Download ADRENERGIC RECEPTORS AS THERAPEUTIC TARGETS

THE PHARMACOLOGY OF
ADRENERGIC RECEPTORS
M.T. Piascik
PHA 824
December 11 & 16, 2008
Learning Objectives
The 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
Heart
Receptor Subtype
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 Target
Agonists- 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
BETA1 RECEPTOR
Epinephrine
800 nM
KD
BETA1 RECEPTOR
KD
ALPHA RECEPTOR
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