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Adrenergic agonists and antagonists

Adrenergic agonists and antagonists. R1 이영석. Adrenergic agonists and antagonists. An analogous group of agents that interacts at adrenergic receptors Norepinephrine & Epinephrine. Adrenoceptor physiology.

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Adrenergic agonists and antagonists

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  1. Adrenergic agonists and antagonists R1 이영석

  2. Adrenergic agonists and antagonists • An analogous group of agents that interacts at adrenergic receptors • Norepinephrine & Epinephrine

  3. Adrenoceptor physiology • Norepinephrine : most of the adrenergic activity of the sympathetic nervous system • end organ tissue 에 위치하는 postganglionic sympathetic fibers에서 유리됨 (eccrine sweat glands 와 some blood vessels 제외)

  4. Adrenergic receptor • Adrenergic agents에 대한 반응성을 기초로 하여 분류 • α (α1, α2) β (β1, β2, β3)

  5. α1-Receptors • α1-Receptors -postsynaptic adrenoreceptors -eye, lung, blood vessels, uterus, gut, genitourinary system등 몸의 smooth muscle 에 위치 -intracellular calcium ion concentration을 증가 시켜 muscle contraction -mydriasis, bronchoconstriction, vasoconstriction, uterine contraction, GI & GU tracts의 sphincter contraction와 연관

  6. α1-Receptors -insulin secretion과 lipolysis 를 inhibition -myocardium : slightly positive inotropic & negative chronotropic effects -> myocardial ischemia 시 반응 -가장 중요한 cardiovascular effect -> vasoconstriction -> pph. vascular resistance, LV afterload, ABP의 증가

  7. α2-Receptors • α2-Receptors -주로 presynaptic nerve terminals에 위치 -adenylate cyclase activity를 inhibition -calcium ion의 neuronal terminal로의 entry 감소 -norepinephrine을 가진 vesicle의 exocytosis를 제한 -Negative feedback에 의해 neuron으로부터의 further norepinephrine의 유리를 inhibition

  8. α2-Receptors -교감신경이 과도하게 자극되었을 때 교감신경 전달물질의 유리를 감소시키는 국소조절기전 -CNS (postsynaptic α2-receptors) -> sedation 유발 & sympathetic outflow 감소 -> pph. vasodilation & lower BP

  9. β1-Receptors • β1-Receptors -주로 heart의 postsynaptic membranes에 존재 -adenylate cyclase(ATP->cAMP)의 activation -chronotropic (HR 증가) dromotropic (conduction 증가) inotropic (contractility증가)

  10. β2-Receptors • β2-Receptors -smooth muscle & gland cell의 postsynaptic adrenoreceptors -β1-Receptors (adenylate cyclase action)와 action mechanism을 공유 -smooth muscle을 relaxation ->bronchodilation, vasodilation, relaxation of uterus, bladder and gut

  11. β2-Receptors -glycogenolysis, lipolysis, gluconeogenesis, insulin release를 stimulation -potassium을 intracellular로 이동 -> hypokalemia, dysarrhythmia

  12. β3-Receptors • β3-Receptors -gallbladder and brain adipose tissue -gallbladder 에서의 역할은 불명확 -brown fat에서 lipolysis and thermogenesis 에 관여할 것으로 추정

  13. Adrenergic receptor

  14. Adrenergic agonist

  15. Adrenergic agonist • Direct acting epinehrine, norepinephrine, dopamine, dobutamine, phenylephrine, clonidine • Indirect acting amphetamine, tyramine • Mixed action ephedrine, mataraminol

  16. Adrenergic agonist • Catecholamine epinehrine, dopamine, norepinephrine -COMT, MAO에 의해서 신속하게 불활성화 -중추신경계로의 낮은 투과성

  17. Adrenergic agonist • Non-catecholamine -phenylephrine, ephedrine, amphetamine -COMT, MAO에 의해 불활성화 되지 않기 때문에 보다 긴 반감기를 가짐

  18. PHENYLEPHRINE PHENYLEPHRINE • Clinical Considerations -direct α1-agonist activity를 가진 non-catecholamine (high doses 는 α2 & β-receptors를 자극) -pph. vasoconstriction -> rise in systemic vascular resistance & arterial blood pr. -reflex bradycardia -> cardiac output 감소 -coronary blood flow의 증가

  19. PHENYLEPHRINE • Dosage & Packaging -small IV boluses of 50-100μg(0.2-1 μg/kg) -> pph. vasodilation (eg. SA) 에 의한 BP 감소를 빠르게 reverse -continuous infusion (100 μg/mL at rate of 0.25-1 μg/kg/min) : arterial BP유지 -must be diluted : 1% solution (10mg/1mL ample) ~100 μg/mL solution

  20. α2-AGONIST Methyldopa • Clinical Considerations -Methyldopa norepinephrine-synthesis pathway로 들어와 α-methylnorepinephrine 과 α-methylepinephrine으로 전환 -이런 false transmitters는 α-adrenoceptors (특히 central α2-receptor) 활성화 -결과적으로 norepinephrine 감소 -> sympathetic tone 감소 -vascular resistance 의 감소로 인해 arterial blood pr.가 감소된다. -Renal blood pr.는 유지되거나 증가된다.

  21. α2-AGONIST Clonidine • Clinical Considerations -최근에 antihypertensive & negative chronotropic effect로 인해 널리 사용됨 -sedative 효과 -anesthetic effect 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)

  22. -anesthetic and analgesic req.(MAC감소)감소 -sedation, anxiolysis -general anesthesia시 catecholamine level을 감소시켜 intraop. circulatory stability 강화 -regional anesthesia시 block을 prolongation -postop. shivering감소 -opioid induced muscle rigidity 를 inhibition, opioid withdrawal synd.을 감소, some chronic pain synd의 치료 -side effect : bradycardia, hypotension, sedation, respiratory depression, dry mouth

  23. α2-AGONIST Dexmedetomidine • Clinical Considerations -higher affinity for α2-receptors than clonidine -sedative, analgesic, sympatholytic effects 가 있어서 수술과 관련된 cardiovascular response를 blunt 하게한다 -intraop.시 IV & volatine anesthetic req. 감소 -postop.시 analgesic & sedative req. 감소

  24. -자극이 없으면 sedation이 지속되고, 자극에 의해 쉽게 깬다 -sympatholytic effect (sympathetic outflow 감소)

  25. α2-AGONIST • long term use시 receptor의 supersensitization과 upregulation이 된다 • 갑작스러운 discontinuation 시 acute withdrawal synd. 유발 -> Hypertensive crisis (dexmedetomidine 사용 중지 후 48h후에 )

  26. EPINEPHRINE EPINEPHRINE • Clinical Considerations -β1-receptors를 direct stimulation -> myocardial contractility 와 HR의 증가 -> cardiac output과 myocardial oxygen 요구량 증가 -α1-stimulation 은 splanchnic & renal blood flow를 감소, coronary and cerebral perfusion pr.를 증가, systolic blood pr. 증가, diastolic pr. 감소 -β2-stimulation 은 bronchial smooth muscle을 relax -anaphylaxis 의 치료 -ventricular fibrillation 의 치료

  27. EPINEPHRINE -Cx : cerebral hrr., coronary ischemia, ventricular dysrhythmias, 흡입마취제(특히 halothane)에 의해 dysrhythmic effects 강화 • Dosage & Packaging -shock이나 allergic reaction과 같은 응급상황 시 iv bolus로 0.05-1mg -continuous infusion : 2-20μg/min -some local anesthetic solution에 사용 1:200,000(5μg/ml), 1:400,000(2.5μg/ml) -> less systemic absorption & longer duration of action

  28. EPHEDRINE EPHEDRINE • Clinical Considerations -cardiovascular effect는 epinephrine과 유사 -BP, HR, CO, contractility 증가, bronchodilation -epinephrine에 비해 longer duration of action -indirect agonist property <- central stimulation, pph. postsynaptic norepinephrine release, inhibition of norepinephrine reuptake -anesthesia동안 vasopressor로 흔히 사용 -uterine blood flow를 감소시키지 않음 -antiemetic property

  29. EPHEDRINE • Dosage & Packaging -bolus 2.5-10mg in adult -0.1mg/kg in children -subsequent doses시에 tachyphylaxis 가 증가

  30. NOREPINEPHRINE NOREPINEPHRINE • Clinical Considerations -Direct α1-stimulation in the absence of β2-activity -> arterial & venous vessel의 vasoconstriction -β1-effect -> myocardial contractility의 증가 -> ABP증가 -그러나 afterload 증가와 reflex bradycardia 는 cardiac output의 증가를 막음 -renal blood flow감소와 myocardial oxygen req.증가 -> refractory shock 치료에 사용하기에는 제한적임 -α-blocker와 함께 사용(eg. Phentolamine) ->α-stimulation로 인한 profound vasoconstriction 을 막음

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

  32. DOPAMINE DOPAMINE • Clinical Considerations -nonselective direct and indirect adrenergic agonist -small dose (<2μg/kg/min) : minimal adrenergic effect, dopaminergic receptor 의 activation -> renal vasculature를 vasodilation, diuresis 촉진 -moderate dose (2-10μg/kg/min) : β1-stimulation -> myocardial contractility, HR, CO 증가 심근산소요구량이 공급량보다 증가

  33. DOPAMINE -higher dose (10-20μg/kg/min) : α1-effect -> pph. vascular resistance증가, renal blood flow감소 -shock 치료 : CO향상, BP support, renal function 유지 -vasodilator 와 combination -> afterload 감소, cardiac output 향상 • Dosage & Packagingcontinuous infusion (400mg in 1000mL D5W [400μg/ml]) :1-20 μg/kg/min

  34. DOBUTAMINE DOBUTAMINE • Clinical Considerations -selective β1-agonist -> myocardial contractility증가-> cardiac output 증가 -β2-activation -> pph. vascular resistance를 slight decline하여 ABP 유지 -HR 증가는 다른 β-agonists보다 덜함

  35. DOBUTAMINE -myocardial oxygen demand를 유의하게 증가시키지 않음 -> congestive heart failure와 coronary artery dis. 가 복합되어 있는 환자, 특히 pph. vascular resistance 와 HR가 이미 증가되어 있는 경우 good choice • Dosage & Packaging -Infusion (1g in 250mL [4mg/mL]) : 2-20 μg/kg/min

  36. Adrenergic antagonists

  37. PHENTOLAMINE • Clinical Considerations -α-receptors의 competitive (reversible) blockade -α1-antagonism and direct smooth muscle relaxation -pph. vasodilation and arterial BP 감소 -BP의 감소 -> reflex tachycardia -이러한 cardiovascular effect는 2분내에 나타나고 15분까지 지속 -excessive α-stimulation 에 의한 HTN (eg, pheochromocytoma, clonidine withdrawal)의 치료에는 reflex tachycardia나 postural hypotension 때문에 그 사용이 제한적임

  38. PHENTOLAMINE • Dosage & Packaging -IV intermittent bolus (1-5mg in adult) -continuous infusion (10mg in100ml D5W[100 μg/ml])

  39. LABETALOL • Clinical Considerations -mixed antagonist (α1, β1, β2-receptors를 block) -α blockade : β blockade = 1:7 -pph. vascular resistance 와 arterial blood pressure을 감소 -HR, CO는 slightly depressed 또는 unchanged -α & β- effects의 combination때문에 reflex tachycardia 없이 BP를 낮춰줌 -peak effect는 iv후 5분 이내 -left ventricular failure, paradoxical HTN, bronchospasm 등이 보고됨

  40. LABETALOL • Dosage & Packaging -Initial recommended dose : 0.1-0.25mg/kg IV 10분 간격으로 원하는 반응 얻을 때까지 투여 -slow continuous infusion (200mg in 250ml 5DW) : 2mg/min 그러나 5시간 이상의 긴 제거 반감기 때문에 prolonged infusions는 비추천됨

  41. 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

  42. 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)

  43. 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

  44. 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

  45. 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

  46. 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

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