Chapter Two

Pharmacology of
Autonomic Nervous System
By: Tewodros A. (B.Pharm, MSc)
Department of Pharmacy
Pharmacology Course Unit

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 Nervous System
• Nervous system along with the endocrine system,
coordinates the regulation and integration of bodily
functions.
• The nervous system is divided into two anatomical
divisions: Central nervous system and Peripheral nervous
system.

• Efferent division: the neurons of which carry signals

away from the brain and spinal cord to the
peripheral tissues
• Afferent division: the neurons of which bring
information from the periphery to the CNS.

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 Nervous System
• Efferent division further divide into:
– Somatic nervous systems
• involved in the voluntary control of skeletal
muscles contraction; essential for locomotion.
– Autonomic nervous systems
• Regulates the everyday requirements of vital
bodily functions without the conscious
participation of the mind.
• Innervate smooth muscle of the viscera, cardiac
muscle, vasculature, and the exocrine glands
Control digestion, cardiac output, blood flow, and
glandular secretions.
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 Autonomic nervous systems(ANS)
• Anatomy of the ANS
Two types of efferent neurons
 preganglionic neuron
• cell body is located within the CNS
• make a synaptic connection in ganglia
• Ganglia- aggregation of nerve cell
bodies located in the peripheral
nervous system
 Postganglionic neuron
• cell body originating in the ganglion
• terminates on effector organs

• ANS is divided into the Sympathetic and

Parasympathetic nervous system. 4
 Sympathetic nervous system

• Anatomically, The preganglionic neurons of the

sympathetic system come from thoracic and lumbar
regions (T1 to L2) of the spinal cord
– Also called the thoracolumbar division
• The preganglionic neurons are Short in comparison to
the postganglionic ones.
• Preganglionic nerve endings are highly branched
– Enabling one preganglionic neuron to interact with
many postganglionic neurons
– activate numerous effector organs at the same time.

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 Sympathetic nervous system
• Functions of the sympathetic nervous system
• Prepares the body for energy-expending, stressful, or
emergency situations.
• the “fight or flight” response.
– increase heart rate and blood pressure
– increase blood flow to skeletal muscles and the heart
– dilation of the pupils and the bronchioles

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Sympathetic nervous system

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 Parasympathetic nervous system
• Preganglionic fibers arise from cranial nerves (III, VII, IX
& X) and sacral region (S2 to S4) of the spinal cord.
• Also known as craniosacral division
• The preganglionic fibers are long, and the postganglionic
ones are short.
• Parasympathetic fibers are activated separately and the
system functions to affect specific organs

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 Parasympathetic nervous system

• Involved with maintaining

homeostasis within the
body
• Maintains essential bodily
functions, such as digestive
processes and elimination
of wastes
• The parasympathetic
division is required for life.

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Sympathetic vs Parasympathetic

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 Neurotransmitters
• Communication between nerve cells, and between nerve
cells and effector organs occurs through the release of
specific chemical signals, called Neurotransmitters.
• This release is triggered by the arrival of the action
potential at the nerve ending.
• Acetylcholine and norepinephrine, EP are the
primary neurotransmitters in the ANS.

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 Neurotransmitters
• Acetylcholine(Ach)
– When Ach is the neurotransmitter, the fiber is termed
cholinergic.
– Ach mediates the transmission of nerve impulses
across autonomic ganglia in both the
sympathetic and parasympathetic nervous
systems.
– It is the neurotransmitter at the adrenal medulla.
– Postganglionic nerves to the effector organs in the
parasympathetic system use Ach as neurotransmitter.

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Cholinergic (red) and adrenergeric (blue) neurons

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 Neurotransmitters
• Norepinephrine and epinephrine:
– When norepinephrine or epinephrine is the
transmitter, the fiber is termed adrenergic.
– In the sympathetic system, norepinephrine
mediates the transmission of nerve impulses
from postganglionic nerves to effector organs.

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Cholinergic (red) and adrenergeric (blue) neurons

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 ANS Drugs
• Drugs affecting the autonomic nervous
system (ANS) are divided into four groups.
– Cholinergic agonist

– Cholinergic antagonist

– Adrenergic agonist

– Adrenergic antagonist

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 Cholinergic agonist
Cholinomimetic ;
Parasympathomimetics
• Agent that stimulate cholinergic transmission
– Interacting with Cholinergic receptors
– increasing availability of Acetylcholine
• Ach. used as a neurotransmitter
– preganglionic fibers terminating in the adrenal
medulla
– autonomic ganglia (both parasympathetic and
sympathetic)
– postganglionic fibers of the parasympathetic division
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Cholinergic transmission

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 Neurotransmission in cholinergic neurons involves six sequential steps:

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 Cholinergic Drugs
• Cholinergic receptors
• Two type muscarinic and nicotinic receptors
• Muscarinic receptors
– Class of G protein–coupled receptors
– Bind to muscarine, an alkaloid that is present in
certain poisonous mushrooms.
– five subclasses of muscarinic receptors: M1, M2, M3,
M4, and M5.
– Found on the autonomic effector organs, such as the
• M2-heart, smooth muscle M4/M5- Brain
• M3- exocrine glands, bladder
• M1- Gastric parietal cell

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 Cholinergic Drugs

• Nicotinic receptors
– Bind to Ach & nicotine but show only a weak affinity
for muscarine.
– ligand-gated ion channel
– Location: In autonomic ganglia of all type (ganglion
type) – Sympathetic, Parasympathetic and also
Adrenal Medulla.

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muscarinic and nicotinic receptors

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 Cholinergic Drugs
• Cholinergic drugs further classified into
two:
1. Direct-acting cholinergic agonists
2. Indirect-acting cholinergic agonists

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 Cholinergic Drugs
• Direct-acting cholinergic agonists
– mimic the effects of ACh by binding directly to
cholinoceptors.
– Ach, carbachol, bethanechol, Methacholine and
Pilocarpine
– They preferentially bind to muscarinic receptors and
are sometimes referred to as muscarinic agents.
– All of the direct-acting cholinergic drugs have longer
durations of action than ACh.
– They show little specificity in their actions to subtype
of muscarinic receptor

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Molecular structures of four choline esters

Structures of some cholinomimetic alkaloids

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 Direct-acting cholinergic agonists
• Absorption, Distribution, and Metabolism
– Choline esters are poorly absorbed and poorly
distributed into the CNS
– carbachol and bethanechol are still more resistant to
hydrolysis by cholinesterase and have
correspondingly longer durations of action.
– The β-methyl group (methacholine, bethanechol)
reduces the potency of these drugs at nicotinic
receptors
– The tertiary natural cholinomimetic alkaloids are well
absorbed from most sites of administration
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Direct-acting cholinergic agonists
PD

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 Cholinergic Drugs
• Acetylcholine
– Acetylcholine is a quaternary ammonium
compound that cannot penetrate membranes.
– lacks therapeutic importance because of its
multiplicity of actions
– its rapid inactivation by the cholinesterases.
– It is not used for therapeutic purpose

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 Cholinergic Drugs
• Methacholine
– Methacholine is administered by inhalation for
the diagnosis of bronchial airway
hyperreactivity in patients who do not have
clinically apparent asthma

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 Cholinergic Drugs
• Bethanechol
– Bethanechol directly stimulates muscarinic receptors
– It lacks nicotinic receptor actions
– increased intestinal motility and tone
– It also stimulates the detrusor muscle of the bladder,
whereas the trigone and sphincter are relaxed result
in urination.
– Used in postpartum or postoperative, non-
obstructive urinary retention
– Adverse effect- include sweating, salivation,
flushing, decreased blood pressure, nausea,
abdominal pain, diarrhea, and bronchospasm.
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 Cholinergic Drugs
• Carbachol
– Effect on both muscarinic & nicotinic receptor.
– profound effects on both the cardiovascular and GI
systems because of its ganglion-stimulating activity.
– Because of receptor non-selectivity, carbachol is
rarely used for systemic therapy
– used topically in ophthalmology for the treatment of
glaucoma and as miotic agent
– Adverse effects: At doses used ophthalmologically,
little or no side effects occur due to lack of systemic
penetration.

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 Cholinergic Drugs
• Pilocarpine
– exhibits muscarinic activity and is used primarily in
ophthalmology.
– Pilocarpine is one of the most potent stimulators of
secretions such as sweat, tears, and saliva.
– The drug is beneficial in promoting salivation in
patients with xerostomia.
– Pilocarpine is used to treat glaucoma (used for
emergency lowering of intraocular pressure)
– Adverse effects: Pilocarpine can enter the brain and
cause CNS disturbances, profuse sweating
(diaphoresis) and salivation.

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 Cholinergic Drugs

• Indirect-acting cholinergic
agonists
– Acetylcholinesterase (AChE) inhibitors
– AChE is an enzyme that specifically
cleaves ACh to acetate and choline
and, thus, terminates its actions.
– Inhibitors of AChE indirectly provide a
cholinergic action by prolonging the
lifetime of ACh produced endogenously
at the cholinergic nerve endings.

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Indirect-acting cholinergic agonists

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 Cholinergic Drugs
• Acetylcholinesterase inhibitors (reversible)
a) Edrophonium
– It binds reversibly to the active center of AChE,
preventing hydrolysis of Ach
– short-acting AChE inhibitor
– It is used in the diagnosis of myasthenia gravis
– Due to the availability of other agents,
edrophonium use has become limited.

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 Cholinergic Drugs
b) Physostigmine
– Reversibly inactivate AChE
– intermediate-acting agent (duration 2-4hr)
– Enter and stimulate the cholinergic sites in the CNS.
– It is used to treat glaucoma, but pilocarpine is more
effective.
– Used in the treatment of overdoses of drugs with
anticholinergic actions, such as atropine &
phenothiazines.
– Adverse effects: convulsions, Bradycardia,
Hypotension, Contraction of visceral smooth
muscle.

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 Cholinergic Drugs
c) Neostigmine
– It is more polar, is absorbed poorly from the GI tract,
and does not enter the CNS
– intermediate duration of action up to 2 hours
– Its effect on skeletal muscle is greater than that of
physostigmine
– used to stimulate the bladder and GI tract
– antidote for tubocurarine poison
– Adverse effects: salivation, decreased blood pressure,
nausea, abdominal pain, diarrhea, and bronchospasm.
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 Cholinergic Drugs
• Acetylcholinesterase inhibitors(irreversible)
• Organophosphate compounds have the capacity to bind
covalently to AChE.
• The result is a long-lasting increase in ACh at all sites
where it is released.
• Many of these drugs are extremely toxic and were
developed by the military as nerve agents (tabun, sarin,
and soman ).
• Related compounds, such as parathion, malathion , are
used as insecticides.
• Echothiophate- Used in treatment of glaucoma.

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 Cholinergic Drugs
• Toxicology of acetylcholinesterase inhibitors
– AChE inhibitors are commonly used as agricultural
insecticides.
– Which leads accidental intoxication/ used for suicidal
and homicidal purposes.
– Sign and symptoms of toxicity: miosis, salivation,
sweating, bronchial constriction, vomiting, and diarrhea.
– Central nervous system involvement (cognitive
disturbances, convulsions, and coma)
– Treatment by reactivation of acetylcholinesterase
and supportive treatment

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 Cholinergic Drugs
• Reactivation of acetylcholinesterase
• Pralidoxime
– Pralidoxime can reactivate inhibited AChE
– But unable to penetrate into the CNS
– Pralidoxime is less effective after aging of the alkylated
enzyme
– With the nerve agents tabun, sarin, and soman which
are employed in warfare and terrorism attacks, aging
within seconds, pralidoxime is less effective.

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 Cholinergic Drugs
• Other treatments
– Atropine is administered to prevent muscarinic
side effects of these agents.
– Such effects include increased bronchial secretion
and saliva, bronchoconstriction, and bradycardia
– Such effects include increased bronchial secretion
and saliva, bronchoconstriction, and bradycardia
– Maintenance of patent airway, oxygen supply, and
artificial respiration

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Cholinergic antagonists

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 Cholinergic antagonists

• Also called cholinergic blockers, parasympatholytics,

or anticholinergic drugs.
• Selectively block muscarinic receptors of the
parasympathetic nerves.
– Antimuscarinic agents
• Parasympathetic innervation are interrupted

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 Cholinergic antagonists
• Antimuscarinic agents
– block muscarinic receptors
1) Atropine
– In contrast to the cholinergic
2) Scopolamine
agonists, which have limited 3) Ipratropium &
usefulness therapeutically, Tiotropium
– The cholinergic blockers are 4) Benztropine &
beneficial in a variety of Trihexyphenidyl
5) Tropicamide
clinical situations and
• Because they do not block Cyclopentolate
nicotinic receptors

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 Cholinergic antagonists
1) Atropine
– It is a tertiary amine belladonna alkaloid with a
high affinity for muscarinic receptors.
– It binds competitively and prevents acetylcholine
(ACh) from binding to those sites.
– Atropine is readily absorbed, partially metabolized
by the liver and eliminated primarily in urine.
– Its general actions last about 4 hours
– Atropine acts both centrally and peripherally.

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 Cholinergic antagonists

• Atropine
– Resulting in persistent mydriasis
– used as an antispasmodic
– Occasionally used in enuresis
(involuntary voiding of urine) among
children.
– Atropine produces divergent effects on
the cardiovascular system
• tachycardia

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 Cholinergic antagonists

• Atropine
– Antidote for cholinergic agonists poisoning.
• AChE inhibitor
– Antisecretory agent to block secretions in the
upper and lower respiratory tracts prior to
surgery.
– Adverse effects- may cause dry mouth, blurred
vision, tachycardia, urinary retention, and
constipation.
• CNS effect include restlessness, confusion,
hallucinations
– Physostigmine- used to overcome atropine
toxicity.
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Adverse effects commonly observed
with cholinergic antagonists

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 Cholinergic antagonists
2) Scopolamine (Hyoscine)
– Obtained from plant alkaloid, produces
peripheral effects similar to those of atropine.
– Scopolamine has greater action on the CNS.
– A longer duration of action in comparison to
those of atropine
– It is one of the most effective anti–motion
sickness drugs available
• it is much more effective prophylactically than for
treating motion sickness once it occurs.
– Pharmacokinetics and adverse effects: similar
to those of atropine. 50
 Cholinergic antagonists
3) Ipratropium and Tiotropium
– Inhaled ipratropium and inhaled tiotropium
derivatives of atropine.
– Used as bronchodilators for patient with chronic
obstructive pulmonary disease (COPD).
– Used for treating asthma in patients who are
unable to take adrenergic agonists.
– Do not enter the systemic circulation or the CNS.
– Tiotropium is administered once daily, a major
advantage over ipratropium
– Both are delivered via inhalation.

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 Cholinergic antagonists
• atropine or scopolamine are frequently used
before the administration of inhalant
anesthetics to reduce the accumulation of
secretions in the trachea and the possibility of
laryngospasm
4) Pirenzepine and telenzepine
• reduce gastric acid secretion with fewer adverse
effects than atropine and other less selective
agents.
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 Cholinergic antagonists
5) Benztropine and trihexyphenidyl
– They are CNS acting antimuscarinic agent
– used for many years in the treatment of
Parkinson disease.
• Useful as adjuncts with other antiparkinsonian
agents
6) Tropicamide and cyclopentolate
– Used similarly to atropine as ophthalmic
solutions for mydriasis
• Used to dilate the pupil
• Used eye examination to better visualize the retina
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Adrenergic Agonist

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 Adrenergic Agonist
 Sympathomimetic
 The adrenergic drugs affect receptors that
are stimulated by norepinephrine or
epinephrine
The adrenergic neuron
– found in the SNS, where they serve as links
between postganglionic nerves to the
effector organs.
– Neurotransmission in adrenergic neurons closely
resembles that already described for the
cholinergic neurons 55
Adrenergic neuron

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Synthesis and release of norepinephrine from the adrenergic neuron

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 Adrenergic Agonist

 Adrenergic receptors (adrenoceptors)

• Two families of receptors, designated α and β.
• Identified on the basis of their responses to the
adrenergic agonists epinephrine, norepinephrine,
and isoproterenol.
• α- α1 & α2 β- β1 & β2

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 Adrenergic receptors

α1-receptor
• Response
 Vasoconstriction
• Location of α1 receptor  Increased
o Eye peripheral
o Blood vessels (arteries, resistance
arterioles & Veins)  Increased blood
o Urinary bladder pressure
(Trigone-sphincter  Mydriasis
muscle)  Increased closure
of internal
sphincter of the
bladder
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 Adrenergic receptors

α2-receptor
• Response
 located primarily on
• α2 receptor presynaptic nerve
o CNS endings

o Gastrointestinal  Inhibition of
Norepinephrine
tract
Release
o Insulin secretion
 Inhibition of insulin
release

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 Adrenergic receptors

β1-receptor • Response
 Heart Rate

• Β1-receptor (chronotropic effect)

o Heart  Heart Contractile
o Kidney force (inotropic effect)
o Adipose tissue  Increased lipolysis

 Increased release of
renin

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 Adrenergic receptors

Β2-receptor • Response
 Vasodilation
• Β2-receptor
 Bronchodilation
o Bronchial smooth muscle
o Blood vessel of skeletal  Increased muscle and
muscle
liver glycogenolysis
o Gastrointestinal tract
o Uterus  Relaxed uterine
o Liver
smooth muscle

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 Adrenergic Agonist
• Mechanism of action of the adrenergic agonists
 Indirect-acting agonists:
– Cocaine & imipramine- block the uptake of
norepinephrine
– Amphetamine- promote the release of
norepinephrine from the cytoplasmic pools or vesicles
of the adrenergic neuron.

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Adrenergic Agonist
Direct-acting adrenergic agonists
Epinephrine (Adernaline)
– It is synthesized from tyrosine in the adrenal
medulla.
– Epinephrine interacts with both α and β receptors
• Actions of Epinephrine:
– Cardiovascular
Positive inotropic
Positive chronotropic Increase in systolic
blood pressure
Increase renin release

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 Adrenergic Agonist
• Actions of Epinephrine
• Respiratory: bronchodilation (β2 action)
– relieves all known allergic- or histamine-induced
bronchoconstriction.
• Hyperglycemia:
– increased glycogenolysis (β2 effect)
– increased release of glucagon (β2 effect)
– decreased release of insulin (α2 effect)
• Lipolysis: Epinephrine initiates lipolysis through
its agonist activity on the β receptors of adipose
tissue
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 Adrenergic Agonist

Epinephrine
• Pharmacokinetics:
– Epinephrine has a rapid onset but a brief
duration of action.
– The preferred route is intramuscular due to
rapid absorption.
– In emergency situations, epinephrine is given
intravenously (IV)
– Oral administration is ineffective, because
epinephrine is inactivated by intestinal enzymes.
– Only the metabolites are excreted in urine.

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 Adrenergic Agonist

Epinephrine
• Therapeutic uses:
– Emergency treatment of bronchoconstriction
• acute asthma and anaphylactic shock
• Not used for chronic treatment of asthma
– Cardiac arrest: restore cardiac rhythm in
patients with cardiac arrest
– Anesthetics: Local anesthetic solutions contain
epinephrine.
• increase the duration of the local anesthesia.

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 Adrenergic Agonist

Epinephrine
• Adverse effects
– Cardiac arrhythmias, Pulmonary edema, induce
cerebral hemorrhage, anxiety, tension, headache.
• Epinephrine may have enhanced cardiovascular
actions in patients with hyperthyroidism.
• In the presence of cocaine, epinephrine produces
exaggerated cardiovascular actions.
• Epinephrine increases the release of endogenous
stores of glucose.
– In the diabetic, dosages of insulin may have to be
increased
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 Adrenergic Agonist
Norepinephrine (levarterenol)
– Stimulate all types of adrenergic receptors.
– In practice, when the drug is given in therapeutic
dose, the α-adrenergic receptor is most affected.
– Norepinephrine causes intense vasoconstriction of
most vascular beds (α1 effect)
• Both systolic and diastolic blood pressures increase
– Weak β2 activity
– Administered through IV for rapid onset of action
– Used to treat shock, because it increases
vascular resistance
– Adverse effects: These are similar to those of
epinephrine.
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 Adrenergic Agonist

Clonidine & Methyldopa

– α2 agonist
– Clonidine acts centrally to produce inhibition
of sympathetic vasomotor centers,
• decreasing sympathetic outflow to the periphery.
– It can be used to minimize the withdrawal
symptoms due to withdrawal of opiates,
tobacco smoking, and benzodiazepines.
– The most common side effects of clonidine
are lethargy, sedation, constipation, and
xerostomia.
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 Adrenergic Agonist
Isoproterenol
– Predominantly stimulates both β1- and β2-
adrenergic receptors.
– Its nonselective and rarely used therapeutically.
– Produces intense stimulation of the heart to
increase its rate and force of contraction
– Isoproterenol can be used to stimulate the heart
in emergency situations(cardiac arrest).
– Adverse effects: The adverse effects of
isoproterenol are similar to those of epinephrine

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 Adrenergic Agonist

Dobutamine
– β1 receptor agonist
– used to increase cardiac output in acute
congestive heart failure.
Phenylephrine
– binds primarily to α1 receptors
– vasoconstrictor that raises both systolic and
diastolic blood pressures.
– Often used topically as a nasal decongestant
and in ophthalmic solutions for mydriasis.

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 Adrenergic Agonist

Albuterol and terbutaline

– They are short-acting β2 agonists used
primarily as bronchodilators and administered
by a metered-dose inhaler.
– Terbutaline is used as a uterine relaxant to
suppress premature labor.
– Side effects include tremor, restlessness,
apprehension, and anxiety.
– Systemically administered agents may cause
tachycardia or arrhythmia.
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 Adrenergic Agonist

 Salmeterol and formoterol

– Are β2-adrenergic selective
agonists that are long-acting
bronchodilators.
– A single dose by a metered-
dose inhalation device,
provides sustained
bronchodilation over 12 hours,
compared with less than 3
hours for albuterol.

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 Adrenergic Antagonists
• Sympatholytic agents
• They bind to adrenoceptors but do not
trigger the usual receptor-mediated
intracellular effects.
• The adrenergic antagonists are classified
according to their relative affinities for α or β
receptors in the peripheral nervous system.
– α- adrenergic blocking agents
– β- adrenergic blocking agents

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 Adrenergic Antagonists

• α- adrenergic blocking agents

– Profoundly affect blood pressure.
– Sympathetic control of the vasculature occurs in large
part through agonist actions on α-adrenergic
receptors
– Blockade of these receptors reduces the sympathetic
tone of the blood vessels.
– Phenoxybenzamine, Phentolamine,
Prazosin, terazosin, doxazosin,
tamsulosin, and alfuzosin

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 Adrenergic Antagonists

 Non selective α-receptor blockers

a) Phenoxybenzamine
– It is nonselective, block is irreversibly both α1- and
α2-receptors. (the actions last about 24 hours)
– Vasodilator of peripheral blood vessels
• This provokes a reflex tachycardia.
– Unsuccessful in maintaining lowered blood pressure
in hypertension.
– Used in the treatment of pheochromocytoma, a
catecholamine-secreting tumor of cells derived from
the adrenal medulla.
– Adverse effect- can cause postural hypotension,
nasal stuffiness, nausea, and inhibition of ejaculation.
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 Adrenergic Antagonists

 Non selective α-receptor blockers

b) Phentolamine
– Block is reversibly both α1- and α2-receptors.
– Action lasts for approximately 4 hours
– it produces postural hypotension
– induced reflex cardiac stimulation and
tachycardia
– used for the short-term management of
pheochromocytoma.

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 Adrenergic Antagonists

 Selective α-receptor blockers

• Prazosin, Terazosin, Doxazosin, Tamsulosin & Alfuzosin
– are selective competitive blockers of the α1 receptor.
– Prazosin, terazosin & doxazosin are used for hypertension
– Decrease peripheral vascular resistance and lower arterial
blood pressure by
• causing the relaxation of both arterial and venous smooth muscle
– Tamsulosin and alfuzosin are indicated for the
treatment of benign prostatic hypertrophy (BPH).
• decreases tone in the smooth muscle of the bladder neck
and prostate and improves urine flow.

80
 Adrenergic Antagonists
• Prazosin, Terazosin, Doxazosin
• The first dose of these drugs
produces an exaggerated
orthostatic hypotensive response
that can result in syncope (fainting)
– Minimized by adjusting the first dose to
one-third or one fourth of the normal
dose and by giving the drug at
bedtime.

First-dos: orthostatic hypotensive 81

 Adrenergic Antagonists

β-adrenergic blocking agents

All the clinically available β blockers are
competitive antagonists
– Nonselective β blockers act at both β1 and β2
receptors
• Propranolol, carteolol, penbutolol, pindolol, timolol
– Cardioselective β antagonists block β1 receptors
• Metoprolol, Acebutolol, Alprenolol, Atenolol, esmolol
– There are no clinically useful β2 antagonists

82
 Adrenergic Antagonists

Nonselective β blockers
Propranolol
– blocks both β1 and β2 receptors
• Actions:
– Negative inotropic and chronotropic effects.
– No postural hypotension occurs
– Contraction of the bronchiolar smooth muscle.
– β Blockade leads to decreased glycogenolysis
– Inhibition of renin release from the kidney

83
 Adrenergic Antagonists

Propranolol
• Pharmacokinetics:
– After oral administration, it is completely
absorbed because it is highly lipophilic.
– It is subject to first-pass effect, and only about 25
percent of an administered dose reaches the
circulation.
– Propranolol is extensively metabolized, and most
metabolites are excreted in the urine.

84
 Adrenergic Antagonists

 Propranolol
• Therapeutic effects:
– Hypertension
– Migraine (prophylactically)
– Hyperthyroidism
widespread sympathetic stimulation
– Angina pectoris
– Myocardial infarction
– Stage fright(off-label use)

85
 Adrenergic Antagonists

Propranolol
• Adverse effects
– Bronchoconstriction
• not used for patient with COPD or asthma
– Arrhythmias:
• Treatment with β blockers must never be stopped quickly because of
the risk of precipitating cardiac arrhythmias.
• The β blockers must be tapered off gradually for at least a few weeks
– Sexual impairment
– Metabolic disturbances: mask hypoglycemic symptoms after
insulin injection.
– CNS effects: depression, dizziness, lethargy, fatigue, weakness,
visual disturbances, hallucinations

86
 Adrenergic Antagonists

Timolol and nadolol

– Nonselective β antagonists
– More potent than propranolol
– Nadolol has a very long duration of action used for
hypertension
– Topical timolol reduces the production of aqueous
humor in the eye (chronic glaucoma)

87
 Adrenergic Antagonists

Labetalol and carvedilol: Antagonists of both

α and β adrenoceptors.
– β blockers with concurrent α1-blocking actions
that produce peripheral vasodilation, thereby
reducing blood pressure.
– useful for treating the elderly hypertensive patient
in whom increased peripheral vascular resistance
is undesirable.
– Orthostatic hypotension and dizziness are
common ADR

88
 Adrenergic Antagonists

• Acebutolol, atenolol, metoprolol, bisoprolol,

betaxolol, nebivolol, and esmolol
– Selective β1 antagonists
– developed to eliminate the unwanted
bronchoconstrictor effect (β2 effect) of
propranolol seen among asthma patients.
– Esmolol has a very short lifetime
– Little effect on carbohydrate metabolism
• useful in diabetic hypertensive patients who are
receiving insulin or oral hypoglycemic agents.

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 Adrenergic Antagonists

• Acebutolol, atenolol, metoprolol,

bisoprolol, betaxolol, nebivolol, and
esmolol
– Useful in hypertensive patients with impaired
pulmonary function.
– Betaxolol used for glaucoma
– large clinical trials have shown clinical benefts
of carvedilol, metoprolol and bisoprolol in
patients with stable chronic heart failure.

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 Neuromuscular-blocking drugs

• These drugs block cholinergic transmission

between motor nerve endings and the nicotinic
receptors on the neuromuscular endplate of skeletal
muscle

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 Neuromuscular-blocking drugs

• Neuromuscular blockers are clinically useful during surgery for

producing complete muscle relaxation.
• less anesthetic is required to produce muscle relaxation.

1. Nondepolarizing (competitive) blockers

2. Depolarizing agents

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 Neuromuscular-blocking drugs
• Nondepolarizing (competitive) blockers
• Tubocurarine Pancuronium, Atracurium,
cisatracurium, vecuronium
– They interact with the nicotinic receptors to
prevent the binding of Acetylcholine(Ach).
– Thus, these drugs prevent depolarization of
the muscle cell membrane and inhibit
muscular contraction.
– These blockers are used therapeutically as
adjuvant drugs in anesthesia during surgery
to relax skeletal muscle
– All neuromuscular-blocking agents are
injected intravenously

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 Neuromuscular-blocking drugs
• Nondepolarizing cont.
• At low doses: prevent the binding
of Ach to the nicotinic receptors
– Their action can be overcome by by
administration of neostigmine,
pyridostigmine, and edrophonium.
• At high doses: block the ion – Drug-drug interaction
channels of the endplate. This • Cholinesterase inhibitors
• Halogenated hydrocarbon
leads to further weakening of anesthetics
neuromuscular transmission • Aminoglycoside antibiotics
• Calcium-channel blockers

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• Nondepolarizing cont.
• Not all muscles are equally sensitive
– face and eye paralyzed first
– limbs, neck, and trunk muscles are paralyzed Nex
– intercostal muscles are aff ected, and, lastly, the
diaphragm muscles are paralyzed.

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 Neuromuscular-blocking drugs

• Depolarizing agents (succinylcholine)

– work by depolarizing the plasma membrane of the muscle fiber,
similar to the action of Ach
– more resistant to degradation by AChE
– remaining attached to the receptor for a relatively longer time and
providing constant stimulation of the receptor.
– With time, continuous depolarization gives way to gradual
repolarization as the sodium channel closes or is blocked.
– This causes a resistance to depolarization and flaccid paralysis.
– Because of its rapid onset and short duration of action,
succinylcholine is useful when rapid endotracheal intubation is
required during the induction of anesthesia

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Depolarizing agents

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Thank you!!

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