ADRENERGIC SYSTEM AND DRUGS

Dr. Nagapati P Bhat MD

Assoc. Professor
Department of Pharmacology
Yenepoya Medical College
 CONTENTS
❑ Specific Learning Objectives

Introduction to adrenergic system and biosynthesis of Catacholamines

Adrenergic receptors- location and function

Pharmacological actions, uses and adverse effects of Adrenaline,

Noradrenaline, Isoprenaline and Dopamine

Classification of Adrenergic Drugs

Therapeutic uses and adverse effects

Summary & References

 SPECIFIC LEARNING OBJECTIVES
At the end of this lecture students will be able to

Explain Adrenergic receptors

Discuss the Pharmacological actions, uses and adverse effects of

Adrenaline, Noradrenaline, Isoprenaline and Dopamine

Classify Adrenergic Drugs

Enumerate the Therapeutic uses and adverse effects of adrenergic

drugs
 Introduction
• 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

Endogenous catecholamines
Noradrenaline (NA)- acts as transmitter at postganglionic
sympathetic sites.

Adrenaline (Adr)- secreted by adrenal medulla and may have a

transmitter role in the brain.

Dopamine (DA) - major transmitter in basal ganglia, limbic

system, CTZ, anterior pituitary, etc.
SYNTHESIS
Synthesis and release of norepinephrine from the adrenergic
neuron. (MAO = monoamine oxidase.)
 Metabolism of CAs

(Homovanillic acid) (Vanillylmandelic acid)

 Receptors and signal transduction in the ANS

Adrenergic Receptors

α1 α2 β

α1A α1B α1D α2A α2B α2C β1 β2 β3

Receptor Location Function
α1 Blood vessels Vasoconstriction
Radial muscle of iris Contraction (pupil
dilatation)
Salivary glands except Increases secretions
parotid
Trigone of urinary Contraction
bladder
Liver Glycogenolysis,
Uterus Contraction
Male sex organs Ejaculation

α2 Medulla Oblangata Decreased central

sympathetic flow
Preganglianic neuron Increases reuptake of NT
Pancreas Insulin secretion inhibited
Recept Location Function
or
β1 Blood vessels Dilatation
Heart Increases rate, force and
conduction velocity
Kidney: JG apparatus ↑ renin release
β2 Bronchial smooth muscle Bronchodilatation
Blood vessels Vasodilatation
Detrusor muscle of UB Relaxation
Liver Glycogenolysis🡪 hypergycaemia
Uterus Relaxatin
GIT Relaxation
Eye Enhance aqueous secretion

β3 Adipose tissue Lypolysis

ADRENERGIC DRUGS (SYMPATHOMIMETICS)
• These are drugs with actions similar to theat of Adr or
o f sympathetic stimulation.
• Direct sympathomimetics:
They act directly as agonists on α and/ or β adrenoceptors
e.g: Adr , NA, isoprenaline (Iso ), phenylephrine,
xylometazoline, salbutamol.
• Indirect sympathomimetics:
They act on adrenergic neuron to release NA, which then
acts on the adrenoceptors
– E,g: tyramine, cocaine & amphetamine.
• Mixed action sympathomimetics:
They act directly as well as indirectly
ephedrine, dopamine
 Mechanisms of action and effects of
adrenergic drugs
• Direct adrenergic drug action
– Examples: epinephrine,norepinephrine, phenylephrine
• Indirect adrenergic drug action
– Examples: cocaine, amphetamines and TCAs
• Mixed action
– ephedrine and pseudoephedrine
 Adrenaline as prototype

• Potent stimulant of alpha and beta receptors

• Complex actions on target organs
 CVS
• Beta-1 mediated action - Powerful Cardiac stimulant -
+ve chronotropic, +ve inotropic

• 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)
❑ 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
• 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 (β-2 and β-3)
• Inhibits insulin secretion (α-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
 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
 ADRs
• Restlessness, Throbbing headache, Tremor,
Palpitations
• Cerebral hemorrhage, cardiac arrhythmias
• Contraindicated in hypertensives, hyperthyroid and
angina poctoris
• Halothane and beta-blockers – not indicated
 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

• 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

 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
– 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)
– 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 Noradrenaline
• 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 α1 and β1
 Dopamine

• In small doses 2-5 μg/kg/minute, it stimulates

D1-receptors in renal, mesenteric and coronary
vessels leading to vasodilatation (Increase in cAMP)
– 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
• Moderate dose (5-10 μg/kg/minute), stimulates β1-receptors in
heart producing positive inotropic and chronotropic actions
actions
• Releases Noradrenaline from nerves by β1-stimulation
• Does not change TPR and HR
• Great Clinical benefit in CVS shock and CCF

• High dose (10-30 μg/kg/minute), stimulates vascular

adrenergic α1-receptors (NA release) – vasoconstriction and
decreased renal blood flow
 Why renal and mesenteric vasodilatation is
useful in Shock?

– Increases renal blood flow and GFR 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
– Increase in force of contraction and cardiac output

• 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, hypertension, angina and fatal arrhythmia

 Adrenergic agonists
• Selective Alpha-1 Agonists:
– Phenylepherine, Ephederine, Methoxamine,
Metaraminol, Mephentermine

• Selective Alpha-2 Agonists:

– Clonidine, α-methyldopa, Guanfacine and
Guanabenz

• Βeta-2 Adrenergic agonists:

– Salbutamol, Terbutaline, Salmeterol, Reproterol,
Oxiprenaline, Fenoterol, Isoxsuprine, Rimiterol,
Ritodrine, Bitolterol and Isoetharine
THERAPEUTIC CLASSIFICATION OF ADRENERGIC
DRUGS
Pressor agents Nasal decongestants
Noradrenaline Phenylephrine
Phenylephrine Naphazoline
Ephedrine Xylometazoline
Methoxamine Pseudoephedrine
Dopamine Oxymetazoline
Mephentermine Phenyl propanolamine
Bronchodilators
Isoprenaline
Salbutamol
(Albuterol)
Terbutaline
Dobutamine
Salmeterol
Formoterol
Bambuterol
Cardiac stimulants CNS stimulants
Adrenaline Amphetamine
Isoprenaline Methamphetamine
Dexamphetamine
Dobutamine

Uterine relaxant
& vasodilators Anorectics
Ritodrine Fenfluramine
Salbutamol Sibutramine
Isoxsuprine Dexfenfluramine
Terbutaline
THERAPEUTIC USES OF ADRENERGIC DRUGS
• Vascular Uses
Hypotensive states (shock, spinal anaesthesia,
hypotensive drugs)
Along with local anaesthetics - Adr 1 in 50,000 to
1 in 200,000 for infiltration, nerve block and spinal
anaesthesia.
• Duration of anaesthesia is prolonged
• systemic toxicity of local anaesthetic is reduced.
• Local bleeding is minimised.
Control of local bleeding- epistaxis- compresses
of Adr 1 in 10,000, phenylephrine/ ephedrine 1 %
soaked in cotton can control arteriolar and
capillary bleeding.
• Nasal decongestant- In colds, rhinitis, sinusitis,
blocked nose or eustachian tube.
• Cardiac uses-
Cardiac arrest (drowning, electrocution, etc) Adr
may be used to stimulate the heart; i.v.
Administration is justified in this setting with
external cardiac massage.
Partial or complete A - V block- Isoprenaline
Congestive heart failure (CHF)- i.v. infusion of
DA/ dobutarmine
• Bronchial asthma

• Allergic disorders (urticaria, angioedema; is life

saving in laryngeal edema & anaphylaxis.- Adr is a
physiological antagonist of histamine

• Mydriatic- Phenylephrine is used to facilitate fundus

examination

• Uterine relaxant- ritodrine, infused i.v.

 SUMMARY
•Catecholamines are absorbed from the intestine but are rapidly
degraded by MAO and COMT present in the intestinal wall and liver,
so orally inactive

•Adrenergic drugs are having actions similar to that of Adrenaline or

that of sympathetic stimulation
 REFERENCES

1. Tripathi K.D., Essentials of Medical Pharmacology 8th ed. Jaypee

Brothers 2021

2. Padmaja Udayakumar., Medical Pharmacology 7th ed. CBS

Publishers 2021.