Med Org

• Adrenergic Agents


  Substances that act on adrenergic receptors
• Catecholamines


  Substances containing the catechol (3,4-dihydroxybenzene) group

  
• Synthesis of Catecholamines


  1. COMT, MAO

  2. Present on cytoplasm of presynaptic cell

  
• Metyrosine


  Inhibits hydroxylation of Tyr to DOPA
• Reserpine


  Inhibits transport of DA in the vesicle via VMAT
• Bretylium, Guanethidine


  Inhibits Ca2+ ion influx
• Cocaine, Amphetamine


  • Stimulates Ca2+ ion influx
  • Inhibits Norepinephrine reuptake by blocking norepinephrine transporter (NET)
• Adrenergic Receptors


  • α-1
  • α-2
  • β-1
  • β-2
  • β-3
• α-1 receptors


  • Located in blood vessels/vasculatures (constrict)
  • Located in pupils (dilate)
  • Located in genito-urinary (GU) and gastrointestinal (GI) sphincters (contract/close)
• α-2 receptors


  Located in pre-synaptic nerve terminal, brain (inhibit NE, ACh, and insulin release)
• β-1 receptors


  • Located in heart (increase HR, contractility)
  • Located in kidneys (increase renin release)
• β-2 receptors


  • Located in lungs (bronchodilation)
  • Located in blood vessels/vasculature (dilate)
  • Located in liver (glucagon release)
  • Located in uterine smooth muscles (relax)
  • Located in ciliary bodies (increase aqueous humor production)
• β-3 receptors


  Located in adipose tissues (lipolysis)
• Classification of adrenergic agonist drugs based on their action


  • Direct acting (non-selective & selective)
  • Indirect acting
  • Mixed actions
• Classification of adrenergic agonist drugs based on their structure


  • Catecholamine and Non-catecholamine
  • Phenylethylamine and Arylimidazoline

  
• Catecholamines


  Adrenergic agonists containing the catechol (3,4-dihydroxybenzene) group

  
• Non-catecholamines


  Adrenergic agonists not containing the catechol group

  
• Catecholamines


  • Metabolized by COMT post-synaptically and by MAO intraneurally
  • Polar and do not readily penetrate into the CNS
  • Have only short duration of action when given parenterally (1-2 mins) and are inactivated when administered orally
• Catecholamine adrenergic agonists


  • Epinephrine
  • Norepinephrine
  • Dopamine
  • Isoproterenol
  • Dobutamine

  
• Phenylethylamine adrenergic agonists


  • Epinephrine
  • Norepinephrine
  • Dopamine
  • Dobutamine
  • Isoproterenol
  • Phenylephrine
  • SABAs (Albuterol, Terbutaline)
  • LABAs (Salmeterol, Formeterol)
  • Ephedrine
  • Pseudoephedrine
  • Amphetamine
  • Methamphetamine

  
• Arylimidazoline adrenergic agonists

  • Clonidine
  • Oxymetazoline, Xylometazoline
  • Tetrahydrozoline
  • Naphazoline
  • Brimonidine
  • Tizanidine

  
• Phenylethylamine structure


  Has three domains: 1) Phenyl ring, 2) Ethylene bridge, 3) Amino terminal group

  
• Phenyl ring (Phenylethylamines)


  • Removal of phenolic group results in significant drop in beta (β) receptor activity

  1. Direct acting adrenergic drugs contain: a) hydroxyl group at the meta and para positions of the aromatic ring, b) β-hydroxyl group of correct orientation
  2. Replacement of catechol by resorcinol increases beta-2 (β2) selectivity and decreases catechol-o-methyl transferase (COMT) degradation, thus, longer duration of action
  3. Replacement of meta-hydroxyl increases beta-2 (β2) selectivity and decreases COMT degradation, thus, longer duration of action
  4. Removal of para-hydroxyl group from epinephrine makes the molecule selective to alpha-1 (α-1) adrenergic receptors
  5. Presence of catechol or monophenol makes the molecule hydrophilic (polar); thus, it does not penetrate the blood-brain barrier
• Ethylene bridge (Phenylethylamines)


  • For optimal adrenergic activity, amino (NH) groups should be separated from the aromatic ring by two (2) carbon atoms

  1. Methyl or ethyl substitution on the (α) carbon decreases degradation by MAO (monoamine oxidase)
  2. β-hydroxyl group introduces chirality. For epinephrine, norepinephrine, and related compounds, R-configuration exhibits more potency

  
• Amino group (Phenylethylamines)


  • Amino group is necessary for direct adrenergic agonist activity

  1. Primary and secondary amines are more potent as compared to tertiary amines
  2. The nature of amino group substituent affects the selectivity of compounds to adrenergic receptors
  3. As the bulky substituent further increases, it increases β2 selectivity
  4. Larger substitution on amino group decreases metabolism by MAO
• Arylimidazoline structure


  Consists of: 1) Aromatic ring, 2) Imidazole group. The phenylethylamine exists within the heterocyclic arylimidazoline structures.

  
• Arylimidazolines (Adrenergic Agonists)


  • A halogen ortho substituent is required for potent α-agonist activity. Two ortho-halogen substituents increase lipophilicity and facilitate CNS action.

  
• Adrenergic Antagonists

  • α-blockers
  • β-blockers
  • α and β-blockers
• Non-selective α-blockers


  Phenoxybenzamine (Dibenzyline) - irreversible

  Phentolamine (Regitine) - reversible

  
• Selective α1-blockers


  Quinazoline α-1 blockers (Prazosin, Terazosin, Doxazosin, Alfuzosin, Tamsulosin, Silodosin)

  Yohimbine
• Non-selective β-blockers


  Propranolol (Inderal), Nadolol (Corgard), Timolol (Betimol), Sotalol (Betapace)
• Selective β-blockers


  Acebutolol (Sectral), Atenolol (Tenormin), Betaxolol (Betoptic), Bisoprolol (Zebeta), Esmolol (Brevibloc), Metoprolol (Lopressor), Nevibolol (Bystolic)
• α and β-blockers


  Labetalol (Trandate), Carvedilol (Coreg), Bucindolol
• Adolol (Corgard)

  • Timolol (Betimol)
  • Sotalol (Betapace)
  • Pindolol
  • Penbutolol
  • Carteolol
  • Metipranolol
  • Levibunolol
  • Labetalol (Trandate)
  • Carvedilol (Coreg)
  • Bucindolol
• Selective


  • Prazosin (Minipress)
  • Terazosin (Hytrin)
  • Doxazosin (Cardura)
  • Alfuzosin (Uroxatal)
  • Tamsulosin (Flomax)
  • Silodosin (Rapaflo)
  • Yohimbine
• Acebutolol (Sectral)<|>Atenolol (Tenormin)<|>Betaxolol (Betoptic)<|>Bisoprolol (Zebeta)<|>Esmolol (Brevibloc)<|>Metoprolol (Lopressor)<|>Nevibolol (Bystolic)


  Adrenergic Antagonists: α-adrenergic blocking agents
• Non-selective (α1 and α2-blocker)


  • Phenoxybenzamine (Dibenzyline)
  • Phentolamine (Regitine)

  
• Phenoxybenzamine


  • It act as non-competitive antagonists, irreversible
  • DOC for pheochromocytoma

  
• Phentolamine

  • It act as a competitive antagonists (reversible)
  • Used for tx of hypertensive crisis due to clonidine withdrawal and ingestion of tyramine-containing foods in patients taking MAO inhibitors
• Quinazoline α-1 blockers


  • Prazosin (Minipress)
  • Terazosin (Hytrin)
  • Doxazosin (Cardura)
  • Alfuzosin (Uroxatal)