By Duy Thai, 1997 Pharmacology Semester 1 page 1 of 3

ADRENERGIC PHARMACOLOGY IV

β agonists
• Both β1 and β2
• Isoprenaline
• Was the initial drug which helped identify the β receptor from the α receptor
• Not used clinically since it is not selective for β1 or β2
• Since it is a catechol, it is readily metabolised by COMT in the tissues and gut and
therefore cannot be taken orally (it is taken sublingually)
• Is was once used as an antiasthmatic but is now superseded by salbutamol since it can also
affect the heart (increasing HR)
• Selective β1 agonist (β1 found in heart and kidney)
• Dobutamide
• Is a very weak agonist
• Because of its weak action, it is good for use in people with heart failure (since we want a
mild stimulation of the heart)
• Selective β2 agonist (β2 found in bronchi, uterus, skeletal blood vessels, liver)
• Salbutamol
• Main use is in the treatment of asthma as a bronchodilator.
• It is given as an aerosol so as to have local effects. However, some of it may be absorbed in
the pulmonary capillaries, and so enter the systemic circulation.
• Some side effects are:
• Skeletal muscle tremor
• This is because the β2 receptors increase cAMP levels in skeletal muscle
cells, increasing Ca2+ which causes tremor
• Reduction in K+
• Cardiac effects (mild palpitations)
• Recall that the heart has predominantly β1 receptors. However, they may
constitute only 60 to 80%. 20 to 40% of the remaining receptors are
others (like β2).
• Also, salbutamol is selective for β2 receptors only at a certain
concentration range. At higher concentrations, salbutamol no longer
becomes selective for β2 receptors.
• Another use of salbutamol, when given intravenously, is to prevent premature labour by
relaxing the pregnant uterus.

β Antagonists
• Both β1 and β2 antagonists (non selective)
• Propranalol
• Membrane stabilising (anaesthetic effect)
• The membrane stabilising effect only occurs at concentrations above therapeutic
levels
• Mainly used to treat arrythmias, angina (reduce the O2 demand by decreasing the work of
the heart), hypertension, anxiety (which is due to increased heart rate and palpitations),
glaucoma, phaeochromocytoma (used in conjunction with PBZ to block all adrenoreceptors,
α and β)
• Heaps of side effects limits its therapeutic use:
• Bronchoconstrictor (inhibiting β2 effect)
• Cardiac failure (too much cardiac depression)
• Cold extremities (preventing vasodilation)
• Hypoglycaemia (inhibiting glycogenolysis and gluconeogenesis)
• Fatigue (due to the hypoglycaemia)
• Vivid dreams (due to the lipid solubility of the drug - able to cross blood brain
barrier)
By Duy Thai, 1997 Pharmacology Semester 1 page 2 of 3

• Oxprenalol
• ISA, membrane stabilising
• Pindolol Both are partial agonists
• ISA
• Timolol
• Given locally as drops. Used as the β antagonist of choice for glaucoma since it is a pure
antagonist (small dose is required for its effect in the eye compared to systemic side effect)
• The eye is a small space and so it is good because only small doses are required.
• It does not have membrane stabilising effects like the other β antagonists
• Glaucoma is due to an increased intraocular pressure as a result of increased aqueous
humor production. This production is cAMP mediated, and so β antagonists work to reduce
cAMP levels.
• Selective β1 antagonist
• Atenolol
• Cardioselective (depends on the concentration)
• Theoretically better
• Care is needed when used in asthmatics (we don’t want to block β2 bonchodilation) and
diabetics (β2 is important in controlling glucose metabolism)
• Selective β2 antagonist
• Butoxamine
• No clinical uses
• Mixed α and β adrenoreceptor antagonist
• Labetalol
• Reduces heart rate (β1 effect)
• Reduces TPR by preventing vasoconstriction (α1 effect) Ideal for hypertension
• Side effects:
• Postural hypotension (because the reflex vasoconstriction is prevented as blood
pools in the legs)
Adrenoreceptor classification
• Receptors were once classified by the development of selective therapeutic agents
• Via agonist structure-activity relationships
• Via antagonist selective inhibition and affinity
• Newer techniques to identify receptors and function are:
• Radioligand binding/autoradiography
• Cellular mechanisms
• Molecule biology and cloning of receptor genes

The new adrenoreceptor classification

• It is now considered that there are 3 main adrenoreceptor subtypes based on sequence, signalling pathway
and pharmacology.

α1 α2 β
Agonist Phenylephrine Clonidine Isoprenaline
Antagonist Prazosin Yohimbine Propranalol

• These subtypes are further divided into:

• α1A, α1B, α1D
• α2A, α2B, α2C
• β 1, β 2, β 3

• β3 receptors are found on adipocytes and are responsible for the lipolytic effects of NA
• Propranalol has a low affinity for this receptor
• There have been specific agonists and antagonists developed experimentally for this receptor (the
names are unimportant to remember)
• Drugs acting at this receptor may have a potential use at treating obesity
By Duy Thai, 1997 Pharmacology Semester 1 page 3 of 3

Molecular features of adrenoreceptors

• They are all 7 transmembrane, G protein coupled receptors
• The intracellular domain carboxyl tail determines whether the receptor is α or β

Coupling mechanisms
• All β receptors cause an increase in cAMP

• α1 receptors activate PI pathway to produce IP3 and DAG, thus causing the increased release of intracellular
Ca2+ stores (causing smooth muscle contraction)

• α2 receptors decrease cAMP levels (which thus prevents release of NA)

Therapeutic uses of endogenous catecholamines

• Noradrenaline
• Not used clinically
• Cannot be given orally since it will be metabolised by MAO in the gut
• Receptor selectivity:

α1 > α2 ≈ β1 >>> β2

• Adrenaline
• Receptor selectivity:

β1 ≈ β2 ≈ α1 > α2

• Is used as an emergency hormone, especially in anaphylactic shock

• Anaphylactic shock is characterised by:
• Difficulty in breathing (due to bronchoconstriction)
• Fall in blood pressure
• Adrenaline helps by:
• Promoting blood flow and heart rate (α1 vasoconstriction, β2 actions on the heart)
• Opening airways (β2 bronchodilation)
• Stimulate metabolism (β2 actions on the liver to stimulate gluconeogenesis and
glycogenolysis.
• Adrenaline is also added to local anaesthetic solutions to cause local vasoconstriction. This isolates
the local anaesthetic and prevents spread.
• Side effects:
• Arrythmias