Pharmacology of the autonomic system 2

• Adrenergic neurons


  Release norepinephrine or epinephrine as the primary neurotransmitter, located either presynaptically or postsynaptically on the effector organ
• "P are, T rue L ove D oes N ot E xist": 'Phenylalanine → Tyrosine → Levodopa (L-Dopa) → Dopamine → Norepinephrine → Epinephrine'
• BIOSYNTHESIS OF CATECHOLAMINES


  Phenylalanine → Tyrosine → Levodopa (L-Dopa) → Dopamine → Norepinephrine → Epinephrine
• FATES OF CATECHOLAMINES


  • Binds to Post synaptic receptors
  • Metabolism by COMT (Catechol-O-Methyltransferase) by methylation and MAO (Monoamine Oxidase) by Oxidation
  • Reuptake of norepinephrine via reuptake transporter (NET) Norepinephrine Transporter
• INHIBITED BY


  • Cocaine
  • TCA (Tricyclic Antidepressant)
  • Robexetin (NE Reuptake Inhibitor)
• Adrenergic drugs


  Sympathomimetics, Adrenergic Agonist, Action is SYMPATHETIC
• Adrenergic Receptors


  • α1
  • α2
  • β1
  • β2
• DESENSITIZATION


  1. Sequestration of the receptors so that they are unavailable for interaction with the ligand

  2. Down-regulation, that is, a disappearance of the receptors either by destruction or by decreased synthesis

  3. Inability to couple to G protein, because the receptor has been phosphorylated on the cytoplasmic side
• CLASSIFICATION OF ADRENERGIC DRUGS

  • DIRECT ACTING SYMPATHOMIMETICS
  • INDIRECT ACTING SYMPATHOMIMETICS
  • CENTRALLY ACTING SYMPATHOMIMETICS
• DIRECT ACTING SYMPATHOMIMETICS


  • I. NON-SELECTIVE
  • II. SELECTIVE AGONIST
• Non-selective direct acting sympathomimetics

  Natural catecholamines: Epinephrine, Norepinephrine, Dopamine
• Natural catecholamines


  • Pharmacodynamic: β > α
  • Pharmacokinetics: Poor Oral Bioavailability, Acid labile/sensitive, IV and SC, Extensive first pass metabolism, Can limit its own absorption
• Epinephrine


  In the adrenal medulla, norepinephrine is methylated to yield epinephrine, stored in chromaffin cells, adrenal medulla releases 80% epinephrine and 20% norepinephrine, interacts with both alpha and beta receptors
• Lower doses of epinephrine

  Beta effects (vasodilation) predominates
• Higher doses of epinephrine

  Alpha effects (vasoconstriction) predominates
• Epinephrine: pharmacokinetics


  Rapid onset, brief duration of action, preferred route: IM (anterior thigh), rapidly metabolized by MAO and COMT, metabolites: metanephrine and vanillylmandelic acid, excreted in the urine
• Actions of Epinephrine


  • CARDIOVASCULAR: Beta 1 effects, Alpha effects, Beta 2 effects
  • RESPIRATORY: Powerful bronchodilator, Inhibits release of allergic mediators
  • HYPERGLYCEMIA: Beta 2 effects, Alpha 2 effect
  • LIPOLYSIS: Initiates lipolysis through agonist activity on the Beta receptors of adipose tissue
• Uses of Epinephrine


  • First stimulant in the heart, Advance Cardiac Life Support, DOC for Anaphylactic Shock, Local vasoconstrictor with Local Anesthetics, Management of Glaucoma
• Epinephrine: adverse effects


  • CNS: Anxiety, fear, tension, headache, and tremor, Trigger arrhythmias especially for patient receiving digoxin, Can induce pulmonary edema, May enhanced cardiovascular actions in patients with hyperthyroidism, Tachycardia, Release of endogenous stores of glucose (Hyperglycemia)
• Norepinephrine


  At therapeutic doses, the alpha adrenergic receptor is most affected, Causes an intense rise in peripheral resistance, Increase both systolic and diastolic blood pressures, Stimulates the baroreceptors, inducing a rise in vagal activity (reflex bradycardia)
• Uses of Norepinephrine


  • Inotropic Agent, 1st line agent for Septic Shock, Given IV for rapid onset of action, Duration of action: 1-2 minutes following the end of infusion, Rapidly metabolized by MAO and COMT, Excretion: in the urine
• Adverse effects of Norepinephrine

  • Similar to Epinephrine, Blanching and sloughing of the skin along an injected vein, Tissue necrosis, Treatment: Phentolamine (α blocker)
• Dopamine


  Immediate metabolic precursor of norepinephrine, Occurs naturally in the CNS in the basal ganglia and adrenal medulla, Can activate both alpha and beta-adrenergic receptors; D1 and D2 receptors
• Actions of Dopamine


  • CARDIOVASCULAR: Exerts a stimulatory effect on the B1 receptor of the heart, Both positive inotropic and chronotropic effects, At higher doses: alpha receptors causing vasoconstriction
  • RENAL AND VISCERA: Dilates renal and splanchnic arterioles by activating dopaminergic receptors
• Uses of Dopamine


  • LOW DOSE: Stimulates D1, Vasodilation, Stimulates β1, ↑force of cariac contraction, ↑ Heart rate
  • HIGH DOSE: Stimulates α1, Vasoconstriction, Management of Septic and Cardiogenic Shock (Acute Heart Failure)
• Selective Adrenergic Agonists


  • β- nonselective: Isoproterenol
  • β1- selective: Dobutamine
  • β2- selective: Ritodrine, Isoxuptine, Terbutaline, Salbutamol, Levalbuterol, Terbutaline, Formoterol, Salmeterol, Bambuterol
  • α1- agonist: Phenylephrine, Methoxamine, Oxymetazoline, Xylometazoline
  • α2- agonist: Clonidine, Apraclonidine, Brimonidine, Methyldopa, Guanfacine, Guanabenz
  • D1- agonist: Fenoldopam
• Isoproterenol


  Direct-acting synthetic cathecholamine that stimulates both Beta 1 and Beta 2 adrenergic receptors, Produces intense stimulation of the heart, Increase heart rate, contractility, and cardiac output, Used as an alternative inotropic agent in the management of shock states and Acute heart failure, Dilates the arteriole of the skeletal muscle, Potent bronchodilator, Used in the management of Bronchial Asthma
• Dobutamine


  1st Line Agent for Cardiogenic Shock, Dobutamine + Dipyridamole = Stress Test, Increase cardiac output in heart failure, Inotropic support after cardiac surgery
• β2 - selective adrenergic agonists

  • Tocolytics: Ritodrine, Isoxuprine, Terbutaline
  • Short Acting Beta 2 Agonists (SABA): Salbutamol, Levalbuterol, Terbutaline
  • Long Acting Beta 2 Agonists (LABA): Formoterol, Salmeterol, Bambuterol
• Ritodrine, Isoxuptine, Terbutaline


  Tocolytics, Used to prevent premature labor, Inhibits uterine contraction
• Salbutamol, Levalbuterol, Terbutaline


  Short acting B2 agonist, Bronchodilators, Administered by metered-dose inhaler, Drug of choice for acute asthma attack, Terbutaline (only SC) also used as uterine relaxant to suppress premature labor
• Formoterol, Salmeterol, Bambuterol


  Long acting beta-2 agonists, Provide sustained bronchodilation for 12 hours, Agents of choice for treating nocturnal asthma in symptomatic patients taking other asthma medications
• Formoterol, Salmeterol, Bambuterol


  • Combined with CORTICOSTEROIDS, 1st Line Controllers for asthma, Inhalational Corticosteroids: Budesonide + Formoterol (SYMBICORT®), Fluticasone + Salmeterol (SERETIDE®), Bambuterol (BAMBEC®)
• α1- agonists


  Phenylephrine, Methoxamine, Oxymetazoline, Xylometazoline
• Oxymetazoline


  Found in many OTC short term nasal spray decongestants and ophthalmic drops, Directly stimulates alpha receptors on blood vessels supplying the nasal mucosa and conjunctiva (Vasoconstriction and decreasing congestion)
• Phenylephrine


  Vasoconstrictor, It has no effect on the heart, Induce reflex bradycardia when given parenterally, Used as Nasal Decongestant, Management of Hypotension, Local Vasoconstrictor with Local anesthetics
• Adverse Effects of Phenylephrine

  • Exacerbation of Hypertension, Precipitate Urinary Retention in patient with Benigh Prostatic Hyperplasia, Tolerance happens when used more than 5 days, "Rhinitis Medicamentosa" - Rebound congestion, Used more than 3 days
• α2- agonists


  Clonidine, Apraclonidine, Brimonidine, Methyldopa, Inhibits Release of Norepinephrine, Inhibitory Effect
• L, BAMBUTEROL


  Combined with CORTICOSTEROIDS
• 1st Line Controllers for asthma

  • Inhalational Corticosteroids
  • Budesonide + Formoterol (SYMBICORT®)
  • Fluticasone + Salmeterol (SERETIDE®)
  • Bambuterol (BAMBEC®)