GENERAL PHARMACODYNAMICS 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, drugs Affinity üthe ability of the ligand to bind to the receptor 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 Receptor-effector system Intrinsic activity (classification of ligands) 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 Spectrum of ligands Image48 Antagonism • • • competitive reversible • non-competitive irreversible • • –at the receptor level –at the function level Antagonism Competitive 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 function Hypersensitivity üincerase of receptor sensitivity/counts after chronic anatagonist exposure Rebound phenomenom after discontinuation of long-term administered drugs return to its original state or ↑ intensity of the original condition (hypersensitivity of receptors to endogenous ligands → up-regulation) Example: chronic administration of β blockers ü Regulation of receptor sensitivity and counts Presynaptic modulation •Release of the primary neurotransmitter from the nerve endings is modified by: • •a) autoreceptors • •b) homoreceptors • •c) heteroreceptors synapse3 autoreceptor homoreceptor heteroreceptor Receptor desensitization •reducing the sensitivity of the receptors after repeated agonist exposure • •Tachyphylaxis – acute drug „tolerance“ –reduced sensitivity to the active substance evolving quickly (minutes) → distortion of the signal cascade –the reactivity of the organism returns to the original intensity after the elimination of the substance –Ex. of tachyphylaxis – nitrates administration • •Tolerance – reduced sensitivity to the active substance, arising from the repeated administration of the drug (days – weeks) → down-regulation, internalization of the receptors –to achieve the original effect required increasingly higher doses of drug –the original reactivity of the organism returns to a certain period of time after discontinuation of the drug –Ex. of tolerance – opioids administration Regulation of receptor sensitivity and counts Receptor classification Receptor classification Receptor classification Non-receptor mechanisms of action Based on phys.-chem. properties - influencing pH - oxidating and reducing agents - protein precipitation - creating protective layers - adsorbentsa - detergents - chelating agents - radionuclides Interaction with „non-receptor“ proteins - enzyme inhibition - nucleoside and nucleotide analogues (cytostatics, antivirotics) - block of transporters - block of ionic channels (Na+) - binding to cellular components (ATB-ribosomes, mitotic spindle) Non-receptor mechanisms of action