Autonomic Nervous System
Dr. Yahya Ibn Ilias
( Pharmacology )
GENERAL ORGANIZATION AND
FUNCTIONS OF THE NERVOUS SYSTEM
The nervous system is divided into two parts:
The central nervous system (CNS) and
The peripheral nervous system (PNS).
The CNS consists of the Brain and spinal cord.
The PNS consists of all afferent (sensory) neurons,
which carry nerve impulses into the CNS from sensory end
organs in peripheral tissues, and
All efferent (motor) neurons, which carry nerve impulses
from the CNS to effector cells in peripheral tissues.
The peripheral efferent system is further divided into t
Somatic nervous system and
Autonomic nervous system.
The effector cells innervated by the somatic nervous system
are skeletal muscle cells.
The autonomic nervous system innervates three types of
(1) Smooth muscle,
(2) Cardiac muscle, and
(3) Exocrine glands.
ANATOMIC DIFFERENCES BETWEEN THE
SOMATIC AND AUTONOMIC NERVOUS
The axon of a somatic motor neuron leaves the CNS and
travels without interruption to the innervated effector cell.
In contrast, two neurons are required to connect the CNS
and a visceral effector cell of the autonomic nervous
The first neuron in this sequence is called the preganglionic
The second neuron, whose cell body is within the
ganglion,travels to the visceral effector cell; it is called the
AUTONOMIC NERVOUS SYSTEM
The Preganglionic neurons of the Sympathetic nervous system
have their cell bodies in the thoracic and lumbar regions of the
spinal cord, termed the thoracolumbar division.
The Preganglionic neurons of the parasympathetic division have
their cell bodies in the brainstem and in the sacral region of the
spinal cord, termed the Craniosacral division.
The cranial part of the Parasympathetic nervous system innervates
structures in the head, neck, thorax, and abdomen (e.g., the
stomach, part of the intestines, and pancreas).
The cranial Parasympathetic fibers leave the CNS in the
Oculomotor, Facial, Glossopharyngeal, and Vagal cranial nerves.
The Sacral division of the Parasympathetic nervous system
innervates the remainder of the intestines and the pelvic viscera.
Location of the Autonomic Ganglia
The sympathetic ganglia consist of two chains of 22 segmentally
arranged ganglia lateral to the vertebral column.
The preganglionic fibers leave the spinal cord in adjacent ventral
roots and enter neighboring ganglia, where they make synaptic
connections with postganglionic neurons.
Some preganglionic fibers pass through the vertebral ganglia
without making synaptic connections and travel by way of
Splanchnic nerves to paired prevertebral ganglia in front of
the vertebral column, where they make synaptic connections with
In addition, some sympathetic preganglionic fibers pass through
the splanchnic nerves into the adrenal glands and make synaptic
connections on the chromaffin cells of the adrenal medulla.
Special Nature of the Sympathetic Nerve
endings in the Adrena Medullae.
Preganglionic sympathetic nerve fibers pass, without
synapsing, all the way from the intermediolateral
horn cells of the spinal cord, through the
sympathetic chains, and finally into the two
There they end directly on modified neuronal cells
that secrete epinephrine and norepinephrine
into the blood stream.
Because Sympathetic ganglia lie close to the vertebral
column, Sympathetic preganglionic fibers are generally
Postganglionic fibers are generally long, since they arise in
vertebral ganglia and must travel to the innervated effector
There are exceptions (e.g., urinary bladder and rectum);
thus, these preganglionic fibers are long and the
postganglionic fibers are short.
In contrast,the parasympathetic ganglia lie very close to or
actually within the organs innervated by the
parasympathetic postganglionic neurons.
Basic Characteristics of Sympathetic and
Principal transmitter agents involved
1. Acetylcholine and
Chemical Divisions of the Autonomic
Divided into cholinergic and noradrenergic divisions :-
1. fibers that secrete acetylcholine are said to be
2. fibers that secrete norepinephrine are said to be
Adrenergic, a term derived from adrenalin, which is
an alternate name for epinephrine.
Cholinergic :- parasympathomimetic; stimulated,
RECEPTORS ON THE AUTONOMIC
The receptors for acetylcholine and related drugs
(cholinoreceptors) and for norepinephrine and related
drugs (adrenoceptors) are different.
Acetylcholine will not interact with receptors for
Norepinephrine, and nor-epinephrine will not interact with
These receptors are selective not only for their respective
agonists but also for their respective antagonist drugs; that
is, drugs that antagonize or block acetylcholine at
cholinoreceptors will not antagonize nor-epinephrine at
adrenoceptors and vice versa.
Synthesis, Storage, Release, and
Removal of Acetylcholine
The initial substrates for the synthesis of acetylcholine are Glucose and
Glucose enters the neuron by means of facilitated transport.
There is some disagreement as to whether Choline enters cells by active or
Pyruvate derived from glucose is transported into mitochondria and
converted to acetylcoenzyme A (acetyl-CoA).
The acetyl-CoA is transported back into the cytosol.
With the aid of the enzyme Choline acetyl-transferase, Acetylcholine is
synthesized from Acetyl-CoA and Choline.
The Acetylcholine is then transported into and stored within the storage
vesicles by as yet unknown mechanisms.
Release of transmitter is dependent on extracellular calcium and occurs
when an action potential reaches the terminal and triggers sufficient influx
of calcium ions. The increased Ca2+ concentration "destabilizes" the
storage vesicles by interacting with special proteins associated with the
Conduction of an action potential through the terminal branches of an axon
causes depolarization of the varicosity membrane, resulting in the release of
transmitter molecules via Exocytosis.
After release from the presynaptic terminal, acetylcholine molecules may
bind to and activate an acetylcholine receptor (cholinoceptor).
Eventually (and usually very rapidly), all of the acetylcholine released
will diffuse within range of an acetylcholinesterase (AChE) molecule.
AChE very efficiently splits acetylcholine into choline and acetate, and
thereby terminates the action of the transmitter. Most cholinergic synapses
are richly supplied with acetylcholinesterase; the half-life of acetylcholine in
the synapse is therefore very short.
Synthesis, Storage, Release, and
Removal of Norepinephrine
Synthesis of Norepinephrine begins with the amino acid
In the neuronal cytosol, Tyrosine. is converted by the enzyme
tyrosine hydroxylase to Dihydroxyphenylalanine (Dopa), which
is converted to dopamine by the enzyme Decarboxylase,
sometimes termed dopa-decarboxylase.
The Dopamine is actively transported into storage vesicles,
where it is converted to Norepinephrine (the transmitter) by
dopamine beta-hydroxylase, an enzyme within the storage
In the Adrenal medulla ,the synthesis is carried one step
further by the enzyme phenylethanolamine N-
methyltransferase, which converts Norepinephrine to
Since the enzyme that converts dopamine to norepinephrine
(dopamine beta-hydroxylase) is located only within the
vesicles, the transport of dopamine into the vesicle is an
essential step in the synthesis of norepinephrine.
This same transport system is essential for the storage of
norepinephrine. There is a tendency for norepinephrine to
leak from the vesicles into the cytosol.
If norepinephrine remains in the cytosol, much of it will be
destroyed by a mitochondrial enzyme, Monoamine oxidase
Following processes contribute to the removal of
norepinephrine from the biophase:
1. Transport back into the noradrenergic neuron (reuptake),
followed by either vesicular storage or by enzymatic
inactivation by mitochondrial MAO. The transport of
norepinephrine into the neurons is a sodium-facilitated process
similar to that for choline transport.
2. Diffusion from the synapse into the circulation and ultimate
enzymatic destruction in the liver and renal excretion.
3. Active transport of the released transmitter into effector
cells (extraneuronal uptake) followed by enzymatic inactivation
Varicosity of a noradrenergic neuron showing synthesis and storage of norepinephrine. Also
shown is the release of norepinephrine (NE) and multiple routes for degradation. COMT,
catechol-O-methyltransferase; MAO, monoamine oxidase.
M 1 :
1. CNS : motor functions
2. Autonomic ganglia : histamine release
3. Gastric glands : acid secretions
4. GI motility : increases
Direct sympathomimetics : They act directly as
agonists on alpha and /or beta adrenoceptors –
adrenaline, NA, isoprenaline (Iso), phenylephrine,
methoxamine, xylometazoline, salbutamol.
Indirect sympathomimetics : They act on adrenergic
neurone to release NA, which then acts on the
adrenoceptors – tyramine, amphetamine.
Mixed action sympathomimetics : They act directly
or indirectly – ephidrine, dopamine, mephentermine.
Adrenoceptor agonists are classified into three types:(based on the
selectivity for the main adrenoceptor subtypes)
α- adrenoceptor agonists:
α 、 β- adrenoceptor agonists:
Adrenaline , Dopamine,
β- adrenoceptor agonists:
α1, α2, β1 and β3, but not β2 action
α1, α2, β1 and β2 and weak β3 action
β1 and β2, but not α action
Action on alpha- adrenoceptors
Contraction of arterioles and veins: raise in BP (α1+
Contraction of radial muscules of iris: mydriasis and
decreased aqueous secretion (α1)
Heart – little action, arrhythmia at high dose (α1)
GIT: intestinal relaxation, contraction of sphincters
Bladder trigone: contraction (α1)
Uterus: contraction (α1)
Blood Vessels :-
Alpha receptors - increase arterial resistance,
Beta - 2 receptors - smooth muscle relaxation
Skin vessels (alpha receptors) - constrict in the presence of
epinephrine and norepinephrine
Skeletal muscle vessels - constrict or dilate depending on whether
alpha or beta receptors are activated.
Overall effects of a sympathomimetic drug on blood vessels
depend on the relative activities of that drug at and receptors and
the anatomic sites of the vessels affected.
Beta-1 receptors, although beta-2 and to a lesser extent alpha receptors
Beta-receptor activation -- increased calcium influx in cardiac cells
Pacemaker activity, both (SA node) and (Purkinje fibers), are increased
(positive chronotropic effect)
Conduction velocity in the AV node is increased, and the refractory period
Intrinsic contractility is increased (positive inotropic effect),
In the intact heart, intraventricular pressure rises and falls more rapidly,
and ejection time is decreased
• NA (α1, α2, β1 and β3, but not β2 action) : causes rise in
systolic and diastolic BP.
• It does not cause vasodilation (no β2 action), peripheral
resistance increases consistently due to alpha action.
• Isoprenaline (β1 and β2, but not α action): rise in systolic
(β1) but marked fall in diastolic (β2) BP.
• Adrenaline or Epinephrine (α1, α2, β1 and β2 but weak β3 action)
Given by slow i.v. infusion or s.c. injection causes rise in systolic
but fall in diastolic BP (β2 receptors are more sensitive than α
• Pulse pressure is increased.
• Rapid i.v. inj. of Adr. Produces a marked increase in both
systolic and diastolic BP (at high conc α response predominates
and vasoconstriction occurs)
Blood vessels of the upper respiratory tract
mucosa contain α receptors; the
decongestant action of adrenoceptor
stimulants is clinically useful.
Relaxation of gastrointestinal smooth muscle (α and
Bladder (urinary continence):-
Detrusor is relax (β) and trigone is constricted (α)
(Urethral pressure normally exceeds bladder pressure, resulting in urine remaining in the
Uterus : nonpregnant (contraction), pregnant
(relaxation at term only)
• Epinephrine is a potent stimulant of both α-
andβ-adrenergic receptor ,and its effects on
target organs are thus complex.
• Particularly prominent are the actions on
the heart and on vascular and other
1.Bioavailability is poor with oral administration
1) Absorption is poor because of the vasoconstriction of
Ad acting on α-adrenergic receptor and rapidly
metabolism in digestive tract.
2) The first pass effect of the drug is patent (obvious).
2. Absorption is slow with subcutaneous injection
because Ad acts on α-adrenergic receptor in
subcutis and leads vasoconstriction.
3. Absorption is rapid with intramuscular injection
because Ad acts on β-adrenergic receptor in
skeletal muscle and leads vasodilatation.
4. In emergencies,it may be necessary in some cases
to administer Ad intravenously.
5. When relatively concentrated solution (1%) are
nebulized and inhaled, the action of the drug largely
are restricted to the respiratory tract ;
However,systemic such as arrhythmias may occur,
particularly if larger amounts are used.
6. Ad is rapidly inactivated in the body .
The liver, which is rich in both of the enzymes responsible for
destroying circulating Ad (COMT and MAO),is particularly important in
this regard .
Although only small amounts appear in the urine of normal persons, the
urine of patients with pheochromocytoma may contain relatively large
amounts of epinephrine , norepinephrine, and their metabolites.
Direct effects on the heart are determined largely by β1receptors.
• In intact heart , intraventricular pressure rises and falls more rapidly and
ejection time is decreased.
(1) contractility(β1) ↑;
(2) heart rate (predominantly β1) ↑;
(3)stroke volume ↑;
(4) cardiac output↑.
- Increase myocardium oxygen consumption,
- Systolic and diastolic BP↑.
2) Blood vessels: (cutaneous and mucous
• Skin vessels have predominantly alpha receptors and
constrict in the presence of epinephrine .
• Small arteriol , precapillary sphincter , vessel constriction.
• The effect on vein and artery is weak .
• Ad combines with β2 receptors, then promote smooth
•For splanchnic vessels (α, β) Ad constricts renal and
mesenteric blood vessels, the effect on cerebral and
pulmonary blood vessels are weak.
•In vivo coronary artery vessels dilate.
3) Blood Pressure:
Ad is one of the most potent vasopressor drugs known.
If a pharmacological dose is given rapidly by an intravenous route, it
evokes a characteristric effect on blood pressure, which rises rapidly to a
peak that is proportional to the dose.
The increase in systolic pressure is greater than the increase in
diastolic pressure, so that the pulse pressure increases.
2. Smooth muscle :
The effect of Ad on the smooth muscles of
different organs and systems depend on the type
of adrenergic receptor in the muscle.
Bronchial smooth muscle: relaxation ,
due to stimulating beta2-adrenergic receptors .
Gastrointestinal smooth muscle:
• Relaxation of gastrointestinal smooth muscle
• The responses of uterine muscle to Ad vary with
species, phase of the sexual cycle ,state of gestation,
and dose given.
• During the last month of pregnancy and at parturition,
Ad inhibits uterine tone and contraction.
• Ad relaxes the detrusor muscle of the bladder as a result of activation
of β receptors and contracts the trigone and sphincter muscles owing
to its α-agonist activity.
• This can result in hesitancy in urination and may contribute to
retention of urine in the bladder .
• Activation of smooth muscle contraction in the prostate promotes
Increase metabolism, activation βreceptors in
fat cells leads to increased lipolysis.
β activates glycogenolysis (liver), inhibit the
secretion of insulin , ↑ blood glucose.
1. Cardiac arrest:
Cardiac arrest induced by drowning, intoxication of
CNS inhibitors, anaesthesia, acute infectious disease .
Intraventricle injection, cardiopulmonary resuscitation.
Anaphylactic shock and related immediate (type 1)
IgE-mediated reactions affect both the respiratory and the
3. Bronchial asthma:
Relaxation of bronchial muscle and inhibition the secretion of
histamine and leukotriene from tissues and mast cells.
4. Local application :
Use with local anaesthesia to constrict the regional blood
vessles for reducing mucous membrane congestion.
epistaxis, gingival bleeding.
Restlessness , anxiety, tremor, and insomnia ,
palpitation, sweating .
Very high dose: severe headache , BP↑, the
danger of cerebral hemorrhage, arrhythmia,
•Sclerosis of cerebral artery,
•Ischemic heart disease,
•Congestive heart failure,
•Use with care for old patients.
Ephedrine is a naturally occurring alkaloid extracted
from Chinese herb, that can cross the blood-brain
barrier and thus exert a strong CNS-stimulating effect
in addition to its peripheral actions.
It has direct effect on αand βreceptors and enhances
the release of NA from adrenergic nerve endings.
It activates αand βreceptors .
It has both direct and indirect
1) . It causes the release of NA from
storage in nerve terminals.
2) . It also produces direct stimulation of
High bioavailability and a relatively long duration of
It is absorbed when taken orally, and it is resistant
to COMT and MAO, so that its action is prolonged.
Ephedrine increases systolic and diastolic blood pressure;
heart rate is generally not increased.
• Ephedrine activates β1 receptor of heart , increase heart
contractility and increase cardiac output.
• Compensatory vagus reflex tends to decrease heart rate.
Ephedrine produces bronchial smooth muscle relaxation of
prolonged duration when administered orally.
Aside from pupillary dilation, ephedrine has little effect on
It causes CNS stimulation, which can result in effects such
as insomnia, nervousness, nausea.
Ephedrine is useful in relieving bronchoconstriction and
mucosal congestion associated with bronchial asthma,
asthmatic bronchitis, chronic bronchitis, and bronchial
It is often used prophylactically to prevent asthmatic
attacks and is used as a nasal decongestant, as a mydriatic,
and in certain allergic disorders.
Although its bronchodilator action is weaker than that of
isoprenaline , its oral effectiveness and prolonged duration of
action make it valuable in the treatment of these conditions.
• Pressor agent: prevent hypotension induced by epidural
anaesthesia or subarachnoid anaesthesia.
Symptoms of overdose are related primarily to
Cardiac and CNS effects.
Tachycardia, insomnia, nervousness, nausea,
vomiting, and emotional disturbances may develop.
Ephedrine should not be used in patients with
cardiac disease, hypertension, or hyperthyroidism.
Dopamine (DA )3,4-dihydroxyphenylethylamine
Dopamine is a naturally occurring catecholamine.
it is the immediate biochemical precursor of the
norepinephrine found in adrenergic neurons and the
It is also a neurotransmitter in the CNS, where it is
released from dopaminergic neurons to act on specific
• It is metabolized by COMT and MAO.
• Intravenous infusion, no effect on CNS,
does not penetrate blood brain barrier.
Dopamine can stimulate D, αand βreceptors .
Dopamine causes an increase of cardiac contractility.
It also causes the release of NA from nerve endings, which
contributes to its effects on the heart, vasoconstriction.
The effect on Dopamine receptor of kidney ,and mesentery
induces dilation of renal and mesenteric blood vessels.
Infusion of low dose of dopamine causes an increase in
glomerular filtration rate, renal blood flow and Na+ excretion.
Large dosage of Dopamine activates α-receptor , leading to renal
Some types of shock: cardiogenic and septic shock,
hemorrhagic BP shock, especially with cardiac
dysfunction, oliguria or anuria.
Dopamine and diuretics to treat acute renal
If infused very fast, it may induce tachycardia,
arrhythmia, headache and hypertension.
α- adrenoceptor agonists
( Noradrenaline, NA )
The pharmacological actions of NE and Epi are
approximately equipotent in stimulating b1 receptors.
They differ mainly in their effectiveness in stimulating
α and β2 receptors.
It has very strong αreceptor activating effect, has
effect on β1 receptor .
NE has relatively little effect on β2 receptor .
ABSORPTION, FATE, AND EXCRETION
NE, like Epi, is ineffective when given orally and is
absorbed poorly from sites of subcutaneous injection.
It is rapidly inactivated in the body by uptake and the
actions of COMT and MAO.
Small amounts normally are found in the urine.
The excretion rate may be greatly increased in
patients with pheochromocytoma.
The effects of norepinephrine on cardiac function are complex
because of the dynamic interaction of the direct effects of
norepinephrine on the heart and the initiation of powerful
The net effect of norepinephrine administration on heart rate
and ventricular contractile force therefore varies with the
Dose of norepinephrine,
Physical activity of the subject,
Any prior cardiovascular and baroreceptor pathology,
Presence of other drugs that may alter reflexes.
Hypotension : for patients with critical hypotension.
It is given intravenously and acts on both α1 and
α2 adrenergic receptors to cause vasoconstriction.
To treat patients in vasodilatory shock states such
as septic shock and neurogenic shock,
Hemorrhage of Upper digestive tract:
Orally : It contricts blood vessels of esophagus and
NA can cause:
Headache and cerebral hemorrhage from the
Pulmonary edema from pulmonary hypertension;
Renal insufficiency from decrease of renal blood
Local necrosis because leakage of NA from blood
α1 receptor selective adrenergic agonist, as such, it
causes a dose- related increase in peripheral vascular
No effect on β receptors.
The major cardiovascular response to the drug is a
rise in blood pressure, which is associated with reflex
bradycardia because of activation of vagal reflexes.
Used to treat hypotensive states.
α1 receptor agonist ； it activates βreceptors only at
much higher concentration.
Phenylephrine is commonly used as anasal decongestant,
although occasional nasal mucosal damage has occurred
from injudicious use of the nasal spray.
It is also employed in ophthalmology as a mydriatic agent.
Phenylephrine, however, should not be given to patients
with closed-angle glaucoma before iridectomy, since
further increases in intraocular pressure may result.
In dentistry, phenylephrine is used to prolong the
effectiveness of a local anesthetic.
Isoproterenol is readily absorbed when given
parenterally or as an aerosol.
It is metabolized primarily in the liver and other tissues
Isoproterenol is a relatively poor substrate for MAO and
is not taken up by sympthetic neurons to the same
extent as are epinephrine and norepinephrine.
The duration of action of Isoproterenol therefore may be
longer than that of epinephrine, but it still is brief.
β1,β2 receptors strong agonist. Little effect on αreceptors.
Intravenous infusion of Isoproterenol lowers peripheral vascular
resistance, primarily skeletal muscle but also in renal and mesenteric
Diastolic pressure falls.
Systolic blood pressure may remain unchanged or rise, although mean
arterial pressure typically falls.
Cardiac output is increased because of the positive inotropic and
The cardiac effects of Isoproterenol may lead to palpitations, sinus
tachycardia and more serious arrhythmias.
Bronchial smooth muscle:
β2 receptor: Relaxation of bronchial muscle, stronger than
Its effects in asthma may be due in part to an additional action
to inhibit antigen –induced release of histamine and other
mediators of inflammation.
Activates βreceptors, enhances glycogenolysis, accelerates the
breakdown of triglycerides to form fatty acid and glycerol,
increases oxygen consumption.
1. Cardiac arrest, heart block( to increase heart rate)
Palpitation, tachycardia, headache and flushed skin are common.
1. It is a direct β1 receptor agonist, and has relatively more prominent
inotropic effects on the heart compared to Isoproterenol, and has a greater
inotropic than chronotropic effect, increase cardiac contractility, cardiac
output, without increase of heart rate.
2. It is used to treat congestive heart failure, acute myocardial infarction.
3. Side effects are BP↑and heart rate↑, arrhythmias.
1. The β2 –selective adrenergic receptor agonist
has a relaxing effect on bronchial smooth muscle
and show little effect on cardiac β1 receptors.
2. It is used for treatment of bronchospasmwith lack
of cardiac stimulation.
• β2-receptor agonist, Orally, inhalation.
•After inhalation, its action may persist for 3~6
•Used in bronchial asthma.
Prazosin is much more potent in blocking α1 than α2 receptors
and is termed α1-selective.
Whereas Yohimbin is α2-selective;
Phentolamine has similar affinities for both of these receptor
Phenoxybenzamin is an irreversible antagonist that binds
covalently to α-adrenergic receptors.
Since blockade of a1 receptors inhibits vasoconstriction,
Pressor responses to adrenaline may be transformed
to vasodepressor effects (adrenaline "reversal") because
of residual stimulation of b2 receptors in the vasculature
with resultant vasodilation.
Alpha adrenergic blocking
1. Nonequilibrium type : Phenoxybenzamine
2. Equilibrium type (competitive)
A. Nonselective : Ergotamine, Ergotoxine,
Dihydroergotamine (DHE), Dihydroergotoxine,
tolazoline, Phentolamine, chlorpromazine
B. Alpha 1 selective : Prazosin, Terazosin,Doxazosin,
C. Alpha 2 selective : Yohimbine
General effects of alpha blockers
1. Fall in BP (vasodilatation)
2. Tachycardia : fall in BP leads to stimulation of
vasomotor centre and withdrawal of vagal tonic
discharge ------ tachycardia
3. Urinary outflow : tone of smooth muscle in bladder
trigone, sphincter and prostate is reduced by
blockade of alpha 1 receptors ------ urine flow in
patients with BPH is improved.
4. GIT : intestinal motility is increased and relaxation of
sphincter --- diarrhoea
5. Postural hypotension : normally, when a person stands up, a
large volume of blood (700ml in 70 kg man) is pooled in the veins
of lower limb due to gravity --- this causes reduction of cardiac
output -- cerebral ischemia and fainting should therefore develop
in every person on standing.
But this does not happen because of compensatory mechanism:
due to reduction of cardiac out put, BP, falls ---- therefore, via
sinu aortic mechanism (baroreceptor reflex), the vasomotor center
is stimulated ---- sympathetic system activated ---- venomotor
tone, via alpha 1 receptors, increased --- venous return to heart
restored ------ cardiac output restored.
Therefore, alpha blocking should lead to postural hypotension.
Conclusion : alpha 1 blockers should cause : fall of BP, postural
6. Nasal stuffiness : vasodilatation (due
to alpha 1 blocking) of nasal mucosal
blood vessels may produce swelling
of the nasal mucosa --- nasal
7. Impotence : alpha blockers can
Alpha -RECEPTOR BLOCKING
The clinically important alpha-blockers fall primarily into
three chemical groups:
Haloalkylamines ( e.g. phenoxybenzamine),
Imidazolines (e.g., phentolamine),
Quinazoline derivatives (e.g. prazosin).
Of these three classes of a-adrenoceptor antagonists, the
quinazoline compounds are of greatest clinical utility.
The use of the haloalkylamines and imidazolines has
diminished in recent years because they lack selectivity for
a1- and a2-receptors.
Non selective blockers
Blocks both alpha 1 and presynaptic alpha 2
PBZ causes a progressive decrease in peripheral
resistance, an increase in cardiac output (due,in
part, to reflex sympathetic nerve stimulation),
Tachycardia accentuated by enhanced release of NE
(due to a2 blockade),
A major use of PBZ is in the treatment of
PBZ is almost always used to treat the patient in preparation
for surgical removal of the tumor.
Major side effects : postural hypotension, palpitation,
nasal blockage, inhibition of ejaculation.
Pharmacokinetics : oral, im and sc inj. Is painful,
excreted in urine in 24 hrs.
Dose : 20-60 mg oral, 1mg/kg slow iv infusion, on rapid iv inj.
Cause nausea and vomiting (lipid soluble, cross BBB)
Rapidly acting alpha blocker with short duration of
Blocks both alpha 1 and 2 receptors
Uses : Phentolamine can be used in short-term
control of hypertension in patients with
Dose : 5 mg iv (10mg/ml)
Tolazoline : similar to phentolamine and less potent.
Also blocks histamine
Alpha 1 selective
Prazosin : highly selective alpha 1 blockers
Fall in BP (venodilatation is much less than arteriolar
dilatation). Because of lack alpha 2 antagonism, tachycardia
is only mild.
Effective orally (bioavailability 60%), highly bound to
plasma protein, metabolized in liver and excreted in bile,
plasma half life 2-3 hours, effect of a single dose lasts for 6-
Uses : antihypertensive, BPH (improve urine flow)
Dose : 0.5, 1, 2 mg tab, start with 0.5 – 1 mg at bed time
Prazosin can cause “first dose effect” ie, postural
hypotension is less marked, dizziness and fainting can
develop after 1st
dose, but if the drug is persistent,
Therefore, the rule is,
1. Very low dose at first
2. Administered at night
3. The patient should be warned of the first dose effect.
Chemically and pharmacologically similar to prazosin;
differences are higher biovailability (90%) and longer
plasma half life (12 hrs), a single dose lowers BP over 24
Uses : BPH (popular for use), antihypertensive
Dose : 1, 2 and 5 mg (2-10 mg od)
Doxazosin : longer acting (t1/2 18 hrs), used in HTN and
BPH, dose : 1, 2 , 4 mg (1 mg od)
Uses of alpha blockers
1. Chronic hypertension (alpha 1 selective, less postural
hypotension than others)
2. Hypertensive emergencies
3. Benign prostatic hypertrophy (BPH)
4. Pheochromocytoma (excess CAs are secreted which can
cause intermittent or persistent HTN)
First generation (nonselective) :
Propanolol, Timolol, Sotalol, Pindolol
Second generation (beta1 selective) :
Metoprolol, Atenolol, Acebutolol, Bisoprolol, Esmolol
Third generation (with additional
alpha blocking and / or vasodilator
Labetalol, Carvedilol, Nebivolol
Beta adrenergic blocking drugs
Pharmacological Actions :
The most important actions of the beta-blocking drugs
are on the cardiovascular system:
Beta-Blockers decrease heart rate, myocardial
contractility, cardiac output, and conduction velocity
within the heart.
These effects are most pronounced when sympathetic
activity is high or when the heart is stimulated by
The actions of beta-blockers on blood pressure are
After acute administration, blood pressure is only
This is because of the compensatory reflex increase in
peripheral vascular resistance that results from a
beta-blocker–induced decrease in cardiac output.
Chronic administration of beta-blockers, however,
results in a reduction of blood pressure, and this is
the reason for their use in primary hypertension.
The mechanism of this effect is not well
understood, but it may include such actions
Reduction in renin release,
Antagonism of beta-receptors in the central
nervous system, or
Antagonism of presynaptic facilitatory beta-
receptors on sympathetic nerves.
Are useful for the prophylactic treatment of angina
pectoris, The chief benefit of the beta-blockers in this
condition derives from their ability to decrease cardiac
work and oxygen demand.
The release of Renin from the juxtaglomerular cells
of the kidney is to be regulated by beta-receptors;
most beta-blockers decrease renin release.
The glycogenolytic and lipolytic actions of
endogenous catecholamines are mediated by beta-
receptors and are subject to blockade by beta-
Beta-blocker increases airway resistance by
Although the resulting bronchoconstriction is not a
great concern in patients with normal lung function, it
can be quite serious in the asthmatic.
The cardioselective beta-blockers produce less
bronchoconstriction than do the non-selective
The beta-receptor blocking agents have widespread
and important uses in the management of cardiac
arrhythmias, angina pectoris, and hypertension.
The beta-blockers also offer proven benefit in
preventing the recurrence of a myocardial infarction
For this purpose, it is best if beta-blocker therapy is
instituted soon after the MI and continued for the long
The beta-blockers significantly reduce the peripheral manifestations of
hyperthyroidism, particularly elevated heart rate, increased cardiac
output , and muscle tremors.
The peripheral manifestations of anxiety may include a number of
symptoms (e.g., palpitations) that are due in part to overactivity of the
sympathetic nervous system.
The beta-blocking agents may offer some benefit in the treatment of
The beta-blockers may offer some value in the prophylaxisof migraine
headache, possibly because a blockade ofcraniovascular beta-receptors
results in reduced vasodilation.
1. CVS :
a) Bradycardia (beta1 blocking effect on SA node, AV node and
b) Fall of cardiac output (fall of contractility of myocardium)
c) Prolonged use reduces BP in hypertensives but in
normotensive the BP is not affected): decrease renin release
2. Respiratory tract : bronchoconstriction (worsened and a
severe attack may be precipitated)
3. CNS : high doses : forgetfulness, increased dreaming and
nightmares. Low dose : suppresses anxiety
4. Local anaesthetic : potent local anaesthetic but
not used because of its irritant property
5. Metabolic : inhibits lipolysis and glycogenolysis
6. Skeletal muscle : inhibits adrenergically tremor.
Absorption: Well absorbed but undergoes
extensive first-pass hepatic metabolism.
Distribution: CNS penetration. Crosses the
placenta; enters breast milk.
Protein Binding: 93%.
Metabolism/Excretion: Almost completely
metabolized by the liver.
Half-life: 3.4–6 hr.
Reversible airways disease, particularly asthma or
chronic obstructive pulmonary disease (COPD)
Bradycardia (<60 beats/minute)
Atrioventricular block (second or third degree)
Uncontrolled congestive heart failure
Others beta blockers
Cardioselective (beta 1) : more potent in blocking cardiac
(beta 1) than bronchial (beta 2) receptors.
There features :
1. Lower tendency to cause bronchoconstriction, but even these
drugs should be avoided, if possible, in asthmatics.
2. Less interference with carbohydrate metabolism and less
inhibition of glycogenolysis during hypoglycaemia – safer in
3. No/ less harmful effect on blood lipid profile
Prototype of cardioselective (beta 1) blockers
Less likely to worsen asthma, but is not entirely safe
First pass metabolism of metoprolol is less than
propraonolol, but 90% or more is ultimately metabolized
Side effects : milder
Given orally, but iv inj. (5-15mg) has been used in MI
Selective beta 1 blocker having low lipid solubility
Incompletely absorbed orally and longer duration of
Most commonly used beta blocker for HTN and angina
Dose : 25, 50 and 100 mg tab (12.5 – 50 mg od)
Alpha and beta adrenergic
5 times more potent in blocking beta than alpha
Fall in BP (both systolic and diastolic) is due to
alpha 1 and beta 1 blockade as well as beta 2
Essential hypertension or idiopathic
Postural hypotension (common)
Failure of ejaculation
It is β1 + β2 + α1 adrenoceptor blocker,
Produce vasodilatation due to alpha 1 blockade and
has antioxidant property (functional inhibitor of acid
Used in HTN and is the beta blocker especially
employed as cardioprotective in CHF.
Bioavailability – 30 %
Plasma half life 6-8 hrs