Adrenergic Receptor Pharmacology

Learning Objectives
1. Describe the anatomy of the sympathetic nervous system. 2. Explain the actions of the transmitters of the autonomic nervous system. 3. Describe responses mediated by adrenergic receptors. 4. Describe how adrenergic receptors regulate cardiovascular function.
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SYMPATHETIC NEUROTRANSMITTERS
Preganglionic
acetylcholine (nicotinic)

Postganglionic
catecholamine (norepinephrine, epinephrine, dopamine) Norepinephrine
primary transmitter released by sympathetic nerves

Epinephrine
released by adrenal medulla, circulating hormone adrenal medulla is a nicotinic site

Dopamine
released by nerve stimulation precursor for norepinephrine

Storage of catecholamines
in dense core vesicles in nerve terminal of adrenergic nerve All released by adrenergic stimulation (exocytosis - calcium-dependent process).
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Adrenergic Neurons

Na+ Tyrosine
Dopa

MAO

Ca++

Dopamine

Dopamine is converted to epinephrine

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Receptor

EFFECTS ON RECEPTORS
Norepinephrine 1, 2, 1 >> 2
postganglionic neurotransmitter activates

receptors and causes vasoconstriction, mydriasis, constriction of pyloric, intestinal and bladder sphincters

activates 1 receptors and increases stored in dense core vesicles (97%) and in cytoplasmic
heart rate, heart contractility - inotropic action, arrhythmias (ectopic beats, etc.)

Epinephrine + effects

pools (3%)

effects occur at lower doses effects occur at higher doses

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SITE OF ACTION OF CATECHOLAMINES ADRENERGIC RECEPTORS

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The Sympathetic Nervous System

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Inactivation of noradrenaline

1. Reuptake

3.

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Adrenergic Receptors
Two Families:
Alpha and Beta Based on affinity to

adrenergic agonists
epinephrinenorepinephrine>> isoproteranol
Epinephrine Norepinephrine Isoproteranol

Alpha affinity: Beta affinity:

Isoproteranol>epinephrine> norepinephrine
Isoproteranol Epinephrine Norepinephrine

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Signaling properties of adrenergic receptors

Adrenergic receptors are G protein coupling receptors

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Drugs Acting on the Sympathetic Nervous System

Direct-acting sympathomimetics
1. 2. 3. 4. 5. 6. 7. Adrenaline (epinephrine) Noradrenaline (norepinephrine) Isoproterenol Phenylephrine Clonidine Dobutamine Salbutamol 1, 2` 1, 2` --------` 1 Presynaptic 2` --------------1, 2 1, 2 1, 2 -------------1 2

Indirect-acting sympathomimetics
1. 2. Facilitate noradrenaline release (amphetamine), Block noradrenaline re-uptake (cocaine)

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Adrenergic Agonists
Direct

Albuterol Dobutamine Dopamine Isoproterenol

Indirect
Amphetamine

Mixed
Ephedrine

NB:
SYMPATHOMIMETIC: Adrenergic drug which acts directly on

adrenergic receptor, activating it

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Adrenergic Agonists
Direct acting:
Epinephrine: interacts with both alpha and

beta

Low dose: mainly beta effects (vasodilation) High dose: alpha effects (vasoconstriction)

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Adrenergic Agonists
Indirect:
Cause NE release only Example:
Amphetamine
CNS stimulant Increases BP by alpha effect on vasculature, beta effect on heart

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Mixed-Action
Causes NE release AND stimulates receptor Example:
Ephedrine:
What type of drug? Alpha and beta stimulant Use: asthma, nasal sprays slower action

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Adrenergic Antagonists
Alpha blockers
Eg: Prazosin
Selective alpha 1 blocker Tmt: hypertension
relaxes arterial and venous smooth muscle Causes first dose response (what is this?)

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Adrenergic Antagonists
Beta Blockers
Example:
Propranolol: Non-selective (blocks beta-1 and beta-2)
Effects: cardiac output, vasodilation, bronchoconstriction

Atenolol, Metoprolol: Selectively blocks beta-1 but no beta-2 effects

(why is beta-1 selective good?)

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Adrenergic Antagonists with Intrinsic Sympathometic Activity

Adrenergic antagonists which also have Intrinsic Sympathometic Activity, i.e they as Partial Agonists too or weakly stimulate beta 1 and beta 2
Pindolol, acebutolol
Causes less bradycardia

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Adrenergic Antagonists
Eg: Nadolol
Nonselective beta blocker Used for glaucoma

Eg: Labetolol
Alpha AND beta blocker Used in treating Pregnancy Induced

Hypertension (Pre-eclampsia)

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Drugs that Affect Uptake/Release

Eg: Cocaine
Blocks Na+/K+ ATPase Prevents reuptake of

epinephrine/norepinephrine

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Assignement
Adrenaline and Noradrenaline
Synthesis Release Storage And degradation

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