PHARMACOLOGY OF PERIPHERAL NERVOUS SYSTEM AUTONOMIC NERVOUS SYSTEM Nervous system Central nervous system Peripheral nervous system Somatic nervous system Autonomic nervous system afferent system central part HYPOTHALAMUS MEDULLA OBLONG. efferent system vegetative nerves + ggl. SYMPATHETIC NERVOUS SYSTEM PARASYMPATHETIC NERVOUS SYSTEM Autonomic nervous system peripheral part - non - myelinized fibers - pain perception - visceral perception Peripheral nervous system: Þautonomic nervous system (ANS) Þenteric NS Þsomatic efferent (motoric) system Þ Þsenzoric (afferent) fibers ANS – mediated the transfer of the impulses between the central nervous system (CNS) and the effector tissues; independent of the control of the will (smooth muscle, myocardium, exocrine glands, etc.), adapts the response of the organism to changes of the external and internal environment Somatic efferent (motoric) system - converts impulses from the CNS to the will of controlled skeletal muscles Main functions of ANS •contractions and relaxations of smooth muscles •function of all exocrine and some of endocrine glands •heart functions •metabolic functions ANS Sympathetic = adrenergnic system •thoracolumbal s. •fight or flight •noradrenaline(NA) •a a ß receptors Parasympathetic = cholinergnic system •craniosacral s. •rest and digest •acetylcholine •N a M receptors Autonomic nervous system The activity is mutually regulated •heterotropic interactions •homotropic interactions •most of visceral organs is inervated by both S and PS •opposite activity - bronchi, heart, bladder,,… •similar action – salivary glands •only S – blood vessels l synapse EFFERENT PART OF ANS: pre-ganglionic neuron vegetative ganglion (sympathetic, parasympathetic) post-ganglionic neuron EFFECTOR (smooth muscle, myocard, glands,…) spinal cord NM motoric neuron Růžový ubrousek skeletal muscle ganglia NN ganglia NN Kytice gland, smooth muscle parasympathetic neuron sympathetic neuron a,b M Ach Ach Ach Ach NOR (ADR) Kytice gland, smooth muscle Auton Note: ggl. S a PS NN receptors neuromusc. plate NMreceptors Autonomic nervous system Autonomic acting pharmaceuticals On the basis of mechanism of action - drugs: 1. binding to the receptors for Ach or NA: la) starting reaction = agonist - DIRECT MIMETICS lb) receptor blockade = antagonist – DIRECT LYTICS ..................................................................................... 2. changing the synaptic concentration of NT – intervene in the fate of the Ach or NA (affect the synthesis, storage, release from nerve endings, inactivation); do not bind directly to receptors on the effector organs la) increase of NT effect = INDIRECT MIMETICS lb) decrease of NT effect = INDIRECT LYTICS l sympathotropic drugs sympatomimetics sympatolytics direct indirect alfa beta alfa1 alfa2 beta1 beta3 indirect direct alfa beta alfa1 alfa2 beta1 beta3 beta2 beta2 Vegetative acting drugs 2. sympatotropic Vegetative acting drugs 2. cholinotropic l parasympatomimetics choline derivatives acetylcholinesterase (ACHE) inhibitors parasympatolytics ganglioplegics neuromuscular- -blocking drugs NM Vegetative acting drugs 2. cholinotropic ANS RECEPTORS cholinergic receptors NICOTINE: N -skeletal muscle NM -vegetative ganglia NN -(CNS) MUSCARINIC: M1, M2, M3, M4, M5 adrenergic receptors a a1 a2 b b1 b2 b3 organ receptor sympathetic parasympathetic system system heart ß1 M + chrono, dromo, - chrono, dromo bathmo, inotropic bathmo, inotrop. eye 1 M 2 mydriasis miosis acomodation into the distance acom.to close respiratory tract (1) M 2 bronchoconstriction bronchoconstriction bronchodilatation secretion blood vessels 1 M (2) 2 vasoconstriction dilatation vasoconstr. dilatation (coronary, blood vessels in skeletal muscles) organ receptor sympathetic parasympathetic system system GIT 1 M 2 2>1 M ↓ motility and tone ↑ motility sphincter contraction sphincter relaxation secretion inhibition secretion stimulation ↑ gastr. secretion urinary bladder 1 M3 2, 3 sphinct. contraction sphinct. relaxation relax. of the bladder contract. of the wall bladder wall kidney 1>2 ↑ renin secretion uterus 1 2 contraction relaxation-tocolysis organ receptor sympathetic parasympathetic system system liver 1, ß2 glycogenolysis gluconeogenesis pancreas 2 2 insulin secretion insulin secretion sexual organs 1 M ejaculation erection glands 1 M 2 sparse secretion sparse significantly viscous secretion increased secretion Note: HEART positive chronotropic effect positive inotropic effect positive dromotropic effect positive bathmotropic effect Adrenergic receptors •metabotropic •a1, a2 a b1, b2 a b3 •stimulated by noradrenaline (norepinephrine) – a1 receptors: sympato11 a2, b receptors: sympato12 Receptor a1 stimulation: •vasoconstriction (skin, mucous membranes, splanchnic area,..) •mydriasis • (+ ↓ intraocular pressure) •contraction of pregnant uterus •ejaculation •urinary bladder sphincter contraction, GIT sphincter contraction •glycogenolysis and gluconeogenesis stimulation •(reduce secretion of bronchial glands) •(presynaptic) increased NA release (espec. in CNS) •stimulation of platelet aggregation •vasoconstriction in local application, otherwise the influence of stimulation of central receptors to reduce sympathetic tone and BP •hypotensive effect of central mechanism •inhibition GIT secretion •inhibition of lipolysis, increased fat storage • • • Receptor a2 stimulation: •heart: •ñ HR (+ chronotropic effect) SA node •ñ automaticity (+ bathmotropic) AV node, ventricles •ñ force of heart contraction (inotropic effect) •ñ conduction (dromotropic effect) •ñ oxygen consumption •ledviny: •ñ renin secretion Receptor b1 stimulation : •vasodilatation, espec. in skeletal muscles ("preparation for fight or flight"), ò diastol. BP, vasodilatation in coronar blood vessels •bronchodilatation •relaxation of uterus (indic. in impending preterm birth) •intestine wall relaxation •intestinal passage decrease •urinary bladder wall relaxation •glycogenolysis - ↑ glycemia, increased insulin secretion •blockade of mast cells degranulation Receptor b2 stimulation: •lipolysis •urinary bladder wall relaxation (m. detrusor) Receptor b3 stimulation: MUSCARINIC: M1(„neural“) – CNS, peripheral neurons,parietal cells of stomach, (glands with external secretion) M2 („heart“) - heart (SA, atria, AV, ventricles), (smooth muscle (GIT), neuronal tissue), presynapt. neur.endings M3 – glands, blood vessels (smooth muscle, hl. sval, endothelium), smooth muscles: bronchial muscles, GIT, urinary bladder, eye M4 – salivary glands, GIT (muscles), eye, CNS M5 – lungs, CNS Cholinergic receptors Cholinergic receptors •M – metabotropic •stimulated by acetylcholine •N – coupled with ion channels •stimulated by nicotine Cholinergic receptors molecular mechanisms of action: 1)phospholipase C activation 2)adenylylcyclase inhibition 3)direct openning of ion channels M receptors N recept. * * M1, M3 receptors M5 PLC M2, M4 receptors AC in heart activation of receptor coupled K+ channel, calcium channel inhibition IP3 DAG NICOTINIC RECEPTOR Pentamer:subunits 2x α and β δ γ β δ ε ion channel for Na+, K+ and Ca2+ after binding of 2 molecules of Ach to the 2 subunit of the α openning of ion channel – rapid entry of Na+ into the cell, output of K+ membrane depolarisation EXCITATION PS S MAO IMAO α,β PARASYMPAT. A SYMPAT. SYNAPSE