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PARASIMPATOMOMETIKA
Prof.Dr.dr.Jazanul Anwar SpFK
Departemen Farmakologi dan Terapetik
Universitas Sumatera Utara
Prof.Dr.dr.Jazanul Anwar SpFK
Departemen Farmakologi dan Terapetik
Universitas Sumatera Utara
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ANS Diagram
Key Points
Division – Anatomical
Usually dual innervation
Usually antagonistic
Usually one dominates
Usually some ANS tone!
ANS Diagram
Key Points
Division – Anatomical
Usually dual innervation
Usually antagonistic
Usually one dominates
Usually some ANS tone!
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Key PointsPreganglionic "i#ers
– mylinated
Postganglionic "i#ers
– non mylinated
SNS $re % $ost &%'(PNS $re % $ost &%&
)e*ce$tion &%&(+(((
Auer#ac,s $le*us-
Key role o" Ac,
Motor "i#er not $art o" ANS
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.,olinergic Rece$tors
• Muscarinic (7 transmembrane)
- M1 -autonomic ganglia, CNS- M2 -heart
- M3 -smooth muscle, glands
- M4, M
- M13 ↑ !"C, M24 ↓ #C
- $-%rotein cou%led
• Nicotinic (ion channel)
- %entamer, subunits- NN or N1 -ganglia, adrenal
medulla (α2β3, α3β2)
- NM or N2 -s&eletal muscle
(in'ant α2βδε, adult α2βδγ )
- α subunit, #ch binding (2)
Na - in
- out
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Acetate
+
Choline
ACh
ACh ACh
N
M1
M2
M3
M4
M5
AChE
Acetate +Choline
Syara" $asca ganglion $arasim$ati/
Tidak langsung
Langsung
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Muscarinic e""ects on organ systems
•Ot,er smoot, muscle
• 0 Eye% %in%oint %u%il (miosis), 'ocus 'or near *ision
• 0 1I0tract% ↑tone to intestine, bladder, ↓ tone to s%hincters
• 0 2ung% contract bronchial SM+ → ↑resistance, ↑ secretions
• 0 E*ocrine glands%↑ seating (cholinergic sm%athetic)↑ sali*ation, ↑ gastric acid secretion (M1)
•3eart )M'-
- ↓ ./, ↓ contractilit, ↓conduction *elocit
0asculature (not inner*ated)
- *asodilation nitric oide (N)
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.,olinergic Stimulants
#ch
!ilocar%ine
Muscarine
#ch
Nicotine
!hsostigmine
Neostigmine
dro%honium
Malathion
56!
Ner*e gas
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Muscarinic rece$tor agonistsMuscarinic rece$tor agonists
•.,oline esters- #C. (muscarinic nicotinic action)- bethanechol (oral or sc, ne*er i* or im → cardiac arrest)- methacholine (not common)- carbachol (direct8indirect9 muscarinic nicotinic)
• Al/aloids%- muscarine (mushrooms)- %ilocar%ine (5C, used in glaucoma emergence)- ootremorine (snthetic) CNS action (basal ganglia)
• Uses%- o%hthalmic (#ch, brie' miosis)- diagnostic 'or belladonna %oisoning (methacholine)- urinar retention (bethanechol)- re*erse $:; de%ression (bethanechol)
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• Adverse reactions% (S"<5)
- Sali*ation
- 2acrimation- Urination- Diarrhea- Emesis (*omiting)
- cardiac sloing (arrest, es%+ bethanechol)
- nausea, cram%s- bronchoconstriction, can %reci%itate asthma- in*oluntar de'ecation, urination- tremor, CNS induced con*ulsions
Adverse Reactions 0 .,olinergics
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1anglionic stimulants
• Clinicall not im%ortant
•
• #cetlcholine (natural transmitter)
• 5M!! (e%erimental)• Nicotine (al&aloid, tobacco)
• "obeline (tobacco)
Nicotinic rece$tor agonists
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Acetylc,olinesterase 4 Irreversi#le In,i#ition
D5P+ Iso"luro$,ate
P
OR1
R2 X
2-!#M
!ralidoime
No cns action
56! #ging3=-4= min
Ner*e gas
secs 8 min
Malathion
4 > ? hr
Acetylc,olinesterase 4 Irreversi#le In,i#ition
D5P+ Iso"luro$,ate
P
OR1
R2 X
2-!#M
!ralidoime
No cns action
56! #ging3=-4= min
Ner*e gas
secs 8 min
Malathion
4 > ? hr
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Indirectly0Acting Parasym$at,omimeticsIndirectly0Acting Parasym$at,omimetics
• Interact 6it, acetylc,olinesterase
;rue and8or %seudocholinesterase (serum)• T6o sites%
- anionic site that binds the @uaternar amine and
%ositions the #ch molecule
- esteratic site hich attac&s the acl carbon
In,i#itors o" c,olinesterase%
- /e*ersible inhibitors (eg+ %hsostigmine)- :rre*ersible inhibitors (eg+ organo%hos%hates)
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Reversi#le in,i#itors
• 7uarternary ammonium com$ounds
- dro%honium (snthetic, ater stable, -1= min)
;ensilon test > Masthenia gra*is
- #mbenonium (snthetic, 4-A hr)
.ar#amates
- !hsostigmine (=+-2 hr)
(tertiar amine, ell absorbed, cns acti*it,
can gi*e to%icall)
- Neostigmine (=+-2 hr)
(@uaternar amine, no cns acti*it, snthetic,
some direct action)
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US Military '0PAM 8 Atro$ine In9ector
':; mg Atro$ine+ <((mg '0PAM
US Military '0PAM 8 Atro$ine In9ector
':; mg Atro$ine+ <((mg '0PAM
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.linical use% Acetylc,olinesterase In,i#itors
• Eye% miosis (s%hincter contraction), accommodation bloc& (ciliar
muscle contraction)<se $laucoma (ide-angle or secondar glaucoma)
!hsostigmine or echothio%hate (long acting)
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Actions on t,e Eye$laucoma treatment
1+ α-#gonist↑ut'lo
2+ M-#gonists↑ut'lo
3+ β-Bloc&er
↓Secretion4+ α2-#gonist
↓Secretion
+ !$s ↑ut'lo
?+ Carbonic acid
inhibitors ↓Secretion
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•1I tract% ↑motilit in %araltic ileus (%ost-o%) or aton o' urinar bladder+Neostigmine (bethanechol better)
Neuromuscular 9unction%
- Neostigmine in Masthenia gra*is
- dro%honium as diagnostic Masthenia gra*is
- /e*erse NM bloc& a'ter surger, Neostigmine
Reverse to*icity #y antic,olinergic agents%- ie+ atro%ine, tricclic antide%ressants (high doses)
- !hsostigmine is %re'erred (CNS action)
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Acetylc,olinesterase In,i#itors
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• Adverse reactions% (S"<5)
- Sali*ation (muscarinic)
- 2acrimation (muscarinic)
- Urination (muscarinic)
- Diarrhea (muscarinic)
- Emesis (*omiting) (muscarinic)
- cardiac sloing (muscarinic)- h%ertension 8 h%otension (nicotinic)
- NM %aralsis (nicotinic)
- cram%s (muscarinic)
- bronchoconstriction (muscarinic)- tremor, nausea, CNS induced con*ulsions
To*icity 4 Treatment o" Ac,E In,i#itors
• Treatment% Muscarinic antagonist ie+ #tro%ine
#ch reacti*ator (!ralidoime, 2-!#M)
mechanical res%iration
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S2UD1E
S - Sali*ation" - "acrimation
< - <rination
5 - 5iarrhea
$ - $astric u%set - mesis
DUM==E2S
5 - 5iarrhea< - <rination
M - Miosis8muscle ea&ness
B - Bronchorrea (Dmucus) B - Bradcar
- mesis
" - "acrimationS - Sali*ation8seating
To*icity o" Ac,E In,i#itors