Adrenergic antagonists


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Adrenergic antagonists

  1. 1. Gs and Gi produce stimulation and inhibition of the enzyme adenylate cyclase respectively, whilst Gq interacts with phospholipase C. H. Zhong, K.P. Minneman European Journal of Pharmacology 375 (1999) 261-276
  2. 2. SympathSympatholyolytic Drugstic Drugs
  3. 3. Wording • Adrenoceptor Blocker • Adrenergic Antagonist • Subgroups in Sympathoplegic drugs • Alpha Blocker, Alpha Antagonist • Beta Blocker, Beta Antagonist
  4. 4. Objectives 1. Describe the effects of E and NE in the presence and in the absence of Alpha Blocker. 2. Compare the effects among Beta Blockers 3. Compare the pharmacokinetics among Beta Blockers 4. Describe the clinical applications and toxicity of typical Alpha- and Beta Blockers.
  5. 5. Outline I. Concepts II. Alpha-Blocking Drugs A. Classification B. Pharmacokinetics C. Mechanism of Action D. Effects
  6. 6. Outline II. Alpha-Blocking Drugs (cont’d) E. Clinical Uses F. Adverse Effects III. Beta-Blocking Drugs A. Classification and Mechanisms B. Effects and Clinical Uses C. Adverse Effects
  7. 7. I. Concepts • Classification is based on receptor selectivity. • These drugs differ markedly in their effects and clinical ap plications.
  8. 8. II. Alpha-Blocking Drugs A. Classification –based on: selective affinity for alpha receptors, reversibility 1. Irreversible, long-acting alpha blockers 2. Reversible, short-acting alpha blockers 3. Alpha1-selective blockers 4. Alpha2-selective blockers
  9. 9. A. Classification 1. Irreversible alpha blockers : Phenoxybenzamine –slightly a 1 -selective, long-acting 2. Reversible alpha blockers: Phentolamine (nonselective), tolazoline (slightly a 2 -selective) 3. a 1 blockers: Prazosin, Doxazosin, Terazosin 4. a 2 blockers: Yohimbine, rauwolscine •
  10. 10. B. Pharmacokinetics • All active orally as well as parenterally • Phenoxybenzamine: short t1/2 but long duration-48 hr (covalent bond) • Phentolamine, tolazoline: parenteral, duration 20-40 min by parenteral rout e • Prazosin: oral, duration 8-10 hr
  11. 11. C. Mechanism of Action • Phenoxybenzamine: binds covalently--irreversible (insurmount able) blockade (slightly a 1 -selective) • Other agents: competitive antagonists--the effects can be overc ome by increased concn of agonist
  12. 12. Chemical sympathectomy Hypertensive Episodes - decreases vascular resistance - lowers BP - smooth muscle relaxation in the bladder Used to treat hypertensive episodes of Pheochromocytoma
  13. 13. D. Effects of Alpha Blockers 1. Nonselective alpha blockers –block alpha-mediated sympathetic responses and exogenous sympathomi metics –Most important effects: CVS effects •vasodilation --reduce arterial and venous pressure (a 1 ) •no significant direct cardiac effects
  14. 14. • Cause reflex tachycardia (due to decreased MAP) • Tachycardia may be exaggerated because a 2 receptors are also blocked. • e.g. phenoxybenzamine, phentolamine, tolazoline D. Effects of Alpha Blockers 1. Nonselective alpha blockers (cont)
  15. 15. Selective a1 blockers cause less reflex tachycardia than Phenoxybenzamine and Phentolamine
  16. 16. 2. Selective a 1 blockers • The same effects as nonselective alpha blockers • But cause much less tachycardia than nonselective blocker • e.g. Prazosin, Doxazosin, Terazosin D. Effects of Alpha Blockers
  17. 17. Epinephrine Reversal occur when alpha blockers are given before Epi ---> Epi produce the opposite effects : decreased BP resulting from b 2 effect (a 1 ,a 2,b 1,b 2 )
  18. 18. Antagonistic effect of alpha blocker on pretreatment with alpha agonist
  19. 19. E. Clinical Uses 1. Nonselective alpha-blockers Presurgery of pheochromocytoma: phenoxybenzamine During surgery: phentolamine (sometimes) Carcinoid tumor: phenoxybenzamine (5-HT blocking) Mastocytosis: phenoxybenzamine (H1 antihistamine)  Accidental local infiltration of alpha agonist: phentolamine Overdose of sympathomimetics (amphetamine, cocaine, phenylpropranolamine) Raynaud’ s phenomenon, erectile dysfunction (phentolamine)
  20. 20. Disorders of the Autonomic Nervous System: Raynaud’s Disease • Raynaud’s disease – characterized by constriction of blood vessels – Provoked by exposure to cold or by emotional stress
  21. 21. Disorders of the Autonomic Nervous System: Hypertension • Hypertension – high blood pressure – Can result from overactive sympathetic vasoconstriction
  22. 22. E. Clinical Uses 2. Selective a 1 -blockers  Prazosin and others  Essential Hypertension  Urinary hesitancy  Prevention of urinary retention in benign prostatic hyperplasia (BPH)
  23. 23. F. Adverse effects of Alpha blockers  Orthostatic hypotension (venodilatation)  Reflex tachycardia (nonselective > selective)  First dose hypotension (take before going to bed)  Nausea/vomiting  Caution in patients with coronary artery disease (CAD or CHD): angina
  24. 24. Receptor Type a1 a2 Selective Agonist Phenylephrine Oxymetazoline Clonidine Clenbuterol Selective Antagonist Doxazosin Prazosin Yohimbine Idazoxan Agonist Potency Order A=NA>>ISO A=NA>>ISO Second Messengers and Effectors PLC activation via Gp/q causes inc. [Ca2+ ]i dec. cAMP via Gi/o causes dec. [Ca2+ ]i Physiological Effect Smooth muscle contraction Inhibition of transmitter release Hypotension, anaesthesia, Vasoconstriction
  25. 25. QUESTIONS
  26. 26. 1. An α adrenergic receptor blocker which is more effective in the management of benign prostate hypertrophy: a) Tamsulosin b) Phenoxybenzamine c) Doxazosin d) Phentolamine e) Terazosin
  27. 27. 2. A non selective α adrenergic receptor blocking agent: a) Phenoxybenzamine b) Prazosin c) Doxazosin d) Tamsulosin e) Terazosin
  28. 28. 3. A drug useful in the treatment of a patient with a slightly enlarged prostate and suffering from hypertension: a) Prazosin b) Labetalol c) Phentolamine d) Propranolol e) Isoproterenol
  29. 29. 4. The reversal of the hypertensive effect of epinephrine (adrenaline) is produced by the blockade of: α)α1 receptors β) α2 receptors χ) β1 receptors δ) β2 receptors e) M1 receptors
  30. 30. Practice Questions • Blockade of which receptors is responsible for the therapeutic and adverse effects of adrenergic receptor agonists? • Therapeutic: a1, b1 • Adverse: a2, b2
  31. 31. • Which type of drugs causes chemical sympathectomy? Give an example? • Non-Competitive a blocker • phenoxybenzamine
  32. 32. III. Beta-Blocking Drugs A. Classification and Mechanisms All are competitive antagonists Propranolol is prototype Classification is based on  Beta subtypes selectivity  Partial agonist activity  Lipid solubility  Local anesthetic action
  33. 33. A. Classification and Mechanisms 1. Receptor selectivity – b 1 -selective: metoprolol, atenolol – b 2 -selective: butoxamine (research only) – Nonselective: propranolol –Combined beta- and alpha- blocking: labetalol
  34. 34. A. Classification and Mechanisms 2. Partial agonist activity –Intrinsic sympathomimetic activity, ISA –eg, pindolol, acebutolol –may be useful in patients with asthma
  35. 35. A. Classification and Mechanisms 3. Local anesthetic activity (membrane-stabilizing activity): –disadvantage when used topically in the eye –timolol: no this activity 4. Lipid solubility –responsible for CNS adverse effects: propranolol
  36. 36. Pharmacokinetics of Beta blockers • For systemic effects, developed for chronic oral use • Esmolol: short-acting--only used parenterally • Nadolol: longest-acting • Atenolol, acebutolol are less lipid- soluble
  37. 37. B. Effects and Clinical Uses • Predict from beta blockade –decreased HR, force of contraction –decreased A-V conduction –slow firing rate of SA node • Cardiovascular and ophthalmic applications are extremly important
  38. 38. α1-antagonist _____ β1-antagonists --------
  39. 39. B. Clinical Uses • CVS: hypertension, angina pectoris, arrhythmia prophylaxis after MI, sup raventricular tachycardias, hypertrop hic cardiomyopathy, congestive heart failure* • Glaucoma: reduce aqueous humor secretion (timolol)
  40. 40. B. Clinical Uses • Migraine: propranolol • Thyroid storm, thyrotoxicosis: propranolol • Famillial tremor, other types of tremor, “stage fright” : propranol ol
  41. 41. C. Adverse effects • CVS: bradycardia, A-V blockade, congestive heart failure • Patients with airway disease: asthmatic attack • Mask sign of hypoglycemia in diabetic patients: tachycardia, tre mor, anxiety • CNS effects: sedation, fatigue, sleep alterations
  42. 42. Drug List Alpha-blockers –Nonselective: phenoxybenzamine*, phentolamine* – a 1 -selective: prazosin*, terazosin, doxazosin – a 2 -selective: yohimbine
  43. 43. Drug List Beta-blockers –Nonselective: propranolol*, timolol, nadolol –Combined a - and b - blocking: carvedilol, labetalol – b 1 -selective: metoprolol, atenolol – b 2 -selective: butoxamine
  44. 44. α1- Contract vascular smooth muscle, iris, bladder sphincter muscle α2-Inhibits NE release β2- Relaxes bronchial, uterine, and vascular smooth muscle α2-mediates platelet aggregation;decrease insulin secretion; decreases secretion of aqueous humor β2-inhibits platelet aggregation; promotes glycogenolysis
  45. 45. Receptor Type b1 b2 b3 b4 Selective Agonist Dobutamine xamoterol Salbutamol salmeterol BRL 37344 none Selective Antagonists Atenolol metoprolol Butoxamine SR59230A Bupranolol Agonist Potency Order ISO>A=NA ISO>A>>NA ISO=NA>A Second Messengers and Effectors Inc cAMP via Gs Inc cAMP via Gs Inc cAMP via Gs Inc cAMP via Gs Physiological Effect Inc heart rate and force Vasodilatation and broncho- dilation Lipolysis and thermogenesis Inc heart rate and force
  46. 46. SUMMARY
  47. 47. 1. A non selective β receptor antagonist: a) Timolol b) Acebutalol c) Atenolol d) Esmolol e) Metoprolol
  48. 48. 2. A β receptor antagonist which also acts as a partial agonist: a) Pindolol b) Propranolol c) Esmolol d) Timolol e) Metoprolol
  49. 49. 3. Propranolol is contraindicated in one of the following diseases: a) Hypertension b) Tachycardia c) Hyperthyroidism d) Angina pectoris e) Bronchial asthma
  50. 50. 4. Propranolol produces its antihypertensive action by: a) Vasodilatation b) Ganglionic blockade c) Decreased cardiac output d) A diuretic action e) Blockade of α1 receptors
  51. 51. The EndThe End