Dr. baltazar s adrenergic agonists


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Dr. baltazar s adrenergic agonists

  2. 2. METABOLIC SYNTHESIS OF NOREPINEPHRINE AND EPINEPHRINE Tyrosine (from ECF  cytoplasm) Tyrosine hydroxylase (mitochondrial) Tetrahydrobioterin (cofactor) DOPA Decarboxylase (cytoplasmic) Pyridoxine PO4 (cofactor) DOPAMINE Dopamine B-oxidase (in specific granules) Ca Mg + ATP Ascorbic acid (cofactor) Exocytosis: Mechanism whereby Ca brings about the release of NE NE Phenylethanolamine N-methyltransferase (in adrenal medulla) EPINEPHRINE Ca++ is needed for membrane excitation and release of catecholamines for adrenergic neurons and adrenal medullary cells.
  3. 3. NEUROTRANSMISSION AT ADRENERGIC NEURONS I. II. III. IV. V. Synthesis of NE – Tyrosine is transported  cytoplasm of adrenergic neuron  DOPA  Dopamine. Storage of NE in Vesicles – Dopamine is transported into synaptic vesicles using an amine transporter (carrier) DOPAMINE  NE. Release of NE – Action potential at nerve ending triggers calcium influx  cytoplasm of neuron causing fusion of vesicles with cell membrane releasing NE  synapse . Binding to Receptor – NE diffuses across the synaptic space and binds to either: 1) post-synaptic receptors on the effector organs or 2) pre-synaptic receptors on the nerve ending. This triggers a cascade of events resulting in the formation of intracellular 2nd messenger (cyclic AMP). Removal of NE – NE diffuses out of the synaptic space  general circulation or it may be recaptured by an uptake system then back into the neuron.
  4. 4. TERMINATION OF ACTIVITY OF NEUROTRANSMITTER 1. 2. 3. • Reuptake into the neuron (uptake I) Enzymatic inactivation (MAO, COMT) Diffusion away from synapse and uptake at extraneuronal sites (perisynaptic glia and smooth muscle cells) (uptake II) STORAGE VESICLES OF NOREPINEPRHINE – Pool I • • • – Rapid turnover of NE T ½ of 2 hrs. NE released into synaptic cleft, metabolized by COMT. Pool II • • • Slow turnover of NE T ½ of 24 hrs. NE released into neuronal cytoplasm, metabolized by MAO.
  5. 5. ADRENERGIC AGONISTS A. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Direct-acting (Release of NE after binding to receptors) Epinephrine (Adrenaline) Norepinephrine (Noradrenaline, Levarterenol) Isoproterenol Isoetharine Dobutamine Phenylephrine Methoxamine Clonidine Metaproterenol Terbutaline Ritodrine Albuterol B. 1. Indirect-acting (Release of NE followed by binding to receptors) Tyramine C. 1. 2. 3. 4. 5. Mixed-acting Ephedrine Metaraminol Dopamine Phenylpropanolamine Amphetamines
  6. 6. CATECHOLAMINES vs NON-CATECHOLAMINES • CATECHOLAMINES – – – – • Norepinephrine Epinephrine Dobutamine Isoproterenol NON-CATECHOLAMINES – – – – – Phenylephrine Methoxamine Ephedrine Amphetamines Phenylpropanolamine
  7. 7. AGONISTS Alpha-AGONISTS Receptors Phenylephrine, Methoxamine Epinephrine, Norepinephrine Clinidine, α-methylnorepinephrine Alpha 1-selective Alpha 1 ~ Alpha 2 Alpha 2-selective Beta−AGONISTS Receptors Norepinephrine, Dobutamine Prenalterol Epinephrine, Isoproterenol Fenoterol, Albuterol (Salbutamol) Terbutaline Ritodrine (uterine muscle) Beta 1-selective Beta 1 ~ Beta 2 Beta 2-selective
  8. 8. ADRENERGIC AGONISTS DRUG Epinephrine RECEPTOR SPECIFICITY USES β1, β2 Acute asthma, open-angle glaucoma, anaphylactic shock, with local anesthetic to increase duration of action, cardiac arrest Norepinephrine α1, α2, β1 Shock Isoproterenol β1, β2 Asthma, cardiac arrest Dopamine β1 Dopaminergic Shock, CHF Phenylephrine α1 Nasal decongestant, supraventricular tachycardia Methoxamine α1 Supraventricular tachycardia Clonidine α2 Hypertension Metaproterenol β1 > β2 Bronchospasm Terbutaline Ritodrine Albuterol β2 Bronchospasm Premature labor α1, α2
  9. 9. SELECTED EXAMPLES OF SYNTHETIC ADRENERGIC AMINES Drug Uses Site of Action Phenylephrine HCl (NeoSynephrine) Vasopressor, nasal decongestant α1 Metaraminol bitartrate (Aramine) Vasopressor α1 Methoxamine (Vasoxyl) Vasopressor α1 Tetrahydrozoline HCl (Tyzine, Visine) Nasal decongestant, topical vasoconstrictor α1 Oxymetazoline LA nasal decongestant α1 Metaproterenol (Alupent, Metaprel) Bronchodilator β2 Terbutaline (Bricanyl) Bronchodilator Dextroamphetamine SO4 (Dexedrine) Neurolepsy , attention deficit disorder β2 Indirect-acting (CNS) Phentermine (Ionamine) Exogenous obesity Indirect-acting Ritodrine HCl (Yutopar) Decreases uterine activity β2 – uterine smooth muscle
  10. 10. ADRENERGIC BLOCKERS β-ADRENERGIC BLOCKERS • – – – – Non-selective (blocks β1 & β2) – – – – – • α-ADRENERGIC BLOCKERS • Non-selective (blocks α1 & α2) Propranolol Pindolol Timolol Labetalol Nadolol Selective (blocks β1) – – – – Metoprolol (Neobloc) Acebutolol Atenolol (Therabloc) Esmolol • Phentolamine Phenoxybenzamine Ergotamine Ergonovine Selective (blocks α1) – Prazosin – Terazosin • Selective (blocks α2) – Yohimbin ADRENERGIC NEURONAL BLOCKERS (blocks nerve terminals to impair biogenic amines (NE, serotonin, DA) Synthesis, storage, release: Reserpine, Guanethidine, Guanadrel, Metyrosine
  11. 11. BETA-BLOCKERS DRUG β1 Selectivity ISA MSA Acebutolol Yes + + Atenolol Yes _ _ Esmolol Yes _ _ Labetalol No _ + Metoprolol Yes _ + Nadolol No _ _ Pindolol No ++ + Propranolol No _ ++ Timolol No _ _
  12. 12. PARTICULAR NEURONAL-BLOCKERS • • RESERPINE – Blocks the ability of adrenergic neurons to transport NE from the cytoplasm into storage vesicles. – Causes ultimate NE depletion in adrenergic neurons, causing impairment of adrenergic function. – Effects: Gradual decline in BP Slows cardiac rate simultaneously – ADR: Insomnia, nightmares, hallucinations, depression, suicidal tendencies GUANETHIDINE – Blocks the release of stored NE. – Gradual lowering of BP. – Displaces NE from storage vesicles – acting as false neurotransmitter. – ADR: Orthostatic hypotension Impairs male sexual function