Agonis dan Antagonis

Muskarinik
P Fajri
Asetilkolin dan Reseptor Muskarinik
• Reseptor muskarinik ditemukan Properties and Subtypes of
terutama pada sel efektor Muscarinic Receptors
otonom yang dipersarafi oleh • Terdiri dari M1-M5
saraf parasimpatis
postganglionic • Tipe reseptor adalah G protein-
coupled receptor (GPCR)
• Pemberian Ach sistemik tidak
memberikan efek terapi rapid
metabolism AChE dan
butyrylcholinesterase plasma
• Efek ACh dan obat terkait pada
tempat kerja disebut muskarinik
Asetilkolin dan Reseptor Muskarinik
Properties and Subtypes of
Muscarinic Receptors
• Terdiri dari M1-M5
• Tipe reseptor adalah G protein-
coupled receptor
Pharmacological Effects of Acetylcholine
Cardiovascular System
• vasodilation
• decrease in heart rate (negative
chronotropic effect)
• decrease in the conduction velocity in the
AV node (negative dromotropic effect)
• decrease in the force of cardiac
contraction (negative inotropic effect)
Respiratory Tract
bronchoconstriction, Increased
tracheobronchial secretion
Urinary Tract
Blader contractions
GI Tract
increases tone, amplitude of contractions,
and secretory activity of the stomach and
intestine
Secretory Effects
stimulates secretion lacrimal,
nasopharyngeal, salivary, and sweat glands
Eye
Miosis, accommodation for near vision
CNS Effects
• has limited CNS penetration, may have an
important role in cognitive function,
motor control, appetite regulation,
nociception, and other processes
Muscarinic Receptor Agonists
• Terbagi menjadi dua golongan
• choline esters, including ACh and
several synthetic esters
• cholinomimetic alkaloids
(pilocarpine, muscarine, and
arecoline)
Muscarinic Receptor Agonists
ADME
• Amin kuartener : Ester kolin
poorly absorbed (oral), limited ability
to cross the blood-brain barrier,
short acting rapid renal
elimination
• Amin tertier: pilocarpine dan
arecoline
Absorbsi baik, dapat menembus
sawar darah otak
• Alkaloid alam dieliminasi lewat
ginjal, eliminasi dapat ditingkatkan
dengan mengasamkan urin MUSKARIN ARECOLINE
Therapeutic Uses of Muscarinic Receptor
Agonists
Acetylcholine
• used topically for the induction of miosis
during ophthalmologic surgery (1%
solution)
Methacholine
• administered by inhalation for the
diagnosis of bronchial airway
hyperreactivity in patients who do not
have clinically apparent asthma
• Contraindications: severe airflow
limitation, recent myocardial infarction or
stroke, uncontrolled hypertension, or
pregnancy
• Available as powder dilute in NaCl 0,9%
 nebulizer
Bethanechol
• treating urinary retention and inadequate
emptying of the bladder.
• postoperative urinary retention,
• diabetic autonomic neuropathy,
• chronic hypotonic, myogenic, or neurogenic
bladder
• GI: treat postoperative abdominal
distention, gastric atony, gastroparesis,
adynamic ileus, and gastroesophageal
reflux.
• Dose: 10-50 mg 3-4 dd ac
miosis during surgery. 0.01%–3% solution
Therapeutic Uses of Muscarinic Receptor
Agonists
Carbachol Cevimeline
• Used topically for the treatment of • agonist M1 and M3 receptors on
glaucoma and the induction of lacrimal and salivary gland
miosis during surgery; 0.01%–3% epithelia
solution • Long lasting, fewer side effects
than pilocarpine
Pilocarpine • Dose: 3 dd 30 mg
• treatment of xerostomia (dry
mouth). Dose: 3 dd 5–10 mg 
lowered with hepatic impairment
• glaucoma and as a miotic agent;
0.5%–6% solution
Contraindications, Precautions, and Adverse
Effects
Contraindication Adverse effects
• asthma, • diaphoresis;
• chronic obstructive pulmonary • diarrhea,
disease, • abdominal cramps,
• urinary or GI tract obstruction, nausea/vomiting, and other GI side
• acidpeptic disease, effects;
• cardiovascular disease • sensation of tightness in the
accompanied by bradycardia, urinary bladder;
hypotension, and hyperthyroidism • difficulty in visual accommodation;
(may precipitate atrial fibrillation in • hypotension
hyperthyroid patients)
Toxicology muscarinic agonis
• Poisoning from the ingestion of plants containing pilocarpine,
muscarine, or arecoline is characterized chiefly by exaggeration of
their various parasympathomimetic effects.
• Treatment
• parenteral administration of atropine in doses sufficient to cross the blood-
brain barrier and
• measures to support the respiratory and cardiovascular systems and to
counteract pulmonary edema.
Muscarinic Receptor Antagonists
EFFECTS OF ATROPINE IN RELATION TO DOSE
• Muscarinic antagonists
mencegah efek ACh dengan
memblok ikatan ACh pada
reseptornya di parasimpatik
neuroeffektor dan pd SSP
• Amin quartener tidak mudah
menembus sawar darah otak
dan membrane
• Beberapa organ mempunyai
sensitivitas yang berbeda
terhada antagonis muskarinik
Pharmacological Effects of Muscarinic
Antagonists
Heart
• Respon dominan takikardia
• Memperpendek refraktori
period nodus AV
Circulary
• Efek sedikit pada pembuluh
darah, namun dapat menlawan
efek vasodilatasi dan penurunan
tekanan darah pada pemberian
ester kolin
Respiratory system
• Bronkodilatasi
• menurunkan sekresi
tracheobronchial, hidung, mulut
dan pharynx  mengatasi iritasi
oleh anastesi inhalasi
• Pada penyakit respiratory
atropine menghambat
bronkokonstriksi yang
disebabkan oleh histamine,
bradykinin, dan eicosanoids.
Pharmacological Effects of Muscarinic
Antagonists
Eye
• dilate the pupil (mydriasis) and paralyze
accommodation (cycloplegia)
• Open angle glaucoma
GI Tract
• Motility reduce tone and amplitude and
frequency of peristaltic contractions  large
dose neded
• Gastric Acid Secretion: partially inhibit gastric
secretion
• Secretion can completely abolish the copious,
watery secretion induced by parasympathetic
stimulation  dry mouth
Urinary Tract
• decrease the normal tone and amplitude of
contractions of the ureter and bladder
Biliary Tract
• mild antispasmodic action on the gallbladder
and bile ducts in humans
• Sweat Glands and Temperature
• inhibit the activity of sweat glands innervated
by sympathetic cholinergic fibers, and the skin
becomes hot and dry
CNS
• Atropine has minimal effects on the CNS at
therapeutic doses, toxic dose restlessness,
irritability, disorientation, hallucinations, or
delirium  depression, leading to circulatory
collapse and respiratory failure after a period
of paralysis and coma
• scopolamine has prominent central effects at
low therapeutic doses pass blod brain
barrier
ADME
• belladonna alkaloids and the
tertiary synthetic and
semisynthetic derivatives are
absorbed rapidly from the GI tract.
• Absorption from intact skin is
limited except scopolamine
• Systemic absorption of inhaled or
orally ingested quaternary
muscarinic receptor antagonists is
limited.
• Atropine has a t1/2 of about 4 h;
hepatic metabolism accounts for
the elimination of about half of a
dose, and the remainder is
excreted unchanged in the urine.
• Ipratropium is administered as an
aerosol or solution for inhalation,
whereas tiotropium is
administered as a dry powder.
• About 90% of the dose is swallowed.
When inhaled, their action is confined
almost completely to the mouth and
airways. Most of the swallowed drug
appears in the feces.
• maximal responses usually develop
over 30–90 min, with tiotropium
having the slower onset.
• The effects of ipratropium last for 4–6
h; tiotropium’s effects persist for 24
h, and the drug is amenable to once-
daily dosing.
Therapeutic Uses of Muscarinic Receptor
Antagonists
Respiratory Tract
• Ipratropium, tiotropium, aclidinium, and
umeclidinium are important agents in the
treatment of chronic obstructive
pulmonary disease
• Ipratropium is administered 4 dd via a
metered-dose inhaler or nebulizer;
aclidinium is 2dd via a dry powder inhaler.
Tiotropium and umeclidinium are 1 dd
• In normal individual can protect
bronchoconstriction from inhalation of
such irritants as sulfur dioxide, ozone, or
cigarette smoke
Genitourinary Tract
• Overactive urinary bladder  reduce
frequency of contraction
• Treatment enuresis in children and spastic
paraplegia.
• Agent: oxybutynin, tolterodine, trospium
chloride, darifenacin, solifenacin, and
fesoterodine.
GI Tract
• Management of peptic ulcer
• belladonna alkaloids and their synthetic
substitutes can reduce tone and motility
• Diarrhea associated with irritation of the
lower bowel
Therapeutic Uses of Muscarinic Receptor
Antagonists
Salivary Secretions
• belladonna alkaloids and
synthetic substitutes are
effective in reducing excessive
salivation, such as drug-induced
salivation and that associated
with heavy-metal poisoning and
Parkinson disease.
Cardiovascular System
• Atropine may be considered in
the initial treatment of patients
with acute myocardial infarction
in whom excessive vagal tone
causes sinus bradycardia or AV
nodal block.
• Atropine occasionally is useful in
reducing the severe bradycardia
and syncope associated with a
hyperactive carotid sinus reflex
Therapeutic Uses of Muscarinic Receptor
Antagonists
CNS Anticholinesterase Poisoning
• Beladona and scopolamine to prevent • treatment of poisoning by
motion sickness anticholinesterase organophosphorus
• Treat extrapyramidal symptom and insecticides
parkinson disease  benztropine • antagonize the parasympathomimetic
mesylate, trihexyphenidyl hydrochloride, effects of pyridostigmine or other
and biperiden anticholinesterases administered in the
Anasthesia treatment of myasthenia gravis
• block vagal reflexes induced by surgical
manipulation of visceral organs.
• Atropine or glycopyrrolate are also used
to block the parasympathomimetic
effects of neostigmine when it is
administered to reverse skeletal muscle
relaxation after surgery.
Contraindications and Adverse Effects
• Side Effect xerostomia, constipation, blurred vision, dyspepsia, and
cognitive impairment.
• Contraindication:
• urinary tract obstruction, GI obstruction, and uncontrolled (or susceptibility to
attacks of) angle-closure glaucoma.
• benign prostatic hyperplasia