Receptor theory of drug action Receptoreffector system complex

Receptor theory of drug action.

Receptor-effector system = complex of processes extracelullar signal -------> intracell. signal cascade-----> effector (own effect) ü receptor = protein, which interacts ligands – involved in signal transduction ü effector = enzyme, ionic channel etc. change in the activity leads to the effect of drug ü ligand (signal molecule) = molecule able to bind to specific receptor – endogenous - neurotransmitters, hormones – exogenous - xenobiotics

Receptor-effector system Affinity ü ochota ligandu vázat se na příslušný receptor ü 1/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

Ligand classification Full agonist - IS= 1 Agonist Partial agonist - dualist - IS in a range from 0‹ to › 1 - Acts as antagonist in the presence of full agonist

Ligand classification Antagonist ü IS = 0 ü Blocks agonist binding to receptor Inverse agonist/superantagonist ü IS = -1 ü Stabilizesthe receptor in the constitutive activity Antagonism ü competitive x non-competitive ü Reversible x irreversible ü on the receptor level x on the level of function

Antagonism Competetive ü ligands compete for the same binding site ü c of antagonist decreases agonist effect and inversely ü the presence of antagonist incerases the amounts of agonist needed to evoke the effect Non-competitive ü allosteric antagonism ü irreverzible bounds ü c of agonist does not interrupt the effect of antagonist

Antagonism Chemical ü drug inactivation by forming complexes with other molecules (protamine + heparin) Physiologic ü drug intereaction on the level of function, drugs evoking opposite effects by different mechanism (diuretics + vassopresin, nitrates + α 1 agonists)

Regulation of receptor sensitivity and counts Desenzitization ü decrease of sensitivity to receptors after repeated exposition to agonists ü interruption of signal cascade– tachyphylaxis (nitrates) ü down-regulation, internalization - opioids

Regulation of receptor sensitivity and counts Hypersensitivity ü incerase of receptor sensitivity/counts after chronic anatagonist exposure ü β blockers

PHARMACOLOGY OF THE PERIPHERAL NERVOUS SYSTEM Pharm. Dr. 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 receptor stimulus Afferent nerve fibre - non-myelinized - perception of pain - visceral perception - blood pressure regulation - breathing - heart rate organ, tissue Central part of ANS - medulla oblongata and hypothalamus Efferent neurons - vegetative neurons and ganglia - sympathetic n. - parasympathetic n.

Autonomic nervous system Efferent part of ANS • 2 neuronal pathway • preganglionic n. • postganglionic n. • chemical transmission of neural impulsevegetative ganglia • fibres forms plexes – innervated area overlap • work in function uniformity

Vegetativní nervový systém

Autonomic nervous system Sympathetic = adrenergnic system l thoracolumbal s. l fight or flight l noradrenaline(NA), acetylcholine, (Ac. Chol) l a ß receptors Parasympathetic = cholinergnic system l craniosacral s. l rest and digest l acetylcholine l N a M receptors

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 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

Cholinergic receptors Nicotinic receptor • all subtypes are pentamers • two binding sites for Ac. Chol

Cholinergnic receptors Muscarinic receptors • 5 types M 1 -M 5, G-protein coupled • M 1 -M 3 well characterized M 1 • neural – CNS and ANS • membrane depolarization • decreased activity in brain = dementia • controls the production of gastric HCL

Cholinergnic receptors M 2 • cardial Rc • autoreceptors • inhibitory influence M 3 • glandular/smooth muscle • stimulation of secretion and contraction/relaxation of smooth muscles M 4, M 5 - in CNS

Cholinergnic receptors M 4 a M 5 • převážně v CNS • úloha není známa M 1, M 3, M 5 – spojené s IP 3 and DAG M 2 a M 4 – spojené s c. AMP

Adrenergic receptors Receptor Typical localization Signal transduction IP 3 a DAG, intracellular Ca Alfa 1 smooth muscles Alfa 2 presynaptic neurons, inhibition of adenylate thrombocytes, lipocytes, smooth cyclase, muscles. concentration c. AMP stimulation of adenylate cyclase, concentration c. AMP Beta 1 heart, lipocytes, brain, kidney Beta 2 smooth muslces, bronchi, myometrium ---- II ---- Beta 3 lipocytes ---- II ----

1 receptors

2, 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

Pharmacology of autonomic nervous system Classification with regard to Mof. A: l ligands of adrenergic and cholinergic receptors l agonists - direct MIMETICS l antagonists – direct LYTICS. . . . . . l drugs changing the synaptic activity of neurotransmitters – influence the synthesis, storage, release or inactivation = INDIRECT PARASYMPATHOMIMETICS/PARASYMPATOLYTI CS

Pharmacology of autonomic nervous system Název diagramu sympathotropic drugs sympathomimetics direct indirect alpha 1 sympatholytics indirect beta alpha 2 beta 1 alpha beta 2 alpha 1 beta alpha 2 beta 1 beta 2

Pharmacology of autonomic nervous system cholinotropic drugs cholinomimetics direct N indirect M cholinolytics indirect N M

organ receptor sympathetic parasympathetic ß 1 M 2 + chrono, dromo bathmo, inotropic 1 2 M 3 mydriasis miosis 1 2 M 3 bronchoconstriction bronchodilatation secretion 1 2, 1 2 M constriction dilatation constriction dilataion - chrono, dromo bathmo, inotropic dilatation

organ receptor sympathetic parasympathetic 1 2 ß 2 M 3 M 1 motility decrease motility increase contraction sphincter relaxation inhibition secretion stimulation 1 2 M 3 contraction sphincter relaxation 1> 2 renin release 1 2 contraction dilatation

organ receptor sympathetic parasympathetic 1 ß 2 glycogenolysis gluconeogenesis 2 2 insuline secretion 1> 2 M 3 ejaculation 1 M 3 erection increased secretion