k - 31.ppt
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k-31TRANSCRIPT
SIMPATOMIMETIKA
SIMPATOLITIK
Jazanul Anwar_Hasanul Arifin
Departemen Farmakologi & Terapeutik
Fakultas Kedokteran USU
2009
SIMPATOMIMETIKA
syaraf pasca ganglion
neurotransmiter
sintesa
penimbunan
penglepasan
perombakan
reseptor perangsangan
perangsangan
Simpatomimetika
perangsangan
TYROSINE _METYLDOPA_> NA ___ NA
2
2
1
1
3
Adrenalin
COMT MAO
Adrenergik dan
Penghambat Adrenergik
NE
NE
NE
D
D
DD
D
reseptor
Simpatomimetik yang bekerja
langsung
/NE
NE
NE
NE
NE
D
D
reseptor
NE
NENE
D
NED
D
reseptor
A
B
C
Simpatomimetik yang bekerja tidak
langsung
Simpatomimetik yang bekerja
campuran
D : obat simpatomimetik
E/NE
amfetamine
Simpatomimetika langsung
Simpatomimetika tak langsung
SIMPATOMIMETIKA (KIMIAWI)
Endogen: adrenalinnoradrenalindopamin
Nonendogen: 1-adrenergik : phenylephrine, methoxamin
2-adrenergik : clonidine, oxymetazoline
-adrenergik : adrenalin
-adrenergik : isoprenaline
1-adrenergik : dobutamine
2-adrenergik : terbutaline, procaterol
Dopamin (D) : dopamin
D1 : fenoldopam
D2 : bromocriptin
CATECHOLAMINE
NONCATECHOLAMINE : amfetamin, metamfetamin
1 Agonists
Methoxamine
Penylpropranolamine
Phenylephrine
Mephentermine
Metaraminol
Mitodrine
1 Agonists Response utama & kegunaan klinik
Methoxamine: i.v. hipotensi
es paroxysmal takhikardi
Phenylephrine: | vasokonstriksi
nasal decongestant
Phenylpropranolamine: vasokonstriksi
nasaldecongestant
Mephentermine: direk & indirek, i.m.
Metaraminol
Mitodrine
Resistens vaskuler perifer naik
1 AgonistsKontraindikasi
• 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 AgonistsCara pemberian
• Oral
• Transdermal
• Topical (to eye)
2 AgonistsEfek samping
• Bradycardia
• SSP (50% of population)– sedasi – mulut kering
• Disfungsi Sexual
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 AgonistsClinical uses
• Bronchodilatasi– Asthma– COPD
• Tocolytic agents– Late term gestation
2 AgonistsEfek 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
2 AgonistsAdverse Effects (Con’t.)
• CNS– Anxiety
– Restlessness
– Apprehension
• Tolerance to bronchodilation– Without tolerance to adverse effect such as
tachycardia.
2 AgonistsContraindications
• Cardiac disease– Coronary artery disease– Arrhythmias
• Diabetes
• Hyperthyroidism
• Co-administration – MAO inhibitors– Indirect-acting sympathomimetics
Adrenergik Reseptor Pemakaian dalam klinik
Epinefrin (Adrenalin) 1, β1, β2 Anafilaktik syok, asma akut, henti jantung
Efedrin 1, β1, β2 Hipotensi, bronkospasme, kongesti hidung
NE 1, β1 Syok vasokonstriktor kuat
Pseudoefedrin 1, β1 Dekongestan
Fenilefrin 1 Dekongestan
Fenilpropanolamin (PPA) 1, β1 Dekongestan
Dopamin β1 Hipotensi
Isoproterenol β1, β2 Payah jantung kongestif aliran darah miokardium dan curah jantung
Metaproterenol Β1, β2 Bronkospasme, blok jantung akut
Albuterol β2 Bronkospasme
Terbutalin β2 Relaksasi uterus
Obat-obat adrenergik /simpatomimetik
SIMPATOLITIKA
syaraf pasca ganglion
neurotransmiter
sintesa
penimbunan
penglepasan
perombakan
reseptor perangsangan
penghambatan
perangsangan
penghambatan
Simpatomimetika Simpatolitika
perangsangan penghambatan
penghambatan
penghambatan
penghambatan
PENGHAMBAT SINTESA
Blokade penimbunan
BLOKADE PENGLEPASAN
BLOKADE RESEPTOR
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
PASCASINAPS
PENGHAMBAT SINTESA
-METHYL DOPA
BLOKADE PENIMBUNAN
RESERPINE
PENGHAMBAT PENGLEPASAN NA
GUANETHIDINE
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 AntagonistsSelective antagonists
•Nonselective (1/2) antagonists
•Selective 1 antagonists
•“Uroselective” 1A antagonists
Selective antagonists
Nonselective (2) antagonists
Selective 1 antagonists
Nonselective adrenergic ( antagonists
Nonselective Antagonists
Clinical Uses: Limited
Pheochromocytoma
Benign prostatic obstruction
(Phenoxybenzamine)
Autonomic hyperreflexia
Adverse Effects
Migraine headache
(Ergot alkaloids)
Cardiovascular
Tachycardia (reflex)Orthostatic hypotentionNasal congestion
Non cardiovascular
GI (Phentolamine)Impotence (Phenoxybenzamine)Potential mutagen (Phenoxybenzamine)
Selective 1 Antagonists
• Advantage over non-selective agents– lack 2 component
• less prejunctional control (less reflex tachycardia)
• less CNS component of action
• Uses – Hypertension
– 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)
– Decrease blood pressure• In heart failure
– Decrease heart work & protect against arrythmias
• Asthma or other bronchospasm– cause bronchoconstriction
• 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
– CV Symptoms of• Hyperthyroidism
• Pheochromocytoma
• Aortic aneurysm
– Migraine headache
• Non-cardiovascular– Glaucoma
– Somatic symptoms of anxiety (e.g. stage fright)
– Fine muscle tremors
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 Reseptor Pemakaian dalam klinik
Tolazolin Hipertensi
Fentolamin Hipertensi
Prazosin Hipertensi
Propanolol β1, β2 Hipertensi, aritmia, angina pectoris, pasca infark miokardium
Nadolol β1, β2 Hipertensi, angina
Pindolol β1, β2 Hipertensi
Timolol β1, β2 Hipertensi, pasca infark miokardium
Metoprolol β1 Hipertensi, angina, pasca infark miokardium
Atenolol β1 Hipertensi, angina
Asebutolol β1 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 musclecontraction
Reversal adrenalinePrejunctional 2 negative feedback on NE release
Non-cardiovascular sites
Bladder
AntagonistsNonselective
Phentolamine (reversible, competitive)
Phenoxybenzamine (irreversible, noncompetitive)
Ergot alkaloids (dirty drugs with multiple sites of action)
Selective 1 antagonists Prazosin
“Uroselective” 1A antagonistsTamsulosin
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