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

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)

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

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

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

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

Phenoxybenzamine Indications: Treatment of pheochromocytoma Prior to surgery to remove pheochromocytoma

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)

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

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

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)

Prazosin causes epinephrine reversal Pretreat with prazosin Blood Pressure Epinephrine Epinephrine

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

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

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

Yohimbine blocks a2 - receptors and thus increases NE release

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

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.

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

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

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

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

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

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

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

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

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

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

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

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

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 1 10 Dose antagonist, mg/kg

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

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