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Sympatholytic pharmacology

Selective vs. Non-selective Antagonist vs. Partial Agonist Reversible vs. Irreversible. Sympatholytic pharmacology. NH. H. O. 3. H. O. C. H. C. H. N. H. 2. 2. O. H. Norepinephrine. Phospho. -. (+). G. lipase C. q. PIP. 2. IP. Diacylglycerol. COOH. 3. 2+.

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Sympatholytic pharmacology

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  1. Selective vs. Non-selective Antagonist vs. Partial Agonist Reversible vs. Irreversible Sympatholytic pharmacology

  2. NH H O 3 H O C H C H N H 2 2 O H Norepinephrine Phospho - (+) G lipase C q PIP 2 IP Diacylglycerol COOH 3 2+ Increase Ca Activate Protein Kinase C Response Receptor agonists activate signal transduction pathways a1 adrenergic receptor

  3. H O H O C H C H N H 2 2 O H Norepinephrine Receptor antagonists block agonist binding to the receptor Antagonist NH 3 Phospho - G lipase C q What effect would an antagonist alone have on receptor activation? COOH

  4. Clinical pharmacology of a-adrenergic receptor antagonists Route of Drug Receptor admin. Clinical uses a , a Phenoxybenzamine Oral Pheochromocytoma, hypertensive crisis 1 2 a , a Phentolamine Parenteral Pheochromocytoma, hypertensive crisis, 1 2 male impotence a Prazosin Oral Hypertension, benign prostatic 1 hypertrophy a Terazosin Oral Hypertension, benign prostatic 1 hypertrophy a Doxazosin Oral Hypertension, benign prostatic 1 hypertrophy Side effects of a1 receptor antagonists: Orthostatic hypotension, inhibition of ejaculation, nasal stuffiness, tachycardia

  5. Non-selective adrenergic receptor antagonists b-Haloalkylamines R= aromatic, alkyl X= Cl-, Br-, etc.

  6. Non-selective adrenergic receptor antagonists b-Haloalkylamines • Non-selective a receptor antagonist • Also blocks acetylcholine, histamine, and serotonin receptors • Irreversible antagonist resulting from covalent modification of receptor Phenoxybenzamine (Dibenzyline)

  7. Non-selective adrenergic receptor antagonists b-Haloalkylamines: Mechanism of receptor inactivation alkylated receptor receptor

  8. Non-selective adrenergic receptor antagonists Imidazolines • Non-selective a receptor antagonist • Competitive (reversible) blocker • Potent vasodilator, but induces pronouced reflex tachycardia • Block of presynaptic a2 receptors may promote release of NE • Also blocks 5-HT receptors, and is a muscarinic and histamine receptor agonist Phentolamine (Regitine)

  9. Reversible vs. Irreversible receptor blockade 1 M Phent 1 M Phenox 10 M Phenox 10 M Phent + Phenoxybenzamine + Phentolamine

  10. a1-adrenergic receptor antagonists • “Quinazolines” • Vary in half-life: • Prazosin 3 hrs • Terazosin 12 hrs • Doxazosin 20 hrs • Undergo extensive metabolism, excreted mainly in the bile • Vasodilators • Relaxation of smooth muscle in enlarged prostate and in bladder base • “First-dose” effect

  11. Other a adrenergic receptor antagonists Ergot alkaloids • Derivatives of Lysergic Acid • Product of the grain fungus Claviceps purpura • 5 Major alkaloids based on R and R’; Ergotamine the most common • Used in the treatment of migraine • Ergots possess strong oxytocic action

  12. a2-adrenergic receptor antagonists • Indole alkaloid • Found in Rubaceae and related trees. Also in Rauwolfia Serpentina. • Blockade of a2 receptors increases sympathetic discharge • Folklore suggests use in the treatment of male impotence Yohimbine (Yocon)

  13. b-adrenergic receptor antagonists Aryloxypropanolamines Note: non-carbon atom in side chain

  14. b-adrenergic receptor antagonists • Non-selective • Lipophilic • Local anesthetic properties • Blockade is activity-dependent P r o p r a n o l o l ( I n d e r a l )

  15. b-adrenergic receptor antagonists Pharmacological effects • Decreased cardiac output and heart rate • Reduced renin release • Increase VLDL, Decrease HDL • Inhibit lipolysis • Inhibit compensatory glycogenolysis and glucose release in response to hypoglycemia • Increase bronchial airway resistance P r o p r a n o l o l ( I n d e r a l ) Therapeutic uses for b-adrenergic receptor antagonists: Hypertension, angina, cardiac arrhythmias, migraine, stage fright, thyrotoxicosis, glaucoma, congestive heart failure (types II and III)

  16. Timolol (Timoptic, Blocadren) Non-selective b-adrenergic receptor antagonists • Less lipophilic than propranolol • Long half-life: ~20 hours • Mostly excreted unchanged in urine • Administered: Oral • Uses: Hypertension, angina, migraine • Thiadiazole nucleus with morpholine ring • Administered: Oral, Ophthalmic • Uses: Hypertension, angina, migraine, glaucoma Nadolol (Corgard) How will -blockers affect pupil size?

  17. Non-selective b-adrenergic receptor antagonists • Possesses “Intrinsic sympathomimetic activity (ISA) • Partial agonist • Less likely to cause bradycardia and lipid abnormalities • Administered: Oral • Uses: Hypertension, angina, migraine Pindolol (Visken) What would a pindolol dose-response curve look like?

  18. Dose-Response Curves and Partial Agonists NE NE + Pindolol Pindolol NE + Propranolol %

  19. Non-selective b-adrenergic receptor antagonists • Possesses “Intrinsic sympathomimetic activity (ISA) • Partial agonist • Less likely to cause bradycardia and lipid abnormalities • Administered: Oral, Opththalmic • Uses: Hypertension, glaucoma

  20. Selective b1-adrenergic receptor antagonists • “Cardioselective” • Less bronchconstriction • Moderate lipophilicity • Half-life: 3-4 hours • Significant first-pass metabolism • Administered: Oral, parenteral • Uses: Hypertension, angina, antiarrhythmic, congestive heart failure

  21. Selective b1-adrenergic receptor antagonists • “Cardioselective” • Less bronchconstriction • Low lipophilicity • Half-life: 6-9 hours • Administered: Oral, parenteral • Uses: Hypertension, angina Atenolol (Tenormin)

  22. Selective b1-adrenergic receptor antagonists • Very short acting • Half-life: 9 minutes • Rapid hydrolysis by esterases found in red blood cells • Administered: Parenteral Note: incompatible with sodium bicarbonate • Uses: Supraventricular tachycardia, atrial fibrillation/flutter, perioperative hypertension Esmolol (Brevibloc)

  23. Side effects of b-blockers: Bradycardia, AV block, sedation, mask symptoms of hypoglycemia, withdrawal syndrome

  24. Action Potential Effect of chronic b-receptor blockade Na+ Presynaptic neuron Tyrosine Na+ Dopamine Tyrosine MAO H+ DA NE NE Ca2+ Uptake 1 Na+, Cl- NE NE NE NE Effector organ

  25. Action Potential Effect of chronic b-receptor blockade: Receptor up-regulation Na+ Tyrosine Na+ Dopamine Tyrosine MAO H+ DA NE NE Ca2+ Uptake 1 Na+, Cl- NE NE NE NE Effector organ

  26. Side effects of b-blockers: Bradycardia, AV block, sedation, mask symptoms of hypoglycemia, withdrawal syndrome Contraindications: Asthma, COPD, congestive heart failure (Type IV)

  27. Mixed adrenergic receptor antagonists • Non-selective b receptor antagonist • a1 receptor antagonist • Two asymmetric carbons (1 and 1’) • (1R, 1’R)-isomer possesses b-blocking activity • (1S, 1’R)-isomer possesses greatest a1 receptor blocking activity • b-blocking activity prevents reflex tachycardia normally associated with a1 receptor antagonists • Administered: Oral, parenteral • Uses: Hypertension, hypertensive crisis Labetalol (Normodyne, Trandate)

  28. Mixed adrenergic receptor antagonists Carvedilol (Coreg) • Non-selective b receptor antagonist • a1 receptor antagonist • Both enantiomers antagonize a1 receptors • Only (S)-enantiomer possesses b-blocking activity • b-blocking activity prevents reflex tachycardia normally associated with a1 receptor antagonists • Administered: Oral • Uses: Hypertension, congestive heart failure (Types II and III)

  29. Action Potential Pharmacologic manipulation of the adrenergic system Na+ Presynaptic neuron Tyrosine Na+ 1 Dopamine Tyrosine 2 MAO H+ DA NE NE Ca2+ Uptake 1 3 Na+, Cl- NE NE NE NE b Effector organ

  30. X Metyrosine Inhibition of norepinephrine synthesis H O C H C H N H T Y R O S I N E 2 2 C O O H t y r o s i n e h y d r o x y l a s e H O H O C H C H N H D O P A 2 2 C O O H a r o m a t i c L - a m i n o a c i d d e c a r b o x y l a s e H O H O C H D O P A M I N E C H N H 2 2 2 b d o p a m i n e - h y d r o x y l a s e H O H O C H C H N H N O R E P I N E P H R I N E 2 2 O H p h e n y l e t h a n o l a m i n e - N - m e t h y l t r a n s f e r a s e H O H O C H C H E P I N E P H R I N E N H 2 O H C H 3

  31. Action Potential Drugs that reduce storage or release of NE Na+ Tyrosine Na+ Dopamine Tyrosine Reserpine Guanethidine MAO H+ NE NE Ca2+ NE Guanethidine, Bretylium Guanethidine b Effector organ

  32. Catecholamine depleters • Slow onset of action • Sustained effect (weeks) • Used in the treatment of hypertension • May precipitate depression Reserpine (Serpasil) • Indole alkaloid obtained from the root of Rauwolfia serpentina • Block vesicular monoamine transporters • Deplete vesicular pool of NE

  33. Drugs that reduce storage or release of NE • Possess guanidino moiety (pKa > 12) • Resonance stabilization of cation “spreads” positive charge over the entire four atom system • Almost completely protonated at physiological pH • “Pharmacologic sympathectomy” • Effects can be blocked by transport blockers • Uses: Hypertension Guanethidine (Ismelin)

  34. Action Potential Drugs that reduce storage or release of NE Na+ Tyrosine Na+ Dopamine Guanethidine Tyrosine MAO H+ NE NE Ca2+ NE Guanethidine, Guanethidine b Effector organ

  35. Drugs that reduce storage or release of NE • Aromatic quaternary ammonium • Precise mechanism unknown • Displace and release NE and prevent further release (depletion) • Local anesthetic • Administered: Parenteral • Uses: Antiarrhythmic (ventricular fibrillation) Bretylium tosylate (Bretylol)

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