Transcript The Autonomic Nervous System

The Autonomic Nervous System
ISRAA OMAR
Autonomic drugs
• Autonomic drugs : Drugs that produce
their primary therapeutic effect by
mimicking or altering the functions of the
autonomic nervous system .
• The autonomic nervous system is composed
of efferent neurons
• These innervate smooth muscle, cardiac
muscle and the exocrine glands, thereby
controlling digestion, cardiac output, blood
flow, and glandular secretions.
Activity of the Sympathetic
Nervous System
• Prepares body for physical action
• Fight or Flight
– Increased heart rate
– Increased blood pressure
– Redistribution of blood flow - ↑ flow to
skeletal muscle, ↓ flow to skin and organs
– ↓ GI activity
– Dilation of pupils and bronchioles
– ↑ blood glucose
Activity of the Parasympathetic
Nervous System
• Opposite effects to SNS
• Prepares the body for feeding and digestion
– Slows heart rate
– Lowers blood pressure
– Promotes GI secretions
– Stimulates GI movement
– Constricts the pupil
– Empties bladder and rectum
In general, the parasympathetic
division and the sympathetic
division of the ANS are antagonistic
in their effects on organ systems.
The enteric division of the ANS
• It is a very large and highly organized
collection of neurons located in the walls of
the gastrointestinal (GI) system.
• It regulates and coordinates the motor activity
and secretory functions of the GI system.
Anatomy of the ANS
Afferent nerve fibers (sensory nerves):
 Non-myelinated; information is carried to the CNS by the
vagus, pelvic, splanchnic and somatic nerves.
Efferent nerve fibers (motor nerves):
a) Sympathetic division

b)


Thoracolumbar division
Parasympathetic division

Craniosacral division
Consists of 2 neurons arranged in series:


Preganglionic nerve fiber
Postganglionic nerve fiber
Adrenal Medulla is the exception to the 2 neuron
arrangement (a modified ganglion that mainly secretes
adrenaline hormone)
The Peripheral Nervous System
PRE-GANGLIONIC
GANGLIA
POST-GANGLIONIC
Cholinergic Agonists
The cholinergic drugs act on receptors that are
activated by acetylcholine.
• Location of cholinergic neurons (releases Ach):
1 - preganglionic fibers terminating in the adrenal
medulla,
2- preganglionic fibers terminating in autonomic
ganglia (both parasympathetic and sympathetic),
3- the postganglionic fibers of the parasympathetic
division .
4- cholinergic neurons innervate the muscles of
the somatic nervous system
5- also found in the central nervous system
(CNS).
Neurotransmission at cholinergic neurons
Involves sequential six steps.
• The first four steps: synthesis, storage, release,
and binding of acetylcholine to a receptor
• fifth step, degradation of the neurotransmitter
in the synaptic gap by acetylcholinesterase
enzyme to choline and acetic acid.
• and the sixth step, the reuptake of choline by
the cholinergic neurons for synthesis of new
ACh.
Synthesis of acetylcholine
• Choline acetyltransferase catalyzes the
reaction of choline with acetyl coenzyme A
(CoA) to form acetylcholine.
choline + acetyl coenzyme A (CoA)
↓ Choline acetyltransferase
acetylcholine
Release of acetylcholine:
• When an action potential arrives at a nerve
ending, voltage-sensitive calcium channels on
the presynaptic membrane open, causing an
increase in the concentration of intracellular
calcium.
• Elevated calcium levels promote the release of
acetylcholine into the synaptic space.
• This release can be blocked by botulinum
toxin.
Cholinergic Receptors (Cholinoceptors)
• The postsynaptic cholinergic receptors on the
surface of the effector organs are divided into
two classes muscarinic and nicotinic.
Muscarinic receptors
• There are five subclasses of muscarinic
receptors: M1, M2, M3, M4, and M5;
• Only M1, M2 and M3, receptors have been
functionally characterized.
Mechanisms of acetylcholine signal
transduction
• Activation of the M1 or M3 receptors: the
receptor undergoes a conformational change
and interacts with Gq protein, which in turn
activates phospholipase C. This leads to an
increase in intracellular Ca2+.
• Ca2+ can then interact to produce the
response (e.g. Secretion, contraction, etc.)
• Activation of M2 subtype on the cardiac
muscle stimulates Gi protein,
• Gi protein inhibits adenylyl cyclase and
increases K+ conductance, to which the heart
responds with a decrease in rate and force of
contraction.
Selective Muscarinic antagonists:
• Pirenzepine, a tricyclic anticholinergic drug,
selective M1 muscarinic receptor antagonist
(such as those of the gastric mucosa).
• Darifenacin is a competitive muscarinic
receptor antagonist at M3 receptor. The drug
is used in the treatment of overactive bladder.
Nicotinic receptors
• The nicotinic receptor is composed of five
subunits, and it functions as a ligand-gated ion
channel.
• Binding of two acetylcholine molecules elicits
a conformational change that allows the
entry of sodium ions, resulting in the
depolarization of the effector cell.
• Nicotine (or high doses of acetylcholine) initially
stimulates and then blocks the receptor.
• Nicotinic receptors are located in the CNS, adrenal
medulla, autonomic ganglia, and the
neuromuscular junction.
• The nicotinic receptors of autonomic ganglia (
called nicotinic neuronal ) differ from those of the
neuromuscular junction (which are called nicotinic
muscular) .
I. Direct-Acting Cholinergic Agonists
• Cholinergic agonists (also known as
parasympathomimetics) mimic the effects of
acetylcholine by binding directly to cholinoceptors.
• Classified into two groups:
1) Choline esters, which include acetylcholine and
synthetic esters of choline, such as carbachol
and bethanechol.
2) Naturally occurring alkaloids, such as
pilocarpine constitue the second group .
• All direct-acting drugs have longer durations
of action than acetylcholine.
• Drugs (e.g. pilocarpine and bethanechol)
which bind to muscarinic receptors are also
referred to as muscarinic agents.
1. Acetylcholine
• Acetylcholine is a quaternary ammonium
compound that cannot penetrate membranes.
• It is not useful therapeutically because of its
multiplicity of actions and its rapid
inactivation by the cholinesterases (unstable).
Major Actions of Acetylcholine
• Acetylcholine has both muscarinic and nicotinic
activity. Its actions include:
1. CVS:
– Decrease in heart rate (negative chronotropic
effect) and cardiac output
– The actions of acetylcholine on the heart
mimic the effects of vagus nerve stimulation.
• Decrease in blood pressure:
– Acetylcholine activates M3 receptors found
on endothelial cells lining the smooth
muscles of blood vessels. This results in the
production of nitric oxide from arginine.
– [Note: nitric oxide is also known as
endothelium-derived relaxing factor and is a
vasodilator]
2. Other actions:
– In the gastrointestinal tract, acetylcholine
increases salivary secretion and stimulates
intestinal secretions and motility.
– Bronchiolar secretions are also enhanced.
– In the genitourinary tract, the tone of the
detrusor urinae muscle is increased, causing
expulsion of urine.
– In the eye, acetylcholine is involved in
stimulating ciliary muscle contraction for near
vision and in the constriction of the pupillae
sphincter muscle (circular muscle), causing
miosis (marked constriction of the pupil).
2. Bethanechol
• Bethanechol is not hydrolyzed by
acetylcholinesterase
• It posses strong muscarinic activity, but lacks
nicotinic activity.
• It is used to treat urinary retention. as well as
megacolon.
• Adverse effects: sweating, salivation, flushing,
decreased blood pressure, nausea, abdominal
pain, diarrhea, and bronchospasm.
3. Carbachol
• Carbachol has both muscarinic as well as
nicotinic actions .
• Is a poor substrate for acetylcholinesterase
• Therapeutic uses: carbachol is rarely used
therapeutically except in the eye as a miotic
agent to treat glaucoma by causing pupillary
constriction and a decrease in intraocular
pressure.
4. Pilocarpine
• The alkaloid pilocarpine is a tertiary amine and
is stable to hydrolysis by acetylcholinesterase .
• Pilocarpine is the drug of choice in both narrowangle (also called closed-angle) and wide-angle
(also called open-angle) glaucoma.
II. Indirect-Acting Cholinergic Agonsists
(Anticholinesterases)
• These drugs can provoke a response at all
cholinoceptors in the body, including:
- both muscarinic and nicotinic receptors of
the autonomic nervous system,
- nicotinic receptors of skeletal muscle
- and muscarinic and nicotinic receptors in the
brain.
A. Reversible anticholinesterases
1. Physostigmine
- Used in treatment of atony of intestine and
bladder as it increases motility of either organ.
- It is used to treat glaucoma
- Used in the treatment of overdoses of drugs
with anticholinergic actions, such as atropine,
phenothiazines, and tricyclic antidepressants.
• Adverse effects (shown by high doses):
- Convulsions .
- Bradycardia and a fall in cardiac output
- Accumulation of acetylcholine and,
ultimately, paralysis of skeletal muscle.
2. Neostigmine
• Similar actions to that of physostigmine.
• Unlike physostigmine, neostigmine has a
quaternary nitrogen; hence, it is more polar
and does not enter the CNS.
• Neostigmine is used to stimulate the bladder
and GI tract, and it is also used as an antidote
for tubocurarine
• Also used in symptomatic treatment of
myasthenia gravis ( an autoimmune disease
caused by antibodies to the nicotinic receptor
at neuromuscular junctions. This causes their
degradation and, thus, makes fewer receptors
available )
• Adverse effects include salivation, flushing,
decreased blood pressure, nausea, abdominal
pain, diarrhea, and bronchospasm.
3. Pyridostigmine and ambenomium
• Cholinesterase inhibitors that are used in the
chronic management of myasthenia gravis.
• Their durations of action are longer than that
of neostigmine.
• Adverse effects of these agents are similar to
those of neostigmine.
4. Demecarium
• Cholinesterase inhibitor used to treat chronic
open-angle glaucoma (primarily in patients
refractory to other agents) and closed-angle
glaucoma after irredectomy.
• Mechanism of actions and side effects are
similar to those of neostigmine.
5. Edrophonium
• Prototype short-acting agent (duration of action
is 10 to 20 minutes).
• The actions are similar to those of neostigmine,
except that it is more rapidly absorbed and has
a short duration of action
• Edrophonium is used in the diagnosis of
myasthenia gravis. Intravenous injection of
edrophonium leads to a rapid increase in muscle
strength.
6. Other reversible anticholinesterases
Tacrine, donepezil, rivastigmine, and
galantamine
• Are useful in patients with Alzheimer's disease
( they have a deficiency of cholinergic neurons
in the CNS).
Gastrointestinal distress is their primary
adverse effect.
B. Irreversible Anticholinesterases
• Some synthetic organophosphate compounds
have the capacity to bind covalently to
acetylcholinesterase. The result is a long-lasting
increase in acetylcholine at all sites where it is
released.
• Many of these drugs are extremely toxic and
were developed by the military as nerve gases
(sarin, soman, tabun).
• Related compounds, such as parathion, are
employed as insecticides.
1. irreversible anticholinesterases
Echothiophate
• Echothiophate is an organophosphate.
• It is an irreversible anticholinesterase
• The enzyme becomes permanently inactivated,
and restoration of acetylcholinesterase activity
requires the synthesis of new enzyme
molecules.
• Echothiophate is used in treatment of openangle glaucoma..
• Atropine in high dosage can reverse many of
the muscarinic and some of the central effects
of echothiophate.
• Pralidoxime can reactivate inhibited
acetylcholinesterase enzyme.
2. Other irreversible anticholinesterases
• Nerve gases: sarin, soman, tabun
These are organophosphorus compounds
Used as chemical warfare
• Malathion and Parathion
These are organophosphorus compounds
Used as insecticides
• Toxic effects could be treated with immediate
administration of pralidoxime and atropine
Cholinergic Antagonists
• The cholinergic antagonists (also called
cholinergic blockers, parasympatholytics or
anticholinergic drugs) bind to cholinoceptors.
Include:
• Antimuscarinic Agents: block muscarinic
synapses of the parasympathetic nerves.
• The ganglionic blockers, which block the
nicotinic receptors of the sympathetic and
parasympathetic ganglia.
• The skeletal neuromuscular blocking agents
A. Antimuscarinic Agents
• Antimuscarinic drugs have little or no action at
skeletal neuromuscular junctions or autonomic
ganglia.
1. Atropine
• Atropine, a tertiary amine belladonna alkaloid,
that binds competitively to muscarinic
receptors , preventing acetylcholine from
binding to those sites.
• Atropine acts both centrally and peripherally.
Pharmacological action:
• Eye:
– persistent mydriasis and cycloplegia (inability to
focus for near vision).
– In patients with narrow-angle glaucoma intraocular
pressure may rise dangerously.
• Gastrointestinal (GI):
– antispasmodic, gastric motility is reduced but
hydrochloric acid production is not significantly
affected.
• Urinary system:
– reduces hypermotility states of the urinary bladder.
• Cardiovacular:
– With higher doses of atropine, the M2
receptors on the sinoatrial node are blocked,
and the cardiac rate increases (tachycardia).
• Secretions:
– Atropine blocks the salivary glands, producing
a drying effect on the oral mucous
membranes (xerostomia).
– Sweat and lacrimal glands are also affected.
[Note: Inhibition of secretions by sweat
glands can cause elevated body temperature.]
Therapeutic uses of atropine
• Ophthalmic: for eye examination. Atropine may
induce an acute attack of eye pain due to
sudden increases in eye pressure in individuals
with narrow-angle glaucoma.
• Antispasmodic: to relax the GI tract and bladder.
• for the treatment of overdoses of cholinesterase
inhibitor insecticides and some types of
mushroom poisoning (muscarine poisoning).
• As preanesthetic medication to block secretions
in the upper and lower respiratory tracts prior
to surgery.
Pharmacokinetics:
• Atropine is readily absorbed, partially metabolized
by the liver, and eliminated primarily in the urine.
It has a half-life of about 4 hours.
Adverse effects:
• dry mouth, blurred vision, tachycardia, and
constipation.
• Effects on the CNS include restlessness, confusion,
hallucinations, and delirium
Contraindications:
• In older individuals, the use of atropine may
exacerbate an attack of glaucoma and / or urinary
retention.
2. Scopolamine
• Tertiary amine belladonna alkaloid,
• Used prophylactically for treatment of
motion sickness.
• Produces sedation (atropine causes
excitation).
• Scopolamine may produce euphoria and is
subject to abuse.
3. Ipratropium
• Inhaled ipratropium, a quaternary derivative of
atropine, is useful in treating asthma.
• Ipratropium is also useful in chronic obstructive
pulmonary disease(COPD).
4. Tropicamide and cyclopentolate
• Used as ophthalmic solutions as mydriatics.
• Their duration of action is shorter than that of
atropine.
B. Ganglionic Blockers
• Ganglionic blockers act on the nicotinic
receptors of both parasympathetic and
sympathetic autonomic ganglia.
• These drugs are not effective as neuromuscular
blockers
1. Nicotine
• A component of cigarette smoke and a poison
with many undesirable actions.
• Nicotine is available as patches, lozenges,
gums, and other forms.
• The drug is effective in reducing the craving
for nicotine in people who wish to stop
smoking.
Pharmacological action
• Nicotine initially stimulates, then blocks all
sympathetic and parasympathetic ganglia.
• The stimulatory effects include increased blood
pressure and cardiac rate (due to release of
noradrenaline from adrenergic terminals and
adrenaline hormone from the adrenal medulla)
• Nicotine causes increased peristalsis and
secretions
2. Mecamylamine and trimethaphan
• These are ganglion blockers.
• They are used to lower blood pressure in
emergency situations.
Drugs affecting the sympathetic
nervous system
• Drugs that act directly on the adrenergic
receptor (adrenoceptor) and activate them are
said to be sympathomimetics.
• Blockers of adrenoceptors are called
sympatholytics
• There are drugs which affect presynaptic
adrenergic function.
Adrenergic neurons
• Adrenergic neurons synthesize, store and release
norepinephrine (noradrenalin).
• Adrenergic neurons are found in the sympathetic
nervous system (postganglionic sympathetic
neurons) and in the central nervous system (CNS).
Neurotransmission at adrenergic
neurons
• The process involves five steps: synthesis,
storage, release, and receptor binding of
norepinephrine, followed by removal of the
neurotransmitter from the synaptic cleft.
Synthesis of norepinephrine
• Tyrosine is transported into the axoplasm of the
adrenergic neuron, where it is hydroxylated to DOPA by
tyrosine hydroxylase.
• This is the rate-limiting step in the formation of
norepinephrine.
• DOPA is then decarboxylated by dopa decarboxylase to
form dopamine.
• Dopamine is hydroxylated to form norepinephrine by
the enzyme, dopamine β-hydroxylase.
• In the adrenal medulla, norepinephrine is methylated
to yield epinephrine (adrenaline).
Binding with adrenoceptors
• Binding of norepinephrine to the membrane
receptors triggers a cascade of events, resulting
in the formation of intracellular second
messengers.
• Adrenergic receptors use both the cyclic
adenosine monophosphate (cAMP) secondmessenger system, and the phosphatidylinositol
cycle, to transduce the signal into an effect.
Termination of norepinephrine actions
Norepinephrine may
1. Diffuse out of the synaptic space and enter the
general circulation,
2. Be metabolized by catechol omethyltransferase (COMT) in the synaptic
space,
3. Be recaptured by an uptake system that pumps
the norepinephrine back into the neuron.
Uptake of norepinephrine into the presynaptic
neuron is the primary mechanism for
termination of norepinephrine's effects.
Fate of reuptaken norepinephrine
• Norepinephrine may be released by another
action potential, or it may stored,
• Alternatively, norepinephrine can be oxidized
by monoamine oxidase (MAO) present in
neuronal mitochondria.
Adrenergic receptors (adrenoceptors)
• Adrenoceptors are designated α and β.
• For α receptors, the rank order of potency is
epinephrine >norepinephrine >> isoproterenol
(isoprenaline).
• For β receptors, the rank order of potency is
isoproterenol > epinephrine > norepinephrine.
α adrenoceptors
• The α adrenoceptors are subdivided into two
subgroups, α1 and α2
α1 Receptors:
• Found on the postsynaptic membrane of the effector
organs .
• Activation of α1 receptors initiates a series of
reactions through a G protein resulting in the
generation of inositol-1,4,5-trisphosphate (IP3) and
diacylglycerol (DAG) from phosphatidylinositol.
• IP3 initiates the release of Ca2+ from the
endoplasmic reticulum into the cytosol, and DAG
turns on other proteins within the cell.
• The α 1 receptors are further divided into α 1A, α 1B, α
1C, and α 1D
α2 Receptors:
• are located primarily on presynaptic nerve endings.
• The stimulation of α2 receptor causes inhibition of
further release of norepinephrine.
• α2 Receptors are also found on presynpatic
parasympathetic neurons. Norepinephrine can
diffuse and interact with these receptors, inhibiting
acetylcholine release.
• The effects of binding at α2 receptors are mediated
by inhibition of adenylyl cyclase and a fall in the
levels of intracellular c-AMP.
• α 2 receptors are further divided into α 2A, α 2B, α 2C,
and α 2D.
Tamsulosin
– is a selective α 1A antagonist
– is used to treat benign prostate hyperplasia.
The drug is clinically useful because it
targets α1A receptors found primarily in the
urinary tract and prostate gland.
2. β-adrenoceptors
• The β-adrenoceptors can be subdivided into
three major subgroups, β1, β2, and β3,.
β1 Receptors :
• have approximately equal affinities for
epinephrine and norepinephrine (mainly found in
the heart)
β2 receptors
• have a higher affinity for epinephrine than for
norepinephrine (mainly found in the bronchioles)
β3 receptors
• are involved in lipolysis.
• Binding of a neurotransmitter at any of the
three β receptors results in activation of
adenylyl cyclase and, therefore, increased
concentrations of cAMP within the cell.
Distribution of receptors
• Tissues such as the vasculature & skeletal
muscle have both β1 and β2 receptors, but the
β2 receptors predominate.
• The heart contains predominantly β1
receptors.
Effects mediated by the adrenoceptors
• Stimulation of β1 receptors characteristically
causes cardiac stimulation,
• Stimulation of β2 receptors produces
vasodilatation (in skeletal vascular beds) and
bronchiolar relaxation.
• Desensitization of receptors: Prolonged
exposure to the catecholamines reduces the
responsiveness of these receptors, a
phenomenon known as desensitization.
Catecholamines
• Sympathomimetic amines that contain the 3,4dihydroxybenzene group (such as epinephrine,
norepinephrine, isoproterenol, and dopamine)
are called catecholamines.
• These compounds share the following
properties:
– High potency
– Rapid inactivation: by COMT and by MAO .
– Poor penetration into the CNS because they
are polar
Adrenergic agonists
• Classification of the adrenergic agonists
• Direct-acting agonists include:
– epinephrine, norepinephrine, isoproterenol,
and phenylephrine.
• Indirect-acting agonists include
– amphetamine, cocaine and tyramine.
• Mixed-action agonists include
– ephedrine, pseudoephedrine and
metaraminol, may act directly and indirectly.
A. Direct-Acting Adrenergic Agonists
1. Epinephrine
• Is a catecholamine.
• Interacts with both α and β receptors. At low
doses, β effects (vasodilatation) predominate,
whereas at high doses, α effects (vasoconstriction)
are strongest.
Pharmacological effects
• Epinephrine strengthens the contractility of the
myocardium (positive inotropic: β1 action) and
increases the heart rate (positive chronotropic:
β1 action).
• Epinephrine increases systolic blood pressure,
coupled with a slight decrease in diastolic
pressure.
• Epinephrine causes powerful bronchodilation (β2
action).
• Epinephrine inhibits the release of allergy
mediators such as histamines from mast cells.
• Epinephrine has a significant hyperglycemic effect
because of increased glycogenolysis in the liver
(β2 effect), increased release of glucagon (β2
effect), and a decreased release of insulin (α2
effect).
• Lipolysis: Epinephrine initiates lipolysis through
its agonist activity on the β receptors of adipose
tissue
Metabolism of Epinephrine
• Epinephrine is metabolized by two enzymatic
pathways: MAO, and COMT.
• The final metabolites found in the urine are
metanephrine and vanillylmandelic acid.
Therapeutic uses
– Treatment of acute asthma and anaphylactic shock,
epinephrine is the drug of choice;.
– Glaucoma: in open-angle glaucoma. It reduces the
production of aqueous humor.
– Cardiac arrest: Epinephrine may be used to restore
cardiac rhythm.
– Anesthetics: Local anesthetic solutions usually contain
1:100,000 parts epinephrine. The effect of the drug is to
greatly increase the duration of the local anesthesia. It
does this by producing vasoconstriction at the site of
injection.
Adverse effects
• CNS disturbances: include anxiety, fear,
tension, headache, and tremor.
• Cerebral hemorrhage: as a result of a marked
elevation of blood pressure.
• Cardiac arrhythmias
• Pulmonary edema.
Interactions:
• Hyperthyroidism: Epinephrine may have
enhanced cardio-vascular actions in patients with
hyperthyroidism.
• Cocaine: In the presence of cocaine, epinephrine
produces exaggerated cardiovascular actions.
• Diabetes: Epinephrine increases the release of
endogenous stores of glucose. In the diabetic,
dosages of insulin may have to be increased.
2. Norepinephrine
• Cardiovascular actions:
– Vasoconstriction: Both systolic and diastolic
blood pressures increase
• Norepinephrine is used to treat shock,
because it increases vascular resistance and,
therefore, increases blood pressure. However,
metaraminol is favored.
3. Isoproterenol
• Isoproterenol is a direct-acting synthetic
catecholamine that predominantly stimulates
both β1- and β2-adrenergic receptors
Therapeutic uses:
• It can be employed to stimulate the heart in
emergency situations.
4. Dobutamine
• Dobutamine is a synthetic, selective β1 agonist.
• Dobutamine is used to increase cardiac output
in congestive heart failure.
5. Oxymetazoline
• Oxymetazoline is a direct-acting synthetic
adrenergic agonist that stimulates both α1and α2-adrenergic receptors.
6. Phenylephrine
• Phenylephrine is a direct-acting, synthetic α 1
receptors agonist.
• It is not a catechol derivative and, therefore,
not a substrate for COMT.
• Phenylephrine is a vasoconstrictor that raises
both systolic and diastolic blood pressures.
• Phenylephrine acts as a nasal decongestant
and produces prolonged vasoconstriction.
7. Methoxamine and clonidine
• Methoxamine is a direct-acting, synthetic α1
receptor agonist.
• Clonidine is an α2 agonist that prevents
further release of noradrenaline.
• It is used in hypertension as it acts on α2
receptors in the CNS..
• It can be used in withdrawal from opiates or
benzodiazepines.
8. Metaproterenol
• The drug is an agonist at β2 receptors, producing
little effect on β1 receptors of the heart.
• The drug is useful as a bronchodilator in the
treatment of asthma
9. Albuterol, pirbuterol, and terbutaline
• are short-acting β2 agonists used primarily as
bronchodilators .
10. Salmeterol and formoterol
• are selective β2-agonists, long-acting
bronchodilators.
• These agents are highly efficacious when combined
with a corticorsteroid.
B. Indirect-Acting Adrenergic Agonists
• They potentiate the effects of norepinephrine
produced endogenously, but these agents do
not directly affect postsynaptic receptors.
1. Amphetamine
• Central stimulant, abused drug
• Its peripheral actions are mediated primarily
through the release of stored norepinephrine
and the blockade of norepinephrine uptake.
2. Tyramine
• It is not a clinically useful drug, but it is
important because it is found in fermented
foods, such as cheese.
• Normally, it is oxidized by MAO in the
gastrointestinal tract, but if the patient is taking
MAO inhibitors, it can precipitate a hypertensive
crisis in him.
3. Cocaine
• Cocaine is a local anesthetic (sodium channel
blocker) and is a CNS stimulant (blocks the
reuptake of norepinephrine, thus potentiating
NA effects).
• Drug of abuse.
C. Mixed-Action Adrenergic Agonists
• Mixed-action drugs induce the release of
norepinephrine, and they activate postsynaptic
adrenergic receptors.
• Ephedrine, and pseudoephedrine are plant
alkaloids, that are now made synthetically.
• Ephedrine produces bronchodilation
• Pseudoephedrine is used to treat nasal and
sinus congestion.
D. Adrenergic Antagonists (also called
blockers or sympatholytic agents)
α-Adrenergic Blocking Agents
• The α-adrenergic blocking agents,
phenoxybenzamine and phentolamine, have
limited clinical applications, they are
nonselective α blockers
1. Phenoxybenzamine
• is used in the treatment of
pheochromocytoma, a catecholaminesecreting tumor of the adrenal medulla.
• Adverse effects: Phenoxybenzamine can cause
postural hypotension, nasal stuffiness, nausea,
and vomiting.
2. Phentolamine
• Phentolamine is also used for the short-term
management of pheochromocytoma.
3. Prazosin terazosin, doxazosin, and tamsulosin
• are selective competitive blockers of the α1
receptor.
• The first three drugs are useful in the treatment
of hypertension.
• Tamsulosin is indicated for the treatment of
benign prostatic hyperplasia.
• Doxazosin is the longest acting of these drugs.
• The first dose of these drugs produces an
exaggerated orthostatic hypotensive response
that can result in syncope (fainting). This
action, termed first-dose effect.
• Tamsulosin is a more potent inhibitor of the
α1A receptors found on the smooth muscle of
the prostate. This selectivity accounts for
tamsulosin's minimal effect on blood pressure.
4. Yohimbine
• Is a selective α2 blocker.
• It is found as a component of the bark of the
yohimbe tree and is sometimes used as a sexual
stimulant (aphrodisiac) or cardiovascular
stimulant.
β-Adrenergic Blocking Agents
• Nonselective β-blockers act at both β1 and β2
receptors, whereas cardioselective β antagonists
block β1 receptors
• [Note: There are no clinically useful β2 blockers].
• Although all β-blockers lower blood pressure in
hypertension, they do not induce postural
hypotension, because the α-adrenoceptors
remain functional.
β-Blockers are also effective in treating
– angina,
– cardiac arrhythmias,
– myocardial infarction,
– congestive heart failure,
– hyperthyroidism,
– glaucoma, as well as serving in the
prophylaxis of migraine headaches.
1. Propranolol
• A nonselective β blocker
• Sustained-release preparations for once-a-day
dosing are available.
• Actions:
• Cardiovascular: Propranolol diminishes cardiac
output, having both negative inotropic and
chronotropic effects.
• Cardiac output, work, and oxygen consumption are
decreased by blockade of β1 receptors; these effects
are useful in the treatment of angina.
• The reduction in cardiac output leads to decreased
blood pressure.
• Bronchoconstriction: Blocking β2 receptors in
the lungs of susceptible patients causes
contraction of the bronchiolar smooth muscle.
• Non-selective β-blockers, are contraindicated
in patients with COPD or asthma.
• β-blockade leads to decreased glycogenolysis
and decreased glucagon secretion, thus
pronounced hypoglycemia may occur after
insulin injection in a patient using propranolol.
• β-Blockers also mask the normal physiologic
response to hypoglycemia.
Mechanisms of action
• Propranolol lowers blood pressure in
hypertension by:
– Decreased cardiac output is the primary
mechanism,
– inhibition of renin release from the kidney
and decreased sympathetic outflow from
the CNS also contribute to propranolol's
antihypertensive effects .
• Adverse effects:
– Bronchoconstriction
– Arrhythmias: Treatment with β-blockers
must never be stopped quickly because of
the risk of precipitating cardiac arrhythmias,
which may be severe.
– Sexual impairment
• Drug interactions:
– Drugs that interfere with the metabolism of
propranolol, such as cimetidine, fluoxetine,
paroxetine, and ritonavir, may potentiate its
antihypertensive effects.
– Conversely, those that stimulate its metabolism,
such as barbiturates, phenytoin, and rifampin,
can decrease its effects.
2. Timolol and nadolol:
• Nonselective β blockers,
• are more potent than propranolol.
3. Acebutolol, atenolol, metoprolol, and
esmolol:
• Selective β1 blockers
• Esmolol has a very short lifetime. It is only
given intravenously if required during surgery
or management of poisoning.
4. Pindolol and acebutolol:
• blockers with partial agonist activity
5. Labetalol and carvedilol:
• blockers of both α- and β- adrenoceptors
• Carvedilol also decreases lipid peroxidation
and vascular wall thickening, effects that have
benefit in heart failure.
• Labetalol may be employed as an alternative
to methyldopa in the treatment of pregnancyinduced hypertension.
• Intravenous labetalol is also used to treat
hypertensive emergencies, because it can
rapidly lower blood pressure.
Drugs Affecting Neurotransmitter
Release or Uptake
• Some agents act on the adrenergic neuron, either
to interfere with neurotransmitter release or to
alter the uptake of the neurotransmitter.
1. Reserpine
• Reserpine, a plant alkaloid that causes the
depletion of biogenic amines.
• Sympathetic function, in general, is impaired
because of decreased release of norepinephrine.
2. Guanethidine
• Guanethidine blocks the release of stored
norepinephrine as well as displaces
norepinephrine from storage vesicles (thus
producing a transient increase in blood
pressure).
• This leads to gradual depletion of
norepinephrine in nerve endings except for
those in the CNS.
• Guanethidine commonly causes orthostatic
hypotension and interferes with male sexual
function.
3. Alpha methyl dopa
• Antihypertensive
• Mechanism: Transformed to alpha methyl
noradrenaline in adrenergic neuron,
• When released, alpha methyl noradrenaline
acts as agonist on presynaptic alpha2
receptors. Thus further release of transmitter
is inhibited.
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