HuBio 543September 24, 2007

Neil M. NathansonK-536A, HSB3-9457nathanso@u.washington.edu

Muscarinic Antagonists

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

Tertiary AntagonistsAtropine *Scopolamine *HomatropineTropicamineTolterodineOxybutynin

Quaternary AntagonistsN- methyl atropine *N- methyl scopolamineIpratropium *PropanthelineTiotropium*

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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

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 AChRelease From Parasympathetic Terminals

ACh

ACh

mAChR ACh

mAChR

XXACh

ACh

ACh

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

Increased ACh Release and Bradycardia WhenPresynaptic mAChR Are Blocked by (Low Doses of)

Atropine

ACh

ACh

mAChR

ACh

mAChRACh

ACh

ACh

Atropine

0 2 4 6 8 10Dose of Atropine (µg/kg)

Heart

Rate

50

60

70

80

Biphasic Effect of Atropine on Human Heart Rate

QuickTime™ and aTIFF (LZW) decompressor

are needed to see this picture.

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

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

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

Tricyclic anti-depressants can act as mAChR antagonists

(of smooth muscle)

Physostigmine reverses anti- muscarinic CNS effects of tricyclic anti-depressants

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

Tertiary AntagonistsAtropine *Scopolamine *HomatropineTropicamineTolterodineOxybutynin

Quaternary AntagonistsN- methyl atropine *N- methyl scopolamineIpratropium *PropanthelineTiotropium*

N-methylatropine does not cross membranes as well as atropine

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

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

Lumen

Gland

SMOOTH MUSCLE

Cholinergic Innervation

Lumen

Cholinergic Innervation of the Airways

Rates of Hospitalization in Control and Ipratropium Groups

0

10

20

30

40

50

60ControlIpratropium

Patients Hospitalized (%)

AllPatients

ModerateAsthma

SevereAsthma

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 Monitoring showed that only 15% of subjects actuallysubjects actuallyused the inhaler as prescribed.used the inhaler as prescribed.

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

FromCNS

ACh

N

Synaptic Transmission Through a Sympathetic Ganglion:

To Target

M

MainPathway

ModulatoryPathway

Effect of Ganglionic Stimulants

+ Hexamethonium:

+ DMPP

+ DMPP

BP

BP

HR

HR

+ McN-A-343

+ 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

%ReceptorsBlocked

DRUG CONCENTRATION

Atropine(atria or ganglia) Pirenzepi

ne (ganglion)

Pirenzepine (atria)

Pirenzepine Selectively Blocks mAChR in Sympathetic Ganglia

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

+ Hexamethonium:

+ DMPP

+ DMPP

BP

BP

HR

HR

+ McN-A-343

+ McN-A-343