AUTONOMIC PHARMACOLOGY

Introduction
The nervous system is divided into two anatomically distinct
regions:
Central nervous system
Peripheral nervous system
The central nervous system (CNS) consists of the brain and
spinal cord. The peripheral nervous system (PNS) consists of
12 pairs of cranial nerves that arise from the brainstem and 31
pairs of spinal nerves arising from the spinal cord.
peripheral nerves carry information between the CNS and the
tissues of the body. The PNS consists of two divisions:
Afferent division
Efferent division
 Cont
The afferent division carries sensory information
toward the CNS and the efferent division carries
motor information away from the CNS toward the
effector tissues (muscles and glands).
The efferent division is further divided into two
components:
(1) the somatic nervous system, which consists of
motor neurons that innervate skeletal muscle
-It is largely concerned with consciously controlled
functions such as movement, respiration, and
posture.
 Cont
2) The autonomic nervous system (ANS), also known as the
visceral or involuntary nervous system, functions below the
level of consciousness.
Because it innervates cardiac muscle, smooth muscle, and
various endocrine and exocrine glands, this nervous system
inuences the activity of most of the organ systems in the
body.
Therefore, it is evident that the ANS makes an important
contribution to the maintenance of homeostasis.
Regulation of blood pressure; gastrointestinal responses to
food; contraction of the urinary bladder; focusing of the
eyes; and thermoregulation are just a few of the many
homeostatic functions regulated by the ANS.
 ANATOMY OF THE AUTONOMIC NERVOUS
SYSTEM
The autonomic nervous system lends itself to division on anatomic
grounds into two major portions: the sympathetic (thoracolumbar)
division and the parasympathetic (craniosacral) division (figure
below).
Both divisions originate in nuclei within the central nervous system
and give rise to preganglionic efferent fibers that exit from the brain
stem or spinal cord and terminate in motor ganglia.
The sympathetic preganglionic fibers leave the central nervous
system through the thoracic and lumbar spinal nerves.
The parasympathetic preganglionic fibers leave the central nervous
system through the cranial nerves (especially the third, seventh,
ninth, and tenth) and the third and fourth sacral spinal roots.
Cont
 NEUROTRANSMITTER CHEMISTRY OF THE AUTONOMIC
NERVOUS SYSTEM
An important traditional classification of autonomic nerves
is based on the primary transmitter molecules
acetylcholine or norepinephrinereleased from their
terminal boutons and varicosities.
A large number of peripheral ANS fibers synthesize and
release acetylcholine; they are cholinergic fibers, ie, they
act by releasing acetylcholine.
As shown in (the above Figure), these include all
preganglionic efferent autonomic fibers and the somatic
(nonautonomic) motor fibers to skeletal muscle as well.
Thus, almost all efferent fibers leaving the central nervous
system are cholinergic.
 Cont
In addition, most parasympathetic postganglionic
and a few sympathetic postganglionic fibers are
cholinergic.
A significant number of parasympathetic
postganglionic neurons utilize nitric oxide or
peptides for transmission.
Most postganglionic sympathetic fibers release
norepinephrine (also known as noradrenaline); they
are noradrenergic (often called simply "adrenergic")
fibers; that is, they act by releasing norepinephrine.
A few sympathetic fibers release acetylcholine.
 Cont
Dopamine is a very important transmitter in the
central nervous system, and there is evidence that it
may be released by some peripheral sympathetic
fibers.
Adrenal medullary cells, which are embryologically
analogous to postganglionic sympathetic neurons,
release a mixture of epinephrine and
norepinephrine.
Five key features of neurotransmitter function
provide potential targets for pharmacologic therapy:
synthesis, storage, release, and termination of action
of the transmitter, and functions of the receptor.
 NEUROTRANSMISSION

Nerve impulses elicit responses in smooth,

cardiac, and skeletal muscles, exocrine glands,
and postsynaptic neurons by liberating
specific chemical neurotransmitters
Neurotransmitters:
Ach,noradrenaline,dopamine,5-
HT,GABA,purines,peptids.
 Acetylecholine

Neurotransmitter at:
all autonomic ganglia
all parasympathetic neuro effector junction
some sympathetic neuroeffector junction
(those innervating sweat glands)
all somatic neuromuscular junction.
 Cont
Cholinergic neurons-neurons that release Ach.
Cholinoreceptors-receptors with which Ach
interacts
Cholinomimetics-drugs mimic Ach on
interaction with cholinergic receptors
Cholinoreceptor antagonists-drugs that
antagonize the effects of Ach.
Nor epinephrine(NE) and epinephrine(Epi)

Neurotransmitter at:-
sympathetic post synaptic neurons except those
innervating sweat glands where Ach is the
neurotransmitter.
Adrenergic neurons- neurons that release NE/Epi.
Adrenoceptors-receptors with which NE/Epi interact.
Adrenomimetic/sympathomimetic-drugs mimic NE/Epi
on interaction with adrenoceptors.
Adrenergic antagonists-drugs that antagonize the
effects of Epi/NE.
 Cont
Acetyl Choline esterase:- Very efficiently splits
Ach in to cholin & acetate & terminates the
action of the transmitters.
It is highly concentrated at the postsynaptic end
plate of the neuromuscular junction .
Butyrylcholinesterase (BuChE; also known as
pseudocholinesterase) :-has low affinity to Ach.
BuChE is synthesized primarily in the liver and is
found in liver and plasma.
 Nicotinic and muscarinic receptors

Nn-stimulated by dimethyl phenyl

piperazinium, blocked by hexamethonium
Nm-stimulated by phenyl trimethyl
ammonium, blocked by tubocurarine.
Muscarinic receptors stimulated by
muscarine,blocked by atropine.
 Subtypes and Characteristics of Cholinoceptors
Receptor Type Location

CNS neurons, sympathetic postganglionic neurons,

M1 some presynaptic sites

M2 Heart, nerves, smooth muscle,Exocrine glands,

vessels
(smooth muscle and endothelium),CNS neurons
M3 Glands, smooth muscle, endothelium, CNS neurons
M4 CNS neurons;possibly vagal nerve endings
M5 Vascular endothelium, especially cerebral vessels;
CNS neurons
NM Skeletal muscle neuromuscular endplates

NN Postganglionic neurons, some presynaptic

cholinergic terminals
 CHOLINOMIMETIC DRUGS

Direct-acting cholinomimetic agents bind to and

activate muscarinic or nicotinic receptors
Indirect-acting agents produce their primary
effects by inhibiting acetylcholinesterase, which
hydrolyzes acetylcholine to choline and acetic
acid.
The excess acetylcholine, in turn, stimulates
cholinoceptors to evoke increased responses.
These drugs act primarily where acetylcholine is
physiologically released and are thus amplifiers of
endogenous acetylcholine
 Properties of Choline Esters
Choline Ester Susceptibility Muscarinic Nicotinic
to Action Action
Cholinesterase
Acetylcholine ++++ +++ +++
chloride

Methacholine + ++++ None

chloride
Carbachol Negligible ++ +++
chloride

Bethanechol Negligible ++ None

chloride
 Cont
Methacoline:-resistant to cholinesterase
activity
Carbacole:-completely resistant to
degradation by cholinesterase.
Bethanecol:-completely resistant to
cholinesterase
 Naturaly occurring alkaloids

Pilocarpine,arecoline,muscarine,nicotine,lobel
ine.
Pilocarpine, nicotine &lobeline:- tertiary
amines & can readily cross membranes.
Muscarine:- quaternary ammonium
compound doesnt cross membranes.
 ORGAN SYSTEM EFFECTS
Eye
Muscarinic agonists cause contraction of the
smooth muscle of the iris sphincter (resulting in
miosis) and of the ciliary muscle (resulting in
accommodation).
Decrease intraocular pressure due to two reasons.
ciliary muscle contraction puts tension on
trabecular meshwork ,opening its pores &
facilitating out flow of aqueous humor into the
canal of schlemm.
contraction of the iris sphincter pulls the
peripheral iris away from the trabecular meshwork,
thereby opening the path for aqueous out flow.
 Cont
Cardiovascular System
The primary cardiovascular effects of
muscarinic agonists are reduction in peripheral
vascular resistance and changes in heart rate,
cause vasodilation, resulting in a reduction in
blood pressure.
The cardiovascular effects of all of the choline
esters are similar to those of acetylcholine, the
main difference being in their potency and
duration of action.
 Cont
Respiratory System
Muscarinic stimulants contract the smooth
muscle of the bronchial tree.
In addition, the glands of the
tracheobronchial mucosa are stimulated to
secrete.
This combination of effects can occasionally
cause symptoms, especially in individuals with
asthma.
 Cont
Gastrointestinal Tract
Increases the secretory and motor activity of
the gut.
The salivary and gastric glands are strongly
stimulated; the pancreas and small intestinal
glands less so.
Peristaltic activity is increased throughout the
gut, and most sphincters are relaxed.
 Cont
Genitourinary Tract
Stimulate the detrusor muscle and relax the
trigone and sphincter muscles of the bladder,
thus promoting voiding.
The human uterus is not notably sensitive to
muscarinic agonists.
Miscellaneous Secretory Glands
Muscarinic agonists stimulate secretion by
thermoregulatory sweat, lacrimal, and
nasopharyngeal glands.
 Therapeutic uses:
Acetylcholine:-is available as an ophthalmic
surgical aid for the rapid production of miosis.
Bethanecol:-postoperative /post
partumnonobstractive urinary
retention,neurogenic bladder
atony,congenitalmegacolon,gastroesophageal
reflex.
Side effect:blenching,colic,involuntary
urination/defication,flushing,sweating,fall in
blood pressure,broncospasm.
Methacoline:-may be administer for diagnosis of
bronchial hyperreactivity.
 Cont
Pilocarpine:-
-the first choic for glaucoma
carbacol is sometimes effective in treating
cases of open angle glaucoma that is resistant
to pilocarpine.
-pilocarpine is administer orally in 5-10 mg TID
for the treatment of xerostoma.
 Cont
Contraindications
-Major contraindications to the use of the
muscarinic agonists are:
asthma,hyperthyroidism,coronary insufficiency,
acid-peptic ulcer disease.
Advers effects
-Advers effects for the use of cholinergic agonists:-
flushing,sweating,abdominalcramps,a sensation
of titgtness in the urinary bladder,difficulty in
visual accommodation,headach & salivation.
 INDIRECT-ACTING CHOLINOMIMETICS
The actions of acetylcholine released from
autonomic and somatic motor nerves are
terminated by enzymatic hydrolysis of the
molecule.
Hydrolysis is accomplished by the action of
acetylcholinesterase, which is present in high
concentrations in cholinergic synapses.
The indirect-acting cholinomimetics have their
primary effect at the active site of this enzyme,
although some also have direct actions at nicotinic
receptors.
The chief differences between members of the
group are chemical and pharmacokinetictheir
pharmacodynamic properties are almost identical.
 Cont
There are three chemical groups of
cholinesterase inhibitors:
(1) simple alcohols bearing a quaternary
ammonium group, eg, edrophonium;
(2) carbamic acid esters of alcohols bearing
quaternary or tertiary ammonium groups
(carbamates, eg, neostigmine); and
(3) organic derivatives of phosphoric acid
(organophosphates, eg, echothiophate).
 Cont
Anticholinesterases
The actions of acetylcholine released from autonomic
and somatic motor nerves are terminated by enzymatic
hydrolysis of the molecule.
Hydrolysis is accomplished by the action of
acetylcholinesterase, which is present in high
concentrations in cholinergic synapses.
The indirect-acting cholinomimetics have their primary
effect to inhibite this hydrolysis.
Reversible: -carbamets(Edrophonium, neostigmine, and
pyridostigmine, neostigmine,rivastigmine).
Irreversible: - organophosphates
(echothiophate,Parathion and malathion,
Soman),carbamets(carbrly,propoxur).
 Cont
Lipid soluble:-physiostigmine,organophosphats-have
CNS effect.
Non lipide soluble:-neostigmine,other quaternary
ammonium cpds marked effect on skeletal muscle.
Pharmacological action
Central Nervous System
In low concentrations, the lipid-soluble cholinesterase
inhibitors cause diffuse activation on the
electroencephalogram and a subjective alerting
response.
In higher concentrations, they cause generalized
convulsions, which may be followed by coma and
respiratory arrest.
 Cont
Cardiovascular System
In the heart, the effects on the parasympathetic
limb predominate.
Thus, cholinesterase inhibitors such as
edrophonium, physostigmine, or neostigmine
mimic the effects of vagal nerve activation on the
heart.
Negative chronotropic, dromotropic, and
inotropic effects are produced, and cardiac
output falls.
The fall in cardiac output is attributable to
bradycardia, decreased atrial contractility, and
some reduction in ventricular contractility.
 Cont
Eye, Respiratory Tract, Gastrointestinal Tract,
Urinary Tract
The effects of the cholinesterase inhibitors on
these organ systems, all of which are well
innervated by the parasympathetic nervous
system, are qualitatively quite similar to the
effects of the direct-acting cholinomimetics.
 Cont
Pharmacokinetics
Absorption of the quaternary carbamates from the conjunctiva,
skin, and lungs is predictably poor, since their permanent charge
renders them relatively insoluble in lipids.
Distribution into the central nervous system is negligible.
Physostigmine, in contrast, is well absorbed from all sites and can
be used topically in the eye.
The organophosphate cholinesterase inhibitors (except for
echothiophate) are well absorbed from the skin, lung, gut, and
conjunctivathereby making them dangerous to humans and
highly effective as insecticides.
The thiophosphate insecticides (parathion, malathion, and related
compounds) are quite lipid-soluble and are rapidly absorbed by all
routes.
All of the organophosphates except echothiophate are distributed
to all parts of the body, including the central nervous system.
 Therapeutic use
Glaucoma:-Topical treatment with long-acting ChE
inhibitors such as echothiophate gives rise to
symptoms characteristic of systemic ChE inhibition.
Echothiophate treatment in advanced glaucoma may
be associated with the production of cataracts.
Low concentrations of physostigmine(0.1 %) are
reported to decrease the blurred vision and pain
associated with this condition.
In alternation with a mydriatic drug such as atropine,
short-acting anti-ChE agents have proven useful for
breaking adhesions between the iris and the lens or
cornea.
 Cont
Myasthenia Gravis:-Myasthenia gravis is a
neuromuscular disease characterized by weakness and
marked fatigability of skeletal muscle; exacerbations
and partial remissions occur frequently.
Treatment started with :neostigmine(15 mg orally 6
hrly adjust the dose according to the
respons),pyridostigmine is alternative which requires
less frequent dosing are the standard anti-ChE drugs
used in the symptomatic treatment of myasthenia
gravis.
All can increase the response of myasthenic muscle to
repetitive nerve impulses, primarily by the
preservation of endogenous ACh.
 Cont
Paralytic Ileus and Atony of the Urinary Bladder.
In the treatment of both these conditions, neostigmine(0.5 -1
mg s.c) generally is preferred among the anti-ChE agents,
provided no organic obstraction presnt.

Alzheimer's Disease:- A deficiency of intact cholinergic

neurons, particularly those extending from subcortical areas
such as the nucleus basalis of Meynert, has been observed in
patients with progressive dementia of the Alzheimer type.
ceroselective anti-ChEs rivastigmine,donepezil & galantamine
have been recently approved for clinical use by FDA.
 Anticholinesterase poisoning
The acute toxic effects of the cholinesterase inhibitors, like
those of the direct-acting agents, are direct extensions of
their pharmacologic actions.
The major source of such intoxications is pesticide use in
agriculture and in the home. Therapy always includes:
(1) maintenance of vital signsrespiration in particular may
be impaired;
(2) decontamination to prevent further absorptionthis
may require removal of all clothing and washing of the
skin in cases of exposure to dusts and sprays; and
(3) atropine parenterally in large doses, given as often as
required to control signs of muscarinic excess.
 Specific antidotes:-
a) Atropine:-
AntiChE poisoning must be prompently given atropine 2
mg i.v. repeated every 10 min. till pupile dilates (up to
200 mg has been administered in a day).
Atropine in sufficient dosage effectively antagonizes the
actions at muscarinic receptor sites, including increased
tracheobronchial and salivary secretion,
bronchoconstriction, bradycardia, and to a moderate
extent, peripheral ganglionic and central actions.
Larger doses are required to get appreciable
concentrations of atropine into the CNS.
Atropine is virtually without effect against the peripheral
neuromuscular compromise, which can be reversed by
pralidoxime, a cholinesterase reactivator.
 Cont
b)cholinesterase reactivators:-
these are used to restore neuromuscular
transmission in case of organophosphate
antiChEpoisoning. This are
pralidoxim,diacetylmonoxime(DAM).
Pralidoxime is not effective for carbamet
poisoning& because of its positive charge does not
enter to CNS so not reverse central effects.
DAM, on the other hand, crosses the BBB & ,can
regenerate some of the CNS cholinesterase.
 Anti cholinergic drugs (muscarinic receptor
antagonist,parasympatholytic)
Atropine highly selective for muscarinic receptors.
at high dose selectivity lost.
some of synthetic substituent of atropine have also
significant nicotinic activity.
All anticholinergic are competitive antagonists.
Classification:
Natural alkaloids:-atropine, hayoscine
Semisynthetic derivatives:
homatropine,atropinemethonitrate,hayoscine butyl
bromide,ipratropiumbromide,tiotropium bromide.
 Cont

Synthetic compounds:-cyclopentolet, tropic

amide,propentaline,clindinium,glycopyrolet,ox
ybutinin,pirezepine,procyclidine,ethoprooazin
e,cycrimine.
Others:tricyclicantidepressant,phenothiazines,
antihistamines,disopyramide.
 Pharmacologic action (atropine):
Central Nervous System
In the doses usually used, atropine has minimal
stimulant effects on the central nervous system,
especially the parasympathetic modullarly
centers, and a slower, longer-lasting sedative
effect on the brain.
Scopolamine has more marked central effects,
producing drowsiness when given in
recommended dosages and amnesia in sensitive
individuals.
 Cont

In toxic doses, scopolamine and to a lesser

degree atropine can cause excitement,
agitation, hallucinations, and coma.
Vestibular disturbances, especially motion
sickness, appear to involve muscarinic
cholinergic transmission.Scopolamine is often
effective in preventing or reversing these
disturbances.
 Cont
Eye
The pupillary constrictor muscle depends on
muscarinic cholinoceptor activation.
This activation is blocked by topical atropine and
other tertiary antimuscarinic drugs and results in
unopposed sympathetic dilator activity and
mydriasis.
The second important ocular effect of
antimuscarinic drugs is to weaken contraction of the
ciliary muscle, or cycloplegia.
Cycloplegia results in loss of the ability to
accommodate (lasting 7-10 days); the fully
atropinized eye cannot focus for near vision .
 Cont
Cardiovascular System
The sinoatrial node is very sensitive to muscarinic
receptor blockade.
Moderate to high therapeutic doses of atropine cause
tachycardia in the innervated and spontaneously
beating heart by blockade of vagal slowing.
Muscarinic effects on atrial muscle are similarly
blocked, but these effects are of no clinical significance
except in atrial flutter and fibrillation.
The ventricles are less affected by antimuscarinic drugs
at therapeutic levels because of a lesser degree of
muscarinic control.
 Cont
Respiratory System
Atropine can cause some bronchodilation and
reduce secretion.
The effect is more significant in patients with
airway disease.
Antimuscarinic drugs are frequently used prior
to administration of inhalant anesthetics to
reduce the accumulation of secretions in the
trachea and the possibility of laryngospasm.
 Cont
Gastrointestinal Tract
Blockade of muscarinic receptors has dramatic effects on
motility and some of the secretory functions of the gut.
However, even complete muscarinic block cannot totally
abolish activity in this organ system since local hormones
and noncholinergic neurons in the enteric nervous system
also modulate gastrointestinal function.
Gastric secretion is blocked less effectively: the volume and
amount of acid, pepsin, and mucin are all reduced, but
large doses of atropine may be required.
Gastrointestinal smooth muscle motility is affected from
the stomach to the colon.
 Cont
Genitourinary Tract
Relaxes smooth muscle of the ureters and
bladder wall and slows voiding.
This action is useful in the treatment of spasm
induced by mild inflammation, surgery, and
certain neurologic conditions, but it can
precipitate urinary retention in men who have
prostatic hyperplasia.
The antimuscarinic drugs have no significant
effect on the uterus.
 Cont
Sweat Glands
Atropine suppresses thermoregulatory sweating.
Sympathetic cholinergic fibers innervate eccrine sweat
glands, and their muscarinic receptors are readily
accessible to antimuscarinic drugs.
Body tempreture:-rise in body temperature occurs at
high doses.
-it is due to inhibition of sweating as well as stimulation of
temperature regulating center at hypothalamus.
-In adults, body temperature is elevated by this effect only
if large doses are administered, but in infants and
children even ordinary doses may cause "atropine fever."
 Hyoscine(scopolamine)
Causes marked sedation in low doses unlike atropine.
in high dose, the effects of atropine & hyoscine are similar on
the CNS(excitation).
Hayoscine also has a useful antiemetic effect (use in motion
sickness).
Pharmacokinetics

The natural alkaloids and most tertiary antimuscarinic drugs

are well absorbed from the gut and conjunctival membranes.
When applied in a suitable vehicle, some (eg, scopolamine) are
even absorbed across the skin (transdermal route).
In contrast, only 1030% of a dose of a quaternary
antimuscarinic drug is absorbed after oral administration,
reflecting the decreased lipid solubility of the charged
molecule.
 Cont

Atropine and the other tertiary agents are widely

distributed in the body.
-Significant levels are achieved in the central
nervous system within 30 minutes to 1 hour, and
this can limit the dose tolerated when the drug is
taken for its peripheral effects.
Scopolamine is rapidly and fully distributed into
the central nervous system where it has greater
effects than most other antimuscarinic drugs.
 Cont
In contrast, the quaternary derivatives are poorly taken
up by the brain and therefore are relatively freeat low
dosesof central nervous system effects.
After administration, atropine disappears rapidly from
the blood with a half-life of 2 hours.
-About 60% of the dose is excreted unchanged in the urine.
-Most of the rest appears in the urine as hydrolysis and
conjugation products.
-The drug's effect on parasympathetic function declines
rapidly in all organs except the eye.
- Effects on the iris and ciliary muscle persist for >72 hours.
 Atropine substitute
Many semi synthetic derivatives of belladonna
alkaloids & large number of synthetic
compounds have been introduce with the aim
of producing more selective action on certain
functions.
Hyoscine butyl bromide (20-40 mg oral, i.m,s.c.).
-less potent & longer acting than atropine.
-used for esophageal & gastrointestinal spastic
condition.
 Cont
Atropine metonitrate (2.5-10 mgoral ,i.m. for
abdominal colics& hyperacoidity.
-as an aerosol it is used in bronchial asthma &
asmathic bronchitis.
Ipratropium bromide (40 -80 microgram):-a
synthetic analog of atropine, is used as an
inhalational drug in asthma.
-Ipratropium has also proved useful in COPD, a
condition that occurs with higher frequency in
older patients, particularly chronic smokers
does not depress mucociliary clearance.
 Cont
Oxybutynin, which is somewhat selective for M3
receptors, is used to relieve bladder spasm after
urologic surgery, eg, prostatectomy.
- It is also valuable in reducing involuntary voiding in
patients with neurologic disease, eg, children with
meningo myelocele.
Imipramine:- a tricyclic antidepressant drug with
strong antimuscarinic actions, has long been used to
reduce incontinence in institutionalized elderly
patients.
- It is moderately effective but causes significant central
nervous system toxicity.
 Cont
Glycopyrolate (0.1-0.3 mg i.m ,1-2 mg oral) potent and
rapidly acting antimuscarinic lacking central effects.
-almost exclusively used for preanaesthetic medication &
during anaesthesia.
Mydriatics
atropine is a potent mydriatic but its low and lasting
action is undesirable for refraction.
-though the pupil dilates in 30 -40 min,cycloplegia takes 1-3
hours, and the subject is visually handicapped for about
a week.
homatropine (onset 45-60 min, DOA 1-3 days)
cyclopentolet(onset 30-60min,DOA 1 days)
tropicamide(onset 20-40 min, DOA 3-4 hours)
 Contraindications

Antimuscarinic drugs are contraindicated in

patients with glaucoma, especially angle-closure
glaucoma.
Even systemic use of moderate doses may
precipitate angle closure (and acute glaucoma) in
patients with shallow anterior chambers.
Adverse Effects
Dry mouth, difficulty in swallowing & talking,
flushed & hot skin, fever,difficulty in
micturation,dilatedpupil,photophobia,blurring of
near
 Adrenergic drugs
Adrenergic transmition:-adrenergic (more
precisely noradrenergic)transmition is
restricted to the sympathetic division of ANS.
There are three closely related endoganous
catecholamins(CAs):-
Noradrenergic(NA):acts as atransmitter at
post ganglionic sympathetic sites(except sweat
glands,hair follicles & some vasodilator fibers)
& in certain area of the brain.
 Cont
Adrenaline:-it is secreted by adrenal meddula & may
have a transmitter role in brain.
Dopamine(DA):-it is a major transmitter in the basal
ganglia,limbic system,CTZ,anterior pituitary.
 Termination of CAs

a)Uptake-1(neuronal type):
active amine pump which is present at neuronal
membrane (rate transport NA >Adr).
the most important mechanism for terminating
action of CAs.
inhibited by cocain,TCA.& phenothiazins
b)Uptake-2(extra neuronal uptake):
diffussion of CAs into tissue.
 Cont
c) Metabolized by enzyms
i)monoaminoxidase(MAO)
attack CAs which are taken by uptake-1
-MAO-Aplacenta & liver(in the periphery)&in
all regions containing CAs in the CNS.
-MAO-B :platlets,lymphocyts,& liver(in the
periphery)& primerly found in regions that are
known to synthesize & store serotonin in the
CNS.
 Cont
ii) catechol-o-methyl transferase(COMT)
metabolize CAs which diffuse in to tissue.
plays a major role in the metabolism of
endogeneous circulating & administered CAs.
 ADRENOCEPTORS

An important factor in the response of any cell or

organ to sympathomimetic amines is the density
and proportion of a and b adrenergic receptors.
catecholamines acted via two principal receptors.
Alpha receptors are those that have the
comparative potencies adrenaline > NA >
isoproterenol.
Beta receptors have the comparative potencies
isoproterenol >Adr >NA.
 Major effects mediated by a & b receptors

a1- effect:-vasoconstriction,
- Increase peripheral resistance
- increase BP
-Mydriasis
-increased closure of internal sphinicter
of the bladder.
a2-effects:-inhibition of NE release
- inhibition of insulin release.
 Cont
B1-effects:-tachycardia
- increased lipolysis
- increased myocardial contractility
-increased released of rennin.
B2-effects:-vasodilation
-slightly increased peripheral resistance
- broncodilation
- increased muscel,liver glycogenolysis
-increased release of glucagon
-relaxed uterine smooth muscle.
Adrenergic drugs(sympathomimetics)

This are drugs with similar action to that of Adr or

sympathetic stimulation.
Classification of sympathomimetic drugs:
Direct acting:-act directly on one or more of the adrenergic
receptors.
e.g. phenylpherine,methoxamine,xylomethazoline.
Indirect acting:-increase the availability of NE & Epi in
synapses.
-release or displace NE from sympathetic nerve varicosities
-block transport of NE into sympathetic neurons
-block the metabolizing enzymes,MAO or COMT
 Cont
Mixed acting:-indirectly release NE & directly activate
receptors.e.g. ephedrine,amphetamine.
Epinephrine :pharmacological action
Heart:-
The heart rate increases and the rhythm often is altered.
Cardiac systole is shorter and more powerful, cardiac
output is enhanced
the work of the heart and its oxygen consumption are
markedly increased.
Cardiac efficiency (work done relative to oxygen
consumption) is lessened.
 Cont
Blood Pressure:-Epinephrine is one of the most potent
vasopressor drugs known.
The mechanism of the rise in blood pressure due to
epinephrine is three fold:
(1) a direct myocardial stimulation that increases the
strength of ventricular contraction (positive inotropic
action);
(2) an increased heart rate (positive chronotropic action)
(3) vasoconstriction in many vascular beds especially in the
precapillary resistance vessels of skin, mucosa, and
kidney along with marked constriction of the vein.
Small doses of epinephrine (0.1 mg/kg rapid i.v.
infusion) may cause the blood pressure to fall.
 Cont
Effects on Smooth Muscles:-
Gastrointestinal smooth muscle is, in general, relaxed by
epinephrine.
This effect is due to activation of both a and b receptors.
Intestinal tone and the frequency and amplitude of
spontaneous contractions are reduced.
The stomach usually is relaxed and the pyloric and
ileocecal sphincters are contracted.
Effect on blood vessles:-
constriction of cutaneous,mucosal & renal blood vessels
(a1 -mediated).
dilation of blood vessels supplying skeletal
muscel,coronary & liver(b2-mediated)
 Cont
During the last month of pregnancy and at
parturition, epinephrine inhibits uterine tone
and contractions (b2-mediated).
relaxes the detrusor muscle of the bladder as
a result of activation of( b receptors) and
contracts the trigone and sphincter muscles
owing to its( a agonist activity).
 Pharmacokinetics
Epinephrine is not effective after oral
administration because it is rapidly conjugated
and oxidized in the GI mucosa and liver.
Absorption from subcutaneous tissues occurs
relatively slowly because of local vasoconstriction
and the rate may be further decreased by
systemic hypotension, for example in a patient
with shock.
Absorption is more rapid after intramuscular
injection.
In emergencies, it may be necessary to
administer epinephrine intravenously.
 Cont
When relatively concentrated solutions (1%) are
nebulized and inhaled, the actions of the drug
largely are restricted to the respiratory tract;
however, systemic reactions such as arrhythmias
may occur, particularly if larger amounts are
used.
Epinephrine is rapidly inactivated in the body.
The liver, which is rich in both of the enzymes
responsible for destroying circulating epinephrine
(COMT and MAO).
 Adverse Effects, and
Contraindications
Epinephrine may cause:-
disturbing reactions, such as restlessness, throbbing
headache, tremor, and palpitations.
cerebral hemorrhage and cardiac arrhythmias.
Angina may be induced by epinephrine in patients
with coronary artery disease.
contraindicated in patients who are receiving
nonselective b receptor blocking drugs, since its
unopposed actions on vascular a1 receptors may lead
to severe hypertension and cerebral hemorrhage.
 Therapeutic Uses
relieve respiratory distress due to bronchospasm
rapid relief of hypersensitivity reactions, including
anaphylaxis, to drugs and other allergens.
prolong the action of local anesthetics, presumably
by decreasing local blood flow
Its cardiac effects may be of use in restoring
cardiac rhythm in patients with cardiac arrest due
to various causes
topical hemostatic agent
to lower intraocular pressur.
 Norepinephrine
Epi & NE are equipotent at b1 receptors.
Norepinephrine is a potent a agonist and has
relatively little action on b2 receptors
somewhat less potent than epinephrine on the
a receptors of most organs.
Cardiovascular Effects
Systolic and diastolic pressures, and usually pulse
pressure, are increased.
Cardiac output is unchanged or decreased, and total
peripheral resistance is raised.
 Cont
Unlike epinephrine, small doses of
norepinephrine do not cause
vasodilation or lower blood pressure,
since the blood vessels of skeletal muscle
constrict rather than dilate; a adrenergic
receptor antagonists therefore abolish
the pressor effects but do not cause
significant reversal (i.e., hypotension).
 Cont
Pharmacokinetics
Ineffective when given orally and is absorbed
poorly from sites of subcutaneous injection.
Adverse Effects and Precautions
The untoward effects of norepinephrine are
similar to those of epinephrine, although there
typically is greater elevation of blood pressure
with norepinephrine.
Excessive doses can cause severe hypertension.
 Dopamine
Cardiovascular Effects
The cardiovascular effects of dopamine are
mediated by several distinct types of receptors
that vary in their affinity for dopamine.
Dopamine also causes the release of
norepinephrine from nerve terminals, which
contributes to its effects on the heart.
At higher concentrations( dopamine exerts a
positive inotropic effect on the myocardium
acting on b1 adrenergic receptors,
activates vascular a1 receptors, leading to more
general vasoconstriction).
 Cont
exerts a positive inotropic effect on the myocardium,
acting on b1 adrenergic receptors
Dopamine usually increases systolic blood pressure
and pulse pressure and either has no effect on
diastolic blood pressure or increases it slightly.
Total peripheral resistance usually is unchanged
when low or intermediate doses of dopamine are
given, probably because of the ability of dopamine
to reduce regional arterial resistance in some
vascular beds, such as mesenteric and renal, while
causing only minor increases in others.
 Cont
Other Effects
Although there are specific dopamine receptors in
the CNS, injected dopamine usually has no central
effects because it does not readily cross the blood-
brain barrier.
Adverse Reactions
Nausea, vomiting, tachycardia, anginal pain, arrhythmias,
headache, hypertension, and peripheral vasoconstriction
may be encountered during dopamine infusion.
Extravasation of large amounts of dopamine during infusion
may cause ischemic necrosis and sloughing.
 Contraindications
should be avoided or used at a much reduced
dosage (one-tenth or less) if the patient has
received a MAO inhibitor.
Careful adjustment of dosage also is necessary in
patients who are taking tricyclic antidepressants.
Therapeutic Uses
treatment of severe congestive failure
cardiogenic and septic shock.
 b ADRENERGIC RECEPTOR AGONISTS
Isoproterenol
Nonselective b receptor agonist with very low affinity
for a receptors.
Pharmacological Actions
lowers peripheral vascular resistance
Diastolic pressure falls
Systolic blood pressure may remain unchanged or rise,
although mean arterial pressure typically falls.
Cardiac output is increased.
relaxes almost all varieties of smooth muscle when the
tone is high, but this action is most pronounced on
bronchial and GI smooth muscle.
 cont
inhibit release of histamine and other mediators of
inflammation; this action is shared by b2 receptor-selective
stimulants.
It is metabolized primarily in the liver and other tissues by
COMT, relatively poor substrate for MAO and is not taken
up by sympathetic neurons to the same extent as are
epinephrine and norepinephrine.
Toxicity and Adverse Effects
Palpitations, tachycardia, headache, and flushing are
common.
Cardiac ischemia and arrhythmias may occur.
Therapeutic Uses
in emergencies to stimulate heart rate in patients with
bradycardia or heart block
In disorders such as asthma and cardiogenic shock.
 Dobutamine
A relatively selective b1 receptor agonist, also acts
on a1 receptors
Pharmacological Actions:
Cardiovascular Effects
has relatively more prominent inotropic than
chronotropic effects on the heart compared to
isoproterenol.
Administration of dobutamine at a rate of 2.5 to 15
mg/kg per minute increases cardiac contractility
and cardiac output.
Total peripheral resistance is not greatly affected.
Heart rate increases only modestly.
 Cont
After administration of b receptor antagonists,
infusion of dobutamine fails to increase cardiac
output, but total peripheral resistance increases.
Adverse Effects:
hypertension,atrial fibrillation, develop
ventricular ectopic activity, increasing myocardial
oxygen demand, development of tolerance.
Therapeutic Uses:-treatment of cardiogenic
shock.
 b2-Selective Adrenergic Receptor
Agonists
This include:- Metaproterenol, Terbutaline,
Formoterol, Ritodrine,salbutamol
They causes :
bronchodilation,vasodilation &uterine relaxation,with
out producing significant cardiac stimulation.
Therapeutic Uses
they are primerly used for bronchia asthma
also used as uterine relaxant to delay premature
labour(ritordine).
Adverse Effects of b2-Selective Agonists: Tremor,
Feelings of restlessness, apprehension, and
anxiety,tachycardia,increase bronchial hypersensitivity.
 a1-SELECTIVE ADRENERGIC RECEPTOR
AGONISTS
Phenylephrine
a selective a1 receptor agonist
it activates b receptors only at much higher
concentrations.
causes marked arterial vasoconstriction.
used as a nasal decongestant and as a mydriatic in
various nasal and ophthalmic formulations.
not a catechol derivative,hence not a substrate for
COMT(acts longer than the CAs).
 CONT
Metaraminol
is a sympathomimetic drug with prominent direct
effects on vascular a adrenergic receptors.
also is an indirectly acting agent that stimulates
the release of norepinephrine.
the treatment of hypotensive states or off-label
to relieve attacks of paroxysmal atrial tachycardia,
particularly those associated with hypotension.
 a2-SELECTIVE ADRENERGIC RECEPTOR
AGONISTS
As antihypertensive agent lower blood
pressure results from activation of a2
receptors in the cardiovascular control centers
of the CNS; such activation suppresses the
outflow of sympathetic nervous system
activity from the brain.
This are clonidine,methyldopa,guanabenz are
usefull in the treatment of hypertension.
 INDIRECT ACTING SYMPATHOMIMETIC
Amphetamine & its congeners,tyramine, Ephedrine
Have weak action on AR but sufficiently resemble NE to
be transported in to nerve terminals by uptake1.
Inside the nerv terminals,they are taken up into
vesicls,displace the NE which escaps in to the cytosol.
Actions:
bronchodilation,raised arterial pressur,peripheral
vasoconstriction,increase heart rate,force of myocardial
contraction,inhibition of gut motility.
 Ephedrine
both an a and a b receptor agonist; in
addition, it enhances release of
norepinephrine from sympathetic neurons
and therefore is a mixed-acting
sympathomimetic drug.
Activation of b receptors in the lungs
promotes bronchodilation.
a potent CNS stimulant.
 Cont
Therapeutic Uses:-
use as a bronchodilator in patients with asthma
treat the hypotension that may occur with spinal
anesthesia,occasionally for postural hypotesion.
Dose 15-60 mg tid.
Untoward effects of ephedrine:
hypertension,insomnia is a common CNS adverse
effect,tachyphylaxis may occur with repetitive
dosing.
 Amphetamines:-include: Methamphetamine,
Methylphenidate, Pemoline
Amphetamine:
stimulates the medullary respiratory center, lessens
the degree of central depression caused by various
drugs, and produces other signs of CNS stimulation.
its pharmacokinetics similar to
ephedrine,however,amphethamine even more
readily enters the CNS,wher it has marked stimulant
effects on mood and alertness &a depressant effect
on appetite.
its peripheral action are mediated primarily through
the release of CAs.
 Cont
Methamphetamine :
It is used principally for its central effects, which
are more pronounced than those of amphetamine
and are accompanied by less prominent peripheral
actions.
Methylphenidate & Pemoline:
are pharmacological properties are essentially the
same as those of the amphetamines.
shares the abuse potential of the amphetamines
are effective in the treatment of narcolepsy and
attention-deficit/hyperactivity disorder(ADHD).
 Cont
Use of amphetamines:
narcolepsy,ADHD,obesity,nocturnal enuresis in
children & urinary incontinence,euphoric.
Advers effects:
produce psycologic dependence,high dose
amphetamine produce euphoria,marked
excitement,mental
confusion,delirium,hallucination & psychotic
state.
Peripheral effects vasomotor
effect,palpitation,arrhythmia.
 Cont
Nasal decongestants:
Are a2 agonists which on topical application
as dilute solution (0.5-1%) produces local
conistriction.
Include:naphazoline,xylometazoline,oxymetaz
oline.
Regular use for long oeriod of time should be
avoided.
 Non-selective a AR antagonists
Phenoxybenzamine and Related
Haloalkylamines,imidazolins(non selective
reversible a AR blockers),quinazoline(a1-AR
blockers).
a1 - antagonists:inhibit vasoconstriction by
CAs,the fall in BP opposed by baroreceptor
reflexes.
a2- antagonists:increase release of NE from
peripheral sympathetic neurons,increase
sympathetic out flow from the CNS hence cause
increase in BP,might cause vasodilation on
some vascular beds.
 a1- Receptor Antagonists
drugs include:prazosin,terazosin, ,tamsulosine
Prazosin, the prototype drug, blockade of a1
receptors in arterioles and veins.
This leads to a fall in peripheral vascular resistance
and in venous return to the heart.
does not increase heart rate.
prazosin has little or no a2 receptor-blocking effect
at concentrations achieved clinically, it probably
does not promote the release of norepinephrine
from sympathetic nerve endings in the heart.
well absorbed after oral administration
bioavailability(50-60%) .
 Cont
Terazosin:
more soluble in water than is prazosin
its bioavailability is high (>90%)
The half-time of elimination of terazosin is
approximately 12 hours, and its duration of action
usually extends beyond 18 hours.
Tamsulosine:
selectivity may favor blockade of a1A receptors in
prostate
efficacious in the treatment of BPH (benign prostatic
hyperplasia).
 Cont
Adverse Effects:
A major potential adverse effect of prazosin and
its congeners is the first-dose effect; marked
postural hypotension
impaired ejaculation(tamsulosine).
Therapeutic Uses:
Prazosin and its congeners have been used
successfully in the treatment of essential
hypertension
congestive heart failure, BPH.
a2 Adrenergic Receptor Antagonist
Yohimbine:
it readily enters the CNS,& acts to increase BP
& heart rate;enhances motor activity &
produces tremors
These actions are opposite to those of
clonidine, an a2 agonist.
 b ADRENERGIC RECEPTOR ANTAGONISTS
Usefull in the treatment of:
hypertension
ischemic heart disease
congestive heart failure
and certain arrhythmias.
Pharmacological Properties:-
Cardiovascular System:
slow the heart rate and decrease myocardial contractility
decreases cardiac output
decrease BP.
 NON-SELECTIVE b ADRENERGIC RECEPTOR
ANTAGONISTS

Propranolol:
interacts with b1 and b2 receptors with equal affinity
lacks intrinsic sympathomimetic activity
does not block a receptors
highly lipophilic and is almost completely absorbed
after oral administration
much of the drug is metabolized by the liver during
its first passage through the portal circulation
on average, only about 25% reaches the systemic
circulation.
 Cont
Therapeutic Uses :For the treatment of:-
Angina
Hypertension
supraventricular arrhythmias/tachycardias
ventricular arrhythmias/tachycardias
premature ventricular contractions
digitalis-induced tachyarrhythmias
myocardial infarction
Pheochromocytoma
the prophylaxis of migraine.
 Cont
Timolol:
potent, non-subtype-selective b receptor
antagonist.
It has no intrinsic sympathomimetic or membrane-
stabilizing activity
It is used to treat:-
hypertension
congestive heart failure
migraine prophylaxis
and has been widely used in the treatment of
open-angle glaucoma and intraocular
hypertension.
 b1-SELECTIVE ADRENERGIC RECEPTOR
ANTAGONISTS
Metoprolol:
b1-selective receptor antagonist that is devoid of intrinsic
sympathomimetic activity and membrane-stabilizing activity.
Therapeutic Uses
For the treatment of hypertension
stable angina,
chronic heart failure.
Atenolol:- b1-selective antagonist that is devoid of intrinsic
sympathomimetic and membrane stabilizing activity.
very hydrophilic and appears to penetrate the CNS only to a
limited extent.
Therapeutic Uses:- for the treatment of hypertension , in
combination with a diuretic, in elderly patients with isolated
systolic hypertension.
 Cont
Esmolol:
b1-selective antagonist with a very short
duration of action.
It has little if any intrinsic sympathomimetic
activity, and it lacks membrane-stabilizing
actions.
it administered intravenously and is used when b
blockade of short duration is desired or in
critically ill patients in whom adverse effects of
bradycardia, heart failure, or hypotension may
necessitate rapid withdrawal of the drug.
half-life of about 8 minutes.
 Cont
Acebutolol:
a selective b1 adrenergic receptor antagonist with some
intrinsic sympathomimetic and membrane-stabilizing
activity.
Is well absorbed, and undergoes significant first-pass
metabolism to an active metabolite, diacetolol.
Therapeutic Uses:-for the treatment of hypertension &
ventricular arrhythmias.
Bisoprolol:highly selective b1 receptor antagonist that does
not have intrinsic sympathomimetic or membrane-
stabilizing activity.
Therapeutic use:- :-for the treatment of hypertension.
 b Receptor Antagonists with
Additional Cardiovascular Effects
b1-selectiv e adrenergic receptor antagonists,
there also are a series of drugs that possess
vasodilatory actions.
Labetalol(a1 -antagonist &b2 -partial agonist)
Carvedilol(membrane stabilizing activity)
Bucindolol(a1-blocking as well asb2 &b3
properties)
ADVERSE EFFECTS AND PRECAUTIONS

Cardiovascular System
b receptor blockade may cause or exacerbate
heart failure in patients with compensated
heart failure
acute myocardial infarction, or cardiomegaly.
Abrupt discontinuation of b receptor
antagonists after long-term treatment can
exacerbate angina and may increase the risk
of sudden death.
 Cont
Pulmonary Function
Drugs with selectivity for b1 adrenergic receptors
or those with intrinsic sympathomimetic activity
at b2 adrenergic receptors may be somewhat less
likely to induce bronchospasm.
Central Nervous System
The adverse effects of b receptor antagonists that
are referable to the CNS may include fatigue,
sleep disturbances (including insomnia and
nightmares), and depression.
 Cont
Metabolism
b adrenergic blockade may blunt recognition of
hypoglycemia by patients
it also may delay recovery from insulin-induced
hypoglycemia.
Drug Interactions:- Aluminum salts, cholestyramine, and
colestipol may decrease the absorption of b blockers.
Drugs such as phenytoin, rifampin, and phenobarbital, as
well as smoking, induce hepatic biotransformation
enzymes and may decrease plasma concentrations of b
receptor antagonists that are metabolized extensively
(e.g., propranolol).
THERAPEUTIC USES:- Myocardial Infarction,Congestive
Heart Failure