Transcript mAChR AntagWEB07

HuBio 543
September 24, 2007
Neil M. Nathanson
K-536A, HSB
3-9457
[email protected]
Muscarinic Antagonists
Tertiary Muscarinic Antagonists
H2 C
CH
CH2
O
CH2OH
NCH3
CHO
C
H2 C
CH
CH2 Atropine
C
H
C
H
CH
NCH3
O
C
CH
H
CH2
O
CH2OH
CHO
C
C
H
CH2
Scopolamine
Tertiary Antagonists
Atropine *
Scopolamine *
Homatropine
Tropicamine
Tolterodine
Oxybutynin
Quaternary Antagonists
N- methyl atropine *
N- methyl scopolamine
Ipratropium *
Propantheline
Tiotropium*
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
Biphasic Effect of Atropine on Human Heart Rate
80
Heart
70
Rate
60
50
0
2
6
4
Dose of Atropine (µg/kg)
8
10
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
Presynaptic Muscarinic Receptors Inhibit ACh
Release From Parasympathetic Terminals
ACh
ACh
ACh
ACh mAChR
XX
ACh
mAChR ACh
Presynaptic Muscarinic Receptors Inhibit ACh
Release From Parasympathetic Terminals
ACh
ACh
ACh mAChR
XX
mAChR ACh
Therefore:
Less ACh is released,
Heart Rate is not slowed as much
Increased ACh Release and Bradycardia When
Presynaptic mAChR Are Blocked by (Low Doses of)
Atropine
ACh
ACh
ACh
ACh mAChR
ACh
Atropine
mAChR
ACh
Biphasic Effect of Atropine on Human Heart Rate
80
Heart
70
Rate
60
50
0
2
6
4
Dose of Atropine (µg/kg)
8
10
Biphasic Effect of Atropine on Human Heart Rate
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
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 HR
Parasymp.
Ganglion
MR
MR
High doses:
Block mAChR on heartBlock effects of ACh, increases HR
Sensitivity of Target Organs to Atropine
Increase or Decrease (%)
80
60
Salivary
Secretion
(-)
Micturition
Speed
(-)
40
20
Heart Rate
(+)
Accomodation
(-)
0
0.5
1
Atropine (mg/70 kg)
2
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
(of smooth muscle)
Tricyclic anti-depressants can act as mAChR antagonists
Physostigmine reverses anti- muscarinic CNS
effects of tricyclic anti-depressants
Quaternary Muscarinic Antagonists
H2 C
H2C
CH
+
H3CNCH3
CH2
O
CH2OH
CHO
C
C
H
CH2
CH
N-methylatropine
H2 C
CH
+
(H3C) 2HCNCH3
H2 C
CH
CH2
O
CHO
C
CH2
CH2OH
C
H
Ipratropium
Tertiary Antagonists
Atropine *
Scopolamine *
Homatropine
Tropicamine
Tolterodine
Oxybutynin
Quaternary Antagonists
N- methyl atropine *
N- methyl scopolamine
Ipratropium *
Propantheline
Tiotropium*
N-methylatropine does not cross membranes as well as atropine
N-methylatropine does not cross membranes as well as atropine
100
80
Cumulative
Adsorption
60
(%)
Atropine
40
20
N-methylatropine
0
50
100
150
200
Distance From the Nose (cm.)
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
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
Cholinergic Innervation of the Airways
Lumen
Lumen
Gland
Cholinergic Innervation
SMOOTH MUSCLE
Rates of Hospitalization in Control and Ipratropium Groups
60
50
Patients
Hospitalized
(%)
Control
Ipratropium
40
30
20
10
0
All
Patients
Moderate
Asthma
Severe
Asthma
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
Medilog: electronic inhaler monitor
Monitoring showed that only 15% of subjects actually
used the inhaler as prescribed.
Patients want to be liked by their physicians
14% of patients actuated inhaler more than 100 times
on the day of a visit.
Synaptic Transmission Through a Sympathetic Ganglion:
From
CNS
N
Main
Pathway
To Target
ACh
M
Modulatory
Pathway
Effect of Ganglionic Stimulants
BP
HR
+ DMPP
+ Hexamethonium:
+ McN-A-343
BP
HR
+ DMPP
+ McN-A-343
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
Pirenzepine Selectively Blocks mAChR in Sympathetic Ganglia
Atropine
(atria or ganglia)
Pirenzepine
(ganglion)
Pirenzepine
(atria)
DRUG CONCENTRATION
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
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
Effect of Ganglionic Stimulants
BP
HR
+ DMPP
+ McN-A-343
+ Hexamethonium:
BP
HR
+ DMPP
+ McN-A-343