hubio 543 september 27, 2007 neil m. nathanson k-536a, hsb 3-9457 [email protected]...
TRANSCRIPT
![Page 2: HuBio 543 September 27, 2007 Neil M. Nathanson K-536A, HSB 3-9457 nathanso@u.washington.edu Adrenergic Antagonists](https://reader030.vdocuments.net/reader030/viewer/2022032612/56649ee75503460f94bf7916/html5/thumbnails/2.jpg)
Alpha- Adrenergic Antagonists
A. Covalent (haloalkylamines) Dibenamine Phenoxybenzamine* B. Noncovalent Phentolamine* Tolazoline II. 1-selective
Doxazosin Prazosin* Terazosin
I. Non-selective alpha adrenergic receptor antagonists
III. 2-selective Yohimbine* (* = Drug List)
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CH2
NO
CH3
CH
CH2
CH2 CH2Cl
CH2
NO
CH3
CH
CH2 CH2
CH2CH2
NO
CH3
CH
CH2 CH2
CH2
+
Ethylene iminium ion Alkylated -receptor
Phenoxybenzamine
Covalent inactivation of -receptor by phenoxybenzamine
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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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BP (mm. Hg)
60
120
100
80
220
140
180
EPINEPHRINE REVERSAL AFTER PHENOXYBENZAMINE
EPINEPHRINE
PRETREAT WITH POB:
EPINEPHRINEBP (mm. Hg)
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BP
HR
POBNE NE EPIEPI
Effect of phenoxybenzamine on responses to EPI and NE
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Phenoxybenzamine
• Indications: – Treatment of pheochromocytoma– Prior to surgery to remove pheochromocytoma
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Alpha- Adrenergic Antagonists
A. Covalent (haloalkylamines) Dibenamine Phenoxybenzamine* B. Noncovalent Phentolamine* Tolazoline II. 1-selective
Doxazosin Prazosin* Terazosin
I. Non-selective alpha adrenergic receptor antagonists
III. 2-selective Yohimbine* (* = Drug List)
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+ Epi5 µg/kg
+ phentolamine15 µg/kg
Epinephrine reversal by phentolamine
+ Epi5 µg/kg
Blood Pressure
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Contraction of
arterial strips
1- receptor)
Concentration of Norepinephrine
Pretreat withPhentolamine
Pretreat withPhenoxybenzamine
No Pretreatment
Comparison of Competitive vs. “Non-equilibrium” Blockade
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Alpha- Adrenergic Antagonists
A. Covalent (haloalkylamines) Dibenamine Phenoxybenzamine* B. Noncovalent Phentolamine* Tolazoline II. 1-selective
Doxazosin Prazosin* Terazosin
I. Non-selective alpha adrenergic receptor antagonists
III. 2-selective Yohimbine* (* = Drug List)
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Epinephrine
Pretreat withprazosin
Prazosin causes epinephrine reversal
Blood Pressure
Epinephrine
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NE
NE
-AdR NE
X
ß-AdR
XNE
Presynaptic Receptors Inhibit NE Release
NE
NE
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Block Presynaptic Receptors: Increase NE Release
NE
NE-AdR
Increased HR
ß-AdR
NE
NE
NE
POBXX
NE
NE
NE
NE-AdRNE
Xß-AdRX NE
NE
Presynaptic Receptors Active: Less NE Release
Less Tachycard
ia
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110
70
Mean Blood ressureP (mm. Hg)
0 6 12
18 2450
130
150
90
Months
Long-lasting anti-hypertensive effect of prazosin therapy
Supine
Standing
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Yohimbine blocks 2 - receptors and thus increases NE release
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QuickTime™ and aTIFF (LZW) decompressor
are needed to see this picture.
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Beta-Adrenergic Antagonists
I. Non-selective ß-blockers
II. ß1-Selective AntagonistsAtenolol*Esmolol*Metoprolol*AcebutololBetaxololPractolol
III. ß2-Selective AntagonistsButoxamine*
Nadolol*Propranolol*Timolol*PindololSotalol
(* = Drug List)
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1 min.
HeartRate
ArterialPressure
CardiacForce
0.2 µg/kg ISO 0.2 µg/kg
ISO1 µg/kg ISO
0.5 mg/kg Propranolol
Propranolol blocks responses to isoproterenol
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+ phentolamine
+ ISO + ISO + ISO
+ propranolol
BP
EFFECT OF ANTAGONISTS ON RESPONSES TO ISO
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NE, 2.5 µg/kg
160
80
240
BP (mm. Hg)
+ Propranolol 2 mg/kg+ Phentolamine
15 mg/kg
Effect of antagonists on pressor response to NE
NE, 2.5 µg/kgNE, 2.5 µg/kg
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+ Epi
+ phentolamine
Both and ß receptors contribute to epinephrine action
+ Epi
Blood Pressure
+ propranolol
+ Epi
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NE
ISO
NE
NE +PRO
NE + PHEN
ISO +PHEN
ISO +PROP
NE + PHEN
NE +PRO
CONCENTRATION OF AGONIST
Contraction of VSM
Relaxation of airway SM
Contraction of heart
Effect of antagonists on responses to adrenergic agonists
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Therapeutic Uses of Beta Blockers
• 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
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Why do ß blockers have anti-hypertensive action?
• Block ß-receptors in heart decrease cardiac output
• Decrease renin secretion from kidney
• Resets baroreceptor sensitivity• Acts in CNS to “decrease” sympathetic activity
Possible reasons:
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6 1
218
24
30
8
6
4
2
0
10
Cumulative mortality Rate (%)
Placebo
Propranolol
MONTHS
Propranolol decreases mortality after heart attack
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Therapeutic Uses of Beta Blockers
• 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
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ADVERSE EFFECTS OF ß-BLOCKERS
MAJOR EFFECTS OTHER SIDE EFFECTS
Heart FailureBronchospasm
Heart Block
Bradycardia
Hypotension
Hypoglycemia
Claudication
Fatigue
Constipation
Diarrhea
Nightmares
Depression
Paresthesias
Skin Rash
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20
60
40
Control Propranolol-treated
Cardiac ß-AdR Number
Chronic propranolol increases density of ß-AdR in heart
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0 1 2 3
-40
-20
0
% Change in
FEV1 From
Control Control Patients
Asthma Patients
Time (hours)
Effects of opthalmic administration of timolol
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Beta-Adrenergic Antagonists
I. Non-selective ß-blockers
II. ß1-Selective AntagonistsAtenolol*Esmolol*Metoprolol*AcebutololBetaxololPractolol
III. ß2-Selective AntagonistsButoxamine*
Nadolol*Propranolol*Timolol*PindololSotalol
(* = Drug List)
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.01 .1 1 1
0Dose antagonist, mg/kg
Block of sympa- thetic nerve-stimulated HR increase
Block of ISO-mediated bronchodilation
Block of ISO-mediated vasodilation
PRO PRACT
PRACT
PRACT
PRO
PRO
Comparison of propranolol vs. practolol
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Beta-Adrenergic Antagonists
I. Non-selective ß-blockers
II. ß1-Selective AntagonistsAtenolol*Esmolol*Metoprolol*AcebutololBetaxololPractolol
III. ß2-Selective AntagonistsButoxamine*
Nadolol*Propranolol*Timolol*PindololSotalol
(* = Drug List)
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Labetalol
• UGLY- 4 optical isomers, with different selectivities
• Non-selective ß-blocker PLUS 1-selective antagonist
• Used for treatment of:– Hypertension– Pheochromocytoma-associated hypertension– Hypertension following abrupt withdrawl of clonidine
• Carvedilol is another non-selective ß PLUS 1 blocker