hubio 543 september 27, 2007 neil m. nathanson k-536a, hsb 3-9457 nathanso@u.washington.edu...
Post on 02-Jan-2016
221 Views
Preview:
TRANSCRIPT
HuBio 543September 27, 2007
Neil M. NathansonK-536A, HSB3-9457nathanso@u.washington.edu
Adrenergic Antagonists
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)
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
Phenoxybenzamine
• Administration causes: – Postural hypotension– Reflex tachycardia– Miosis– Impaired ejaculation– Can act on the CNS (nausea and sedation)
BP (mm. Hg)
60
120
100
80
220
140
180
EPINEPHRINE REVERSAL AFTER PHENOXYBENZAMINE
EPINEPHRINE
PRETREAT WITH POB:
EPINEPHRINEBP (mm. Hg)
BP
HR
POBNE NE EPIEPI
Effect of phenoxybenzamine on responses to EPI and NE
Phenoxybenzamine
• Indications: – Treatment of pheochromocytoma– Prior to surgery to remove pheochromocytoma
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)
+ Epi5 µg/kg
+ phentolamine15 µg/kg
Epinephrine reversal by phentolamine
+ Epi5 µg/kg
Blood Pressure
Contraction of
arterial strips
1- receptor)
Concentration of Norepinephrine
Pretreat withPhentolamine
Pretreat withPhenoxybenzamine
No Pretreatment
Comparison of Competitive vs. “Non-equilibrium” Blockade
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)
Epinephrine
Pretreat withprazosin
Prazosin causes epinephrine reversal
Blood Pressure
Epinephrine
NE
NE
-AdR NE
X
ß-AdR
XNE
Presynaptic Receptors Inhibit NE Release
NE
NE
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
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
Yohimbine blocks 2 - receptors and thus increases NE release
QuickTime™ and aTIFF (LZW) decompressor
are needed to see this picture.
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)
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
+ phentolamine
+ ISO + ISO + ISO
+ propranolol
BP
EFFECT OF ANTAGONISTS ON RESPONSES TO ISO
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
+ Epi
+ phentolamine
Both and ß receptors contribute to epinephrine action
+ Epi
Blood Pressure
+ propranolol
+ Epi
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
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
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:
6 1
218
24
30
8
6
4
2
0
10
Cumulative mortality Rate (%)
Placebo
Propranolol
MONTHS
Propranolol decreases mortality after heart attack
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
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
20
60
40
Control Propranolol-treated
Cardiac ß-AdR Number
Chronic propranolol increases density of ß-AdR in heart
0 1 2 3
-40
-20
0
% Change in
FEV1 From
Control Control Patients
Asthma Patients
Time (hours)
Effects of opthalmic administration of timolol
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)
.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
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)
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
top related