Adrenergic Agonists & Antagonists

Terrell Gibbs
Adrenergic Synapse
catechol
Agonist Potency Defines Receptor Subtypes
Adrenergic Signal Transduction via Adenylyl Cyclase
Adrenergic Signal Transduction via Phospholipase C
Major Adrenergic Receptor Subtypes
Subtype
2
nd
Messengers
Effects
o1 | PLC activity
| DAG, IP
3

Vascular, genitourinary smooth muscle: contraction,
|arterial resistance
+venous capacitance
Intestinal smooth muscle: relaxation
Radial muscle (eye): contraction (mydriasis)
Liver: glycogenolysis, gluconeogenesis
o2 + cAMP Pancreas: + insulin secretion
Nerve terminals: + NE release
CNS: + sympathetic tone
Platelets: aggregation
|1 | cAMP Heart: | force (+ inotropic), |r ate (+ chronotropic),
|AV conduction velocity
Kidney: | renin release
|2 | cAMP
Smooth muscle: relaxation
Skeletal muscle: glycogenolysis
Liver: glycogenolysis, gluconeogenesis
D1
| cAMP
Dilates renal vasculature

o2
Adrenergic Agonists
o, | o, |1
D1, |1 > o1
o1
|
|1
|2
|2
Indirect-acting Sympathomimetics
Cocaine
Adverse reactions to ephedra
QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture.
Baroreceptor Reflex Arc
Cardiovascular Effects
Cardiovascular Effects of Adrenergic Agonists
Epinephrine

Norepinephrine Isoproterenol
Peripheral resistance + (|2 > o1) | (o1)

+ (|2 )

Systolic | (|1) || (|1 + o1) | (|1)
Diastolic + (|2 > o1) | (o1) + (|2 )
B.P. (average) | +
H.R. | (|1) + (vagal reflex; ACh
M2)
| (|1; isoproterenol
direct + reflex NE
release)
(Human, 10 g/min)
Case
A pregnant woman aged 30, 39 weeks
gestation, is admitted for elective cesarean
delivery. Prior to spinal anesthesia with
bupivacaine and fentanyl, she receives
phenylephrine to maintain blood pressure
during the procedure.
Therapeutic Uses of Adrenergic Agonists
Cardiovascular
Maintaining blood pressure in spinal anesthesia (o1)
Cardiogenic shock (DA, |1)
Nasal decongestants (o 1)
Extend local anesthetic action (o1)
Hypotensive agent overdose (o1)
Restoring heartbeat after cardiac arrest (|1, Epi)
Allergic
Asthma (|2)
Anaphylactic shock (|2, o1)
Ophthamology
Mydriasis (o1)
Glaucoma (o1, o2)
Obstetrics: Delay premature labor (|2)
Attention Deficit Disorder


Treatment of Glaucoma
Class Action
|1-blockers production
o2 agonists outflow, production
mACh agonists outflow
AChE inhibitors outflow
Carbonic anhydrase
inhibitors
production
Prostaglandins outflow
Toxicity & Side Effects of Adrenergic Agonists
Vasoconstriction, ischemia (o1)
Hypertensive reactions (o1)
Rebound nasal congestion (o1)
Tachycardia (|1)
Myocardial ischemia
Cardiac ventricular arrhythmias (|1)
CNS stimulation
Withdrawal syndrome (o2 agonists)


Adrenergic Antagonists
o1
o1+o2
o1 + o2
o2
|1 + |2
|1
|1 + |2
|1+|2+o1
|1+|2+o1
|1
Therapeutic Uses of o Antagonists
Hypertension
Pheochromocytoma
Raynauds Disease
Congestive Heart Failure
Benign prostatic hyperplasia
Antidote to o-agonist vasoconstriction
Therapeutic Uses of |-Blockers
Hypertension
Congestive heart failure
Reducing mortality after myocardial
infarction
Angina
Cardiac arrhythmias
Hyperthyroidism (propranolol)
Anxiety (stage fright)
Migraine prophylaxis
Open-angle glaucoma
Protective effect of |-blockers in heart failure
QuickTime and a TI FF (Uncompressed) decompressor are needed t o see t his picture.
QuickTime and a TI FF (Uncompressed) decompressor are needed t o see t his picture.
CIBIS = Cardiac Insufficiency Bisoprolol Study; COPERNICUS = CarvedilOl ProspEctive RaNdomIzed CUmulative Survival
Trial; MERIT-HF = MEtoprolol CR/XL Randomized Intervention Trial in chronic Heart Failure (Bangalore et al., J Am Coll Cardiol
2007.
Packer et al. (US Carvedilol Heart Failure Study Group) New Eng J Med, 1996
Results of COMET study
QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture.
Lancet 362(2003)1713
Therapeutic Uses of |-Blockers
Hypertension
Congestive heart failure
Reducing mortality after myocardial
infarction
Angina
Cardiac arrhythmias
Hyperthyroidism (propranolol)
Anxiety (stage fright)
Migraine prophylaxis
Open-angle glaucoma
Protective Effect of |-Blockers after MI
Petersen, TR, N Engl J Med 1985;313(17):1055-8.
Therapeutic Uses of |-Blockers
Hypertension
Congestive heart failure
Reducing mortality after myocardial
infarction
Angina
Cardiac arrhythmias
Hyperthyroidism (propranolol)
Anxiety (stage fright)
Migraine prophylaxis
Open-angle glaucoma
Toxicity & Side Effects of o-Antagonists
Postural hypotension
Reflex tachycardia
Myocardial ischemia
Salt & water retention
Peripheral edema
GI stimulation
Inhibition of ejaculation
Toxicity & Side Effects of |-Blockers
Bronchoconstriction
Bradycardia
Withdrawal: exacerbation of angina, risk
of sudden death
Fatigue
Cold extremities
Potentiation of epinephrine
vasoconstriction
Precipitation of congestive heart failure
Additive interaction with Ca
2+
channel
blockers