Ch. 12 Adrenergic agonists & antagonists

1. Ch. 12 Adrenergic agonists & antagonists R1. 이송이

2. Adrenoceptor Physiology Analogous group of agents that interacts at adrenergic Rc • Norepinephrine • Responsible for most of adrenergic activities of the sympathetic nervous system (except eccrine sweat gl. & some blood vessels) • Released by postgaglionic sympathetic fibers at end organ tissues

3. Adrenoceptor Physiology • Adrenergic Receptor • Classified according to the reaction to Adrenergic agents • α (α1, α2) β (β1, β2, β3)

4. Adrenoceptor Physiology • α1 – receptor • Postsynaptic adrenoceptor • Located in smooth m. throughout the body (eye, lung, blood vessels, uterus, gut, GU) • Activation  Increase in intracellular Ca. ion  muscle contraction • Mydriasis, bronchoconstriction, vasoconstriction, uterus contracture, contraction of sphincter in GI & GU tracts • Inhibit insulin secretion & lipolysis

5. Adrenoceptor Physiology • α1 – receptor • Myocardium – slightly positive inotropic & negative chronotropic effects • Cardiovascular effect – vasoconstriction • ↑ Pph. Vascular resistance • ↑ Left ventricle afterload • ↑ Arterial Blood Pressure

6. Adrenoceptor Physiology • α2 – receptors • Presynaptic nerve terminals • Activation inhibit adenylate cyclase activation decrease Ca. into nerve terminal limits exocytosis of Norepinephrine • Creates negative feedback – Inhibition of further Norepinephrine release • Stimulation in CNS  Sedation & decreased sympathetic outflow  pph. Vasodilation & decreased BP

7. Adrenoceptor Physiology • β1 – receptors • Postsynaptic neurons in the heart • Stimulation Adenylate cyclase(ATP  cAMP) activation • Positive chronotropic (increased HR) • Positive dromotropic (increased conduction) • Positive inotropic (increased contractility)

8. Adrenoceptor Physiology • β2 – receptors • Postsynaptic adrenoceptor • Located in smooth muscle & gland cells • Common mechanism as β1– adrenoceptors • Relaxes smooth m. Bronchodilation, vasodilation, relaxation of uterus, bladder and gut • Stimulates Glycogenolysis, lipolysis, gluconeogenesis, and insulin release • Potassium intracellularly hypokalemia, dysarrhythmia

9. Adrenergic Agonists

10. Adrenergic Agonists • Catecholamine • Epinehrine • Dopamine • Norepinephrine • Short acting because of their metabolism by COMT & MAO

11. Adrenergic Agonists • Noncatecholamine • Phenylephrine • Ephedrine • Amphetamine • Longer half-life

12. Adrenergic Agonists • Varying selectivity at α and β-adrenoceptors

13. Phenylephrine • Clinical Considerations • Noncatecholamine • Direct α1-agonist activity (high doses may stimulate α2 &β-receptors) • Effects • Vasoconstriction  Rise in systemic vascular resistance and ABP • Reflex bradycardia can reduce CO • Increase in coronary blood flow

14. Phenylephrine • Dosage and Packaging • To reverse reductions in BP caused by pph. Vasodilation (eg. Spinal anesthesia) small IV boluses of 50-100μg (0.2-1 μg/kg) • To maintain arterial BP continuous infusion (100 μg/mL at rate of 0.25-1 μg/kg/min) • Must be diluted : 1% solution ~100 μg/mL solution

15. α2 - Agonists • Methyldopa : Enters the norepinephrine-synthesis pathway • converted to ①α-methylnorepinephrine ②α-methylepinephrine • These false transmitters activate α-adrenoceptors (esp. central α2) • Norepinephrine release and sympathetic tone are diminished * Renal blood flow is maintained or increased

16. α2 - Agonists • Clonidine : • Commonly used for its antihypertensive and negative chronotropic effects • Sedative properties oral (3-5μg/kg), intramuscular(2μg/kg), intravenous(1-3 μg/kg), transdermal(0.1-0.3 mg release per day), intrathecal(75-150 μg), epidural(1-2 μg)

17. α2 - Agonists • Clonidine : • Decrease anesthetic and analgesic requirements (Decrease MAC) • Provide sedation and anxiolysis • During G/A : Enhance intraoperative circulatory stability by reducing catecholamine levels • During R/A : prolongs the duration of the block • Decreased postop shivering, inhibition of opioid-induced m. rigidity, treatment of some chronic pain syndromes • Side Effects : bradycardia, hypotension, sedation, respiratory depression, dry mouth

18. α2 - Agonists • Dexmedetomidine • Higher affinity for α2-receptors than clonidine • sedative, analgesic, sympatholytic effects blunts cardiovascular response related to surgery • When used Intraoperatively  Reduces IV & volatile anesthetic requirements • When used postoperatively  Reduces analgesic & sedative requirements (Pts. remain sedated until stimulated)

19. α2 - Agonists • Long term use leads to supersensitization and upregulation of receptors • With abrupt discontinuation acute withdrawal syndrome manifests (hypertensive crisis)

20. Epinephrine • Clinical Considerations • Direct stimulation of β1-receptors • Increased myocardial contractility & HR • Increased cardiac output & myocardial oxygen demand • α1-stimulation • Decrease splanchnic & renal blood flow • Increase coronary and cerebral perfusion pr. • Increase systolic blood pr. • Decrease diastolic pr. • β2-stimulation relaxes the bronchial smooth muscle • Treatment of anaphylaxis • Treatment of ventricular fibrillation

21. Epinephrine • Clinical Considerations • Cx : cerebral hrr., coronary ischemia, ventricular dysrhythmias Volatile anesthetics (esp. halothane) potentiate dysrhythmic effects • Dosage & Packaging • In an Emergency (Shock, Allergic rxn) • 0.05-1mg IV bolus • To Improve myocardial contractility or HR • continuous infusion : 2-20μg/min • Used in some local anesthetic solutions • 1:200,000(5μg/ml), 1:400,000(2.5μg/ml) • less systemic absorption & longer duration of action

22. Ephedrine • Clinical Considerations • Cardiovascular effects are similar to epinephrine • Increase in BP, HR, CO, contractility • Bronchodilation • Has a longer duration of action than epinephrine • Has indirect and direct agonist properties • Indirect properties are due to • central stimulation • pph. postsynaptic norepinephrine release • inhibition of norepinephrine reuptake • Commonly used as a vasopressor during anesthesia • Does not reduce uterine blood flow • Has antiemetic properties

23. Ephedrine • Dosage & Packaging • bolus 2.5-10mg in adult • 0.1mg/kg in children • Subsequent doses are increased to offset tachyphylaxis

24. Norepinephrine • Clinical Considerations • Direct α1-stimulation (in the absence of β2-activity) • Vasoconstriction of arterial & venous vessels • β1-effects • Increased myocardial contractility  Increased ABP • Increased afterload & reflex bradycardia  no increase in CO • Renal blood flow is decreased • Increased myocardial oxygen demands  Limited in the treatment of refractory shock • Used with α-blockers (eg. Phentolamine)  To prevent profound vasoconstriction caused by α-stimulation

25. Norepinephrine • Dosage & Packaging • Bolus (0.1μg/kg) • Continuous (4mg of drug 500ml D5W[8μg/ml]) : 2-20μg/min

26. Dopamine • Clinical Considerations Nonselective direct and indirect adrenergic agonist • In small doses (<2μg/kg/min) • minimal adrenergic effect • Activation of dopaminergic receptors • Vasodilation of renal vasculature  diuresis • In moderate doses (2-10μg/kg/min) • β1-stimulation • Increased myocardial contractility, HR, CO • Myocardial 02 demand increases more than supply

27. Dopamine • Clinical Considerations • In higher doses (10-20μg/kg/min) • α1-effect • Increased pph. vascular resistance • Decreased renal blood flow • Commonly used in the treatment of shock • Improve CO, BP support, maintain renal function • Used in combination with a vasodilator • Dosage & Packaging • Continuous infusion (400mg in 1000mL D5W [400μg/ml]) :1-20 μg/kg/min

28. Dobutamine • Clinical Considerations • selective β1-agonist  Increased myocardial contractility  Increased cardiac output • β2-activation  Slight decline in pph. vascular resistance  Maintain ABP • Good choice for pts with congestive heart failure and CAD • Dosage and Packaging • Infusion (1g in 250mL [4mg/mL]) : 2-20 μg/kg/min

29. Adrenergic Antagonists

30. α-blockers : Phentolamine • Clinical Considerations • Competitive (reversible) blockade of α-receptors • α1-antagonism and direct smooth muscle relaxation  pph. vasodilation and decreased arterial BP  reflex tachycardia • Cardiovascular effects appear within 2 min and last up to 15 min • Limited in the treatment of hypertension caused by excessive α-stimulation (eg, pheochromocytoma, clonidine withdrawal) • Dosage & Packaging • IV intermittent bolus (1-5mg in adult) • continuous infusion (10mg in100ml D5W[100 μg/ml])

31. Mixed Antagonists : Labetalol • Clinical Considerations • mixed antagonist (blocks α1, β1, β2-receptors) • α blockade : β blockade = 1:7 • Decreased pph. vascular resistance & arterial blood pressure • HR, CO are slightly depressed or unchanged • Because of the combination effects of α & β- blockade decreased BP without reflex tachycardia • peak effect occurs within 5 min • left ventricular failure, paradoxical HTN, bronchospasm

32. Mixed Antagonists : Labetalol • Dosage & Packaging • Initial recommended dose : 0.1-0.25mg/kg IV Until the desired BP response is obtained twice the initial dose may be given at 10-min interval • Slow continuous infusion (200mg in 250ml 5DW) : 2mg/min Due to its long elimination half life (>5 hr), prolonged infusions are not recommended

33. β-Blockers • β-receptor blockers는 β1-receptor에 대해 다양한 정도의 selectivity를 갖고 있음 • selective β1-blockers는 β2-receptors의 inhibitory effect가 약하다 -> COPD, pph. vascular dis. 환자에 적용

34. ESMOLOL • Clinical Considerations -Ultra short-acting selective β1-antagonist -> HR, BP감소 -perioperative stimuli (eg. Intubation, surgical stimulation, emergence)로 인한 tachycardia와 HTN 시 유용 -short duration of action <- rapid redistribution (distribution half-life is 2min) <- red blood cell esterase 의 hydrolysis (elimination half-time 9min)

35. ESMOLOL • CIx- sinus bradycardia, 1도 이상의 heart block, cardiogenic shock, overt heart failure • Dosage & Packaging -bolus (0.2-0.5mg/kg) for short term therapy (laryngoscopy and intubation 에 의한 cardiovascular response 낮춰줌) -long term Tx (loading dose : 0.5mg/kg over 1 min로 시작, continuous infusion : 50μg/kg/min) 만약 5분 이내 효과가 없다면 loading dose를 다시 주고 매 5분마다 용량을 증가시켜 최대 200μg/kg/min까지 증가

36. PROPRANOLOL • Clinical Considerations -nonselectively β1 and β2-receptor blocker -ABP 감소, myocardial contractility감소, HR 감소, renin release 감소 -cardiac output, myocardiac oxygen demand 감소 특히 BP증가, HR증가와 연관된 myocardial ischemia 에 효과적 -AV conduction을 늦추고 myocardial membrane을 안정화 -supraventricular tachycardia에서 ventricular response를 늦추는데 효과적

37. PROPRANOLOL thyrotoxicosis, pheochromocytoma에서 β-adrenergic effect 차단 -Side effect bronchospasm, CHF, bradycardia, A-V heart block -Withdrawal syndrome : 24-48시간 동안 β-blocker therapy 후 중단 ->HTN (rebound HTN), tachycardia, angina pectoris

38. PROPRANOLOL • Dosage & Packaging Baseline sympathetic tone에 의해 용량 결정 Beginning 0.5mg Progressing 3-5min 마다 0.5mg 씩 증량 Total dose가 0.15mg/kg이 넘지 않도록