THE PHARMACOLOGY OF ADRENERGIC RECEPTORS

M.T. PiascikPHA 824December 11 & 16, 2008

Learning ObjectivesThe student should be able to explain or describe;

• The pharmacodynamic principles that aid in the understanding of adrenergic receptors and the actions of drugs on these receptors.

• The criteria upon which alpha and beta receptors are defined.

• The second messenger systems utilized by alpha and beta receptors and how activation of these receptors leads to a change in physiologic function.

Learning Objectives(cont.)

The student should be able to explain or describe;

• The effects of alpha and beta receptor activation on the heart and blood vessels.

• The effects of isoproterenol, epinephrine and norepinephrine on the cardiovascular system.

• The clinical uses and potential toxicities of epinephrine, norepinephrine and isoproterenol with emphasis on epinephrine.

The Adrenergic Receptors

Beta Adrenergic Receptors

DRUG KD BETA1 RECEPTOR KD BETA2 RECEPTOR

Epinephrine 800 nM 800 nM

Norepinephrine 1000 nM 10,000 nM

Isoproterenol 80 nM 80 nM

Which of the dose-response curves represents activation of the beta1 receptor and which

represents activation of the beta2 receptor?

Beta Adrenergic Receptor Systems

Tissue Receptor Subtype

Heart beta1

Adipose tissue beta1

Vascular smooth muscle beta2

Airway smooth muscle beta2

Kidney-renin release from JG cells beta1

Cellular Signaling Activated by the Beta1 Receptor in the

Heart

Physiologic Consequences of Beta1 Receptor

Activation

Rhythm disturbances are a major concern with drugs that activate the beta1 receptor.

The BETA1-Adrenergic Receptor as a Therapeutic

Target

1) Agonists- congestive heart failure

2) Antagonists- hypertension, ischemic heart disease, congestive heart failure, supraventricular tachyarrhythmias.

Cellular Signaling Activated by the Beta2 Receptor in Smooth

Muscle

Physiologic Consequences of Beta2 Receptor

Activation

The Beta2-Adrenergic Receptor as a Therapeutic

TargetAgonists- Airways dysfunction (asthma,

chronic bronchitis emphysema), tocolytics

Antagonists- No therapeutic uses.

The BETA2-Adrenergic Receptor as a Therapeutic

Target

1) Agonists- congestive heart failure

2) Antagonists- hypertension, ischemic heart disease, congestive heart failure, supraventricular tachyarrhythmias.

Alpha Adrenergic Receptors

KD KD KD

BETA1 RECEPTOR BETA1 RECEPTOR ALPHA RECEPTOR

Epinephrine 800 nM 800 nM 5000 nM

Norepinephrine 1000 nM 10,000 nM* 6000 nM

Isoproterenol 80 nM 80 nM 10,000 nM**

* At doses used in therapeutics, Norepinephrine is void of Beta2 activity

** At doses used in therapeutics, Isoproterenol is void of Alpha1 activity

Presynaptic Alpha2 Receptors

Postsynaptic Alpha1 Receptors

Physiologic Consequences of Alpha1 Receptor

Activation

Interaction Between Vascular Alpha1 and Beta2 Receptors

Integrated Cardiovascular Responses

Integrated Cardiovascular Response to Isoproterenol and Norepinephrine

Integrated Cardiovascular Response to

Epinephrine

Therapeutic Uses of Epinephrine

Oral dosing of epinephrine, norepinephrine or isoproterenol is not possible due to its rapid metabolism in the gut by MAO.

Epinephrine can be given topically, by injection (s.c., i.m. i.v) or inhalation

Therapeutic Uses of Epinephrine (cont.)

Actions at the Beta2 Receptor• The treatment of respiratory distress or

bronchspasm caused for example by asthma (i.e. status asthmaticus) or anaphylaxis as a result of allergic responses.

Actions at the Beta1 Receptor• Epinephrine is also used to provide rapid

inotropic support in cardiopulmonary resuscitation

Therapeutic Uses of Epinephrine (cont.)

Actions at the Beta2 Receptor• The treatment of respiratory distress or

bronchspasm caused for example by asthma (i.e. status asthmaticus) or anaphylaxis as a result of allergic responses.

Actions at the Beta1 Receptor• Epinephrine is also used to provide rapid

inotropic support in cardiopulmonary resuscitation

Therapeutic Uses of Epinephrine (cont.)

Actions at the Alpha1 Receptor• Epinephrine is often used in combination with

local anesthetic agents (such as articaine, bupivacaine or lidocaine) to prolong the duration

of anesthetic action. • Epinephrine is used in

surgery to reduce bleed.

Epinephrine Toxicities• Arrhythmias• Hypertension• Toxicity can occur following systemic

administration or systemic absorption following oral administration.

Epinephrine Toxicities• Arrhythmias• Hypertension• Toxicity can occur following systemic

administration or systemic absorption following oral administration.

Epinephrine Toxicities

• Toxicity can be potentiated in patients taking tricyclic antidepressants, nonselective beta blockers, cocaine and amphetamine-like drugs and those under general anesthesia.

Beta2-AR Beta1-AR