hubio 543 september 28, 2007
DESCRIPTION
HuBio 543 September 28, 2007. Neil M. Nathanson K-536A, HSB 3-9457 [email protected] Adrenergic Neuron Blockers and Other Stuff. X. X. X. ADRENERGIC NEURON BLOCKERS. Tyrosine. TH. Tyrosine. DOPA. DDC. Dopamine. Reserpine. DA. ++. Ca. ++. Ca. DßH. NE. Bretylium. NE. - PowerPoint PPT PresentationTRANSCRIPT
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HuBio 543September 28, 2007
Neil M. NathansonK-536A, [email protected] Adrenergic Neuron Blockers and Other Stuff
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ADRENERGIC NEURON BLOCKERS
DOPA
Dopamine
Tyrosine
Ca++
TyrosineTH
DDC
DA
NEDßH
NE
NE
Ca++
Reserpine X
X
Bretylium XGuane-thidine
NE
Guane-thidine
Bretylium
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Reserpine blocks catecholamine transport into vesicles
DOPA
Dopamine
Ca++
TyrosineTH
DDC
DA
NE
DßH
NE
NE
Ca++
Reserpine X
NE
Depletes catecholamines because: 1. Blocks DA transport into vesicle-blocks de novo synthesis of NE 2. Blocks reuptake into vesicle of previously released NE 3. Blocks reuptake of NE that leaks out of vesicle
MAO
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RESERPINE-TREATED CONTROL
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+ Tyramine + Norepinephrine
Pretreat with Reserpine:
Reserpine blocks vasopressor response to tyramine and but not to norepinephrine
+ Norepinephrine+ Tyramine
BP
BP
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Reserpine
• Decreases blood pressure and heart rate• Increases GI tone and motility• Causes:
– Postural hypotension– Diarrhea– Sexual dysfunction– CNS effects: sedation, depression
• Can be used for treatment of hypertension
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Sym.Term. CNS
AdrenalMedulla
Cocaine-Like Effect
Guanethidine
Bretylium
Reserpine
ADRENERGIC NEURON BLOCKERS
YES YESYES NO
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Bretylium blocks evoked release of NE
DOPA
Dopamine
Ca++
TyrosineTH
DDC
DA
NEDßH
NE
NE
Ca++
X
Bretylium X NE
Bretylium
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+ Hexa-methonium
+ Bretylium
Pregang-lionicStimulation
+ NE
Effects of pretreatments on smooth muscle contraction
Control
Postgang-lionicStimulation
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+ Phenoxyben- zamine
+ Bretylium
+ Reserpine Nerve
Stimu-lation
+ NE
Control
Effects of pretreatments on smooth muscle contraction
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Sym.Term. CNS
AdrenalMedulla
Cocaine-Like Effect
Guanethidine
Bretylium
Reserpine
ADRENERGIC NEURON BLOCKERS
YES YESYES NO
YES YESNONO
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Guanethidine (and guanadrel)
DOPA
Dopamine
Ca++
TyrosineTH
DDC
DADßH
NE
NE
Ca++
X
X
Guane-thidine
NE
Guane-thidine
NE
NE
1. Displaces NE from vesicle2. Blocks evoked release3. Also blocks NE transport into terminal
MAO
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NERelease
VSMContraction
+ Guanethidine
Effect of guanethidine on NE release & VSM contraction
NS NSNSNSNSNS
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Effect of Guanethidine on Blood Pressure Responses
+ NE
+ Tyramine
+ Amphetamine
After Guanethidine:Control:
+ NE
+ Tyramine
+ Amphetamine
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Sym.Term. CNS
AdrenalMedulla
Cocaine-Like Effect
Guanethidine
Bretylium
Reserpine
ADRENERGIC NEURON BLOCKERS
YES YESYES NO
YES
YES
YES
YES
NO NO
NONO
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Guanethidine can lead to supersensitivity of target organs:Increased numbers of adrenergic receptors
0
10
20
30
40
50
60Cardiac ß-
Adrenergic
Receptor Number
Control Guanethidine-
Treated
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6040200
-20
+20
0
Change in mean arterial pressure
(mm Hg)
Minutes
30 µg/kg IV
1 µg/kg ICV
Effect of clonidine on arterial pressure in rabbit
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Sympathetic activitybefore clonidine:
Sympathetic activityafter clonidine:
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Patients w/ complete cervical SC transection (C3- C7) with separation of central from spinal and peripheral sympatehtic pathways
SBP 126 ± 4 109 ± 5†
+ Clonidine, SBP 104 ±3* 105 ± 5
DBP 74 ±3 66 ± 5†
+Clonidine, DBP 59 ± 3* 59 ± 4
Transected Controls SC
Clonidine does not decrease BP in patients with transected spinal
cord
† p<0.05, different from controls
* p<0.05, different from treated
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-30 -10
-10
-30
Change in Heart
Rate
Change in BP, mm Hg
Decreased Blood Pressure and Heart Rate in Patients Taking
Clonidine
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-30 -10
10
-50
-100
1 wk
3 mo.
Change in Plasma
CA pg/ml
Change in BP mm Hg
Decreased Blood Pressure and Plasma Catecholamines in Patients Taking Clonidine
X
X
X
XX
X
X
X
XX
XX
XX
X
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Clonidine
• Selective 2 agonist• Acts in the CNS to decrease sympathetic outflow:
Sympathetic activitybefore clonidine:
Sympathetic activityafter clonidine:
Other 2 agonists used therapeutically: apraclonidine, guanfacine, guanabenz
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Dopa DDC DßH Norepinephrine
-Me-Dopa -Me- Norepinephrine
NENE
NE
NE
NE
E NE NE NE
NE
NEMe-NE
NE
NE
Me-NE
Me-NE
Me-NE
Me-NE Me-NE
-methyldopa is converted to -methylnorepinephrine
NORMAL+ -METHYLDOPA
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-Methyldopa
-methyldopa converted in nerve terminal to -methylnorepinephrine
-methylnorepinephrine is an 2-adrenergic agonist:acts in CNS to decrease sympathetic outflow
-methylnorepinephrine is stored in vesicles and released with nerve stimulation
-methyldopa is used for the treatment of hypertension
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Do not confuse -methyldopa with -methyltyrosine
-methyltyrosine (metyrosine):- Inhibits tyrosine hydroxylase activity- decreases catecholamine synthesis- Used occasionally for treatment of pheochromocytoma
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MAO Inhibitors(pargyline)
• Cause increased levels of catecholamines in both CNS and periphery
• Introduced for the treatment of depression
• Can cause hypotension
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In presence of MAO inhibitor, dietary tyramine is converted to octopamine
DßHTyramine
Octopamine
NENE
NE
NE
NE
NE NE NE
NE
NE
Octop
NE
NE
Octop
OctopOctop
Octop Octop
NORMAL: + MAO INHIBITOR:
Less NE released
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Foods With High Levels of Tyramine
which can cause hypertensive crisis if ingested with MAO inhibitor
• Cheese• Pickled herring
• Canned figs• Chocolate• Yeasts• Yogurt
• Game• Red wine• Chicken livers
• Fava beans• Beer• Meat extracts
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MAO Inhibitors(pargyline)
• Cause hypotension- dietary tyramine converted to octopamine in nerve terminal– Octopamine acts as false transmitter
• High levels of dietary tyramine (with MAO inhibitor) can cause hypertensive crisis– Tyramine causes NE release
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11/500 patients w/ hypertension or suspected pheo had baroreflex failure- volatile BP and HR
4 patients - tumors in carotid body3 patients - neck irradiation for
throat carcinoma1 patient - surgical ressection of
glossopharyngeal nerve1 patient- loss of cells in brainstem2 patients - ?
MAP 85 141 128
Plasma NE 524 1840 570
Phenylephrine-induced HR -13 ± 4 -1 ± 1 -9 ± 4increase
Baroreflex EssentialNormal Failure Hypertension
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Clonidine alleviates symptoms of baroreflex failure
# of attacks Increase in Increase inTreatment per day systolic press. HR
Placebo 4.7 ± 1.1 92 ± 23 58± 9
Clonidine 0.9 ± 0.3 32 ± 16 33 ± 6
POB 4.4 ± 1.2 37 ± 21 62 ± 14
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6-Hydroxydopamine
• Taken up by adrenergic nerves• Oxidized to toxic compounds• Causes “chemical sympathectomy”:– Causes destruction of nerve terminals
– In newborns, also destroys cell bodies
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NGF: Nerve Growth Factor
• NGF and its receptors are important for survival of sympathetic and sensory neurons
• Antibodies against NGF destroy newborn’s sympathetic nervous system: “immunosympathectomy”
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NGF Promotes neuronal outgrowth from cultured DRG
+ NGF CONTROL
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Immunosympathectomy by anti- NGF Antibody
Treated with anti- NGF Ab
Control
Treated with anti- NGF Ab
Control
Sympathetic chains
Ganglion
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TYRAMINE
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