Adrenergic System

Dr. D. K. Brahma
Department of Pharmacology
NEIGRIHMS, Shillong, Meghalaya

Neurotransmission in ANS

Noradrenergic transmission

Nor-adrenaline is the major

neurotransmitter of the
Sympathetic system
Noradrenergic neurons are
postganglionic sympathetic
neurons with cell bodies in
the sympathetic ganglia
They have long axons
which end in varicosities
where NA is synthesized
and stored

Adrenergic transmission
Catecholamines:
Natural: Adrenaline, Noradrenaline, Dopamine
Synthetic: Isoprenaline, Dobutamine
Non-Catecholamines:

Ephedrine, Amphetamines, Phenylepherine, Methoxamine,

Mephentermine

Also called sympathomimetic amines as most of them

contain an intact or partially substituted amino (NH2)
group

 Catecholamines:

Compounds containing
a catechol nucleus
(Benzene ring with 2
adjacent OH groups)
and an amine
containing side chain
Non-catecholamines
lack hydroxyl (OH)
group

Biosynthesis of
Catecholamines
Phenylalanine
PH

Alpha-methyl-ptyrosine

Rate limiting Enzyme

5-HT, alpha Methyldopa

Storage of Noradrenaline

Release of NA Feedback Control

Regulators of NA release

Uptake of Catecholamines

Reuptake

Sympathetic nerves take up amines and release

them as neurotransmitters
Uptake I is a high efficiency system more specific
for NA

Located in neuronal membrane

Inhibited by Cocaine, TCAD, Amphetamines

Uptake 2 is less specific for NA

Located in smooth muscle/ cardiac muscle

Inhibited by steroids/ phenoxybenzamine
No Physiological or Pharmacological importance

Metabolism of CAs
Mono

Amine Oxidase (MAO)

Intracellular bound to mitochondrial membrane

Present in NA terminals and liver/ intestine
MAO inhibitors are used as antidepressants

Catechol-o-methyl-transferase

(COMT)

Neuronal and non-neuronal tissue

Acts on catecholamines and byproducts
VMA levels are diagnostic for tumours

Metabolism of CAs

(Homovanillic acid)

(Vanillylmandelic acid)

Adrenergic neurotransmission

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Adrenergic Receptors

Adrenergic receptors (or adrenoceptors) are a class of Gprotein coupled receptors that are the target of catecholamines
Adrenergic receptors specifically bind their endogenous ligands
catecholamines (adrenaline and noradrenline)
Increase or decrease of 2nd messengers cAMP or IP3/DAG
Many cells possess these receptors, and the binding of an
agonist will generally cause the cell to respond in a flight-fight
manner.
For instance, the heart will start beating quicker and the pupils
will dilate

How Many of them ????

Adenoreceptors

Alpha ()

Beta ()

2A 2B 2C
1A

1B

1D

Differences - Adrenergic
Receptors ( and ) !
Alpha

() and Beta ()
Agonist affinity of alpha ():

adrenaline > noradrenaline > isoprenaline

Antagonist: Phenoxybenzamine
IP3/DAG, cAMP and K+ channel opening

Agonist affinity of beta ():

isoprenaline > adrenaline > noradrenaline

Propranolol
cAMP and Ca+ channel opening

Potency of catecholamines on
Adrenergic Receptors
Aortic strip contraction

Adr

Bronchial relaxation
NA

Iso

Adr

NA
Iso

Log Concentration

Molecular Effector Differences

- Vs

Receptors:
IP3/DAG
cAMP
K+ channel opening

Receptors:
cAMP
Ca+ channel opening

Recall: Adenylyl cyclase: cAMP

pathway
PKA alters the functions of many
Enzymes, ion channels,
transporters
and structural proteins.

Other
Functional
proteins

PKA
Troponin
Cardiac
contractility

Increased
Interaction with
Ca++

Phospholamban

Faster sequestration of
Ca++ in SR

Faster
relaxation

Also Recall: Phospholipase C:

IP3-DAG pathway

PKc

Beta receptors

All receptors activate adenylate cyclase, raising the intracellular cAMP

concentration
Type 1:

Type 2:

These are present in heart tissue, and cause an increased heart rate by
acting on the cardiac pacemaker cells
These are in the vessels of skeletal muscle, and cause vasodilatation, which
allows more blood to flow to the muscles, and reduce total peripheral
resistance
Beta-2 receptors are also present in bronchial smooth muscle, and cause
bronchodilatation when activated
Stimulated by adrenaline, but not noradrenaline
Bronchodilator salbutamol work by binding to and stimulating the 2
receptors

Type 3:

Beta-3 receptors are present in adipose tissue and are thought to have a
role in the regulation of lipid metabolism

Differences between 1, 2 and 3

Beta-1

Beta-2

Location

Heart and JG cells

Bronchi, uterus,
Blood vessels,
liver, urinary tract,
eye

Adipose
tissue

Agonist

Dobutamine

Salbutamol

Antagonist

Metoprolol, Atenolol Alpha-methyl

propranolol

Action on
NA

Moderate

Strong

Weak

Beta-3

Clinical Effects of -receptor

stimulation

1: Adrenaline, NA and Isoprenaline:

2: Adrenaline and Isoprenaline (not NA)

Bronchi Relaxation
SM of Arterioles (skeletal Muscle) Dilatation
Uterus Relaxation
Skeletal Muscle Tremor
Hypokalaemia
Hepatic Glycogenolysis and hyperlactiacidemia
3: Increased Plasma free fatty acid increased O2 consumption increased heat production

Tachycardia
Increased myocardial contractility
Increased Lipolysis
Increased Renin Release

Adrenergic receptors - alpha

Type 1

Blood vessels with alpha-1 receptors are present in the

skin and the genitourinary system, and during the fight-orflight response there is decreased blood flow to these
organs
Acts by phospholipase C activation, which forms IP3 and
DAG
In blood vessels these cause vasoconstriction

Type 2

These are found on pre-synaptic nerve terminals

Acts by inactivation of adenylate cyclase, cyclic AMP levels
within the cell decrease (cAMP)

Differences between 1 and 2

Alpha-1

Alpha-2

Location

Post junctional blood vessels Prejunctional

of skin and mucous
membrane, Pilomotor muscle
& sweat gland, radial muscles
of Iris

Function

Stimulatory GU,
Vasoconstriction, gland
secretion, Gut relaxation,
Glycogenolysis

Inhibition of transmitter
release, vasoconstriction,
decreased central symp.
Outflow, platelet
aggregation

Agonist

Phenylephrine, Methoxamine

Clonidine

Antagonist

Prazosin

Yohimbine

1 adrenoceptors
Clinical effects

Eye -- Mydriasis
Arterioles Constriction (rise in BP)
Uterus -- Contraction
Skin -- Sweat
Platelet - Aggregation
Male ejaculation
Hyperkalaemia
Bladder Contraction
2 adrenoceptors on nerve endings mediate negative
feedback which inhibits noradrenaline release

Molecular Basis of Adrenergic

Receptors

Also glycogenolysis
in liver

Inhibition of
Insulin
release and
Platelet
aggregation
Gluconeogen
esis

Dopamine receptors
D1-receptors

are post synaptic receptors

located in blood vessels and CNS

D2-receptors

are presynaptic present in CNS,

ganglia, renal cortex

Summary of agents modifying

adrenergic transmission
Step

Actions

Drug

Synthesis of NA

Inhibition

- methyl-p-tyrosine

Axonal uptake

Block

Cocaine, guanethidine,
ephedrine

Vesicular uptake

Block

Reserpine

Vesicular NA

Displacement

Guanethidine

Membrane NA pool

Exchange diffusion

Tyramine, Ephedrine

Metabolism

MAO-A inhibition
MAO-B inhibition
COMT inhibition

Moclobemide
Selegiline
Tolcapone

Receptors

1
2
1 + 2
1

Prazosin
Yohimbine
Propranolol
Metoprolol

Adrenaline as prototype
Potent

stimulant of alpha and beta receptors

Complex actions on target organs

Heart

Beta-1 mediated action - Powerful Cardiac stimulant - +ve

chronotropic, +ve inotropic
Acts on beta-1 receptors in myocardium, pacemaker cells and
conducting tissue

Heart rate increases by increasing slow diastolic depolarization of cells in

SAN
High doses cause marked rise in heart rate and BP causing reflex
depression of SAN unmasking of latent pacemaker cells in AVN and PF
arrhythmia (sensitization of arrhythmogenic effects by Halothane)
Cardiac systole is shorter and more powerful
Cardiac output is enhanced and Oxygen consumption is increased
Cardiac efficiency is markedly decreased

Conduction velocity in AVN, atrial muscle fibre, ventricular fibre and

Bundle of His increased benefit in partial AV block

Reduced refractory period in all cardiac cells

Blood Vessels
Seen

mainly in the smaller vessels

arterioles Vasoconstriction (alpha) and
vasodilatation (beta) depends on the drug
Decreased blood flow to skin and mucus
membranes and renal beds alpha effect (1
and 2) Increased blood flow to skeletal muscles,
coronary and liver vessels - (Beta-2 effect)
counterbalanced by a vasoconstrictor effect
of alpha receptors

Blood Pressure
Depends on the Catecholamine involved
NA causes rise in Systolic, diastolic and mean BP
(no beta-2 action) unopposed alpha action
Isoprenaline causes rise in systolic but fall in
diastolic BP mean BP falls (beta-1 and beta-2)
Adr causes rise in systolic BP, but fall in diastolic
BP mean BP generally rises (slow injection)

Decreased peripheral resistance at low conc. Beta

receptors are more sensitive to Adr than alpha
receptors

Blood Pressure contd.

Rapid IV injection of Adrenaline marked rise in

Systolic and diastolic BP

Large concentration alpha action predominates

vasoconstriction even in skeletal muscle

But BP returns to normal in few minutes

A secondary fall in mean BP occurs
Mechanism rapid uptake and dissipation of Adr
at low conc. Alpha action lost but beta action
predominates Dale`s Vasomotor reversal
phenomenon

Dale`s Vasomotor Reversal

Phenomenon

Actions of Adrenaline

Respiratory:
Powerful bronchodilator
Relaxes bronchial smooth muscle (not NA)
Beta-2 mediated effect
Physiological antagonist to mediators of bronchoconstriction
e.g. Histamine
GIT : Relaxation of gut muscles (alpha and beta) and constricted
sphincters reduced peristalsis not clinical importance

Bladder: relaxed detrusor muscle (beta) muscle but constriction of

Trigone both are anti-voiding effect

Uterus: Adr contracts and relaxes Uterus (alpha and beta action) but
net effect depends on status of uterus and species pregnant relaxes
but non-pregnant - contracts

Actions of Adrenaline contd.

Skeletal

Muscle:

Facilitation of Ach release in NM junction (alpha -1)

Beta-2 acts directly on Muscle fibres
Abbreviated active state and less tension in slow
conducting fibres and enhanced muscle spindle firing
tremor
CNS: No visible clinical effect in normal doses as low
penetration except restlessness, apprehension and
tremor

Activation of alpha-2 in CNS decreases sympathetic outflow and

reduction in BP and bradycardia - clonidine

Metabolic effects
Increases concentration of glucose and lactic acid
Calorigenesis (-2 and -3)
Inhibits insulin secretion (-2)
Decreases uptake of glucose by peripheral tissue
Simulates glycogenolysis - Beta effect
Increases free fatty acid concentration in blood
Hypokalaemia initial hyperkalaemia

ADME
All

Catecholamines are ineffective orally

Absorbed slowly from subcutaneous tissue
Faster from IM site
Inhalation is locally effective
Not usually given IV
Rapidly inactivated in Liver by MAO and
COMT

Clinical Question!

Question: A Nurse was injecting a dose of penicillin

to a patient in Medicine ward without prior skin test
and patient suddenly developed immediate
hypersensitivity reactions. What would you do?
Answer: As the patient has developed Anaphylactic
reaction, the only way to resuscitate the patient is
injection of Adrenaline

0.5 mg (0.5 ml of 1:10000) IM and repeat after 5-10 minutes

Antihistaminics: Chlorpheniramine 10 20 mg IM or IV
Hydrocortisone 100 200 mg

Adrenaline Clinical uses

Injectable preparations are available in dilutions

1:1000, 1:10000 and 1:100000
Usual dose is 0.3-0.5 mg sc of 1: 10000 solution
Used in:

Anaphylactic shock
Prolong action of local anaesthetics
Cardiac arrest
Topically, to stop bleeding
Hyperkinetic children ADHD, minimal brain dysfunction
Anorectic

CPR - Image

ADRs
Restlessness,

Throbbing headache, Tremor,

Palpitations
Cerebral hemorrhage, cardiac arrhythmias
Contraindicated in hypertensives,
hyperthyroid and angina poctoris
Halothane and beta-blockers not indicated

Other Adrenergic Drugs

Noradrenaline
Neurotransmitter

released from
postganglionic adrenergic nerve endings
(80%)
Orally ineffective and poor SC absorption
IV administered
Metabolized by MAO, COMT
Short duration of action

Actions and uses

Agonist at 1(predominant), 2 and 1 Adrenergic receptors

Equipotent with Adr on 1, but No effect on 2

Increases systolic, diastolic B.P, mean pressure, pulse pressure

and stroke volume

Total peripheral resistance (TPR) increases due to vasoconstriction -

Pressor agent

Increases coronary blood flow

Decreases blood flow to kidney, liver and skeletal muscles
Uses: Injection Noradrenal bitartrate slow IV infusion at the rate
of 2-4mg/ minute used as a vasopressor agent in treatment of
hypovolemic shock and other hypotensive states in order to raise
B.P

Problems: Down regulation of receptors, Renal Vasoconstriction

Septic and neurogenic shock (?)

Noradrenaline - ADRs
Anxiety,

palpitation, respiratory difficulty

Acute Rise of BP, headache
Extravasations causes necrosis, gangrene
Contracts gravid uterus
Severe hypertension, violent headache,
photophobia, anginal pain, pallor and
sweating in hyperthyroid and hypertensive
patients

Isoprenaline

Catecholamine acting on beta-1 and beta-2 receptors negligible

action on alpha receptor

Main Actions: Fall in Diastolic pressure, Bronchodilatation and

relaxation of Gut
ADME: Not effective orally, sublingual and inhalation (10mg tab. SL)
Overall effect is Cardiac stimulant (beta-1)

Therefore main action on Heart and muscle

vasculature

Increase in SBP but decrease in DBP (beta-2)

Decrease in mean BP

Used as Bronchodilator and for treatment of AV block, Stokes-Adam

Syndrome etc. but not preferred anymore

Adrenaline, NA and
Isoprenaline - Summary

Dopamine
Immediate

metabolic precursor of
Noradrenalin
High concentration in CNS - basal ganglia,
limbic system and hypothalamus and also in
Adrenal medulla
Central neurotransmitter, regulates body
movements ineffective orally, IV use only,
Short T 1/2 (3-5minutes)

Dopamine
MECHANISM:

Agonists at dopaminergic D1, D2 receptors

Agonist at adrenergic 1 and 1

Dopamine

In small doses 2-5 g/kg/minute, it stimulates D1receptors in renal, mesenteric and coronary vessels
leading to vasodilatation (Increase in cAMP)

Recall: Renal vasoconstriction occurs in CVS shock due to

sympathetic over activity

Increases renal blood flow, GFR an causes natriuresis

Interaction with D2 receptors (present in presynaptic adrenergic

neurones) suppression of NA release (no alpha effect)

Dopamine cond.

Moderate dose (5-10 g/kg/minute), stimulates 1receptors in heart producing positive inotropic and
chronotropic actions actions
Releases Noradrenaline from nerves by 1stimulation
Does not change TPR and HR
Great Clinical benefit in CVS shock and CCF
High dose (10-30 g/kg/minute), stimulates vascular
adrenergic 1-receptors (NA release)
vasoconstriction and decreased renal blood flow

Why renal and mesenteric

vasodilatation is useful in Shock?
Increases

renal blood flow, GFR an

causes natriuresis
In CVS shock excessive sympathetic
activity leading to ischemia of gut,
sloughening and entry of Bacteria to
systemic circulation - septicemia

Dobutamine - Derivative of
Dopamine

MOA:
Acts on both alpha and beta receptors but more prominently in beta-1
receptor increase in contractility and CO
Does not act on D1 or D2 receptors No release of NA and thereby
hypertension
Predominantly a beta-1 agonist with weak beta-2 and selective alpha-1
activity
Racemic mixture consisting of both (+) and () isomers - the (+) isomer
is a potent 1 agonist and 1 antagonist, while the () isomer is an 1
agonist
Overall beta-1 activity and weak beta-2 activity
Increase in force of contraction and cardiac output but no change in
heart rate
Uses: Clinically give in dose of 2-8 mcg/kg/min IV infusion in Heart
failure in cardiac surgery, Septic and cardiogenic shock, Congestive Heart
failure
ADRs: Tachycardia, hyperension, angina and fatal arrhythmia

Adrenergic agonists
Selective

Phenylepherine, Ephederine, Methoxamine,

Metaraminol, Mephentermine

Selective

Alpha-2 Agonists:

Clonidine, -methyldopa, Guanfacine and

Guanabenz

-2

Alpha-1 Agonists:

Adrenergic agonists:

Salbutamol, Terbutaline, Salmeterol, Reproterol,

Oxiprenaline, Fenoterol, Isoxsuprine, Rimiterol,
Ritodrine, Bitolterol and Isoetharine

Adrenergic Drugs
Therapeutic Classification

Pressor agents:

Cardiac Stimulants:

Ritodrine, Salbutamol, Isoxsuprine

Anorectics

Isoprenaline, Salbutamol, Salmeterol, Terbutaline, Formeterol

Uterine Relaxants:

Phenylepherine, Xylometazoline, Oxymetazoline, Naphazoline and

Tetrahydrazoline and Phenylpropanolamine and Pseudoephidrine

Bronchodilators:

Adr, Dobutamine and Isoprenaline, Dopexamine

Nasal Decongestants:

NA, Phenylephrine, ephedrine, Methoxamine, Dopamine

Fenfluramine, Dexfenfluramine and Sibutramine

CNS Stimulants:

Amphetamine, Methamphetamine

Ephedrine

Plant alkaloid obtained from Ephedra vulgaris Mixed acting drug

(also metaraminol) effective orally
Crosses BBB and Centrally Increased alertness, anxiety,
insomnia, tremor and nausea in adults. Sleepiness in children
Effects appear slowly but lasts longer (t1/2-4h) 100 times less
potent
Tachyphylaxis on repeated dosing (low neuronal pool)
Used as bronchodilator, mydriatic, in heart block, mucosal
vasoconstriction & in myasthenia gravis
Not used commonly due to non-specific action
Uses: Mild Bronchial asthma, hypotension due to spinal anaesthesia
Available as tablets, nasal drop and injection

Phenylepherine - Selective,
synthetic and direct 1 agonist

Actions qualitatively similar to noradrenaline

Long duration of action
Resistant to MAO and COMT
Does not cross BBB, so no CNS effects
Peripheral vasoconstriction leads to rise in BP but Reflex
bradycardia
Produces mydriasis and nasal decongestion
Use:

hypovolaemic shock as pressor agent

Sinusitis & Rhinitis as nasal decongestant (common in oral preparations)
Mydriatic in the form of eye drops and lowers intraocular pressure

ADRs: Photosensitivity, conjunctival hyperemia and hypersensitivity

Administered parenteraly & topically (eye, nose)

What are Mucosal Decongestants?

Nasal and bronchial decongestants are the drugs used in

allergic rhinitis, colds, coughs and sinusitis as nasal
drops - Sympathomimetic vasoconstrictors with - effects
are used
Drugs: Phenylepherine, xylometazoline, Oxymetazoline,
PPA, Pseudoephidrine etc.
Drawbacks:

Rebound congestion due to overuse

However, mucosal ischaemic damage occurs if used excessively
(more often than 3 hrly) or for prolonged periods (>3weeks)
CNS Toxicity
Failure of antihypertensive therapy
Fatal hypertensive crisis in patients on MAOIs
Use only a few days since longer application reduces ciliary action

Nasal Decongestants

Pseudoephedrine to Ephedrine but less CNS and Cardiac

effects

Poor Bronchodilator

Given in combination with antihistaminics, antitussives and NSAIDs

in common cold and, allergic rhinitis, blocked Eustachian tube etc.
Rise in BP inhypertensives

Phenylpropanolamine (PPA) is similar to ephedrine and used

as decongestants in many cold and cough preparations

Also as weight loosing agent

Xylometazoline, Oxymetazoline etc.

Amphetamine

Synthetic compound similar to Ephedrine Pharmacologically

Known because of its CNS stimulant action psychoactive drug and
also performance enhancing drug
Actions:

alertness, euphoria, talkativeness and increased work capacity fatigue

is allayed (acts on DA and NA neurotransmitters etc. reward pathway)
increased physical performance without fatigue short lasting (Banned
drug and included in the list of drugs of Dope Test) deterioration
occurs
RAS Stimulation wakefulness, sleep deprivation (then physical
disability)

However, anxiety, restlessness, tremor and dysphoria occurs

Other actions: Stimulation of respiratory centre, Hunger

suppression, also anticonvulsant, analgesic and antiemetic actions

Amphetamine contd.

Drug of abuse marked psychological effect but little

physical dependence
Generally, Teenage abusers - thrill or kick
High Dose Euphoria, excitement and may progress to
delirium, hallucination and acute psychotic state

Also peripheral effects like arrhythmia, palpitation, vascular

collapse etc.

Repeated Dose Long term behavioural abnormalities

Starvation acidic urine
Uses: Hyperkinetic Children (ADHD), Narcolepsy,
Epilepsy and Parkinsonism

Anorectics
Drugs

used for suppression of appetite

MOA: Inhibition of NA/DA or 5-HT uptake
enhancement of monoaminergic transmission

NA agents affect the appetite centre and

Serotonergics act on satiety centre

Fenfluramine, dexfenfluramine and

sibutramine ALL ARE BANNED NOW
Reasons: Heart valve defects, fibrosis and
pulmonary hypertension etc.

Clonidine

Centrally acting: Agonist to postsynaptic 2A

adrenoceptors in brain vasomotor centre in
brainstem (presynaptic Ca++ level increased NA
release)

Decrease in BP and cardiac output

Peripherally action: High dose activates peripheral

presynaptic autoreceptors on adrenergic nerve ending
mediating negative feedback suppression of
noradrenaline release
Overdose stimulates peripheral postsynaptic 1
adrenoceptors & cause hypertension by
vasoconstriction

Clonidine contd.

Uses: ADHD in children, opioid withdrawal (restless legs, jitters and

hypertension), alcohol withdrawal (0.3 to 0.6 mg)
Abrupt or gradual withdrawal causes rebound hypertension

Onset may be rapid (a few hours) or delayed for as long as 2 days and
subsides over 2-3 days
Never use beta-blockers to treat

Available as tablets, injections and patches

Sedation, dry mouth, dizziness and constipation etc.
TCAs antagonize antihypertensive action & increase rebound
hypertension of abrupt withdrawal
Low dose Clonidine (50-100g/dl) is used in migraine prophylaxis,
menopausal flushing and chorea
Moxonidine, Rilmenidine Newer Imidazolines

2 Adrenergic Agonists
discussed elsewhere!

Short acting : Salbutamol, Metaproterenol, Terbutaline,

pirbuterol
Selective for 2 receptor subtype
Used for acute inhalational treatment of bronchospasm.
Onset of action within 1 to 5 minutes
Bronchodilatation lasts for 2 to 6 hours
Duration of action longer on oral administration
Directly relax airway smooth muscle
Relieve dyspnoea of asthmatic bronchoconstriction
Long acting: Salmeterol, Bitolterol, colterol

Uterine Relaxants - discussed

elsewhere!

Antioxytocics or tocolytic agents

2 agonists relax uterus
Used by i.v. infusion to inhibit premature labour
Isoxsuprine, Terbutaline, Ritodrine, Salbutamol
Tachycardia & hypotension occur
Use minimum fluid volume using 5% dextrose as
diluents
Ritodrine: 50 g/min, increase by 50 g/min every
10 minutes until contractions stop or maternal heart
rate is 140 beats/minute. Continue for 12-48 hours
after contractions stop

Remember ?
Steps

of Biosynthesis of Catecholamine
Distribution of adrenergic receptors
Individual Functions of Adrenergic receptors
All aspects of adrenaline Dale`s
Phenomenon
Dopamine/Dobutamine actions
Nasal decongestants - Phenylephrine
Amphetamine and Clonidine - Desirable

/Khublei