ADRENERGIC AGONIST

• Adrenergic Drugs
• Lecture Guide - Learner's Copy
• Prepared by: Athena Andre A. Sabellano, RPh
• Outline


  • Symapathetic Nervous System
  • Sympathomimetic/Adrenoceptor Agonists
  • Drugs affecting the adrenergic transmission
• Sympathetic Nervous System


  • It is an important regulator of virtually all organ systems
  • The receptors involved are: Alpha 1, Alpha 2, Beta 1, Beta 2, D1, D2

  
• Neurotransmitters involved


  • Dopamine
  • Norepinephrine
  • Epinephrine
• Alpha 1 Receptor


  Gq-linked, forms inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) which promotes the stored Ca2+ from intracellular stores, increasing cytoplasmic free Ca2+
• Alpha 2 Receptor


  Gi-linked, inhibits adenylyl cyclase activity = decreased levels of cAMP
• Activation of alpha 2 receptors can also cause platelet aggregation (mechanism is unclear)
• Beta Receptor


  Gs-linked Beta 1,2, and 3, stimulated adenylyl cyclase = increased cAMP, the major secondary messenger of B-receptor activation
• Beta Receptor Activation


  • In the liver, presence of cAMP activates glycogen phosphorylase
  • In the heart, the presence of cAMP increases the influx of Ca2+ inside the cells of the heart = action potential = activity = increase activity of the heart
  • In the smooth muscle, the cAMP causes relaxation of smooth muscle
• Beta 3 Receptor


  Lower affinity receptor compared with B1 and B2 receptor but more resistant to desensitization, expressed in the detrusor muscle of the bladder and induce its relaxation
• D1 Receptor


  Gs-linked, increased adenylyl cyclase activity = increased cAMP, causes relaxation of smooth muscle = vasodilator
• D2 Receptor


  Gi-linked, decrease adenylyl cyclase activity = decreased cAMP
• Agonists and antagonists can be selective but selectivity is not usually absolute, and at higher concentrations, a drug may also interact with related classes of receptor
• Organ system effects of sympathomimetic drugs

  • Prominent cardiovascular effects due to widespread distribution of alpha and beta adrenoceptors in the heart, blood vessels, and neural and hormonal system involved in blood pressure regulation
  • Alpha 1 receptor activation leads to arterial and venous vasoconstriction, their cardiac function is of relatively less importance
  • Activation of alpha receptors may cause slowing of heart rate as a reflex response to vasoconstriction, not a direct effect of alpha 1 receptor activation
  • Alpha 2 receptor activation leads to vasoconstriction when given locally or in high doses, but when given systemically their central effects lead to inhibition of sympathetic tone and reduced blood pressure
  • Beta 1 receptor activation increases cardiac activity (increased heart rate, conduction velocity, contractility)
  • D1 receptor activation promotes vasodilation and natriuresis
• Organ system effects of sympathomimetic drugs

  • Bronchial smooth muscle (B2 receptors = bronchodilation)
  • Eye (Alpha receptors = increased outflow of aqueous humor, Beta antagonists = decreased production of aqueous humor)
  • Genitourinary (Alpha 1 receptors = urinary continence)
  • Fat cells (B3 receptors = increased lipolysis)
  • Extracellular component (B2 receptors = increased K+ uptake into cells)
  • Pancreatic islets (Beta receptors = increased insulin secretion, Alpha receptors = decreased insulin secretion)
  • Kidney (Beta 1 receptors = increased renin secretion, Alpha 2 receptors = inhibition of renin secretion)
  • Glands (Adrenoceptors modulate secretion of PTH, Calcitonin, Thyroxine, Gastrin)
  • CNS (Adrenoceptor activity depends on ability to cross blood-brain barrier)
• Sympathomimetic/Adrenoceptor Agonist Drugs


  • Epinephrine (A1=A2, B1=B2)
  • Norepinephrine (A1=A2, B1>>B2)
  • Dopamine (D1=D2 >> B >> A)
• Epinephrine


  Alpha receptors = potent vasoconstrictor, Beta 1 receptor = cardiac stimulant, Beta 2 receptor = skeletal muscle vasodilation. Used for anaphylactic shock, cardiac arrest, pharmacologic hemostasis. Caution for acral vascular beds to prevent ischemic necrosis.
• Norepinephrine


  Alpha receptors = vasoconstriction, increased peripheral vascular resistance. Drug of choice for septic shock.

  
• Dopamine


  Alternative for cardiogenic shock. All 3 (epinephrine, norepinephrine, dopamine) are used in shock.
• Types of Shock


  • Septic - huge dip in blood pressure after an infection
  • Cardiogenic - the heart cannot pump enough blood
  • Hypovolemic
• Treatment for Shock


  • Constrict the blood vessels/vasoconstrictors
• Direct-acting Sympathomimetic Drugs


  • Alpha 1 receptor agonists: Phenylephrine, Oxymetazoline, Methoxamine, Tetrahydrozoline, Midodrine
  • Alpha 2 selective agonists: Clonidine, Methyldopa, Guanfacine, Guanabenz, Apraclonidine, Brimonidine
  • Nonselective Beta agonist: Isoproterenol
  • Beta 1 selective agonist: Dobutamine
  • Beta 2 selective agonists: Salbutamol/Albuterol, Terbutaline, Pirbuterol, Metaproterenol, Salmeterol, Formoterol, Bambuterol, Indacaterol
  • Dopamine agonists: Levodopa, Fenoldopam
• Indirect-acting Sympathomimetic Drugs


  • Releasers: Tyramine, Ephedrine, Pseudoephedrine, Amphetamine, Methamphetamine, Methylphenidate, Modafinil
  • Reuptake Inhibitors: Tricyclic Antidepressants, Cocaine, Atomoxetine, Reboxetine, Sibutramine, Duloxetine
• Drugs affecting adrenergic transmission