Prajogo Wibowo

AUTONOMIC NERVES SYSTEM

2 fungsi tubuh
SISTEM SARAF
SISTEM ENDOKRIN

PERSAMAAN
INTEGRASI DALAM OTAK
KEMAMPUAN MEMPENGARUHI PROSES

JARAK JAUH ADANYA MEKANISME NEGATIVE FEED BACK

PERBEDAAN
TRANSMISI INFORMASI - HORMON MELALUI ALIRAN DARAH

- SARAF MELALUI IMPULS SARAF

PERIPHERAL NERVES SYSTEM

KOMPONEN SSO

perbedaan
NOR EPINEPHRINE
RESEPTOR

ACETYLCHOLINE
RESEPTOR

: 1 , 2
: 1 , 2

N : Nicotinic
M : Muscarinic

Receptor location & responses

RANGSANGAN SARAF SIMPATIS

Seperti orang marah (FIGHT) dan takut (FLIGHT) Glukosa darah (Glikogenolisis ) Dilatasi pupil (midriasis) Kecepatan kontraksi jantung (chronotropic) , Kekuatan kontraksi jantung (inotropic) Tekanan darah Vasodilatasi di otot skelet Vasokonstriksi di kulit & viscera Kontraksi limpa Relaksasi saluran cerna & vesica urinaria Kontraksi sphincter

RANGSANGAN SARAF PARASIMPATIS

Penyimpanan energi Pemeliharaan organ selama istirahat Melindungi retina dari sinar berlebihan

(miosis) Chronotropic , Inotropic BP Pergerakan saluran cerna Percepat pengosongan rectum & VU Hipersekresi kelenjar, hipersalivasi

INERVASI GANDA
PARASIMPATIS PENIS
UTERUS

SIMPATIS Ejaculasi
Tidak Hamil : relaksasi 2 Hamil Muda : kontraksi 1 Hamil Tua : relaksasi 2

Ereksi
Tergantung kadar hormon : Estrogen kontraksi Progesteron relaksasi

VESICA URINARIA

M. Detrusor kontraksi M3 Relaksasi 2 Sphincter relaksasi 1 (open) Sphincter kontraksi 1 (close)

INERVASI TUNGGAL
SIMPATIS M. Dilatator pupillae 1 (midriasis)
Pembuluh darah 1, 2, M3 Vas deferens 1 Kelenjar keringat apokrin Semua kelenjar (eksokrin) kecuali kelenjar keringat

PARASIMPATIS M. Constrictor pupillae M3 (miosis)

Otot polos bronchus 2, M3

Kelenjar saliva sekret mukus (kental) 1 Sekret serous (encer) M3 M. Ciliaris (tidak dirangsang simpatis) M. Ciliaris kontraksi M3

penggolongan obat otonomik

Parasimpatomimetik aktivitas parasimpatis Parasimpatolitik >< aktivitas parasimpatis
Simpatomimetik aktivitas simpatis Simpatolitik >< aktivitas simpatis

Parasimpatomimetik (cholinomimetic)
Cholinester Acetylcholine (ACh) Metacholine Carbachol Betanechol (Urecholin)
Cholinomimetic Alkaloid Pilocarpin Muscarin Arecholin

Sintesis

Serat cholinergic
Serat post-ganglion parasimpatis
Serat pre-ganglion otonomik Serat cholinergic SSP Serat saraf motorik (otot skelet) Serat sympathocholnergic

ach
Storage of Ach : Ach is transported into synaptic vesicles via a proton antiporter (inhibited by vesamicol)
Release of Ach: Action potential triggers Ca2+ influx, causing release of vesicle content through exocytosis

Degradation of ach
Through the action of acetylcholinesterase (AchE), present in cholinergic synapses. AchE rapidly converts Ach to choline and acetic acid with a turnover time of 150 microseconds

HIDROLISE ACH
ACH eterase Ujung saraf cholinergic
Sel efektor Eritrosit

Pseudo cholin Esterase Plasma

Jaringan glial Kapiler

Proses hidrolise ach

Ach + enzyme esterase Ach esterase complex
Ach esterase complex Choline + Acetylated

enzym Acetylated enzym + H2O Acetate + enzym

EFEK FARMAKOLOGIS
Bila Ach diinjeksikan : A. Muscarinic : CVS :
pembuluh darah dilatasi BP shock Jantung chronotropic & inotropic , BP

Organ lain
Pupil miosis

 Nicotinic
Efek simpatis BP
Why? Syarat rec M dihambat atropin, Ach

merangsang rec N pada ganglion rilis NE

PENGGUNAAN KLINIK
RETENSIO URINE (Betanechol)
PARALYTIC ILEUS (Post op) INTOKSIKASI ATROPIN : antagonis

kompetitif atropin & Ach GLAUCOMA: M. ciliaris kontraksi

KONTRA INDIKASI
Asthma bronchiale: hipersekresi kelenjar bronchus sesak Insufisiensi Coronary Ulcus pepticum
Hipertiroidi Hipertensi

CHOLIN-ESTERASE INHIBITOR / cholin-esterase blocking agents

REVERSIBLE

DOA pendek
Edrophonium
Ambephonium

DOA agak lama Physostigmin (eserin) Neostigmin (Prostigmin)

 IRREVERSIBEL
Organophosphate Parathion Malathion (Baygon) Echothiophate

EFEK CH-E INHIBITOR

EFEK NICOTINIC
SSP : gelisah, tremor, konvulsi, depresi pusat

vasomotor & pusat nafas, coma CVS :

Dosis terapi : Jantung : CO BP Vascular : simpatis (tdk punya PS) medulla adrenalis Dosis Toxic : bradikardi , BP

NE BP

 OTOT SKELET
Ach kontraksi otot depolarisasi terus

menerus paralisa

INDIKASI CH-E I
Ileus obstruktif, Atonia usus : Neostigmin
Retensio Urinae : Neostigmin Glaucoma : Physostigmin topikal eye drop Intoksikasi atropin : Physostigmin Mengakhiri efek curare (d-tubocurarine) :

Neostigmin Myasthenia Gravis : Neostigmin + Atropin

KONTRAINDIKASI
Asthma brochiale
Ulcus pepticum Hipertiroidi

Side effects
Nausea
Kolik abdomen Hipersekresi keringat, saliva Cholinergic crisis

simpatomimetik
Penggolongan: Cathecolamine Non cathecolamine 1. Ephedrine 2. Amphetamine 3. Phenylephrine 4. Tyramine Incomplete Sympathomimetic

ADRENERGIC TRANSMISSION
SYNTHESIS : Catecholamines seperti Epinephrine, Norepinephrine, & Dopamine disintesis dari Tyrosine Tyrosine hydroxylases is the rate limiting step in the synthesis of CA

ADRENERGIC TRANSMISSION
STORAGE : The granules take up dopamine from the cytoplasm and synthesis of NE occurs within the granules. NE is stored in the granules within the adrenergic terminal . Released by exocytosis

RELEASE : Rilis Cathecolamines melaluui exocytosis Indirectly acting amines (tyramine and amphetamine) merangsang rilis NE

UPTAKE OF CA : It is an efficient mechanism after the release of NE Axonal uptake (Uptake 1 ) : Transports NE at a higher rate than E. It is the most important mechanism for the termination of the NE. Cocaine, Imipramine inhibits this uptake 1.

 METABOLISM : by 2 enzyme systems MAO and COMT. NE after uptake -1 into the axoplasm is acted upon by MAO. NE which diffuses into the circulation is acted upon by COMT, mainly in the liver The major metabolites excreted in urine is VMA (Vanillyl mandelic acid)

 Adrenergic receptors are G protein coupled receptors which acts by increasing or decreasing the production of c AMP

ADRENERGIC RECEPTORS ALPHA 1 -- A , B , D ALPHA 2 -- A , B , C

ALPHA 1 : Acts by activating Phospholipase C production of inositol triphosphate (IP3) and DAG IP3 promotes the release of calcium from the intracellular stores --increase cytoplasm calcium

ALHA 1 receptors
EYE radial fibers contraction mydriasis Arterioles and veins contraction can increase

peripheral resistance. Bladder trigone and sphincter contraction urinary retention Liver Glycogenolysis. Vas deferens ejaculation.

ALPHA 2 : acts by inhibiting adenylyl cyclase cAMP Platelets - aggregation Prejunctional receptors decrease release of transmitter (NE) Pancreas -- decrease insulin release (predominant)

BETA : beta receptors stimulate adenylyl cyclase increasing the c AMP Beta 1 Heart JG cells in kidney (increase renin release).

Beta 2 receptors : cAMP Blood vessels to skeletal muscle Vasodilation Uterus Relaxation Bronchioles Dilatation Skeletal muscles tremors Liver - Glycogenolysis

Dopamine 1 receptors : Acts by stimulation of adenylyl cyclase and increased cAMP Renal and mesenteric vasculature vasodilation and increase blood flow and Na excretion. Dopamine 2 receptors : Acts by inhibition of adenylyl cyclase, decrease cAMP, open potassium channels, Brain

Adrenergic Drugs: Directly acting : Epinephrine, Norepinephrine, Phenylephrine, Albuterol Indirectly acting : acts by release of NE : Tyramine, Amphetamine Mixed : Ephedrine

 Epinephrine acts on alpha 1, 2

beta 1, 2 Nor epinephrine acts on alpha 1, 2 beta 1 Isoprenaline acts on beta 1 , 2

Dopamine 1 receptors agonist :

Dobutamine, Fenoldopam

 MAO
MAO A present in the nerves /intestine/ liver

or Anywhere Metabolizes NE, 5-HT and tyramine Inhibitors are Phenelzine, Tranylcypromine

MAO B Present mainly in the Brain Metabolizes preferentially dopamine Inhibitors are Selegiline COMT INHIBITORS : Tolcapone -Long acting Entacapone -Short acting

Agonist acting on Alpha 1 receptors Phenylephrine, Methoxamine Given systemically they increase the mean blood pressure via vasoconstriction with minimal effect on pulse pressure (PP). The increase in BP can elicits reflex bradycardia.

Agonist acting specifically on Alpha 2 receptors : Clonidine, Alpha Methyldopa Beta 1 and beta 2 : Isoproterenol Beta 1 : Dobutamine Beta 2 : Terbutaline, Albuterol, Ritodrine, Metaproterenol

 Beta agonists : Beta 1 and Beta 2

Isoproterenol It cause a decrease in peripheral resistance, a

decrease in mean BP due to beta 2 receptor action and a reflex increase in heart rate. Systolic blood pressure does not fall significantly as diastolic, due to beta 1 receptor action, so the pulse pressure increases .

Norepinephrine : It has little effect on beta 2 receptors. It increases TPR and both diastolic and systolic blood pressure. Positive inotropic action results in increase of pulse pressure. Compensatory vagal reflexes tend to overcome the direct chronotropic action of NE -- reflex bradycardia may occur.

Epinephrine : Acts on alpha 1, 2 and beta 1 and 2. Epinephrine increase the HR, systolic BP and PP. Its effects on diastolic blood pressure depends on dose.

Epinephrine :
At low dose, beta 2 activation predominates resulting in decrease of diastolic pressure and

TPR, although mean BP may not decrease significantly. At medium dose, increase in heart rate, increase in mean blood pressure and increase in pulse pressure due to both beta 1 and 2 receptor action.

Epinephrine at low dose resulting in decrease diastolic pressure and increase in heart rate.

Epinephrine at medium dose increase the mean blood pressure, heart rate and pulse pressure

Epinephrine : At high dose, increase in blood pressure and reflex bradycardia similar to norepinephrine.

ALPHA BLOCKERS: Non-selective Phenoxybenzamine, Phentolamine Alpha -1 selective Prazosin, Terazosin, Tamsulosin Alpha-2 selective Yohimbine

BETA BLOCKERS: Non selective : Propranolol, Nadolol, Timolol With Partial agonist : Pindolol Beta 1 selective : Atenolol, Metoprolol Beta and alpha 1 blocker : Labetolol, Carvedilol

 PRESSOR AGENTS : Metaraminol, Phenylephrine, Ephedrine. CARDIAC STIMULANTS : Dobutamine. BRONCHODILATORS : Albuterol, Epinephrine, Isoproterenol. NASAL DECONGESTANTS : Pseudoephedrine, Xylometazoline. CNS STIMULANTS : Amphetamine, Ephedrine UTERINE RELAXANTS : Terbutaline, Ritodrine.

ADRENERGIC DRUGS
EPINEPHRINE
PHARMACOLOGICAL ACTIONS

CVS : Increases the force of contraction of heart. Increases the heart rate. Increases the conduction through AV node.

EPINEPHRINE VASCULAR BLOOD VESSELS : Constriction of vessels -- rise in BP (alpha 1) -- high dose. Dilatation of vessels of skeletal muscle: (beta 2) low dose.

Epinephrine at low dose resulting in decrease diastolic pressure and increase in heart rate.

Epinephrine at medium dose increase the blood pressure, heart rate and pulse pressure

Epinephrine at high dose results in reflex bradycardia due to high blood pressure

Effect of epinephrine on blood pressure, heart rate and peripheral resistance

Dale's vasomotor reversal:

2 receptors.

Epinephrine Reversal : when alpha-1 receptors are blocked , epinephrine will produce hypotension because of uninhibited beta

CATECHOLAMINES
EPINEPHRINE SMOOTH MUSCLES GIT : Peristalsis is reduced and sphincters are constricted BLADDER : Trigone is contracted and Detrusor is relaxed UTERUS : Relaxation at term

EPINEPHRINE EYE : Mydriasis due to radial muscle contraction METABOLIC ACTIONS : Activation of beta 2 receptors result in uptake of K into the cells leading to hypokalemia Renin secretion is increased by adrenaline beta-1 Epinephrine produces glycogenolysis and lipolysis

DOPAMINE :
Acts on dopamine, alpha 1 and beta 1 receptors. D1 in the renal and mesenteric blood vessels

dilates most sensitive at low dose . Moderate high dose positive inotropic action on the heart beta 1 Large dose vasoconstriction alpha 1 receptors Dopamine agonist : FENOLDOPAM / DOPEXAMINE

DOBUTAMINE : It does not act on D1 and D2 receptors. Considered as beta 1 agonist. It increases the force of contraction of the heart but not increase the heart rate significantly. Used in CCF, Myocardial infarction with failure.

EPHEDRINE : Acts directly on alpha and beta receptors and indirectly also. Effective orally - resistant to MAO Crosses the BBB CNS stimulation. Used in bronchial asthma and hypotension

AMPHETAMINE : Orally active CNS action more prominent. Alertness, increased concentration, increased work capacity. RAS is activated wakefulness. Used in ADHD and narcolepsy.

Alpha 2 agonist : Clonidine Alpha methyl dopa

CLONIDINE: Activation of alpha 2 receptors in the brain causes inhibition of sympathetic system Suppression of release of NE by presynaptic alpha 2 receptors. Excellent oral bioavailability. Transdermal patches are also available.

CLONIDINE : Adverse effects : Sedation, bradycardia, sexual dysfunction, rebound hypertension. Uses: Adjuvant in anesthesia. Glaucoma. Hypertension.

Beta 2 agonist : Terbutaline Ritodrine Albuterol Formoterol long acting Salmeterol long acting

USES OF SYMPATHOMIMETICS : Vascular hypotension, control bleeding, Nasal decongestants Bronchial asthma Allergic disorders

USES OF SYMPATHOMIMETICS : CNS Narcolepsy Attention deficit Hyperactivity disorder (ADHD) Obesity Nocturnal enuresis Uterine relaxants

 Alpha receptors mediates the actions of epinephrine.

Alpha 1

contraction of arterioles and venules. contraction of radial fibers in the eye. contraction of vas deferens (ejaculation). contraction of bladder trigone.

ALPHA BLOCKERS
Classification of alpha blockers :
Irreversible and Nonselective Phenoxybenzamine Reversible : Nonselective Ergot alkaloids Ergotamine Others -- Phentolamine, Tolazoline Reversible Selective Prazosin, Terazosin, Doxazosin, Tamsulosin. Alpha 2 selective : Yohimbine

GENERAL EFFECTS OF ALPHA BLOCKADE : Blockade of vasoconstriction - hypotension Postural reflex is interfered postural hypotension Reflex tachycardia due to fall of BP Failure of ejaculation

Phenoxybenzamine : forming covalent bond with alpha receptors. Effects lasts 3-4 days. Penetrates BBB. Oral absorption is erratic. Used in Phaeochromocytoma.

PRAZOSIN :selective alpha -1 blocker It inhibits phosphodiesterase thus increase c AMP and vasodilatation. No significant tachycardia Postural hypotension first dose phenomenon. Used in hypertension and benign prostrate hypertrophy.

USES OF ALPHA BLOCKERS:

Pheochromocytoma Hypertension CCF BHP Migraine prophylaxis

ADVERSE EFFECTS :
Postural hypotension Impotence

BETA BLOCKERS
Cornerstone of Ischemic Heart Disease therapy except Prinzmetals angina
Standard therapy for unstable and effort

angina One of the preferred therapies for HTN. One of the anti-arrhythmic groups of drugs

 Beta 1 -- heart ; also beta 2.

It is a G protein linked receptor to Adenylyl

Cyclase when activated produce c AMP from ATP C AMP is the intracellular messenger.

BETA BLOCKERS
SELECTIVE
NON SELECTIVE

NON-SELECTIVE No intrinsic sympathetic activity : Propranolol, Timolol, Sotalol, Nadolol Intrinsic sympathetic activity : Pindolol.

 SELECTIVE Beta 1 : Metoprolol, Esmolol.

Alpha 1 and Beta blocker :

Atenolol,
Labetalol,

Carvedilol.

PROPRANOLOL : Orally absorbed ( 25 % ) Extensively metabolized in the liver Lipophilic and enters the brain Excreted in urine as glucuronide metabolites

PROPRANOLOL : PHARMACOLOGICAL ACTIONS : Heart : negative inotropic action negative chronotropic action negative dromotropic action AV conduction is decreased

PROPRANOLOL : Respiratory tract : bronchoconstriction and can precipitate bronchial asthma. Eyes : decrease the IOT due to decreased aqueous humor production CNS : sedation, lethargy, depression, sleep disturbances Skeletal muscle : antagonizes the adrenaline induced tremors

PROPRANOLOL : Metabolic effects : blocks the hypoglycemia induced tachycardia blocks epinephrine induced glycogenolysis (in hypoglycemia)

PRECAUTIONS AND ADVERSE EFFECTS : AV block Bradycardia COPD and asthma Diabetes mellitus

USES OF BETA BLOCKERS: HTN IHD Arrhythmia CCF low dose and in mild and moderate patients Glaucoma Hyperthyroidism

USES OF BETA BLOCKERS Pheochromocytoma Migraine prophylaxis Anxiety or panic attacks.

 Precautions : in bronchial asthma and diabetic patients

Up regulation : chronic beta blocker therapy

results in proliferation of the receptors -sudden stoppage of blockers result in rebound hypertension and angina