Receptor theory of drug action. Receptor-effector system = complex of processes extracelullar signal -------------> intracell. signal cascade---------> effector (own effect) • üreceptor = protein, which interacts ligands –involved in signal transduction üeffector = enzyme, ionic channel etc. change in the activity leads to the effect of drug üligand (signal molecule) = molecule able to bind to specific receptor –endogenous - neurotransmitters, hormones –exogenous - xenobiotics Affinity üochota ligandu vázat se na příslušný receptor ü1/Kd § Instrinsic activity ü ability to evoke an effect after binding to receptor § !!!the presence of sufficient number of receptor for the induction of pharmacological effect is essential as well as sufficient amounts of receptor ligand!!! Receptor-effector system Relation between dose and effect Receptor-effector system Ligand classification Ligand classification Antagonist üIS = 0 üBlocks agonist binding to receptor Inverse agonist/superantagonist üIS = -1 üStabilizesthe receptor in the constitutive activity Antagonism ücompetitive x non-competitive üReversible x irreversible üon the receptor level x on the level of function Image44 Antagonism Competetive üligands compete for the same binding site ü c of antagonist decreases agonist effect and inversely üthe presence of antagonist incerases the amounts of agonist needed to evoke the effect Non-competitive üallosteric antagonism üirreverzible bounds ü c of agonist does not interrupt the effect of antagonist Antagonism Chemical üdrug inactivation by forming complexes with other molecules (protamine + heparin) ü Physiologic üdrug intereaction on the level of function, drugs evoking opposite effects by different mechanism (diuretics + vassopresin, nitrates + α1 agonists) Regulation of receptor sensitivity and counts Desenzitization üdecrease of sensitivity to receptors after repeated exposition to agonists üinterruption of signal cascade– tachyphylaxis (nitrates) üdown-regulation, internalization - opioids ü [USEMAP] Hypersensitivity üincerase of receptor sensitivity/counts after chronic anatagonist exposure ü β blockers Regulation of receptor sensitivity and counts PHARMACOLOGY OF THE PERIPHERAL NERVOUS SYSTEM PharmDr. Ondřej Zendulka, Ph.D. Peripheral nervous system • Autonomic •smooth muscles •regulation of visceral organs •part of neurohumoral regulation Somatic •voluntary control •skeletal muscles Autonomic nervous system • l Afferent nerve fibre - non-myelinized - perception of pain - visceral perception - blood pressure regulation - breathing - heart rate Efferent neurons - vegetative neurons and ganglia - sympathetic n. - parasympathetic n. l Central part of ANS - medulla oblongata and hypothalamus organ, tissue stimulus receptor synapse Efferent part of ANS • 2 neuronal pathway • preganglionic n. • postganglionic n. • chemical transmission of neural impulse- vegetative ganglia • fibres forms plexes – innervated area overlap • work in function uniformity barskinner1 Autonomic nervous system Vegetativní nervový systém l Sympathetic = adrenergnic system lthoracolumbal s. lfight or flight lnoradrenaline(NA), acetylcholine, (AcChol) la a ß receptors Parasympathetic = cholinergnic system lcraniosacral s. lrest and digest lacetylcholine lN a M receptors Autonomic nervous system Nicotinic receptors • 3 types: muscular(NM), ganglionic(NG) and CNS (NB) • ligand-gated ion channels Muscular Rc • neuromuscular junction Ganglionální Rc • ANS ganglionic transmission CNS Rc •in brain Cholinergnic receptors Nicotinic receptors • 3 types: muscular(NM), ganglionic(NG) and CNS (NB) • ligand-gated ion channels Muscular Rc • neuromuscular junction Ganglionální Rc • ANS ganglionic transmission CNS Rc •in brain Cholinergnic receptors Nicotinic receptors • 3 types: muscular(NM), ganglionic(NG) and CNS (NB) • ligand-gated ion channels Muscular Rc • neuromuscular junction Ganglionální Rc • ANS ganglionic transmission CNS Rc •in brain Cholinergnic receptors Nicotinic receptors • 3 types: muscular(NM), ganglionic(NG) and CNS (NB) • ligand-gated ion channels Muscular Rc • neuromuscular junction Ganglionální Rc • ANS ganglionic transmission CNS Rc •in brain Cholinergnic receptors Nicotinic receptors • 3 types: muscular(NM), ganglionic(NG) and CNS (NB) • ligand-gated ion channels Muscular Rc • neuromuscular junction Ganglionální Rc • ANS ganglionic transmission CNS Rc •in brain Cholinergnic receptors Nicotinic receptors • 3 types: muscular(NM), ganglionic(NG) and CNS (NB) • ligand-gated ion channels Muscular Rc • neuromuscular junction Ganglionální Rc • ANS ganglionic transmission CNS Rc •in brain Cholinergnic receptors Nicotinic receptor • all subtypes are pentamers • two binding sites for AcChol Cholinergic receptors Muscarinic receptors • 5 types M1-M5, G-protein coupled • M1-M3 well characterized M1 • neural – CNS and ANS • membrane depolarization • decreased activity in brain = dementia • controls the production of gastric HCL Cholinergnic receptors M2 • cardial Rc • autoreceptors • inhibitory influence M3 • glandular/smooth muscle • stimulation of secretion and contraction/relaxation of smooth muscles M4,M5 - in CNS Cholinergnic receptors M4 a M5 • převážně v CNS • úloha není známa M1, M3, M5 – spojené s IP3 and DAG M2 a M4 – spojené s cAMP Cholinergnic receptors Receptor Typical localization Signal transduction Alfa1 smooth muscles IP3 a DAG, intracellular Ca Alfa2 presynaptic neurons, thrombocytes, lipocytes, smooth muscles. inhibition of adenylate cyclase, ¯ concentration cAMP Beta1 heart, lipocytes, brain, kidney stimulation of adenylate cyclase, ¯ concentration cAMP Beta2 smooth muslces, bronchi, myometrium -------- II -------- Beta3 lipocytes -------- II -------- Adrenergic receptors a1 receptors sympato11 a2, b receptors: sympato12 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 Autonomic nervous system Classification with regard to MofA: lligands of adrenergic and cholinergic receptors lagonists - direct MIMETICS lantagonists – direct LYTICS ..................................................................................... ldrugs changing the synaptic activity of neurotransmitters – influence the synthesis, storage, release or inactivation = INDIRECT PARASYMPATHOMIMETICS/PARASYMPATOLYTICS l Pharmacology of autonomic nervous system l Název diagramu sympathotropic drugs sympathomimetics sympatholytics direct indirect alpha beta alpha1 alpha2 beta1 beta2 indirect direct alpha beta alpha1 alpha2 beta1 beta2 Pharmacology of autonomic nervous system l cholinotropic drugs cholinomimetics cholinolytics direct indirect N M indirect direct N M Pharmacology of autonomic nervous system l organ receptor sympathetic parasympathetic ß1 M2 + chrono, dromo, - chrono, dromo dromo bathmo, inotropic bathmo,inotropic a1 M3 b2 mydriasis miosis a1 M3 b2 bronchoconstriction bronchodilatation secretion a1 M a2, b1 b2 constriction dilatation dilatation constriction dilataion l organ receptor sympathetic parasympathetic a1 M3 a2 ß2 M1 motility decrease motility increase contraction sphincter relaxation inhibition secretion stimulation a1 M3 b2 contraction sphincter relaxation b1>b2 renin release a1 b2 contraction dilatation l organ receptor sympathetic parasympathetic a1 ß2 glycogenolysis gluconeogenesis a2 b2 ¯insuline secretion insuline secretion b1>b2 M3 ejaculation erection a1 M3 b increased secretion