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HuBio 543 September 27, 2007 Neil M. Nathanson K-536A, HSB 3-9457
Adrenergic Antagonists
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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)
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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
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Phenoxybenzamine Administration causes: Postural hypotension
Reflex tachycardia Miosis Impaired ejaculation Can act on the CNS (nausea and sedation)
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EPINEPHRINE REVERSAL AFTER PHENOXYBENZAMINE
220 BP (mm. Hg) 180 140 EPINEPHRINE PRETREAT WITH POB: 120 100 BP (mm. Hg) 80 60 EPINEPHRINE
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Effect of phenoxybenzamine on responses to EPI and NE
HR BP EPI NE EPI POB NE
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Phenoxybenzamine Indications: Treatment of pheochromocytoma
Prior to surgery to remove pheochromocytoma
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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)
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Epinephrine reversal by phentolamine
15 µg/kg Blood Pressure + Epi 5 µg/kg + Epi 5 µg/kg
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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
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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)
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Prazosin causes epinephrine reversal
Pretreat with prazosin Blood Pressure Epinephrine Epinephrine
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X X Presynaptic Receptors Inhibit NE Release NE NE NE NE ß1- AdR a2-
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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
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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
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Yohimbine blocks a2 - receptors and thus increases NE release
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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)
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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.
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EFFECT OF ANTAGONISTS ON RESPONSES TO ISO
+ phentolamine + propranolol BP + ISO + ISO + ISO
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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
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Both a and ß receptors contribute to
epinephrine action + phentolamine + propranolol Blood Pressure + Epi + Epi + Epi
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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
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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
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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
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Propranolol decreases mortality after heart attack
10 8 Placebo 6 Cumulative mortality Rate (%) 4 Propranolol 2 6 12 18 24 30 MONTHS
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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
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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
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Chronic propranolol increases density of ß-AdR in heart
60 40 Cardiac ß-AdR Number 20 Control Propranolol-treated
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% 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)
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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)
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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
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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)
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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
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