Download - HuBio 543 September 24, 2007
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Atropine
H2C
H2C
CH
NCH3
CH
CH2
CH2
CHOOC C
CH2OH
H
C
C
CH
NCH3
CH
CH2
CH2
CHOOC C
CH2OH
HO
H
H
Scopolamine
Tertiary Muscarinic Antagonists
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Tertiary AntagonistsAtropine *Scopolamine *HomatropineTropicamineTolterodineOxybutynin
Quaternary AntagonistsN- methyl atropine *N- methyl scopolamineIpratropium *PropanthelineTiotropium*
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QuickTime™ and aTIFF (LZW) decompressor
are needed to see this picture.QuickTime™ and aTIFF (LZW) decompressor
are needed to see this picture.
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0 2 4 6 8 10Dose of Atropine (µg/kg)
Heart
Rate
50
60
70
80
Biphasic Effect of Atropine on Human Heart Rate
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Why the biphasic dose-response curve to atropine?
1. CNS- Low doses of atropine may act preferentially in the CNS to increase parasympathetic outflow
2. Presynaptic effect- Low doses of atropine may act preferentially on presynaptic mAChR on parasympathetic terminals, resulting in increased ACh release onto the heart
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Presynaptic Muscarinic Receptors Inhibit AChRelease From Parasympathetic Terminals
ACh
ACh
mAChR ACh
mAChR
XXACh
ACh
ACh
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Presynaptic Muscarinic Receptors Inhibit AChRelease From Parasympathetic Terminals
ACh
ACh
mAChR ACh
mAChR
XXACh
Therefore: Less ACh is released, Heart Rate is not slowed as much
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Increased ACh Release and Bradycardia WhenPresynaptic mAChR Are Blocked by (Low Doses of)
Atropine
ACh
ACh
mAChR
ACh
mAChRACh
ACh
ACh
Atropine
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0 2 4 6 8 10Dose of Atropine (µg/kg)
Heart
Rate
50
60
70
80
Biphasic Effect of Atropine on Human Heart Rate
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QuickTime™ and aTIFF (LZW) decompressor
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Biphasic Effect of Atropine on Human Heart Rate
Low doses preferentially:1. Act in CNS to increase parasympathetic outflow- decreases HR
2. Blocks presynaptic receptor on parasympathetic nerve terminal-increases ACh release, decreases HRParasymp.
GanglionMR MR
High doses:Block mAChR on heart-Block effects of ACh, increases HR
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80
60
40
20
0210.
5
SalivarySecretion
(-)Micturition
Speed(-)
Heart Rate(+)
Accomodation(-)
Increase or Decrease (%)
Atropine (mg/70 kg)
Sensitivity of Target Organs to Atropine
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Toxic Effects of 3o mAChR Antagonists
• Visual problems• Constipation and urinary retention• Glaucoma in predisposed individuals• Hallucinations and delirium• Decreased sweating and salivation• Erectile problems/impaired vaginal lubrication
Can use AChE inhibitors as an antidote
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Tricyclic anti-depressants can act as mAChR antagonists
(of smooth muscle)
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Physostigmine reverses anti- muscarinic CNS effects of tricyclic anti-depressants
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Ipratropium
N-methylatropine
H2C
H2C
CH
NCH3
CH
CH2
CH2
CHOOC C
CH2OH
H(H3C) 2HC
+
H2C
H2C
CH
NCH3
CH
CH2
CH2
CHOOC C
CH2OH
HH3C
+
Quaternary Muscarinic Antagonists
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Tertiary AntagonistsAtropine *Scopolamine *HomatropineTropicamineTolterodineOxybutynin
Quaternary AntagonistsN- methyl atropine *N- methyl scopolamineIpratropium *PropanthelineTiotropium*
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N-methylatropine does not cross membranes as well as atropine
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N-methylatropine does not cross membranes as well as atropine
80
60
40200
100
CumulativeAdsorption
(%)Atropine
N-methylatropine
Distance From the Nose (cm.)100 20015050
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Therapeutic uses of mAChR Antagonists
• (Preanesthetic medication)• Ophthalmological- mydriasis and cylcoplegia
• GI and Urinary Tract- decrease tone & motility
• Decrease excessive sweating• CV- block vagally-mediated bradycardia• CNS- motion sickness• Respiratory tract- bronchodilation
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Therapeutic uses of mAChR Antagonists
• (Preanesthetic medication)• Ophthalmological- mydriasis and cylcoplegia
• GI and Urinary Tract- decrease tone & motility
• Decrease excessive sweating• CV- block vagally-mediated bradycardia• CNS- motion sickness• Respiratory tract- bronchodilation
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Lumen
Gland
SMOOTH MUSCLE
Cholinergic Innervation
Lumen
Cholinergic Innervation of the Airways
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Rates of Hospitalization in Control and Ipratropium Groups
0
10
20
30
40
50
60ControlIpratropium
Patients Hospitalized (%)
AllPatients
ModerateAsthma
SevereAsthma
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Patient compliance is a big problem
Patients prescribed ipratropium inhalers:
-Self- reported compliance was 60- 70%
-This was confirmed by canister weight
BUT: Compliance was also determined by
electronic monitoring and found to be much poorer
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Medilog: electronic inhaler monitor
Monitoring showed that only 15% of Monitoring showed that only 15% of subjects actuallysubjects actuallyused the inhaler as prescribed.used the inhaler as prescribed.
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14% of patients actuated inhaler more 14% of patients actuated inhaler more than 100 times on the day of a visit.than 100 times on the day of a visit.
Patients want to be liked by their physicians
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FromCNS
ACh
N
Synaptic Transmission Through a Sympathetic Ganglion:
To Target
M
MainPathway
ModulatoryPathway
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Effect of Ganglionic Stimulants
+ Hexamethonium:
+ DMPP
+ DMPP
BP
BP
HR
HR
+ McN-A-343
+ McN-A-343
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Muscarinic Receptors in Sympathetic Ganglia
• Excitatory (normally modulate transmission through the nicotinic pathway)
• Selectively activated by McN-A-343• (McN-A-343 therefore causes increased BP)
• Selectively blocked by pirenzepine
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%ReceptorsBlocked
DRUG CONCENTRATION
Atropine(atria or ganglia) Pirenzepi
ne (ganglion)
Pirenzepine (atria)
Pirenzepine Selectively Blocks mAChR in Sympathetic Ganglia
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Subtypes of mAChR• Five different mAChR in humans (all in CNS)• M1- in sympathetic ganglia (and adrenal medulla), activated by McN-A-343, blocked by pirenzepine
• M2- cardiac mAChR; can contribute to contraction of some smooth muscles; a presynaptic receptor on some nerve terminals
• M3- mediates contraction of smooth muscle, relaxation of vasculature, and secretion from many glands
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Cevimeline• Selective M3 agonist• Used for treatment of xerostomia and Sjorgren’s syndrome
• Long-lasting sialogogic agent• May have fewer side effects than pilocarpine
Tiotropium• Selective M3 antagonist
– Very slow dissociation from M3 mAChR– 4° antagonist– like ipratropium, is an inhaled bronchodilator
• Used for treatment of COPD
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Effect of Ganglionic Stimulants
+ Hexamethonium:
+ DMPP
+ DMPP
BP
BP
HR
HR
+ McN-A-343
+ McN-A-343