HuBio 543 September 27, 2007

1. HuBio 543September 27, 2007 Neil M. Nathanson K-536A, HSB 3-9457 nathanso@u.washington.edu Adrenergic Antagonists

2. Alpha- Adrenergic Antagonists I. Non-selective alpha adrenergic receptor antagonists A. Covalent (haloalkylamines) Dibenamine Phenoxybenzamine* B. Noncovalent Phentolamine* Tolazoline II. a1-selective Doxazosin Prazosin* Terazosin III. a2-selective Yohimbine* (* = Drug List)

3. CH2 N CH2Cl CH2 CH CH2 O CH3 CH2 CH2 + N CH CH2 O CH2 CH3 Covalent inactivation of a-receptor by phenoxybenzamine Phenoxybenzamine CH2 CH2 N CH CH2 O CH2 CH3 Ethylene iminium ion Alkylated a-receptor

4. Phenoxybenzamine • Administration causes: • Postural hypotension • Reflex tachycardia • Miosis • Impaired ejaculation • Can act on the CNS (nausea and sedation)

5. EPINEPHRINE REVERSAL AFTER PHENOXYBENZAMINE 220 BP (mm. Hg) 180 140 EPINEPHRINE PRETREAT WITH POB: 120 100 BP (mm. Hg) 80 60 EPINEPHRINE

6. HR Effect of phenoxybenzamine on responses to EPI and NE BP EPI NE NE EPI POB

7. Phenoxybenzamine • Indications: • Treatment of pheochromocytoma • Prior to surgery to remove pheochromocytoma

8. Alpha- Adrenergic Antagonists I. Non-selective alpha adrenergic receptor antagonists A. Covalent (haloalkylamines) Dibenamine Phenoxybenzamine* B. Noncovalent Phentolamine* Tolazoline II. a1-selective Doxazosin Prazosin* Terazosin III. a2-selective Yohimbine* (* = Drug List)

9. Epinephrine reversal by phentolamine + phentolamine 15 µg/kg Blood Pressure + Epi 5 µg/kg + Epi 5 µg/kg

10. Comparison of Competitive vs. “Non-equilibrium” Blockade Pretreat with Phentolamine No Pretreatment Contraction of arterial strips (a1- receptor) Pretreat with Phenoxybenzamine Concentration of Norepinephrine

11. Alpha- Adrenergic Antagonists I. Non-selective alpha adrenergic receptor antagonists A. Covalent (haloalkylamines) Dibenamine Phenoxybenzamine* B. Noncovalent Phentolamine* Tolazoline II. a1-selective Doxazosin Prazosin* Terazosin III. a2-selective Yohimbine* (* = Drug List)

12. Prazosin causes epinephrine reversal Pretreat with prazosin Blood Pressure Epinephrine Epinephrine

13. NE NE Presynaptic Receptors Inhibit NE Release NE ß1- AdR NE X X NE a2- AdR NE

14. NE NE NE NE Block Presynaptic Receptors: Increase NE Release NE Increased HR NE ß1- AdR NE NE a2- AdR XX NE POB Presynaptic Receptors Active: Less NE Release NE ß1- AdR Less Tachycardia X X NE a2- AdR NE

15. Long-lasting anti-hypertensive effect of prazosin therapy 150 130 Supine 110 Mean Blood ressureP (mm. Hg) Standing 90 70 50 24 0 18 6 12 Months

16. Yohimbine blocks a2 - receptors and thus increases NE release

19. Beta-Adrenergic Antagonists I. Non-selective ß-blockers Nadolol* Propranolol* Timolol* Pindolol Sotalol II. ß1-Selective Antagonists III. ß2-Selective Antagonists Butoxamine* Atenolol* Esmolol* Metoprolol* Acebutolol Betaxolol Practolol (* = Drug List)

20. Propranolol blocks responses to isoproterenol 0.5 mg/kg Propranolol 0.2 µg/kg ISO 0.2 µg/kg ISO 1 µg/kg ISO Cardiac Force Arterial Pressure Heart Rate 1 min.

21. EFFECT OF ANTAGONISTS ON RESPONSES TO ISO + propranolol + phentolamine BP + ISO + ISO + ISO

22. Effect of antagonists on pressor response to NE + Propranolol 2 mg/kg + Phentolamine 15 mg/kg 240 160 BP (mm. Hg) 80 NE, 2.5 µg/kg NE, 2.5 µg/kg NE, 2.5 µg/kg

23. Both a and ß receptors contribute to epinephrine action + phentolamine + propranolol Blood Pressure + Epi + Epi + Epi

24. Effect of antagonists on responses to adrenergic agonists NE NE + PHEN NE + PRO Contraction of VSM ISO ISO + PHEN ISO + PROP Relaxation of airway SM NE Contraction of heart NE + PRO NE + PHEN CONCENTRATION OF AGONIST

26. Cardiovascular Angina Pectoris Arrhythmias Hypertension Recurrence of heart attack CNS Prophylaxis of migraine Alleviation of anxiety Endocrine Hyperthyroidism Pheochromocytoma Other Glaucoma Certain types of tremor Therapeutic Uses of Beta Blockers

27. Why do ß blockers have anti-hypertensive action? Possible reasons: • Block ß-receptors in heart decrease cardiac output • Decrease renin secretion from kidney • Resets baroreceptor sensitivity • Acts in CNS to “decrease” sympathetic activity

28. Propranolol decreases mortality after heart attack 10 8 Placebo 6 Cumulative mortality Rate (%) 4 Propranolol 2 0 6 12 18 24 30 MONTHS

29. Therapeutic Uses of Beta Blockers • Endocrine • Hyperthyroidism • Pheochromocytoma • Other • Glaucoma • Certain types of tremor • Cardiovascular • Angina Pectoris • Arrhythmias • Hypertension • Recurrence of heart attack • CNS • Prophylaxis of migraine • Alleviation of anxiety

30. ADVERSE EFFECTS OF ß-BLOCKERS MAJOR EFFECTS OTHER SIDE EFFECTS Fatigue Heart Failure Bronchospasm Constipation Heart Block Diarrhea Bradycardia Nightmares Hypotension Depression Hypoglycemia Paresthesias Claudication Skin Rash

32. Chronic propranolol increases density of ß-AdR in heart 60 40 Cardiac ß-AdR Number 20 Control Propranolol-treated

33. Effects of opthalmic administration of timolol 0 Control Patients % Change in FEV1 From Control -20 Asthma Patients -40 0 1 2 3 Time (hours)

34. Beta-Adrenergic Antagonists I. Non-selective ß-blockers Nadolol* Propranolol* Timolol* Pindolol Sotalol II. ß1-Selective Antagonists III. ß2-Selective Antagonists Butoxamine* Atenolol* Esmolol* Metoprolol* Acebutolol Betaxolol Practolol (* = Drug List)

35. Comparison of propranolol vs. practolol Block of sympa- thetic nerve-stimulated HR increase PRO PRACT PRO Block of ISO-mediated vasodilation PRACT Block of ISO-mediated bronchodilation PRO PRACT .01 1 10 .1 Dose antagonist, mg/kg

36. Beta-Adrenergic Antagonists I. Non-selective ß-blockers Nadolol* Propranolol* Timolol* Pindolol Sotalol II. ß1-Selective Antagonists III. ß2-Selective Antagonists Butoxamine* Atenolol* Esmolol* Metoprolol* Acebutolol Betaxolol Practolol (* = Drug List)

37. Labetalol • UGLY- 4 optical isomers, with different selectivities • Non-selective ß-blocker PLUS a1-selective antagonist • Used for treatment of: • Hypertension • Pheochromocytoma-associated hypertension • Hypertension following abrupt withdrawl of clonidine • Carvedilol is another non-selective ß PLUS a1 blocker