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

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adrenoceptor physiology
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
adrenoceptor physiology1
Adrenoceptor Physiology
  • Adrenergic Receptor
    • Classified according to the reaction to Adrenergic agents
    • α (α1, α2) β (β1, β2, β3)
adrenoceptor physiology2
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
adrenoceptor physiology3
Adrenoceptor Physiology
  • α1 – receptor
    • Myocardium – slightly positive inotropic & negative chronotropic effects
    • Cardiovascular effect – vasoconstriction
      • ↑ Pph. Vascular resistance
      • ↑ Left ventricle afterload
      • ↑ Arterial Blood Pressure
adrenoceptor physiology4
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
adrenoceptor physiology5
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)
adrenoceptor physiology6
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
adrenergic agonists1
Adrenergic Agonists
  • Catecholamine
    • Epinehrine
    • Dopamine
    • Norepinephrine
  • Short acting because of their metabolism by COMT & MAO
adrenergic agonists2
Adrenergic Agonists
  • Noncatecholamine
    • Phenylephrine
    • Ephedrine
    • Amphetamine
  • Longer half-life
adrenergic agonists3
Adrenergic Agonists
  • Varying selectivity at α and β-adrenoceptors
phenylephrine
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
phenylephrine1
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
2 agonists
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

2 agonists1
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)

2 agonists2
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
2 agonists3
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)
2 agonists4
α2 - Agonists
  • Long term use leads to supersensitization and upregulation of receptors
  • With abrupt discontinuation acute withdrawal syndrome manifests (hypertensive crisis)
epinephrine
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
epinephrine1
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
ephedrine
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
ephedrine1
Ephedrine
  • Dosage & Packaging
    • bolus 2.5-10mg in adult
    • 0.1mg/kg in children
  • Subsequent doses are increased to offset tachyphylaxis
norepinephrine
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

norepinephrine1
Norepinephrine
  • Dosage & Packaging
    • Bolus (0.1μg/kg)
    • Continuous (4mg of drug 500ml D5W[8μg/ml])

: 2-20μg/min

dopamine
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
dopamine1
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

dobutamine
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
blockers phentolamine
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])
mixed antagonists labetalol
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
mixed antagonists labetalol1
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

blockers
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

esmolol
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)

esmolol1
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

propranolol
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

propranolol1
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

propranolol2
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