Adrenergic System

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
5-HT, alpha Methyldopa
Rate limiting Enzyme

Storage of Noradrenaline

NORADRENALINE RELEASE
• Transmitter release occurs normally by Ca2+
the
mediated exocytosis from varicosities on
terminal network.
• Non-exocytotic release occurs in
sympathomimetic drugs
response to
(e.g.
which displace nor adrenaline from
indirectly acting
amphetamine),
vesicles.
escapes via the NET transporter
• Noradrenaline
(reverse transport).
• Transmitter action is terminated mainly by
reuptake of nor adrenaline into nerve terminals via
• Nor adrenaline with ATP are released by exocytosis.

Feedback control of noradrenaline (NA) release.
The
presynapti
c
α2 receptor
Ca+2
inhibits
influx in
response to
membrane
depolarisation
via an
action of the
βγ subunits
of the
associated G
protein on
the voltage-
dependent

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

Adrenergic Receptors

How Many of them ????
Alpha (α) Beta (β)
Adenoreceptors
α 1
β3
β2
β1
α2
α2B α2C
α2A
α1A α1B α1D

Differences - Adrenergic
Receptors (α and β) !
Alpha (α) and Beta (β)
Agonist affinity of alpha (α):
adrenaline > noradrenaline > isoprenaline
Antagonist: Phenoxybenzamine
IP3/DAG, cAMP and K+ channel opening
Agonist affinity of beta (β):
isoprenaline > adrenaline > noradrenaline
Propranolol
cAMP and Ca+ channel opening

Molecular Effector Differences
- α Vs β
α Receptors:
IP3/DAG
cAMP
K+ channel opening
β Receptors:
cAMP
Ca+ channel opening

Beta receptors
All β receptors activate adenylate cyclase, raising the intracellular cAMP
concentration
Type β1:
These are present in heart tissue, and cause an increased heart rate by
acting on the cardiac pacemaker cells
Type β2:
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 β2
receptors
Type β3:
Beta-3 receptors are present in adipose tissue and are thought to have a
role in the regulation of lipid metabolism

Differences between β1, β2 and β3
Location
Beta-1
Heart and JG cells
Beta-3
Adipose
tissue
Agonist
Antagonist
Dobutamine
Metoprolol, Atenolol
Beta-2
Bronchi, uterus,
Blood vessels,
liver, urinary tract,
eye
Salbutamol
Alpha-methyl
propranolol
-
-
Action on
NA
Moderate Weak Strong

Clinical Effects of β-receptor
stimulation
β1: Adrenaline, NA and Isoprenaline:
Tachycardia
Increased myocardial contractility
Increased Lipolysis
Increased Renin Release
β2: Adrenaline and Isoprenaline (not NA)
Bronchi – Relaxation
SM of Arterioles (skeletal Muscle) – Dilatation
Uterus – Relaxation
Skeletal Muscle – Tremor
Hypokalaemia
Hepatic Glycogenolysis and hyperlactiacidemia
β3: Increased Plasma free fatty acid – increased O2 consumption -
increased heat production

Adrenergic receptors - alpha
Typeα1
Blood vessels with alpha-1 receptors are present in the
skin and the genitourinary system, and during the fight-or-
flight 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 α2
These are found on pre-synaptic nerve terminals
Acts by inactivation of adenylate cyclase, cyclic AMP levels
within the cell decrease (cAMP)

Differences between α1 and α2
Location
Alpha-2
Prejunctional
Function
Alpha-1
Post junctional – blood vessels
of skin and mucous
membrane, Pilomotor muscle
& sweat gland, radial muscles
of Iris
Stimulatory – GU,
Vasoconstriction, gland
secretion, Gut relaxation,
Glycogenolysis
Agonist
Antagonist
Phenylephrine, Methoxamine
Prazosin
Inhibition of transmitter
release, vasoconstriction,
decreased central symp.
Outflow, platelet
aggregation
Clonidine
Yohimbine

Dopamine receptors
D1-receptors are post synaptic receptors
located in blood vessels and CNS
D2-receptors are presynaptic present in CNS,
ganglia, renal cortex

Adrenaline as prototype
Potent stimulant of alpha and beta receptors
Complex actions on target organs

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

Metabolic effects
Increases concentration of glucose and lactic
acid
Decreases uptake of glucose by peripheral
tissue
Simulates glycogenolysis - Beta effect
Increases free fatty acid concentration in blood

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

ADRs
Restlessness, Throbbing headache, Tremor,
Palpitations
Cerebral hemorrhage, cardiac arrhythmias
Contraindicated in hypertensives,
hyperthyroid and angina poctoris

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 α1(predominant), α2 and β1 Adrenergic receptors
Equipotent with Adr on β1, but No effect on β2
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
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

Noradrenaline - ADRs
Anxiety, palpitation, respiratory difficulty
Acute Rise of BP, headache
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
Therefore main action on Heart and muscle
vasculature
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)

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)

Adrenergic agonists
Selective Alpha-1 Agonists:
Phenylepherine, Ephederine, Methoxamine,
Metaraminol, Mephentermine
Selective Alpha-2 Agonists:
Clonidine, α-methyldopa, Guanfacine and
Guanabenz
Β-2 Adrenergic agonists:
Salbutamol, Terbutaline, Salmeterol,
Reproterol, Oxiprenaline, Fenoterol,
Isoxsuprine, Rimiterol, Ritodrine, Bitolterol and
Isoetharine

Adrenergic Drugs –
Therapeutic Classification
Pressor agents:
NA, Phenylephrine, ephedrine, Methoxamine, Dopamine
Cardiac Stimulants:
Adr, Dobutamine and Isoprenaline, Dopexamine
Nasal Decongestants:
Phenylepherine, Xylometazoline, Oxymetazoline, Naphazoline and
Tetrahydrazoline and Phenylpropanolamine and Pseudoephidrine
Bronchodilators:
Isoprenaline, Salbutamol, Salmeterol, Terbutaline, Formeterol
Uterine Relaxants:
Ritodrine, Salbutamol, Isoxsuprine
Anorectics
Fenfluramine, Dexfenfluramine and Sibutramine
CNS Stimulants:
Amphetamine, Methamphetamine

Ephedrine
Plant alkaloid obtained from Ephedra vulgaris – Mixed acting drug
– 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

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
)

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
Uses: Hyperkinetic Children (ADHD)

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 α-
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
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 in hypertensives
Phenylpropanolamine (PPA) is similar to ephedrine and used
as decongestants in many cold and cough preparations
Xylometazoline, Oxymetazoline etc.

Clonidine
Centrally acting: Agonist to postsynaptic α2A
adrenoceptors in brain – vasomotor centre in
brainstem
Decrease in BP and cardiac output

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.
Low dose Clonidine (50-100μg/dl) is used in migraine prophylaxis,
menopausal flushing and chorea
Moxonidine, Rilmenidine – Newer Imidazolines

β2 Adrenergic Agonists –
Short acting : Salbutamol, Metaproterenol, Terbutaline,
pirbuterol
Selective for β2 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

Hypertension
Angina
Arrhythmias
Panic attacks