beta1, beta2
 chemical classification: catecholamine
 Therapeutic Uses
A. Because of its ability to cause alpha-mediated
vasoconstriction, adrenaline is used to:
delay absorption of local anaesthetics
control of superficial bleeding
produce nasal decongestion
elevate blood pressure
B. stimulation of alpha1 receptors on the iris is
employed to produce mydriasis during
ophthalmologic procedures 56
 C. adrenaline is used to restore cardiac arrest
D. promotes bronchodilation in patients with asthma
E. adrenaline is the drug of choice for treating
anaphylactic shock
 Pharmacokinetics
 adrenaline is administered topically, by injection( IM,
SC ) and by inhalation, but not administered by mouth
 It has a short plasma half-life because of 2 processes:
a. enzymatic inactivation and
b. uptake into adrenergic nerves
 Adverse effects
 hypertensive crisis- may induce cerebral hemorrhage
Arrhythmias
Angina 57
 necrosis of the extremities
Hyperglycemia
anxiety, restlessness, headache , tremor
 Contra indications
– coronary diseases
– hyperthyroidism
– hypertension
– digitalis therapy
– injection around end arteries
 Drug Interactions- include that of
» Cocaine: prevent reuptake of epinephrine
» Inhalation anesthetics: sensitize the heart to the
effects of epinephrine (tachycardia)
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 Noradrenaline
• Similar pharmacokinetics with adrenaline
• Potent vasoconstrictor
• Treatment of shock
• A/Es
– Similar with adrenaline
– blanching and sloughing

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 isoproterenol
– is considered a nearly pure ß-agonist
– has a high affinity for ß1- and ß2-adrenoceptors
 increase heart rate and force of contraction
 rapid bronchodilation
 Pharmacokinetics:
– given parenterally or as an inhaled aerosol
– can be absorbed systemically by the sublingual
mucosa but may be unreliable
 Therapeutic uses
– now rarely used as a broncho-dilator in asthma.
– can be employed to stimulate the heart in
emergency situations.
– Similar adverse effects to those of epinephrine 60
Dopamine
– is immediate metabolic precursor of NE and
occurs naturally in the CNS as well as in the
adrenal medulla
– can activate  and ß adrenergic receptors
– Activate D1 and D2 dopaminergic receptors found
in peripheral mesenteric and renal vascular beds
and produce vasodilation
– D2 receptors are also found on presynaptic
adrenergic neurons, where their activation
interferes with norepinephrine release.

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– effect on the ß1
• having both inotropic and chronotropic effects
– 1 receptors
• at very high doses dopamine activates receptors
on the vasculature, resulting in vasoconstriction
– dopaminergic receptors
• dilates renal and splanchnic arterioles by activating
dopaminergic receptors, thus increasing blood
flow to the kidneys and other viscera
»Therefore, dopamine is clinically useful in
the treatment of shock, in which significant
increases in sympathetic activity might
compromise renal function

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 Therapeutic uses
• drug of choice for shock and is given by
continuous infusion
»( and ß effects as well as increased
renal perfusion by dopaminergic
receptor effect)
• Adverse effect
– Nausea
– Hypertension
– Anginal pain
– Arrhythmia
• D/Is:
– TCAs, MAOI, anesthetics, diuretics
63
Dobutamine
– synthetic, direct-acting catecholamine
– is a ß1-receptor agonist
–exerts a greater effect on the contractile
force of the heart relative to its effect on the
heart rate than does dopamine
– Increases the oxygen demands on the heart to a
lesser extent than does dopamine.
– Dobutamine may be more useful than dopamine
in the treatment of cardiogenic shock.

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 Therapeutic uses:
• Dobutamine is used to increase cardiac output in
CHF as well as for inotropic support after cardiac
surgery
»It increases cardiac output with little change
in heart rate and it does not significantly
elevate oxygen demands of the myocardium
(a major advantage over other
sympathomimetic drugs)
 Adverse effects:
– should be used with caution in atrial fibrillation
because the drug increases AV conduction
– Other adverse effects are the same as those for
epinephrine.
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Phenylephrine
 non-catecholamine with receptors specificity for 1
 induces reflex bradycardia when given parenterally
 It is given locally to alleviate nasal congestion and
parentally to elevate blood pressure. It can also be
applied to the eye to dilate the pupil
 Large doses can cause hypertensive headache and
cardiac irregularities

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 Albuterol and Terbutaline
– are short-acting ß2 agonists used primarily as
bronchodilators
– longer duration of action than isoproterenol because
they are not metabolized by COMT
– are effectively administered either orally or SC
– used to treat bronchial asthma and bronchospasm
associated with bronchitis and emphysema
• Side effects include nervousness, tremor, palpitations
tachycardia, etc
– Can be minimized by giving via inhalational

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Salmeterol and formoterol
– ß2-adrenergic selective, long-acting bronchodilators
–the agents of choice for treating nocturnal
asthma in symptomatic patients taking other
asthma medications
– Single inhalation dose has bronchodilation over 12
hours, compared with less than 3 hours for albuterol
– salmeterol has a somewhat delayed onset of action
than formoterol

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Ephedrine
mixed-acting adrenergic agent i.e release stored NE
and interact with  and ß adrenoceptors
direct receptor stimulation particularly in its
bronchodilating effect
have a long duration of action excellent absorption
orally and penetrate into the CNS
often used prophylactically to prevent asthmatic
attacks , as a nasal decongestant, and as a mydriatic
but terbutaline and albuterol are replacing
ephedrine for bronchodilation
»Nocturnal enuresis
»Narcolepsy
–Insomnia
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Oxymetazoline
– stimulates both 1- and 2-adrenergic receptors
– primarily used locally in the eye or the nose as a
vasoconstrictor
– absorbed in the systemic circulation regardless of
the route of administration and may produce
nervousness, headaches, and trouble sleeping
– When administered in the nose, burning of the
nasal mucosa and sneezing may occur.
– Rebound congestion is observed with long-term
use.

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• Indirect-Acting Adrenergic Agonists
– cause NE release from presynaptic terminals or
inhibit its uptake
– potentiate the effects of norepinephrine produced
endogenously, but these agents do not directly
affect postsynaptic receptors
 amphetamine
• blocks NE uptake and its release
 tyramine
– enter the nerve terminal and displace stored NE
– it is not a clinically useful drug but can be found in
foods
 cocaine- affects uptake of NE
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 Adrenergic Antagonists
• prevent stimulation of adrenergic receptors from
neurotransmitters or drugs
Alpha Adrenergic Blocker
  non selective- blocker: eg phenoxybenzamine
and phentolamine
  1 selective- bloker: eg Prazosin and terazosin
Therapeutic applications of Alpha blockade
a) Treatment of hypertension
b) Reversal of toxicity caused by Alpha1 Agonists
c) Treatment of Pheochromocytoma
d) BPH
e) Raynaud’s disease 72
Adverse Effect of Alpha Blockade
1) Orthostatic (postural) hypotension
2) Nasal congestion
3) Inhibition of Ejaculation
4) Reflex tachycardia
phenoxybenzamine
– nonselective, linking covalently to both 1-
postsynaptic and 2-presynaptic receptors
– block is irreversible and noncompetitive
– the drug has been unsuccessful in maintaining
lowered blood pressure in hypertension and has
been discontinued for this purpose.
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 Therapeutic uses
treatment of pheochromocytoma
»a catecholamine secreting tumor of cells
derived from the adrenal medulla
 Adverse effects
postural hypotension, nasal stuffiness, nausea,
and vomiting, can inhibit ejaculation
may induce reflex tachycardia and is
contraindicated in patients with decreased
coronary perfusion.

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 prazosin, terazosin
are selective competitive blockers of the 1
receptor
are useful in the treatment of hypertension
the first dose of these drugs produces an
exaggerated orthostatic hypotensive response
that can result in syncope (fainting)
»may be minimized by adjusting the first
dose to one-third or one-fourth of the
normal dose and by giving the drug at
bedtime
• Tamsulosin, alfuzosin
– BPH

75
 Beta blockers:
–β1-selective:
 metoprololol
 acebutolol
 atenolol
 betaxolol
 esmolol
–β-non selective blockers:
 propranolol
 Pindolol
 Timolol, nadolol
All the clinically available ß-blockers are competitive 76
antagonists
Therapeutic application of beta blockade
a) Hypertension
b) Angina pectoris
c) Cardiac Arrhythmias
d) Glaucoma
Adverse Effects of Beta1 Blockade
1) Bradycardia
2) Reduction of cardiac output
3) Production of congestive heart failure
Adverse Effects of Beta2 Blockade
a. Bronchial constriction
b. Inhibition of glycogenolysis
77
 Properties of individual Beta Adrenergic
Antagonists
Propranolol
– the prototype non selective ß-adrenergic
antagonist
 Pharmacokinetics
– it is highly lipid soluble and hence can readily
cross membranes.
 Therapeutic Uses:
The most important indications are:
a) hypertension
b) angina pectoris
c) cardiac arrhythmias 78
 Adverse Effects:
Bradycardia, bronchoconstriction, inhibit
glycogenolysis, HF,
 Central nervous system effects: nightmares,
hallucinations and depression
 C/Is: HF, DM, asthma
Atenolol
is selective to beta1
useful in hypertensive patients with impaired
pulmonary function
useful in diabetic hypertensive patients who
are receiving insulin or oral hypoglycemic
agents
79
reserpine
blocks the Mg2+/adenosine triphosphate
dependent transport of norepinephrine
causes the ultimate depletion NE
has a slow onset, a long duration of action, and
effects that persist for many days after
discontinuation
methyldopa (aldomet)
substrate for the enzymes that synthesizes NE
Is changed to a-methylnoradrenaline that cannot
be metabolised by MAO and selectively stimulates
the 2 in the CNS
results in a fall in blood pressure

80
Clonidine
an 2 agonist that is used in essential
hypertension to lower blood pressure because
of its action in the CNS
»acts centrally to produce inhibition of
sympathetic outflow to the periphery

81