FARMAKOLOGI SUSUNAN SARAF OTONOM PARASIMPATIS

Kolinergik dan Antikolinergik

Syaraf pasca ganglion parasimpatik

AChE
Acetate + Choline ACh ACh ACh

M1

Acetate +Choline

M2
M3 M4

Parasimpatotomimetika langsung

M5

Cholinergic Neurotransmission

Rate limiting step Uptake of choline into nerve terminal Termination Enzymatic by acetylcholinesterase (AchE)

Syaraf pasca ganglion parasimpatik

AChE
Acetate + Choline ACh ACh ACh Tidak langsung

M1

Acetate +Choline

M2
M3 M4

Langsung

M5

Cholinergic Stimulants

Ach Pilocarpine Muscarine

Ach Nicotine

Physostigmine Neostigmine Edrophonium

Malathion DFP Nerve gas

A
Ach Ach Ach

D D D D D Ket : D : obat parasimpatomimetik

reseptor

Parasimpatomimetik yang bekerja langsung (obat kolinergik)

B
Ach

Ach

AchE D Ach

reseptor /

Ach D AchE

Ach

Parasimpatomimetik yang bekerja tidak langsung

A. Obat-obat kolinergik menyerupai asetilkolin dan bekerja langsung pada reseptor B. Penghambat kolinesterase menginaktivasi enzim asetilkolinesterase (kolinesterase), sehingga memungkinkan asetilkolin bereaksi dengan reseptor

Muscarinic effects on organ systems

Heart (M2) - HR, contractility, conduction velocity Vasculature (not innervated) - vasodilation: nitric oxide (NO) Other smooth muscle Eye: pinpoint pupil (miosis), focus for near vision GI-tract: tone to intestine, bladder, tone to sphincters Lung: contract bronchial SM. resistance, secretion Exocrine glands: sweating (cholinergic sympathetic) salivation, gastric acid secretion (M1)

PARASIMPATOMIMETIKA TIDAK LANSUNG

MEKANISME KERJANYA: MENGHAMBAT AChE REVERSIBLE: AChE + I EDROFONIUM: ` NEOSTIGMINE: PHYSOSTIGMINE IRREVERSIBLE: AChE + I AChEI AChEI IONIK IONIK KOVALEN

SENYAWA ORGANOFOSFAT: KOVALEN

Clinical use: Acetylcholinesterase Inhibitors Eye: miosis (sphincter contraction), accommodation block (ciliary
muscle contraction) Use: Glaucoma (wide-angle or secondary glaucoma) Physostigmine or echothiophate (long acting)

Efek-efek Obat Kolinergik

Jaringan tubuh Kardiovaskular* Gastrointestinal Mata Kelenjar* Paru-paru (Bronki)* Genitourinarius Otot lurik Respons Denyut jantung , TD akibat vasodilatasi Tonus & motilitas otot polos dari lambung dan usus halus. peristaltik & relaksasi otot sfingter Miosis, menambah akomodasi Salivasi , berkeringat, air mata Kontraksi otot polos bronkial. Sekresi bronkial Kontraksi otot k. kemih, tonus ureter, relaksasi otot sfingter k.kemih. Merangsang berkemih transmisi neuromuskular dan mempertahankan kekuatan dan tonus otot.

*Jaringan berespons terhadap dosis tinggi dari obat-obat kolinergik Jaringan utama berespons terhadap dosis normal dari obat-obat kolinergik

Obat-obat Kolinergik
Nama Obat Bekerja langsung Betanekol Karbakol berkemih, merangsang motilitas lambung Tekanan intra okuler, miosis PO : 10-50 mg, bid-qid 0,75-3%, 1 tts 0,5-4%, 1 tts Penggunaan Dosis

Pilokarpin
Bekerja Tidak Langsung AchE Reversibel Fisostigmin Neostigmin AchE Irreversibel Demekarium Ekotiofat

Tekanan intra okuler, miosis

TIO, miosis , masa kerja singkat Menambah kekuatan otot pada miastenia gravis, masa kerja singkat

0,25-0,5%, 1 tts PO: mula-mula 15 mg, tid dosis max. 50 mg, tid

TIO, miotikum masa kerja panjang TIO, miotikum masa kerja panjang

0,125-0,25%, 1 tts 0,03-0,06%, 1 tts

Toxicity & Treatment of AchE Inhibitors Adverse reactions: (SLUDE) - Salivation (muscarinic) - Lacrimation (muscarinic) - Urination (muscarinic) - Diarrhea (muscarinic) - Emesis (vomiting) (muscarinic) - cardiac slowing (muscarinic) - hypertension / hypotension (nicotinic) - NMJ paralysis (nicotinic) - cramps (muscarinic) - bronchoconstriction (muscarinic) - tremor, nausea, CNS induced convulsions Treatment: Muscarinic antagonist ie. Atropine AchE reactivator (Pralidoxime, 2-PAM) mechanical respiration

Toxicity of AchE Inhibitors

SLUDGE S - Salivation L - Lacrimation U - Urination D - Diarrhea G - Gastric upset E - Emesis

DUMBBELS D - Diarrhea U - Urination M - Miosis/muscle weakness B - Bronchorrea (mucus) B - Bradycard E - Emesis L - Lacrimation S - Salivation/sweating

Antikolinergik

parasimpatolitika

Acetate + Choline ACh ACh

AChE

ACh

M1

Acetate +Choline

M2
M3 M4

Penghambat reseptor

M5

Cholinergic Inhibitors

Receptor -Antagonists

Muscarinic

nicotinic

Atropine

Neuromuscular Curare, Succinylcholine

PARASIMPATOLITIKA
Antimuscarinic (parasympatholytic)
blockade is competitive and can be overcome by increasing Ach levels

"parasympatholytic" block at the NEJ (M-3)

Antimuscarinic Drugs
block M-1 receptors in CNS and ganglia block M-2 receptors in heart (vagus) block M-3 receptors at the parasympathetic NEJ

Antimuscarinic Drugs
Naturally occurring Belladonna

Anticholinergics/Antispasmodics
Drugs Quaternary amine

Alkaloids Semi-syn derivatives of Belladonna Alkaloids Synthetic

cycloplegic mydriatics / Antiparkinson's agents Ipratropium Bromide

Naturally occurring Belladonna Alakaloids

atropine scopolamine HBr (Hyoscine HBr) L-hyoscyamine (Anaspaz) L-alkaloids of Belladonna (Belafoline) tincture of belladonna alkaloids

Semi-synthetic Derivatives of Belladonna

homatropine HBr homatropine ethylbromide methscopolamine (Pamine)

Ipratropium Br (Atrovent) used

only treatment of asthma

Parasympathetic NEJ not all

antimuscarinic drugs :

most sensitive : salivary, sweat respiratory tract glands

next most sensitive: pupil (mydriasis) lens (cycloplegia - loss of accomodation - lens is thin and fixed for far (vision) vagus nerve (tachycardia)

D
Ach Ach Ach Ach D D D

reseptor

Obat-obat antikolinergik menempati tempat reseptor, sehingga menghambat asetilkolin

Obat-obat Antikolinergik
Nama Obat Gastrointestinal Atropin Propantelin Skopolamin Mata Prabedah untuk mengurangi salivasi dan sekresi bronkial Antispasmodik untuk irritable bowel syndrome (IBS) Obat praanastesi, IBS, mabuk perjalanan IM:0,4 mg, IV: 0,5-2 mg PO:7,7-15 mg,tid,qid
PO:0,5-1 mg,tid,qid. IM:0,3-0,6 mg

Penggunaan

Dosis

Homatropin
Neuromuskular/ antiparkisnonism Triheksifenidil Benztropin

Midriasis dan sikloplegia (paralisis otot siliaris sehingga akomodasi hilang) utk pemeriksaan mata

Lar.2-5%, 1-2 tts

Penyakit parkinson Parkinson. Mengatasi ES fenotiazin dan agen antipsi

PO: 1 mg/hr, dpt diaikkan sp. 515 mg/hr, dalam dosis terbagi PO:0,5-6 mg/hr dlm dosis terbagi

Clinical uses of Antimuscarinic Agents

respiratory (decrease bronchial secretion) ie. atropine asthma ie. ipratropium ophthalmologic (mydriasis, cycloplegia) eg. iritis (ie. atropine) Parkinsons disease ie. benztropine cardiovascular ie. atropine motion sickness ie. scopolamine GI disorders (peptic ulcers (pirenzepine), diarrhea) pesticide poisoning (malathion) ie. atropine mushroom poisoning (muscarine) ie. atropine nerve gases (sarin) ie. atropine + 2-PAM

Toxicity and treatment

Toxicity: dry mouth, mydriasis, tachycardia, hot flushed skin, agitation and delirium. High concentrations may cause ganglionic-blockade leading to hypotension Treatment: - quaternary cholinesterase inhibitor eg. neostigmine or physostigmine (cns action) - for hypotension: sympathomimetics (-agonist, eg.methoxamine)

Symptoms of Antimuscarinic Toxicity

Belladonna (beautiful lady) poisoning

mad as a hatter: red as a beet: blind as a bat: hot as hell (a hare):

CNS, delirium direct vasodilation cycloplegia sweat, thermoregulation

dry as a bone:

decreased secretions

Mad as a Hatter
Mercury was used to treat hats. It was applied on to the fur to roughen the fibres and make them mat more easily Mercury is a cumulative poison that causes kidney and brain damage. Physical symptoms include trembling (known at the time as hatter's shakes), loosening of teeth, loss of co-ordination, and slurred speech; mental ones include irritability, loss of memory, depression, anxiety, and other personality changes. This was called mad hatter syndrome.

Pharmacology of the Eye

The eye is a good example of an organ with multiple ANS functions, controlled by several different autonomic receptors. (Katzung) Increased intraocular pressure: Untreated blindness Glaucoma: - Open-angle (wide, chronic) treated with betablockers and other agents - Closed-angle (narrow-angle) dilated iris can occlude outflow. Pilocarpine or surgical removal of part of iris (iridectomy)

Glaucoma
Increased intraocular pressure: Untreated blindness Glaucoma:- Open angle (wide, chronic) treated with beta-blockers and other agents - Closed-angle (narrow-angle) dilated iris can occlude outflow Pilocarpine or surgical removal of part of iris (iridectomy)

Glaucoma treatment
1. -Agonist: Outflow 2. M-Agonists: Outflow 3. -Blocker: Secretion 4. 2-Agonist: Secretion 5. Prostaglandins: Outflow

Ach effects on smooth muscle in the eye

Contraction of sphincter muscle miosis Contraction of ciliary muscle for near vision

Actions on the Eye

Glaucoma treatment 1. -Agonist Outflow 2. M-Agonists Outflow 3. -Blocker Secretion 4. 2-Agonist Secretion 5. Prostaglandins Outflow 6. Carbonic acid inhibitors Secretion