Pharmacology of the Autonomic Nervous System (39

‫الرحيم‬ ‫الرحمن‬ ‫ا‬ ‫بسم‬‫الرحيم‬ ‫الرحمن‬ ‫ا‬ ‫بسم‬
Pharmacology of AutonomicPharmacology of Autonomic
Nervous SystemNervous System
Mohaned M. Elzobair
B. Pharm
M. Pharm, Pharmacology

Pharmacology of AutonomicPharmacology of Autonomic
nervous systemnervous system
• Nervous system:

Autonomic nervous systemAutonomic nervous system
• Autonomic effectors tissues include cardiac
muscles, smooth muscles and glands.
• Axon that form synapse with ganglionic
cell is called pregaglionic autonomic fiber.
• Axon that innervate the effector cell is
called postganglionic autonomic fiber.

• Sympathetic and parasympathetic divisions
typically function in opposition to each
other. But this opposition is better termed
complementary in nature rather than
antagonistic.

• The sympathetic division typically
functions in actions requiring quick
responses.
• The parasympathetic division functions
with actions that do not require immediate
reaction.
• Consider sympathetic as "fight or flight"
and parasympathetic as "rest and digest".

Activity of the SympatheticActivity of the Sympathetic
• 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 ParasympatheticActivity of the Parasympathetic
• 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

• Acetylcholine is the preganglionic
neurotransmitter for both divisions of the
ANS, as well as the postganglionic
neurotransmitter of parasympathetic
neurons.
• In the parasympathetic system,
postganglionic neurons use acetylcholine as
a neurotransmitter, to stimulate muscarinic
receptors.

• At the effector organs, sympathetic
ganglionic neurons release noradrenaline
(norepinephrine), along with other
cotransmittors such as ATP, to act on
adrenergic receptors, with the exception of
the sweat glands and the adrenal medulla.

• At the adrenal cortex, there is no postsynaptic
neuron. Instead the presynaptic neuron
releases acetylcholine to act on nicotinic
receptors.
• Stimulation of the adrenal medulla releases
adrenaline (epinephrine) into the bloodstream
which will act on adrenoceptors, producing a
widespread increase in sympathetic activity.

• The parasympathetic fibers originate from
the cranial and sacral regions (craniosacral),
while the sympathetic fibers are
(thoracolumbar fibers).

Autonomic fibersAutonomic fibers

Cholinergic transmissionCholinergic transmission
• Synthesis of acetylcholine
• ACh synthesized from Choline and acetyl Co A
by reaction catalyzed by Choline Acetyl
transferase (CAT)
• CAT is synthesized in the ribosome of cell
body, transported by axoplasmic flow to the
axon terminal

Synthesis of acetylcholineSynthesis of acetylcholine
• Acetyl CoA is formed in the mitochondria
converted to citrate, diffuses and then
reconverted to acetyl CoA.
• Choline is synthesized in the liver and
obtained from diet actively cotransported
with Na+ because it cannot diffuse through
the cell membrane

Synthesis of acetylcholineSynthesis of acetylcholine

Drugs that impair acetylDrugs that impair acetyl
Choline synthesis:-Choline synthesis:-
1. Direct inhibitors of CAT e.g.
BromoacetylCoA, chloroacetylCoA and
transnaphthylvinylpyrinide (more specific)
2. Inhibitors of choline transport e.g.
hemicholinium compete for choline carrier,
causes gradual failure of transmission at
cholinergic sites, enhanced by nerve
stimulation .

Storage of acetylcholineStorage of acetylcholine
• ACh is stored in vesicles which contains
also ATP and protein, Ach accumulated
inside the vesicles by (Ach – transporter)
which is inhibited by vesamicol.

Release of AChRelease of ACh
• Depolarization of nerve axon by nerve
impulse triggers Ca++
influx, vesicles come
in contact with the site of release fuse with
membrane and ACh is released by
exocytosis.

Drugs affecting ACh releaseDrugs affecting ACh release
1. Botulinum toxin from Clostridium botulinum:
it cause prevention of transmission at all
peripheral cholinergic junctions and
agglutination of RBC (lethal effect paralysis of
respiratory muscles)
2. Morphine.
3. catecholamines
4. β bungarotoxins (snake poisons).

Hydrolysis of the ACHHydrolysis of the ACH
• Ach hydrolyzed by cholinesterase’s which are
of two types:-
1.True or specific cholinesterase occur in
nervous tissues, striated muscles, and RBCs
specific substrate is acetyl β methyl choline.
2. Pseudo cholinesterase in plasma, intestine
and skin specific substrate is succinylcholine
and benzoylcholine.
- They both act on acetylcholine.

ACh receptorsACh receptors
• They are muscarinic and nicotinic receptors.
• Muscarinic receptors: are classified into 5
subtypes:
• M1 (Neuronal)
• occur in CNS , Peripheral neurons and gastric
parietal cells.
• Function: (excitatory) CNS excitation, gastric acid
secretion and GIT motility.

M1 (Neuronal)
• Effects:
Activate phospholipase C (PLC), which
converts phosphatidylinositol 4,5 – bisphosphate
(PIP2) to IP3 & DAG)  increase IP3 and DAG
 ↑ Ca2+
conductance  depolarization.
decrease K+
conductance  increase
intracellular K+
 depolarization.
• Selective antagonist: pirenzepine.

• M2 (cardiac)
• Occur in heart, presynaptic terminals of
peripheral and central nerves
• Functions: (inhibitory; cardiac inhibition and
presynaptic inhibition)
Inhibit Adenylate cyclase (Adenylyl cyclase)  ↓
cAMP  ↓ Ca+
conductance  ↓ depolarization.
Increase k+
conductance  ↓ depolarization.
• Selective antagonist: gallamine.

• M3 (Glandular & smooth muscles)
• Function: excitatory mainly, glandular, sweat,
salivary and bronchial secretion, contraction of
viscera smooth muscles.
• Selective antagonist: Darifenacin and
hexahydrosiladifenol (HHSD)

• Muscarinic receptors are G-protein coupled
receptors
• M1, M3, M5, stimulate PLC  increase IP3
(inositol triphosphate).
• M2,M4 inhibit Adenylate cyclase  decease
cAMP.

Nicotinic receptors: include
• Nm (muscle) occur at neuromuscular junction
(NMJ).
• Nn (neuronal) at autonomic ganglia and brain.
• They are both ion channel linked receptors
(ion channel linked receptors).

ACh receptors (NicotinicACh receptors (Nicotinic
receptors)receptors)
Nm Nn
agonist Suxamethonium
Decamethonium
Nicotine
Lobeline
Epibatidine
antagonists Tubocurarine
Pancuronium,
α bungarotoxins
Trimetaphan
Mecamylamine
Hexamethonium

Acetylcholine receptorAcetylcholine receptor
stimulantsstimulants
1. Directly acting agent: produce primary
effect by activation of muscarinic or
nicotinic receptors
2. Indirectly acting agents: inhibit acetyl
cholinesterase  increase level of
endogenous Ach.

Directly acting cholinoceptorDirectly acting cholinoceptor
* Quaternary group induce: acetylcholine,
methacholine, carbachol, and bethanechol.
* Tertiary cholinomimetics: includes
pilocarpine, nicotine and lobeline.
• Acetylcholine is not useful therapeutically
because of its multiplicity of actions and its
rapid inactivation by the cholinesterases
(unstable).

Directly acting cholinoceptorDirectly acting cholinoceptor
• Methacholine is three times more resistant
to hydrolysis.
• Carbamic acid derivatives (carbachol and
bethanechol) are completely resistant to
hydrolysis by cholinesterases.

Pharmacodynamic effects of muscaPharmacodynamic effects of musca
1. Eye
• The parasympathetic innervates the constrictor
pupillae muscle of the iris which is important
for adjusting the pupil in response to change in
light intensity, and also important in regulating
the intraocular pressure.

Pharmacodynamic effect ofPharmacodynamic effect of
muscarinic stimulantsmuscarinic stimulants
• Eye

• Ciliary muscle adjusts the position of the
ciliary body in the anterior chamber,
contraction of ciliary muscle pulls the ciliary
body forward and inward, relaxing the
tension on the suspensory ligaments of the
lens, the lens bulge more  decrease focal
length this parasympathetic relaxation is
essential for accommodation for near vision.

• Aqueous humour secreted by cells of
epithelium covering the ciliary body, it
removed continuously by drainage into the
canal of schlemm.
• Normal intraocular pressure is 10-15 mm Hg
increase in intraocular pressure (glaucoma)
can cause retinal detachment  blindness.

• Sometimes the drainage of aqueous humour
is impeded when the iris is dilated due to
folding of the iris tissue, which blocks the
drainage angle  increase intraocular
pressure, activations of constrictor pupillae
muscle by cholinomimetic drugs, decrease
the IOP, also increasing of the tension in the
ciliary body allows drainage.

2. Cardiovascular effects:
• Cholinomimetic drugs cause cardiac
slowing, decrease cardiac output and
decrease force of contraction of the atrium,
ventricle has sparse parasympathetic
innervations.
• Decrease in BP by parasympathetic is
opposed by reflex sympathetic discharge.

3. Respiratory system
• Muscarinic stimulants contract smooth muscles
of the bronchial tree, increase glandular
secretion, may cause symptoms in individuals
with asthma.
4. GIT
• Increase secretion of the gastric gland, increase
motor activity and peristaltic movement,
sphincters relaxed.

5. Genitourinary Tract
• Stimulates muscles of bladder and relax
sphincters, promoting urine voiding.
• Human uterus is not sensitive to muscarinic
agonists
6. Secretory glands
• Stimulates secretion of sweat, lacrimal, and
nasopharyngeal glands.

7. CNS
• Both muscarinic and nicotinic receptors are
found. Nicotine and lobeline have alerting
action. High levels of nicotine causes
convulsion and coma.

Clinical uses directly actingClinical uses directly acting
cholinomimetic drugscholinomimetic drugs
1. Glaucoma (e.g. pilocarpine) they reduce the
IOP by facilitating the out flow of aqueous
humour and decrease its rate of secretion.
2. Postoperative ileus atony and
postoperative urinary retention .e.g.
bethanechol.

Clinical uses directly actingClinical uses directly acting
cholinomimetic drugscholinomimetic drugs
3. Pilocarpine is administered orally in 5- to
10-mg doses given three times daily for the
treatment of xerostomia (abnormal dryness
of the mouth due to insufficient secretions)
that follows head and neck radiation
treatments or that is associated with
Sjogren's syndrome.

Cholinergic AntagonistsCholinergic 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

Muscarinic AntagonistsMuscarinic Antagonists
• Antimuscarinic drugs have little or no action at
skeletal neuromuscular junctions or autonomic
ganglia.
• They include atropine, hyoscine
(Scopolamine) (naturally occurring),
homatropoine, (synthesized from atropine),
tropicamide, cyclopentolate, ipratropium,
propentheline, darifenacin (selective M3
antagonist) and pirenzepine (selective M1
antagonist).

Pharmacokinetics
• They well absorbed, atropine widely distributed
through out the body, it disappear rapidly from
blood, 80% excreted in urine, affect on
parasympathetic system decline rapidly except
in the eye persists for 48-72 hr.

• Pharmacodynamic effect:
1. Inhibition of secretions (salivary, lacrimal,
bronchial, and sweat gland), by low doses
of atropine (sensitive).
2. Heart: tachycardia due to block of cardiac
muscarinic receptors very low doses of
atropine can cause bradycardia due to
central action increasing vagal activity.

3. Eye: mydriasis, cycloplegia (paralysis
(relaxation) of the ciliary muscles), impair
accommodation for near vision, and
increase IOP.
4. GIT: decrease GIT motility (Hyoscine use
as antispasmodic), pirenzepine (M1
selective antagonist) inhibit gastric acid
secretion.

5. Bronchial smooth muscles relaxation
(ipratropium).
6. CNS: low doses of atropine produce
excitatory effect on CNS causing mild
restlessness, high dose of atropine produce
agitation and disorientation (atropine
poising)

• Hyoscine in low dose has different central
action causing marked sedation in low dose
and similar effect to atropine in high doses.
• Hyoscine has useful antiemetic activity so it
use in treatment of motion sickness.

Clinical uses of muscarinicClinical uses of muscarinic
antagonistsantagonists
1. Treatment of bradycardia (after MI) e.g.
atropine.
2. To dilate the pupil (tropicamide,
cyclopentolate eye drop)
3. Prevention of motion sickness (Hyoscine).
4. Parkinsonism (benzhexol, benzatropine).
5. Asthma (ipratropium inhaler).

Clinical uses of muscarinicClinical uses of muscarinic
antagonistsantagonists
6. Anaesthetic pre-medication to dry secretion
(atropine)
7. Antispasmodic (Hyoscine)
8. To facilitate GIT endoscope and GI radiology
(hyoscine)
9. Irritable bowels syndrome (e.g. clinidium)
10. Peptic ulcer (pirenzepine)
11. Treatment of overactive bladder (darifenacin
(selective M3 antagonist) decreases the urgency to
urinate).

Anticholinergic side effectsAnticholinergic side effects
1. dry mouth.
2. blurred vision, (mydriasis).
3. urinary retention.
4. Constipation.
5. Tachycardia.
6. Dizziness.
7. Confusion.
8. nausea.

Contraindications ofContraindications of
anticholinergic drugsanticholinergic drugs
• Glaucoma.
• Elderly people with prostatic hypertrophy.

Indirectly acting cholinoceptorsIndirectly acting cholinoceptors
stimulants (anticholinesterases)stimulants (anticholinesterases)
• Pharmacological actions:
• Mainly due to enhancement of cholinergic
transmission at autonomic synapse and
NMJ include:-
• Bradycardia, hypotension, excessive
secretion, bronchoconstriction, GI hyper
motility, decrease IOP and depolarization
block.

stimulants (anticholinesterases)stimulants (anticholinesterases)
• They include:-
1. Short acting anticholinesterase e.g. edrophonium
(simple alcohol) bearing quaternary ammonium
group) use in diagnosis of myasthenia gravis.
2. Medium duration anticholinesterase e.g.
neostigmine (quaternary) physostigmine
(tertiary) pyridostigmine, demecarium and
ambenonium.

AnticholinesterasesAnticholinesterases
• 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.

stimulants (anticholinesterase)stimulants (anticholinesterase)
3. Irreversible anticholinesterase:
• 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.
• They include dyflos (diisopropyl
fluorophosphate), parathion, sarin, soman, tabun,
cyclosarin (chemical weapon) and ecothiopate.

Irreversible anticholinesteraseIrreversible anticholinesterase
• Recovery of the enzymatic activity depend on
the synthesis of new enzyme molecules which
may take weeks.
• 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.
• Toxic effects could be treated with immediate
administration of pralidoxime and atropine

Cholinesterase reactivatorCholinesterase reactivator
• Pralidoxine (cholinesterase reactivator) use
for reactivate the enzyme (cholinesterase)
from phosphorylation. It should be taken
early in order to work; because the
phosphorylated enzyme with few hours
undergoes a change (aging) renders it no
longer susceptible to reactivation.

Clinical uses of anticholinesteraseClinical uses of anticholinesterase
1. In anaesthesia to reverse the action of non-
depolarizing blocker e.g. neostigmine.
2. In treatment of myasthenia gravis
(pyridostigmine and neostigmine) excessive
use cause cholinergic crisis.
3. In treatment of glaucoma e.g. ecothiopate
eye drops.
4. Alzheimer's disease (Tacrine, donepezil,
rivastigmine, and galantamine).

Myasthenia GravisMyasthenia Gravis
• It is autoimmune disease which causes a loss of
nicotinic acetylcholine receptor from the NMJ
resulting in muscle weakness and increase
fatigability (in ability of the muscle to produce
sustained contraction).
• Myasthenic patients characterize by dropping
eyelids.

• Treatment by:
1.Anticholinesterase, neostigmine and
physostigmine.
2.Immunosuppressant e.g. prednisolone.
3.Thymecotomy (thymus gland synthesize T
lymphocytes which attack foreign substances)

• If the disease progress too far, the number
of receptors remaining become too few to
produce and adequate end plate potential
and anticholinesterase drugs will then cease
to be effective.

Cholinergic crisisCholinergic crisis
• It is a condition result from large doses
(excessive doses) of anticholinesterase
characterize by various muscarinic effects
salivation, GI cramps, lacrimation, poor
vision etc. with muscle weakness resulting
from depolarization blocks.

Cholinergic crisisCholinergic crisis
• Edrophonium use to distinguish between this
drug induced weakness and weakness of the
myasthenia gravis, when giving edrophonium
(short acting anticholinesterase), if the weakness
is transiently improves it is due to myasthenia
and more anticholinesterase is indicated.
• If it gets worse the weakness is due to
cholinergic crisis and the anticholinesterase dose
should be reduced.

Drugs affecting autonomicDrugs affecting autonomic
gangliaganglia
• Ganglion stimulating drugs:
• Include nicotine ,lobeline, epibatidine and
dimethyldiphenylpiperazinium, they stimulate
both sympathetic and parasympathetic ganglia so
its effects are complex including tachycardia ,
increase BP ,variable effects on GIT secretion
and motility, increased bronchial , salivary and
sweat secretions .It may followed by
depolarization block .
• They have no therapeutic uses.

NicotineNicotine
• Nicotine initially stimulates, then blocks all
sympathetic and parasympathetic ganglia
• It is a component of cigarette smoke and a
poison with many undesirable actions.
• Nicotine is available as patches, lozenges,
gums, and other forms, it is effective in
reducing the craving for nicotine in people
who wish to stop smoking.

Ganglionic BlockersGanglionic Blockers
• Ganglionic blockers act on the nicotinic
receptors (Nn) of both parasympathetic and
sympathetic autonomic ganglia.
• These drugs are not effective as neuromuscular
blockers

Ganglion – blocking drugs:Ganglion – blocking drugs:
• Ganglion blocks can occur by several
mechanisms:
1.By interference with acetylcholine synthesis
and release e.g. Botulinum toxins and
hemicholinium.
2.By prolonged depolarization e.g. nicotine.

3. By interfering with the post synaptic Ach
action e.g. hexamethonium, trimetaphan,
mecamylamine and pempidine (non-
depolarizing blockers).
• Trimetaphan, and mecamylamine
competitive block receptors, while
hexamethonium and pempidine block ion
channel associated with it.

Pharmacodynamic effects (organ system
effect):-
• They cause eye cycloplegia, loss of
accommodation, mydriasis.
• Hypotension, loss of cardiovascular reflexes.
• Inhibitions of secretions GI paralysis.
• Impairment of micturition.

• They clinically absolute except trimetaphan
use to lower BP in emergency (anesthesia)
also in acute pulmonary edema to decrease
pulmonary vascular pressure.
• Tubocurarine bocks ganglion as well as
neuromuscular junction, on ganglion its
action on ion channels where as at NMJ it
bind mainly to receptors.

Neuromuscular blocking drugsNeuromuscular blocking drugs
• They fall into two categories:-
• Non-depolarizing blocking agents
(competitive):-
• E.g. tubocurarine, pancuronium,
vecuronium and gallamine.
• They act as competitive antagonists at
acetylcholine nicotinic receptors (Nm) at
the NMJ.

Non-depolarizing blockingNon-depolarizing blocking
agents (competitive):-agents (competitive):-
• Tubocurarine (quaternary ammonium cpd) doesn’t
enter placenta and cannot be absorbed when taken
orally (safety in hunting animals).
• Their effects are mainly due to motor paralysis, the
first muscle to be affected are extrinsic eye muscles
causing double vision then, the small muscle of the
face, limbs and pharynx (causing difficult in
swallowing). Respiratory muscles are the last to be
affected and the first to recover is the diaphragm.

Side effects of curare:-Side effects of curare:-
I. Fall in arterial pressure due to ganglion
block (vasodilatation).
II. Release of histamine from mast cells which
can lead to bronchospasm in sensitive
individuals.
III. Gallamine and pancuronium block the
muscarinic receptor particularly in the heart
leading to tachycardia.

Clinical uses:-Clinical uses:-
1. Skeletal muscle paralysis for all surgical
requirements.
2. To control ventilation in patient with
ventilatory failure from various causes, to
control ventilation to provide adequate
volumes and expansion of lung.
3. Treatment of convulsions due to status
epilepticus.

Depolarizing blocking agents:-Depolarizing blocking agents:-
• E.g. Suxamethonium (succinylcholine) &
decamethonium
• They work by depolarizing plasma membrane
of the muscle fiber similar to Ach, (they
resistant to cholinesterases).
• ACh + receptor  propagation of action
potential (AP), AP  contraction of skeletal
muscles cell, (depolarization), this is followed
by rapid cleavage of Ach by cholinesterase.

• Suxamethonium + receptor  AP 
contraction, (Suxamethonium not degraded by
cholinesterase) Persistent depolarization of
end plate  New AP and contraction cannot
be elicited (depolarizing block).

• There are two phases of depolarizing
block:-
• Phase1. (Depolarizing phase) it cause
muscular fasciculation (twitches) followed
by:
• Phase2. (Desensitizing phase) in which the
muscle will not response to the ACh
release.

Side effects ofSide effects of
Suxamethonium:-Suxamethonium:-
1. Bradycardia; due to direct muscarinic
action, prevented by atropine.
2. K+
release  hyperkalaemia which may
cause cardiac arrhythmias and cardiac
arrest.
3. Increase IOP  contraction of extra ocular
muscles causes the eye to be squeezed from
the outside (contraindicated in glaucoma).

Side effects ofSide effects of
Suxamethonium:-Suxamethonium:-
4. Malignant hyperthermia: rare and inherited,
treated by dantrolene.
5. Prolonged paralysis.

Comparison between non depolarizingComparison between non depolarizing
and depolarizing blocking agents:and depolarizing blocking agents:
1. The action of non-depolarizing blockers
can be reversed by anticholinesterases
(competitive) while the action of
depolarizing agents will not be affected.
2. In chicks extensor spasm occurs with
depolarizing blockers, while flaccid
paralysis occurs with non-depolarizing
blockers.

Comparison between non depolarizingComparison between non depolarizing
and depolarizing blocking agents:and depolarizing blocking agents:
3. Fasciculation occurs only with
depolarizing blockers.
4. Tetanic fade (failure of muscles to
maintain a fused tetany at sufficiently-
high frequencies of electrical
stimulation) occurs in case of non-
depolarizing blockers.

Adrenergic transmissionAdrenergic transmission
• Adrenergic neurons are found in the
sympathetic nervous system (postganglionic
sympathetic neurons) and in the central
nervous system (CNS).
• The process involves five steps: synthesis,
storage, release, and receptor binding of
norepinephrine, followed by removal of the
neurotransmitter from the synaptic cleft.

Biosynthesis of catecholamines:Biosynthesis of catecholamines:
Metabolic precursor is L-tyrosine
which taken up to the nerve
terminals by specific transport
system.

Biosynthesis of catecholamines:Biosynthesis of catecholamines:
• 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.

Synthesis (cont.)Synthesis (cont.)
• Dopamine is hydroxylated to form
norepinephrine by the enzyme, dopamine β-
hydroxylase.
• In the adrenal medulla, norepinephrine is
methylated to yield epinephrine
(adrenaline).

Drugs that affect the biosynthesisDrugs that affect the biosynthesis
of catecholamines:-of catecholamines:-
1 ά methyl tyrosine:
• It inhibits tyrosine hydroxylase use in
treatment of phaeochromocytoma.
2 Carbidopa and Benserazide:
• They inhibit peripheral dopa decarboxylase
use in treatment of parkinsonism.

Drugs that affect the biosynthesisDrugs that affect the biosynthesis
of catecholamines:of catecholamines:
3 Methyldopa: which taken by the neuron
decarboxylated, then hydroxylated to form
ά-methyl NA (false neurotransmitter) (is not
eliminated by MAO), displace NA in the
vesicles and released as a false
neurotransmitter.
.

Drugs that affect theDrugs that affect the
biosynthesis of catecholamines:biosynthesis of catecholamines:
4 6- Hydroxydopamine (oxidopamine) and
MPTP (methyl phenyl tetrahydropyridine):
• They are neurotoxins that taken up selectively
by adrenergic neuron terminals, where they
converted to reactive quinone that destroy the
nerve terminal (chemical sympathoectomy).
(Cell bodies survive sympathetic innervations
recover)
• They use in research to induce parkinsonism in
laboratory animals.

NA storage:NA storage:
• Stores in vesicles with ATP and proteins
(chromogranin A), by special active carrier,
Reserpine (the first drug in history use to
treat hypertension), interfere with carrier
causes depletion.

NA release:-NA release:-
• Depolarization,  Ca++
entry, promote fusion
of vesicles and discharge of NA by exocytosis.
• Regulation NA release:-
• NA by acting on presynaptic receptor, can
regulate its own release (Auto-inhibitory feed
back mechanism) through activation of α2
receptors  decrease adenylate cyclase 
decrease Ca++  decrease exocytosis.

Effect of Guanethidine on NAEffect of Guanethidine on NA
release:-release:-
• Guanethidine inhibits release of NA from
sympathetic nerve terminals it has little effect on
the adrenal medulla, and non on nerve terminals
that release transmitters, other than NA, it
selectively accumulated (Uptake 1) by adrenergic
nerve terminals causing impairment of impulse
conduction in the nerve terminals.
• It used as antihypertensive, but now due to its
severe side effects which associated with loss of
sympathetic reflexes it not use clinically

Up take and degradation ofUp take and degradation of
catecholamines:catecholamines:
• Two active transport system are occur
uptake1 (Neuronal) and uptake 2 (extra
neuronal) they differ in location, substrate
(tyrosine – histamine) and inhibitors
(cocaine –steroids hormone).
• Uptake 1 act as a co transporter of Na+
Cl-
,
and NA use electro chemical gradient for
Na+
as a driving force.

Up take and degradation ofUp take and degradation of
catecholamines:catecholamines:
• Uptake 1 is inhibited by TCA, cocaine,
amphetamine, phenoxybenzamine and
guanethidine.
• Uptake 2 is important in clearing circulating
adrenaline from blood stream, it inhibited
by phenoxybenzamine, and corticosteroids.

Metabolism of catecholamines:Metabolism of catecholamines:
• Endogenous catecholamine are metabolized
by MAO & COMT
• Monoaminoxidase bound to mitochondria
presence in the liver, intestinal epithelium
converts catecholamine to aldehyde.

Metabolism of catecholamines:Metabolism of catecholamines:
• Catechol -o- methyl transferase is wide spread
enzyme occur in both neuronal and non neuronal
tissues, it add methyl group to one hydroxyl
group of the catechol.
• Vanillyl mandelic acid (VMA) is the final
metabolite of adrenaline and noradrenaline.
• In case of phaeochromocytoma (tumor of
adrenal medulla) VMA excretion in urine is

The main pathways ofThe main pathways of
noradrenaline metabolismnoradrenaline metabolism

Adrenergic receptorsAdrenergic receptors
(adrenoceptors)(adrenoceptors)
• Adrenoceptors are designated α and β.
– The α 1 receptors are further divided into α 1A, α 1B,
and α 1D
– α 2 receptors are further divided into α 2A, α 2B, α 2C,
and α 2D (in animals).

Adrenoceptors:-Adrenoceptors:-
ά1:-
• Found on the postsynaptic membrane of the
effector organs in blood vessels (constrict),
bronchioles (constrict), GIT (relax), GI sphincters
(contract), uterus (contract), seminal tract
(contracts), iris (mydriasis) (by contraction of the
iris radial (dilator) muscles), liver (glycogenolysis).
• Second messengers and effects: act by activation
phopholipase C  increase IP3 and DAG 
increase Ca++
.

ά1:-
• agonist potency order A= Na > ISO
• Selective agonist: phenylephrine and
oxymetazoline.
• Selective antagonist: prazosin, doxazosin.
• Non selective ά antagonist:
phenoxybenzamine and phentolamine.

• 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 presynaptic
parasympathetic neurons. Norepinephrine
can diffuse and interact with these receptors,
inhibiting acetylcholine release.

ά2:-
• Also occurs postsynaptically in blood
vessels (arteries) constrict, GIT ( relax ),
pancreatic islets (inhibit insulin release),
platelet (aggregation), male genitalia
• Second messenger and effects: decrease
cAMP, decrease Ca++
, and increase K+

ά2:-
• Agonist potency order: A= Na> ISO.
• Selective agonist: clonidine.
• Selective antagonist: yohimbine.
• Non selective άantagonist:
phenoxybenzamine and phentolamine.

β1:-
• occur in heart (increase heart rate and the force of
contraction), adrenergic nerve
terminal (increase release), salivary gland
(increase amylase secretion)
• Second messenger and effects: increase cAMP.
• Agonist potency order: ISO> A=NA

β1:-
• Selective agonist: Dobutamine, xamoterol.
• Selective antagonist: atenolol, metoprolol.
• Non selective antagonist: propranolol,
timolol.

β2:-
• occur in blood vessels (dilate), bronchi
(dilate), GIT (relax), uterus (relax), bladder
sphincter (relax), ciliary muscle (relax),
mast cell (inhibition of histamine release)
• Second messenger: increase cAMP.

β2:-
• Agonist potency order: ISO > A> NA
• Selective agonist: sabutamol, salmeterol,
terbutaline.
• Selective antagonist: butoxamine.

β3
• occurs in skeletal muscles (thermogenesis), liver
(lipolysis), bladder (relax), GIT (relax).
• Second messenger: increase cAMP.
• Agonist potency order: ISO= NA>A
• Selective agonist: BRL37344 develop for control of
obesity. Solabegron develop for treatment of
overactive bladder and IBS.
• SR59230A is β3 antagonist, it also block ά1receptor.

Adrenergic agonistsAdrenergic 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.

CatecholaminesCatecholamines
• They are sympathomimetic amines that contain
the 3,4-dihydroxybenzene 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

Specific sympathomimetic drugs:Specific sympathomimetic drugs:
CatecholaminesCatecholamines
• Adrenaline:
• Has +ve inotropic and chronotropic action
(β1) increase systolic pressure, potent
vasopressive, α → vasoconstrictor.
• In Β2→ vasodilatation in certain blood
vessels, fall in total PVR explains decrease
in diastolic pressure.

Noradrenaline:Noradrenaline:
• Has similar effects to adrenaline on β1
receptors, less potent at α receptors, little
effect on β2receptors → increase PVR →
increase systolic and diastolic pressure.
• Compensating vagal activation overcomes
chronotropic effect, inotropic effect is
maintained.

Isoprenaline (isoproterenol):Isoprenaline (isoproterenol):
• Potent β– receptor agonist, little effect on α
receptors has +ve inotropic and
chronotropic action
• Potent vasodilator increase cardiac output,
decrease diastolic pressure. Lesser increase
in systolic pressure.

Schematic representation of the cardiovascular effectsSchematic representation of the cardiovascular effects
of intravenous infusions of adrenaline, noradrenalineof intravenous infusions of adrenaline, noradrenaline
and isoproterenol (isoprenaline) in humansand isoproterenol (isoprenaline) in humans

Dopamine:Dopamine:
• Low dose actives dopamine receptors,
dilates renal and visceral vessels,
• High doses activates β1receptors.
• Higher rate of infusion activates α receptors
→ vasoconstriction.

Other sympathomimeticOther sympathomimetic
amines:amines:
• Phenylephrine:
• Relatively pure α agonist, not inactivated by
COMT, much longer duration of action.
• Effective mydriatic and decongestant.
• Can be used to increase BP (raises both
systolic and diastolic blood pressures).

Clonidine:Clonidine:
• 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 used in treatment of withdrawal symptoms of
opiates and benzodiazepines (primarily reduces
anxiety, agitation, muscle aches, sweating, runny
nose and cramping).
• It also to reduce menopausal flushing; and
frequency of migraine attacks.

Clinical uses of adrenoceptorsClinical uses of adrenoceptors
direct-acting agonists:-direct-acting agonists:-
1. Cardiac arrest (adrenaline), cardiogenic
shock (dobutamine) and heart block
(dobutamine and isoprenaline)
2. Anaphylactic reaction (adrenaline).
3. Asthma (salbutamol).

Clinical uses of adrenoceptorsClinical uses of adrenoceptors
direct-acting agonists:-direct-acting agonists:-
4. Nasal decongestion (oxymetazoline).
5. Prolongation of local anesthetic action
(adrenaline).
6. Inhibition of premature labour
(salbutamol).
7. Hypertension (clonidine).

Indirectly actingIndirectly acting
sympathomimetic aminessympathomimetic amines
• They include tyramine, cocaine and
amphetamine.
• They sufficiently resemble NA to be
transported into nerve terminals by uptake1.

Indirectly actingIndirectly acting
sympathomimetic aminessympathomimetic amines
• Tyramine in the diet is destroyed by MAO
in the gut and liver. In case patients on
MAOI tyramine rich food causes sudden
dangerous rise in BP (cheese reaction).
• Tolerance and tachyphylaxis develop to
their action.

Peripheral effects:Peripheral effects:
• Their peripheral effect resembles NA
include:-
1. Bronchodilatation
2. Increase arterial blood pressure
3. Peripheral vasoconstriction
4. Increase force of myocardial contraction
5. Inhibition of GI motility

amphetamine:-amphetamine:-
• Central stimulant, abused drug.
• Its peripheral actions are mediated
primarily through the release of stored
norepinephrine and the blockade of
norepinephrine uptake.
• Central effects depend on its ability to
release not only NA, but also 5-HT and
dopamine in the nerve terminal in the brain
which lead to its abuse include:-

amphetamine:-amphetamine:-
1. Euphoria and excitement.
2. Wakefulness and alertness.
3. Loss of appetite.
4. Large doses  schizophrenia like
syndrome and hallucination.
• Amphetamine used for treatment of
narcolepsy, obesity and hyperkinetic
syndrome in children (in normal people it
cause hyperkinesias)

CocaineCocaine
• Drug of abuse.
• Cocaine is a local anesthetic (sodium
channel blocker) and is a CNS stimulant
(blocks the reuptake of norepinephrine,
thus potentiating NA effects).

Mixed-Action AdrenergicMixed-Action Adrenergic
AgonistsAgonists
• Mixed-action drugs induce the release of
norepinephrine, and they activate postsynaptic
adrenergic receptors, they include ephedrine,
pseudoephedrine and metaraminol.
• Ephedrine, and pseudoephedrine are plant
alkaloids, that are now made synthetically.
• Ephedrine produces bronchodilatation
• Pseudoephedrine is used to treat nasal and sinus
congestion.

Ephedrine:Ephedrine:
• has a higher bioavailability and longer duration
of action.
• Significant fraction excreted unchanged in urine.
• Similar spectrum to adrenaline but les potent,
also act through the release of NA. Penetrate
BBB, produces stimulant action, pressor action,
• Can be use for asthma and nasal decongestant.
• Side effects: restlessness, tremor, insomnia and
anxiety

MetaraminolMetaraminol
• Metaraminol (ά1agonist with some β
effects) is used in treatment of hypotension,
particularly as complication of anaesthesia.

Adrenergic AntagonistsAdrenergic Antagonists
(blockers or sympatholytic(blockers or sympatholytic
agents)agents)

Alpha (ά) blockersAlpha (ά) blockers
• They include non selective ά antagonists:
phentolamine, tolazoline (reversible) and
phenoxybenzamine (irreversible)
• Selective ά1antagonist: prazosin, terazosin
doxazosin, Tamsulosin (selective α 1A antagonist)
• Selective (ά2) antagonist: yohimbine.
• Ergot derivatives (e.g. ergotamine,
dihydroergotamine). They have many actions in
addition to α-receptor block, Their action on α-
adrenoceptors is not used therapeutically.

Pharmacodynamic effects:Pharmacodynamic effects:
• They decrease PVR and BP, prevent pressor
effect of α – agonists.
• They produce postural hypotension and
reflex tachycardia by inhibiting α –
mediated vasoconstriction.
• They decrease pupillary dilator tone.

Phentolamine:Phentolamine:
• It is a potent competitive antagonist of α
receptors, equally potent on both α1 and α2
receptors, decrease PVR, cause reflex cardiac
stimulation, poorly absorbed after oral
administration.
• ADR: cardia stimulation, severe tachycardia,
arrhythmias, angina, GIT stimulation →
diarrhea and acid secretion.
• It used to terminate dental anesthesia when
adrenaline is used to provide vasoconstriction.

Phenoxybenzamine:Phenoxybenzamine:
• Bind covalently causing irreversible bock, long
duration 24 – 48 hrs, blocks Ach, H1, 5HT receptors.
• It decreases BP when sympathetic tone is high e.g.
upright position, reduced blood volume, absorbed
after oral administration, low bioavailability. Could
be given I.V.
• ADR: postural hypotension, tachycardia, nasal
stuffiness, inhibit ejaculation, fatigue, sedation and
nausea.

Other (ά) blockers:Other (ά) blockers:
• Tolazoline: Less potent than phentolamine,
better absorbed, rapidly excreted in urine.
• Prazosin: Highly selective for α1receptors, low
affinity for α2receptors, no tachycardia, relaxes
arterioles and veins, metabolized by the liver, t12
= 3 hrs, first – dose effect.
• Yohimbine: α2selective, useful in autonomic
insufficiency by promoting neurotransmitter
release, aphrodisiac.

Side effects of ά blockers:Side effects of ά blockers:
• The major adverse effect of
phenoxybenzamine is postural
hypotension. This often is accompanied by
reflex tachycardia and other arrhythmias.
• Reversible inhibition of ejaculation may
occur because of impaired smooth muscle
contraction in the vas deferens and
ejaculatory ducts.

Side effects of ά blockers:Side effects of ά blockers:
• A major potential adverse effect of prazosin
and its congeners is the first-dose effect;
marked postural hypotension and syncope
sometimes are seen 30 to 90 minutes after a
patient takes an initial dose.
• Nonspecific adverse effects such as
headache, dizziness, and asthenia (physical
weakness and loss of strength) rarely limit
treatment with prazosin.

Clinical uses of ά blockers:Clinical uses of ά blockers:
1. Phaeochromocytoma (phenoxybenzamine
and phentolamine). Phaeochromocytoma
is diagnosed by measuring circulation
catecholamines, urinary VMA, or by
phentolamine greater than average drop in
BP.
2. Hypertension (Prazosin & Doxazosin).

Clinical uses of ά blockers:Clinical uses of ά blockers:
3. Tamsulosin 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
4. Peripheral vascular disease Raynaud`s
syndrome (reversible vasospasm).
5. Use to reverse intense local vasoconstriction
as in prolonged local anesthesia.

Raynaud's syndromeRaynaud's syndrome

Beta (β) blockersBeta (β) blockers
• Metoprolol, acebutolol, esmolol, bisoprolol and
atenolol are selective β1 blockers.
• Nadolol, Pindolol, Timolol and propranolol are
non selective β blockers.
• Pindolol, and acebutolol have agonist activity
(intrinsic sympathomimetic activity ISA)
• Propranolol is potent as procaine in blocking
nerve action potential.

Beta (β) blockers:Beta (β) blockers:
• Labetalol and carvedilol: blockers of both
α- and β- adrenoceptors
• Labetalol it uses to treat hypertension in
pregnancy.
• Intravenous labetalol is also used to treat
hypertensive emergencies, because it can
rapidly lower blood pressure.

Cardiovascular effects:
• They ↓ CO → ↓ BP, ↓ renin angiotensin system.
• Negative inotropic and chronotropic effect, slow
AV conduction, ↑ PR interval.
• In the vascular system it oppose β2– mediated
vasodilation → ↑ PVR from unopposed α receptor
mediated effect.

Effects on respiratory tract: Blockage of β2
receptors → ↑ airway resistance, especially in
asthmatic patients.
Metabolic and endocrine effects:
• 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.

Effect on the eye:
• ↓ intraocular pressure, mechanism not well
understood, may ↓ aqueous humour formation or ↑
out flow.
Effects not related to β– blockage:
• Retention of some intrinsic activity, desired to
prevent untoward effects, e.g. pindolol and
acebutalol.
• Local anesthetic action: e.g. propranolol, this effect
does not produced when used systemically.

Pharmacokinetics:Pharmacokinetics:
• most are well absorbed after oral
administration, peak conc 1 -3 hrs,
(sustained release) preparations are
available, propranolol undergoes extensive
first – pass metabolism.
• Pindolol has better bioavailability, large Vd.
• Propranolol crosses BBB, rapidly
eliminated t12 = 2 – 5 hrs.

Clinical uses ofClinical uses of ββ blockers:-blockers:-
1. Hypertension most often use with diuretic or
vasodilator.
2. Ischaemic heart disease decrease frequency of
anginal episodes, improve exercise tolerance in
patients with angina, (decrease cardiac work, and
decrease O2 demand).
3. Cardiac arrhythmic, effective in supraventricular
and ventricular arrhythmia by prolonging AV
conduction time, they decrease ventricular response,
and decrease rate in arterial flutter and fibrillation.

4. Glaucoma; topical and systemic
administration decrease IOP e.g. timolol
(preferred because they lack local anesthetic
effect and pure antagonist) mechanism may
due to decrease in aqueous formation (not
well understood).

5. Hyperthyroidism, results in excessive
adrenergic activity especially in the heart
(use to prevent palpitation).
6. Migraine prophylaxis.
7. Benign essential tremor.

Toxicity and side effects of βToxicity and side effects of β
blockers:-blockers:-
1. Manifestation of drug allergy, rash and fever.
2. Increase airway resistance
(Bronchoconstriction).
3. Bradycardia, heart failure in person who
depends on sympathetic output to maintain
cardiac output. Abrupt withdrawal in patients
with ischemic heart disease → risk, (gradual
tapering rather than abrupt withdrawal).

4. Incidence of hypoglycemia in insulin
dependent diabetes (mask symptom of
hypoglycemia).
5. Mask clinical signs of developing
hyperthyroidism.
6. Physical fatigue and Sexual impairment (↓
Sexual function).
7. Cold extremities (decrease peripheral
blood flow), rarely cause necrosis.

8. CNS effects: sedation, depression and sleep
disturbance (bad dreams).
9. ↓ HDLLDL value.
10.Oculomucocutaneous syndrome (practolol)
(eye dryness which can lead to blindness).
The use of practolol (selective β1 blocker)
has been referred to as the practolol disaster
which considered the worst medical blunder
since thalidomide.

THANK YOU
(‫د‬ُ ‫ه‬َ ‫ش‬ْ ‫أ‬َ ، ‫ك‬َ ‫د‬ِ ‫م‬ْ ‫ح‬َ ‫ب‬ِ ‫و‬َ ‫م‬ّ ‫ه‬ُ ‫ل‬ّ ‫ال‬ ‫ك‬َ ‫ن‬َ ‫حا‬َ ‫ب‬ْ ‫س‬ُ
‫ه‬َ ‫إل‬ِ ‫ل‬ ‫ن‬ْ ‫أ‬َ)‫ك‬َ ‫ي‬ْ ‫ل‬َ ‫إ‬ِ ‫ب‬ُ ‫تو‬ْ ‫أ‬َ ‫و‬َ ‫ك‬َ ‫ر‬ُ ‫ف‬ِ ‫غ‬ْ ‫ت‬َ ‫س‬ْ ‫أ‬َ ‫ت‬َ ‫ن‬ْ ‫أ‬َ ‫ل‬ّ ‫إ‬ِ

Pharmacology of the Autonomic Nervous System (39

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