SIMPATOLITIKA

Adrenoceptor Antagonists

Prof.Dr.dr.Jazanul Anwar SpFK

Dr. Hasanul Arifin Departemen Farmakologi dan Terapetik Universitas Sumatera Utara

2
TYROSINE METYLDOPA NA NA

1 2 3

Adrenalin

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

Tyrosine Tyrosine hydroxylase DOPA DOPA carboxylase Dopamine Dopamine - hydroxylase Noradrenaline PNMT Adrenaline

PENGHAMBAT SINTESA NA
PHENYLALANINE
TYROSINE TYROSINE

DOPA

METHYLDOPA

METHYLDOPA

DOPAMINE

METHYLDOPAMINE

NORADRENALINE

METHYLNORADRENALINE

ADRENALINE

SIMPATOLITIKA

PRASINAPS

PENGHAMBAT SINTE4SA -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 PENGELEPASAN NA

GUANETHIDINE

Selectivity of Antagonists
Selective 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 muscle contraction
Reversal adrenaline Prejunctional 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 antagonists Tamsulosin

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
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) 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)

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

 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.