5. simpatolitika kuliah.kbk 2010
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simpatolitikaTRANSCRIPT
SIMPATOLITIKA
Adrenoceptor Antagonists
Prof.Dr.dr.Jazanul Anwar SpFK
Dr. Hasanul Arifin
Departemen Farmakologi dan Terapetik
Universitas Sumatera Utara
TYROSINE METYLDOPA NA NA
2
2
1
1
3
Adrenalin
syaraf pasca ganglion
neurotransmiter
sintesa
penimbunan
penglepasan
perombakan
reseptor perangsangan
penghambatan
perangsangan
penghambatan
Simpatomimetika Simpatolitika
perangsangan penghambatan
penghambatan
penghambatan
penghambatan
Pra sin
Pasca sin
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
Tyrosine
Tyrosine hydroxylase ↓
DOPA
DOPA carboxylase ↓
Dopamine
Dopamine β- hydroxylase ↓
Noradrenaline
PNMT ↓
Adrenaline
PHENYLALANINE
TYROSINE
DOPA
DOPAMINE
NORADRENALINE
ADRENALINE
TYROSINE
METHYLDOPA
METHYLDOPAMINE
METHYLNORADRENALINE
METHYLDOPA
PENGHAMBAT SINTESA NA
SIMPATOLITIKA
PRASINAPS
PASCASINAPS
PENGHAMBAT SINTE4SA
-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 PENGELEPASAN 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
Antagonists
Mechanism & Sites of Actions
Cardiovascular - vascular smooth musclecontraction
Reversal adrenalinePrejunctional 2 negative feedback on NE release
Non-cardiovascular sites
Antagonists
Nonselective
Phentolamine (reversible, competitive)
Phenoxybenzamine (irreversible, noncompetitive)
Ergot alkaloids (dirty drugs with multiple sites of action)
Selective 1 antagonists D.
“Uroselective” 1A antagonistsTamsulosin
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
• Response in “normal” resting person
– Few effects in cardiovascular system or lungs
• Low tone in heart
• Lungs – no epi being presented
• Wrong receptors in vasculature
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
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)
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
Antagonists
• Nonselective– Propranolol
– Nadolol: long half-life
– Timolol: use in glaucoma
– Pindolol: ISA
• Selective1 – Metoprolol
– Atenolol: limited entry
– Esmolol: short half-life
– Acebutolol: ISA
– Celiprolol: partial 2 agonist thus causing vasodilation
–Bisoprolol
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
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.