SYMPATHOMIMETIC Akhmad Edy Purwoko Pharmacology & Toxicology Dept. FMMS MUY • sympathomimetic /sym·pa·tho·mi·met·ic/ (-mi-met´ik) 1. mimicking the effects of impulses conveyed by adrenergic postganglionic fibers of the sympathetic nervous system. • 2. an agent that produces such an effect. Dorland's Medical Dictionary for Health Consumers. © 2007 by Saunders, an imprint of Elsevier, Inc. All rights reserved. sympathomimetic [sim′pəthō′mimet′ik] a pharmacologic agent that mimics the effects of stimulation of organs and structures by the sympathetic nervous system. It functions by occupying adrenergic receptor sites and acting as an agonist or by increasing the release of the neurotransmitter norepinephrine at postganglionic nerve endings. Mosby's Medical Dictionary, 8th edition. © 2009, Elsevier. Comparison of Somatic and Autonomic Systems Diagram of the efferent autonomic pathways. Preganglionic neurons are shown as solid lines, an postganglionic neurons as dashed lines. The heavy dashed lines are parasympathetic fibers; the light dashed lines are sympathetic. (Modified from Youmans W: Fundamentals of Human Physiology, 2nd ed. Year Book, 1962.) Physiology: Sympathetic and parasympathetic produce reciprocal function i.e. if one produces increase in physiological function the other produces decrease, heart rate for example is increased by sympathetic stimulation while decreased by parasympathetic stimulation. This rule is valid except for: 1- Atrial conduction & salivary secretion both system increase them. 2- Parasympathetic produces erection and sympathetic produce ejaculation (complementary effect) The parasympathetic division maintains essential body functions such as digestive processes and elimination of wastes, and is required for life. In fact the parasympathetic is the system of rest and digest. Sympathetic Adrenaline Mimetic lytic Para-sympathetic Acetylcholine Action Type: Aim: Pupil: Saliva: Bronchi: Heart: Bl.Press: G.I.T. U.Blader Lcalized conserve energy Miosis +++ watery Constriction Decrease all properties H.R, Contract, Cond, hypotension Cont. wall Relax spincter Cont. wall Relax spincter Generalized. Stress “fight” Active mydriasis +viscid Dilatation increase all properties H.R, Contract, Cond, hypertension. relax wall contract sphincter relax wall contract sphincter 7 Dual Innervation on Bronchial smooth muscle Without Dual Innervation Sympathetic and Vasomotor Tone Sympathetic division prioritizes blood vessels to skeletal muscles and heart in times of emergency. Blood vessels to skin vasoconstrict to minimize bleeding if injury occurs during stress or exercise. Autonomic Pharmacology Anatomy: • Autonomic Nervous System (ANS) is classified into : Sympathetic (thoracolumber) Parasympathetic (craniosacral). • Autonomic nerve consists of: Preganglionic that takes its origin from CNS Postganglionic that takes its origin from autonomic ganglia. Autonimic ganglia in which preganglionic ends and the postganglionic starts (relay station). Autonomic nervous system supply most tissues and organs (blood vessels, ventricles, dilator pupillae and piloerector muscles are not supplied by (parasympathetic) Autonomic Nervous System (ANS) • The ANS consists of motor neurons that: – Innervate smooth and cardiac muscle and glands – Make adjustments to ensure optimal support for body activities – Operate via subconscious control – Have viscera as most of their effectors Neurotransmitter Effects • All somatic motor neurons release Acetylcholine (ACh), which has an excitatory effect • In the ANS: – Preganglionic fibers release ACh – Postganglionic fibers release norepinephrine or ACh and the effect is either stimulatory or inhibitory – ANS effect on the target organ is dependent upon the neurotransmitter released and the receptor type of the effector Cholinergic Receptors • The two types of receptors that bind ACh are nicotinic and muscarinic • These are named after drugs that bind to them and mimic ACh effects Nicotinic Receptors • Nicotinic receptors are found on: – Motor end plates (somatic targets) – All ganglionic neurons of both sympathetic and parasympathetic divisions – The hormone-producing cells of the adrenal medulla • The effect of ACh binding to nicotinic receptors is always stimulatory Muscarinic Receptors • Muscarinic receptors occur on all effector cells stimulated by postganglionic cholinergic fibers • The effect of ACh binding: – Can be either inhibitory or excitatory – Depends on the receptor type of the target organ Adrenergic Receptors • The two types of adrenergic receptors are alpha and beta • Each type has two or three subclasses (1, 2, 1, 2 , 3) • Effects of NE binding to: – receptors is generally stimulatory – receptors is generally inhibitory • A notable exception – NE binding to receptors of the heart is stimulatory Adrenergic Drugs • Also called sympathomimetics because they produce effects similar to those produced by the sympathetic nervous system. • Classified into two groups catecholamines and noncatecholamines. • Also classified according to their action direct-acting, indirect-acting, and dualacting. Sympathomimetics Definition: sympathomimetics are drugs that produce effects similar to sympathetic nerve stimulation. Classifications: There are different classification, however the most appropriate are: I: Classification according to the chemical structure: catecholamine non-Catecholamine Adrenaline Noradrenaline Isoprenaline Dopamine Dobutamine Phenyl-alkyl amine Ephedrine Amphetamine Mephentramine Phenmetrazine Monohydroxyphenyl Methoxyphenyl alkylamine alkylamine Tyramine Methoxamine Heterocyclic alkylamine Naphazoline Phenylephrine Xylometazoline Metaraminolo Tetrahydrozoline II: Classification according to the mode of actions and the type of receptors IA- Direct Acting Non-selective All receptors Non-selective (α & β) (β1 & β2) Adrenalin isoprenaline Noradrenaline selective α1 α2 β1 β2 phenylephrine clonidine dobutaminwe salbutamol methoxamine α –methylnterbutaline noradrenaline Fenoterol Salmeterol B- Indirect by releasing catecholamine Amphetamine Tyramine by inhibiting neuronal-reuptake cocaine tricyclic antidepressant Dual (Direct & Indirect) Ephedrine Metaraminol Aktivasi respon 1. stimulasi reseptor 1 oleh cathecolamin Menimbulkan aktivasi protein penghubung G. sub unit alfa protein G ini meng Aktivasiefektornya, phospholipase C , yang menimbulkan rilis IP3 (inositol 1,4,5 triphosphate) dan DAG (diacylglyserol) dari phosphatidylinositol 4,5-bi phosphat (Ptdlns 4,5 P2). IP3 menstimulasi rilis simpanan kalsium yang tersebar, menyebabkan peningkatan konsentrasi Ca2+ sitoplasma . Ca2+ kemudian mengaktivasi protein kinase yang bergantung - Ca2+ yang pada gilirannya memfosforilasi substrat mereka. DAG mengaktivasi protein kinase C Aktivasi dan inhibisi (penghambatan) adenyl cyclase oleh agonis agonis yang berikatan dengan reseptor reseptor cathecolamin. Mekanismenya: Pengikatan dengan adrenoseptor β menstimulasi adenyl cyclase melalui aktivasi protein G stimulatorik Gs yang menimbulkan disosiasi subunit alfanya yang dimuati GTP Sub unit alfas ini secara langsung mengaktivasi adenyl cyclase, menghasilkan peningkatan Laju sintesis cAMP. Ligan-ligan adrenoseptor alfa 2 menghambat adenyl cyclase melalui terjadinya disosiasi protein G inhibitorik G1, menjadi subunitnya: misalnya Sub unit alfa 1 dimuati GTP dan sebuah subunit beta-gama. Mekanisme subunit-subunit yang menghambat adenylyl cyclase ini tidak jelas. cAMP berkaitan Dengan subunit regulatorik (R) dari protein kinase yang tergantung-cAMP, menimbulkan liberasi subunit katalitik aktif (C) yang memfosforilasi substrat protein spesifik dan memodifikasi aktivitas mereka. Unit-unit katalitik tersebut juga memfosforilasi cAMP response elemen binding protein (CREB), yang memodifikasi ekspresi gen Adrenergic Drugs • Therapeutic uses depend on which receptors they stimulate and to what degree - alpha-adrenergic, betaadrenergic, and dopamine receptors. • Most adrenergic drugs stimulate alpha and beta receptors mimicking the action of norepinephrine and epinephrine. • Dopaminergic drugs act primarily on SNS receptors stimulated by dopamine. Catecholamines • Stimulate the nervous system, constrict peripheral blood vessels, increase heart rate, and dilate the bronchi. • Can be natural or synthetic and include: dobutamine, dopamine, epinephrine, norepinephrine, and isoproterenol. Catecholamines Pharmacokinetics: • Not administered orally; when administered sublingually are absorbed rapidly through the mucous membranes; when administered SC absorption is slowed due to vasoconstriction around the injection site; when administered IM absorption is more rapid. Catecholamines • Widely distributed throughout the body; predominantly metabolized by the liver; excreted primarily in the urine. Pharmacodynamics: • Are primarily direct-acting. • Activation of alpha receptors generates an excitatory response except for intestinal relaxation. Catecholamines • Activation of the beta receptors mostly produces an inhibitory response except in the heart cells where norepinephrine produces excitatory effects. • The clinical effects of catecholamines depend on the dosage and route of administration. Catecholamines • Positive inotropic effects - heart contracts more forcefully. • Positive chronotropic effects - heart beats faster. • Positive dromotropic effects - increased conduction through the AV node. Catecholamines Pharmacotherapeutics: • Use depends on the particular receptor site that is activated. • Norepinephrine - alpha activity. • Dobutamine and isoproterenol - beta activity. • Epinephrine - alpha and beta activity. • Dopamine – dopaminergic, beta, and alpha activity. Catecholamines • Catecholamines that stimulate alpha receptors are used to treat hypotension caused by a loss of vasomotor tone or hemorrhage. • Catecholamines that stimulate beta1receptors are used to treat bradycardia, heart block, low cardiac output, paroxysmal atrial or junctional tachycardia, ventricular fibrillation, asystole, and cardiac arrest. Catecholamines • Catecholamines that stimulate beta2receptors are used to treat acute and chronic bronchial asthma, emphysema, bronchitis, and acute hypersensitivity reactions to drugs. • Dopamine that stimulates dopaminergic receptors is used to improve blood flow to kidneys. Adrenaline Source: adrenaline is secreted by A-cells of adrenal medulla. Chemical straucture: adrenaline is a catecholamine, formed from noradrenaline by the action of n-methyl transferase that is present only in adrenal medulla. Chemical properties: adrenaline is unstable in air due to rapidly oxidation to adrenochrome, so it is usually reserved in weak acidic solution. Pharmacokinetics: Absorption: Oral : No absorption (adrenaline is destroyed by GIT secretion and oxidized by MAO enzyme in the intestinal epithelium). s.c.: slow absorption (adrenaline produces vasoconstriction of skin & m.m. blood vessels). i.m: rapid absorption (adrenaline produces vasodilatation of skeletal muscles blood vessels). Distribution: Not pass BBB. Metabolism: Major part is metabolized by COMT & MAO enzymes to VMA. Minor part is taken up by adrenergic nerve endings to be subsequently released on arrival of nerve action potential. Excretion: urine Pharmacodynamics: Mechanism of action: Adrenaline is a non selective agonist for all adrenergic receptors. α1→ stimulates PLC → membrane phospholipids → ↑IP3 +↑DAG → ↑Ca2+ → calmodulin → effects. α2 → ↓ cAMP. β1, β2 & β3 →↑ cAMP. PLC Phospholipase C IP3 Inositol 1,4,5 triphosphate DAG Diacylglycerol Effects: Local: applied on mucus membrane it produces decongestion. It can stop bleeding from nose (hemostasis). On eye: adrenaline is rapidly destroyed by alkaline tears, however, adrenaline derivative dipivefrin is stable and decrease intraocular pressure). Systemic: Cardiovascular Effects: Heart: Adrenaline stimulates all properties of the heart → ↑COP. Blood vessels: v.c. of coetaneous and m.m blood vessels → ↑peripheral resistance. v.d. of coronary & skeletal muscles →↓ peripheral resistance. Blood pressure: according to the dose: Small dose: initial fall followed by rise. Large dose: rise from the start. N.B. Adrenaline reversal: drop of blood pressure after phentolamine. Catecholamines • Synthetic catecholamines have a short duration of action which can limit their therapeutic usefulness. • Drug interactions/adverse reactions: • Can be serious including hyper and hypotension, arrhythmias, seizures, and hyperglycemia. Non-catecholamines Uses include: • local or systemic constriction of blood vessels - phenylephrine (Neo-Synephrine). • nasal and eye decongestion and dilation of bronchioles - albuterol (Proventil/Ventolin). • smooth muscle relaxation – terbutaline sulfate (Brethine, Bricanyl). Non-catecholamines Pharmacokinetics: • Since the drugs have different routes of administration, absorption and distribution vary; can be administered orally; metabolized primarily by the liver; excreted primarily in the urine. Non-catecholamines Pharmacodynamics: • Direct-acting noncatecholamines that stimulate alpha activity include phenylephrine (Neo-Synephrine). • Direct-acting noncatecholamines that stimulate beta2 activity include albuterol (Proventil/Ventolin) and terbutaline (Brethine). Non-catecholamines • Indirect-acting - phenylpropanolamine (Acutrim). • Dual-acting - ephedrine. Non-catecholamines Pharmacotherapeutics: • Stimulate the sympathetic nervous system and produce a variety of effects in the body. • Example - ritodrine (Yutopar) - used to stop pre-term labor. • Drug interactions/adverse reactions: • Taken with monoamine oxidase inhibitors can cause severe hypertension and death Alpha1 Agonists • Profound vasoconstriction – Increases afterload & blood pressure when given systemically – Decreases drug absorption & bleeding when given topically Adrenergic Receptor Specificity Drug Epinephrine Ephedrine Norepinephrine Phenylephrine Isoproterenol Dopamine Dobutamine terbutaline α1 α2 β1 β2 Dopaminergic PR Cari farmakokinetik, efek toksik- efek samping, Indikasi-Kontraindikasi, penggunaan klinik (Phenylephrin, Isoproterenol, Terbutalin, Dopamin, Dobutamin) ditulis tangan seperti anda nulis contekan diselembar kertas HVS kuarto di scan dan di e-mail ke [email protected] (s/d 27-3-14 24:00)
