HuBio 543 September 26, 2007 Neil M. Nathanson K-536A, HSB Adrenergic Agonists &Other Sympathomimetics
CLASSES OF SYMPATHOMIMETICS Direct-acting Indirect-acting Mixed-acting Albuterol Dobutamine Dopamine Epinephrine Fendolopam Isoproterenol Norepinephrine Phenylephrine Ritodrine Salmeterol Terbutaline Ephedrine Amphetamine Tyramine
Reminder: Subtypes of Adrenergic Receptors : EPI > NOR >>ISO ß: ISO > EPI > NE 1 : contraction of smooth muscle (incl. VSM) 2 : presynaptic receptors ( decrease NE release) ß 1 : in heart and juxtaglomerular cells (and some fat cells) ß 2 : relaxation of smooth muscle ß 3 : some fat cells NOTE ON ß 2 : (1) mediate relaxation of skeletal muscle vasculature (2) P’cologically administered NE is not effective
EPINEPHRINE: MORE POTENT AT ß2 THAN AT 1 The Ugly Truth About Epinephrine Therefore: you would predict that low doses of EPI preferentially activate ß2 receptors over 1 receptors Low doses of EPI: preferentially activate ß2 receptors in skeletal muscle vasculature: cause vasodilation, leading to a decrease in total peripheral resistance (TPR) High doses of EPI: activate both ß2 and 1 receptors: 1 response predominates, resulting in vasoconstriction, which causes an increase in total peripheral resistance (TPR)
Effects of Epinephrine on the Cardiovascular System Drug Direct Reflex Action Effect Effect Result Stimulate ß-AdR Increase rate and force Cardiac output, HR, Systolic pressure Stimulate ß 2 -AdR (preferentially over 1 -AdR) Vaso- dilation TPR Diastolic pressure
Slow IV administration in humans
NE EPIISO DA PHEN. HR BP TPR Effects of agonists on cardiovascular function (slow IV administration)
“In the Corner With the Gladiators: Trying Out the Life of the Cut Man” by Harry Hurt, III NYT, 8/26/07
Necrosis Following Extravasation of Epinephrine
Effects of Norepinephrine on the Cardiovascular System Drug Direct Reflex Action Effect Effect Result Strongly stimulate ß-AdR (Increase rate and force) HR Cardiac output, HR, Stimulate 1 -AdR Vaso- constriction TPR Diastolic pressure Systolic pressure
Slow IV administration in humans
NE EPIISO DA PHEN. HR BP TPR Effects of agonists on cardiovascular function (slow IV administration)
Effects of Isoproterenol on the Cardiovascular System Drug Direct Reflex Action Effect Effect Result Stimulate ß-AdR Increase rate and force Cardiac output, HR, Systolic pressure Stimulate ß 2 -AdR Much vaso- dilation TPR Diastolic pressure HR, Force
Slow IV administration in humans
NE EPIISO DA PHEN. HR BP TPR Effects of agonists on cardiovascular function (slow IV administration)
DOPAMINE D1 > ß > 1 Can activate: (1) vasodilatory dopamine (D1) receptors in renal, mesenteric, and coronary vascular beds (2) beta receptors in heart (greater effect on contractile force that rate) (3) stimulates NE release from nerve terminals (contributes to cardiac effects) (4) high doses can activate vascular 1 receptors
NE EPIISO DA PHEN. HR BP TPR Effects of agonists on cardiovascular function (slow IV administration)
Effects of Phenylephrine on the Cardiovascular System Drug Direct Reflex Action Effect Effect Result (No Effect) HR Stimulate 1 -AdR Vaso- constriction TPR Diastolic pressure Systolic pressure
NE EPIISO DA PHEN. HR BP TPR Effects of agonists on cardiovascular function (slow IV administration)
BP mm Hg. Symp. Nerve act. Vagus Nerve act HR bpm Time (min) + phenylephrine
BP, mm Hg. Pulse Interval (msec.) Sec after phenylephrine Systolic Pressure (mm Hg.)
ß 2 - Adrenergic Agonists Albuterol Ritodrine Terbutaline Salmeterol
% reduction of intraluminal pressure % increase in rate % increase in force of contraction Tracheal Muscle Cardiac Muscle (Rate) Cardiac Muscle (Force) Concentration (µg/ml) ISO ALB
SALMETEROL ALBUTEROL PLACEBO FIRST DOSE SECOND DOSE FEV 1 Time (Hours) Time Course of Bronchodilation Produced by Albuterol and Salmeterol
% Increase Over Basal Value ISOPROTERENOL ALBUTEROL Pulse Rate FEV 1.0 Pulse Rate FEV 1.0 DOSE (IV) EFFECTS OF ISOPROTERENOL & ALBUTEROL IN HUMANS
“ß 1 - Adrenergic Agonists” One isomer is ß1 agonist and 1 agonist Other isomer is ß1 agonist (and apparently weak 1 antagonist) Increases contractile force, little effect on heart rate or TPR Used to increase cardiac output (e.g., CHF) Why does dobutamine have little effect on HR and TPR? 1. Human atria: % ß1; human ventricle: %ß1 2. Little or no ß2- mediated vasodilation, so no reflex tachycardia 3. 1 agonist activity may also contribute to direct stimulation of ventricles and lack of vasodilation Dobutamine
Dopamine D 1 receptor agonist IV administration causes rapid vasodilation Used for emergency management of severe hypertension Fenoldopam
IV Administration of Fenoldopam Patients with Postcardiac Surgery Hypertension Time (minutes) Pressure (mm Hg) Heart Rate (bpm) Diastolic BP Heart Rate Systolic BP
NE Re-Up NE Indirect-acting sympathomimetics NE TYRAMINE AMPHETAMINE
+ Tyramine+ Norepinephrine Pretreat with Cocaine: Cocaine blocks vasopressor response to tyramine and potentiates response to norepinephrine + Norepinephrine + Tyramine BP
NE Re-Up NE Re-Up NE X Normal uptake of NE NE uptake blocked by cocaine Cocaine potentiates sympathetic transmission (and effects of NE administration)
BP (mm. Hg) EPINEPHRINE EPHEDRINE Effects of epinephrine and ephedrine on blood pressure in dog BP (mm. Hg)
1 min. EPHEDRINE TACHYPHYLAXIS IN THE DOG Ephedrine (3 mg/kg) administered, every 10 min BP