SIMPATOMIMETIKA

SIMPATOLITIK
Jazanul Anwar_Hasanul Arifin

Departemen Farmakologi & Terapeutik

Fakultas Kedokteran USU

2009

SIMPATOMIMETIKA

Simpatomimetika
syaraf pasca ganglion

perangsangan

neurotransmiter sintesa penimbunan penglepasan perombakan reseptor perangsangan perangsangan

COMT

MAO

2
TYROSINE _METYLDOPA_> NA ___ NA

1 2

Adrenalin

D NE NE NE D D D D

reseptor

Simpatomimetik yang bekerja langsung

E/NE

B
NE

NE

D NE

reseptor /

NE amfetamine D

NE

Simpatomimetik yang bekerja tidak langsung

Adrenergik dan Penghambat Adrenergik

D NE NE NE D

NE

reseptor

Simpatomimetik yang bekerja campuran

D : obat simpatomimetik

Simpatomimetika tak langsung

Simpatomimetika langsung

SIMPATOMIMETIKA (KIMIAWI)
CATECHOLAMINE
Endogen:
adrenalin noradrenalin dopamin
adrenalin phenylephrine, methoxamin clonidine, oxymetazoline isoprenaline dobutamine terbutaline, procaterol dopamin fenoldopam bromocriptin amfetamin, metamfetamin

Nonendogen: -adrenergik : 1-adrenergik : 2-adrenergik : -adrenergik : 1-adrenergik : 2-adrenergik : Dopamin (D) : D1 D2 NONCATECHOLAMINE : : :

1 Agonists
Methoxamine Penylpropranolamine Phenylephrine Mephentermine Metaraminol Mitodrine

1 Agonists
Response utama & kegunaan klinik
Resistens vaskuler perifer naik
Methoxamine: i.v. hipotensi
es paroxysmal takhikardi

Phenylephrine: | vasokonstriksi nasal decongestant Phenylpropranolamine: vasokonstriksi nasaldecongestant Mephentermine: direk & indirek, Metaraminol Mitodrine i.m.

1 Agonists
Kontraindikasi

Hypertension Ischemic organ diseases Pembesaran Prostrat Pemberian bersama dg obat-obat jg menambah kadar NA
MAO inhibitors sympathomimetika tak langsung

2 Agonists
Prototype Clonidine Brimonidine

2 Agonists
Response utama & tempat kerja
Response
Vasodilatasi Produksi cairan mata berkurang

Tempat kerja
Peripheral
Prejunctional: mengurangi penglepasan NA Some postjunctional sites (eye, pancreas, platelets)

SSP: mengurangi sympathetic outflow

2 Agonists
Kegunaan klinik Antihypertensives Menurunkan tekanan intraocular glaucoma sudut terbuka

2 Agonists
Cara pemberian

Oral Transdermal

Topical (to eye)

2 Agonists
Efek samping Bradycardia SSP (50% of population)
sedasi mulut kering

Disfungsi Sexual

1 Agonists
Prototype Dobutamine Response utama - Kardiostimulasi Kegunaan klinik
Gagal jantung Shock Cardiogenic

Efek tak diinginkan

Arrythmias

2 Agonists
Prototypes Albuterol Salbutamol Salmeterol Ritodrine

2 Agonists
Responses

Bronchodilation
Albuterol Salbutamol Salmeterol Terbutalin

Uterine dilation
Ritodrine

2 Agonists
Clinical uses Bronchodilatasi
Asthma COPD

Tocolytic agents
Late term gestation

2 Agonists
Efek tak diinginkan
Symptoms stimulasi 1
Tachycardia Widening pulse pressure (systolic pressure rise)

Symptoms of 2 stimulation
Widening pulse pressure (diastolic pressure drop) Drop in serum K+ (skeletal muscle uptake) Skeletal muscle tremor

Adverse Effects (Cont.)

CNS
Anxiety Restlessness Apprehension

2 Agonists

Tolerance to bronchodilation
Without tolerance to adverse effect such as tachycardia.

2 Agonists
Contraindications

Cardiac disease
Coronary artery disease Arrhythmias

Diabetes Hyperthyroidism Co-administration

MAO inhibitors Indirect-acting sympathomimetics

Obat-obat adrenergik /simpatomimetik

Adrenergik Epinefrin (Adrenalin) Reseptor 1, 1, 2 Pemakaian dalam klinik Anafilaktik syok, asma akut, henti jantung

Efedrin
NE Pseudoefedrin Fenilefrin Fenilpropanolamin (PPA) Dopamin Isoproterenol

1, 1, 2
1, 1 1, 1 1 1, 1 1 1, 2

Hipotensi, bronkospasme, kongesti hidung

Syok vasokonstriktor kuat Dekongestan Dekongestan Dekongestan Hipotensi Payah jantung kongestif aliran darah miokardium dan curah jantung Bronkospasme, blok jantung akut Bronkospasme Relaksasi uterus

Metaproterenol Albuterol Terbutalin

1, 2 2 2

SIMPATOLITIKA

Simpatomimetika
syaraf pasca ganglion

Simpatolitika penghambatan

perangsangan

neurotransmiter sintesa penimbunan penglepasan perombakan reseptor perangsangan perangsangan penghambatan penghambatan penghambatan penghambatan penghambatan

PENGHAMBAT SINTESA

BLOKADE RESEPTOR

Blokade penimbunan

BLOKADE PENGLEPASAN

NT inhibition
On presynaptic ending Drug affecting NT synthesis Drug affecting NT storage Drug affecting NT release
On postsynaptic ending Drug affecting parasympathetic receptors Drug affecting sympathetic receptors

SIMPATOLITIKA

PRASINAPS

PENGHAMBAT SINTESA -METHYL DOPA BLOKADE PENIMBUNAN RESERPINE PENGHAMBAT PENGLEPASAN NA

GUANETHIDINE

PASCASINAPS

BLOKADE RESEPTOR BLOKADE RESEPTOR

BLOKADE PENYIMPANAN NA
RESERPINE (RAUWOLFIA SERPENTINE)
KEGUNAAN KLINIK: HIPERTENSI EFEK SAMPING: ssp- DEPRESI SEDASI PERIFERI NASAL CONGESTI

PENGHAMBAT PENGLEPASAN NA
GUANETHIDINE

Selectivity of Antagonists
Selective antagonists Nonselective (1/2) antagonists Selective 1 antagonists Uroselective 1A antagonists Selective antagonists Nonselective (12) antagonists Selective 1 antagonists Nonselective adrenergic ( antagonists

Nonselective
Clinical Uses: Limited
Pheochromocytoma Benign prostatic obstruction

Antagonists
Adverse Effects Cardiovascular
Tachycardia (reflex) Orthostatic hypotention Nasal congestion

(Phenoxybenzamine)
Autonomic hyperreflexia Migraine headache (Ergot alkaloids)

Non cardiovascular
GI (Phentolamine) Impotence (Phenoxybenzamine) Potential mutagen (Phenoxybenzamine)

Selective 1 Antagonists
Advantage over non- Uses selective agents Hypertension
lack 2 component
less prejunctional control (less reflex tachycardia) less CNS component of action

Congestive heart failure Benign prostatic hyperplasia

Prazosin (BID dosage) Doxazosin &Terazosin (QD dosage)

Pheochromocytoma

Selective 1 Antagonists
Adverse Effects
Orthostatic hypotension
Usually becomes tolerated Give first dose at night

Nasal congestion

Uroselective 1A Antagonist
Tamsulosin
QD dosage

Clinical Use
Benign Prostatic Hyperplasia

Adverse Effects
Retrograde ejaculation NOTE: Avoids orthostatic hypotension in most

Selective 2 Antagonists
Yohimbine Apparent Mechanism of Action
major mechanism of action appears to be increasing sympathetic outflow from CNS

Clinical Uses - (limited):

Impotency Diabetic neuropathy pain Orthostatic hypotension

 Antagonists
In hypertensive (hyperkinetic heart-induced) In heart failure
Decrease blood pressure
Decrease heart work & protect against arrythmias cause bronchoconstriction

Asthma or other bronchospasm Diabetes

mask symptoms of insulin-induced hypoglycemia augment insulin-induced hypoglycemia

 Antagonists
Prototype - Propranolol
Pure antagonist, no Intrinsic Sympathomimetic Activity(ISA) (i.e. not a
partial agonist)

Nonselective to subtypes

High lipid solubility - Enters gut & CNS

High first pass metabolism - causing low bioavailability Has membrane-stabilizing activity
Quinidine-like effects, Na+ channel blockade, (local anesthetic)

 Antagonists
Nonselective
Propranolol Nadolol: long half-life Timolol: use in glaucoma Pindolol: ISA Selective1
Metoprolol Atenolol: limited entry Esmolol: short half-life Acebutolol: ISA

Bisoprolol

Uses of Antagonists
Cardiovascular
Hypertension Angina Arrhythmias Myocardial infarction Heart failure

Non-cardiovascular
Glaucoma Somatic symptoms of anxiety (e.g. stage fright) Fine muscle tremors

CV Symptoms of
Hyperthyroidism Pheochromocytoma Aortic aneurysm

Migraine headache

Nonselective Adrenergic Antagonists

Labetalol: and 1 antagonist Partial 2 agonist Carvedilol and 1 antagonist Antioxidant Anti-ischemic agent Recent report supports it improves cardiac performance > than metoprolol in chronic heart failure

 Antagonists
Adverse Effects
Cardiovascular
Induce CHF or bradycardial arrhythmia Sudden withdrawal - in anginal patients may cause sudden death (due to receptor supersensitivity)

Bronchospasm CNS - sleep disturbance, depression Lacking recognition of hypoglycemia

Penghambat Adrenergik / Simpatolitik

Penghambat Adrenergik Tolazolin Reseptor Pemakaian dalam klinik Hipertensi

Fentolamin
Prazosin Propanolol Nadolol Pindolol Timolol Metoprolol

1, 2 1, 2 1, 2 1, 2 1

Hipertensi
Hipertensi Hipertensi, aritmia, angina pectoris, pasca infark miokardium Hipertensi, angina Hipertensi Hipertensi, pasca infark miokardium Hipertensi, angina, pasca infark miokardium

Atenolol Asebutolol

1 1

Hipertensi, angina Hipertensi, aritmia ventrikel

Thank you

Benign prostatic hyperplasia (BHP)

Incidence 50% of age >60 90% of age >85 Definition: Nonmalignant enlargement of prostate due to growth of
Epithelia/glandular (mechanical obstruction) Smooth muscle (dynamic obstruction - urethra)

Symptoms: hesitancy, urgency, frequency, dysuria, nocturia, straining, dribbling, etc.

 Antagonists
Mechanism & Sites of Actions
Cardiovascular - vascular smooth muscle contraction
Reversal adrenaline Prejunctional 2 negative feedback on NE release

Non-cardiovascular sites
Bladder

 Antagonists
Nonselective

Phentolamine (reversible, competitive)

Phenoxybenzamine (irreversible, noncompetitive) Ergot alkaloids (dirty drugs with multiple sites of action) Selective 1 antagonists Prazosin Uroselective 1A antagonists Tamsulosin

 Antagonists
Response in normal person during stress
Short-term effect
Block heart sympathetic response
rate and contraction - decrease CO block of sympathetic control of rhythm & automaticity

Increase TPR (block vascular 2 & increased reflex sympathetic tone)

Long term effect

CO remains down TPR returns to normal