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.