Fig. 2.22.

La sinapsi
colinergica.

 Nuclei colinergici nel SNC.

Fig. 2.20. I sistemi colinergici periferici.

Recettori muscarinici
M1 (neural)

M2 (cardiac)

M3 (glandular/
smooth muscle)

M4

M5

IP3, DAG

cAMP

IP3

cAMP

IP3

Depolarisation

Inhibition

Stimulation

Inhibition

Excitation

Excitation (slow epsp)

Ca2+ conductance

[Ca2+]i

K+ conductance

K+ conductance

Functional response

CNS excitation (?
memory) Gastric
secretion

Cardiac inhibition
Neural inhibition
Central muscarinic
effects (e.g. tremor,
hypothermia)

Gastric, salivary secretion

Gastrointestinal smooth muscle
contraction
Ocular accommodation
Vasodilatation

Enhanced
locomotion

Not known

Agonists (nonselective)

Acetylcholine
Carbachol
Oxotremorine
Betanecol

As M1

As M1

As M1

As M1

Antagonists (nonselective, except

those in italics)

Atropine
Dicycloverine
Ipratropium
Pirenzepine

Atropine
Dicycloverine
Ipratropium

Atropine
Dicycloverine
Ipratropium
Darifenacin

Atropine
Dicycloverine
Ipratropium

Atropine
Dicycloverine
Ipratropium

Cellular response

Recettori

Nicotinici

Muscle type

Ganglion
type

CNS

CNS type

Main
molecular
form

(1)21(adult
form)

(3)2(4)3

(4)2(2)3

(7)5

Main
synaptic
location

Skeletal
neuromuscular
junction: mainly
postsynaptic

Autonomic
ganglia: mainly
postsynaptic

Many brain
regions: pre- and
postsynaptic

Many brain
regions: pre- and
postsynaptic

Membrane
response

Excitatory
Increased cation
permeability
(mainly Na+, K+)

Excitatory
Increased cation
permeability
(mainly Na+, K+)

Pre- and
postsynaptic
excitation
Increased cation
permeability
(mainly Na+, K+)

Pre- and
postsynaptic
excitation
Increased Ca2+
permeability

(7)5 receptor produces

large Ca2+ entry, evoking
transmitter release

Agonists

Acetylcholine
Carbachol
Succinylcholine

Acetylcholine
Carbachol
Nicotine
Dimethylphenylpiperazinium

Nicotine
Epibatidine
Acetylcholine
Cytosine

Dimethylphenylpiperazinium

(4)2 (2)3 is brain

'nicotine receptor'

Antagonists

Tubocurarine
Pancuronium
Atracurium
Vecuronium
-Bungarotoxin
-Conotoxin

Mecamylamine
Trimetaphan
Hexamethonium

Mecamylamine

-Bungarotoxin
-Conotoxin
Methylaconitine

Notes

Farmaci colinomimetici
-Esteri della Colina ad azione diretta-

Farmaci colinomimetici ad azione diretta

-Alcaloidi-

Nicotiana Tabacum

La Nicotiana tabacum un'erba annuale, poco

ramificata, con grandi foglie verdi e lunghi fiori biancorosato a forma di tromba. Tutte le parti sono vischiose e
coperte di peli corti ghiandolari, che trasudano una
secrezione gialla contenente nicotina

Sostanze ad attivit anticolinesterasica -Colinomimetici indirettiEsempi rappresentativi di

agenti anticolinesterasici reversibili
impiegati in clinica

INIBITORI DELL ACETILCOLINESTERASI NELLALZHEIMER

Drug

Type of inhibition

Duration
of action

Main side effects

Notes

Tacrine

Short acting, reversible

affects both AChE and
BuChE

6h

Few cholinergic side

effects Can cause
hepatotoxicity

The first anticholinesterase shown to

be effective in Alzheimer's disease
Monitoring for hepatotoxicity needed

Donepezil

Short-acting, reversible AChEselective

24 h

Slight cholinergic side

effects

Rivastigmine

Slowly reversible
Affects both AChE and
BuChE

8 h

Cholinergic side
effects that tend to
subside with
continuing treatment

Gradual dose escalation to minimise

side effects

Galantamine

Reversible, non-selective
Also enhances nicotinic
acetylcholine receptor
activation by allosteric
mechanism

8 h

Few side effects

Dual mechanism of action postulated

AD approved treatments transiently maintain

cognitive abilities
Cognitive abilities deteriorate with time,
indicating that the treatment does not stop the
progression of AD
1993

1994

1995

Tacrine
(Cognex)

1996

1997

1998

1999

2000

2001

Donepezil

Rivastigmine

(Aricept)

(Exelon)

Approved for patients with mild to moderate AD

NEW SINCE 2001:

Galantamine
(Razadyne,
Reminyl)

Rivastigmine (Exelon) oral solution and transdermal patch

Memantine (Ebixa), NMDA antagonist, Approved for patients with moderate to
severe AD

This treatment provides only transient improvement

Sostanze ad attivit anticolinesterasica

Classificazione chimica dei pi rappresentativi

composti organofosforici

di particolare interesse farmacologico o tossicologico

Sostanze ad attivit anticolinesterasica: composti organofosforici

Gruppo
A

Formula di struttura

Nomi comuni, chimici e

altri nomi

Commenti

Sostanze ad attivit anticolinesterasica: composti organofosforici

Gruppo

Formula di struttura

Nomi comuni, chimici e

altri nomi

Commenti

Fig. 2.23. Formula di struttura della pralidossima.

Farmaci anticolinesterasici
Drug

Structure

Duration of action

Main site of action

Notes

Edrophonium

Short

NMJ

Used mainly in diagnosis of myasthenia gravis

Too short acting for therapeutic use

Neostigmine

Medium

NMJ

1) Used intravenously to reverse competitive

neuromuscular block
2) Used orally in treatment of myasthenia gravis
Visceral side effects

Physostigmine

Medium

Postganglionic
parasympathetic
junction

Used as eye drops in treatment of glaucoma

Pyridostigmine

Medium

NMJ

Used orally in treatment of myasthenia gravis

Better absorbed than neostigmine and has longer
duration of action

Dyflos

Long

Postganglionic
parasympathetic
junction

Highly toxic organophosphate, with very prolonged

action
Has been used as eye drops for glaucoma

Ecothiopate

Long

Postganglionic
parasympathetic
junction

Used as eye drops in treatment of glaucoma

Prolonged action; may cause systemic effects

Parathion

Long

Converted to active metabolite by replacement of

sulfur by oxygen
Used as insecticide but commonly causes
poisoning in humans

EFFETTI AVVERSI DEI FARMACI

COLINOMIMETICI

 Atropina e scopolamina sono antagonisti muscarinici non selettivi

ad azione sia centrale che periferica

IMPIEGO DELLA SCOPOLAMINA

Farmaci ganglioplegici

Azioni bloccanti gangliari

Bloccano tutti i gangli autonomi
Gli effetti principali sono:
Ipotensione e perdita dei riflessi cardiovascolari
Inibizione delle secrezioni
Paralisi gastrointestinale
Inibizione della minzione

Sono clinicamente superati ad esclusione del trimetafano, a

volte usato per ottenere unipotensione controllata durante
lanestesia.