k - 31.ppt

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