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Transcript
Mgr.Tereza Havlíčková DRUGS ACTING VIA ION CHANNELS AND TRANSPORTERS ION CHANNELS Voltage – gated channels Activated by change of membrane voltage Sodium Calcium Potassium Ligand – gated channels Extracelular ligands GABA receptors, NMDA receptros, nicotin receptors Intracelular ligands ATP – K+- channels ION CHANNELS VOLTAGE – GATED CHANNELS Calcium channels Smooth muscles cells (L-channels) Vascular smooth muscles Open by membrane depolarization Allows calcium input into muscle cell – contraction In therapy – calcium channel blockers Thalamic Calcium neurons (T-channels) input into brain cells inhibition Epilepsy therapy CALCIUM CHANNEL (L-TYPE) CALCIUM CHANNEL BLOCKERS Drugs which blocks L-type of calcium channel Affects vascular smooth muscles and myocardium Specifically bloks channel proteins – bloks calcium input into cell – no contractions of vascular muscles, slow contractions of heart CALCIUM CHANNEL BLOCKERS Kationic drugs Positive charge Bind on channel protein, modulating heart action Verapamil, Diltiazem I – angina pectoris, tachycardia, hypertension Side effects – bradycardia, hypotension, obstipation, headaches CALCIUM CHANNEL BLOCKERS Dihydropyridines Nifedipine, isradipine, felodipine, amlodipine, lacidipine, nitrendipine No charge on nitrogen No direct effect on heart Vasodilatation I – angina pectoris, hypertension Side effects – hypotension, reflex tachycardia (prolonged forms, combination with beta-blockers) CALCIUM CHANNELS BLOCKERS – T-TYPE Brain neurons Calcium input inhibition, inhibition of excitation Some antiepileptics – etosuximid, valproate Etosuximid – children state of absence Side effects – nausea, vomit, tiredness, sleep disorder Valproate – wide activity, blocks natrium channels too VOLTAGE – GATED ION CHANNELS Potassium channels In heart – antidysrhytmic drugs Sodium channels Localization Neurons and nerve endings (key channels for action potential transmission) Myocardial cells Group of drugs which affects sodium channels antidysrhytmic drugs Local anesthetic drugs Antiepileptic drugs POTASSIUM CHANNELS INHIBITORS Antidysrhytmic drugs Phase of repolarization - output of K ions from the cell Amiodaron Blocks Ca and Na channels too Extends phase of repolarization Reduces heart rate Side effects – pulmonary fibrosis, skin pigmentation SODIUM CHANNELS INHIBITORS Antidysrhytmic drugs Fast input of sodium into cell affects depolarization – growth of action potential (AP) Lidocaine – effect during high frequency of AP Low excitability, prolong phase of depolarization Tachycardias Also local anesthetic Chinidine Except Na channels blocks K channels too Atrial fibrillations SODIUM CHANNELS INHIBITORS Local anesthetics Blocks sodium channels, thereby inhibit action potential Vasodilator effect – vasoconstrictor addition Hydrophobic substances with protonable nitrogen – can enter to cell through membrane, than protonized – active substance blocks channel During inflammation – changes of pH – changes of effect Structure changes of cocaine molecule Types of anesthesia – topical, infiltration, nerve – block anesthesia and subarachnoid anesthesia Important anesthetics – lidocaine, cinchocaine, mesocane, tetracaine, procaine, articaine SODIUM CHANNELS INHIBITORS Antiepileptic drugs Selective for hyperactive cells Carbamazepine, oxcarbamazepine Valproate Blocks calcium channels too, affects also absences, inhibition of transaminase, slower GABA degradation Fenytoin Grand-mal attacks Antidysrhytmic use too No effect against absences, just convulsions Lamotrigine Presynaptic sodium channels inhibition On glutamatergic neurons – lower release of glutamate (excitation amino acid) LIGAND – GATED ION CHANNELS Opening of channel is not acted by membrane depolarization, but by binding of specific molecule to channel receptor Controlled by extracellular ligand Nicotine muscular receptor GABA receptor NMDA receptor Controlled by intracellular ligand ATP controlled channel for potassium in B – cells of pancreatic islands NICOTINE RECEPTOR Nicotine receptors in CNS (NN) and nicotine receptors in neuromuscular junction (NM) After occupation of receptor for acetylcholine (or similar substance) is channel for sodium and potassium opened Can be affected by myorelaxans Depolarising Atrakurium (tubocurarine like drugs) Nondepolarising Suxamethonium (acetylcholine like drugs) MYORELAXANS GABA RECEPTOR BENZODIAZEPINES Binding to binding space for benzodiazepines on GABA receptor Increase of affinity binding space for GABA Increase of opening frequency of chloride channel – due to input chlorides into cell is hyperpolarized membrane and thereby lower excitability of cell Effects – sedation, anxiolytic effect, central myorelaxation Use – anxiety, insomnia, status epilepticus, premedication before narcosis Side effects – somnolence, confusion, loss of coordination Overdose – flumazenil (competitive antagonist) BENZODIAZEPINES NMDA RECEPTOR NMDA RECEPTOR Receptor for excitatory amino acid glutamate – non-specific channel for calcium, sodium and potassium Inhibition by ketamine – injectable anesthetic Short-term surgery, induction of anesthesia Blackout, low respiratory depression High levels of ketamine - hallucinations ATP RELATED POTASSIUM CHANNEL Controlled by intracelular ligand B - cells of pancreatic islets (islets of Langerhans) Channels are closed after binding of ATP (from glycolysis) – membrane depolarization – insulin release from vesicles INSULIN SECRETAGOGUES Blocks potassium channels – earlier membrane depolarization and insulin release Patients with low stimulation of insulin secretion (after food intake) Side effects – hypoglycaemia, weigh gain Important drugs – sulfonylureas (glibenclamide, glipizide, glimepiride), glinides (repaglinide, nateglinide) TRANSPORT PROTEINS „Pumps“ Sodium pump – Na+/K+ ATPase – transports sodium and potassium ions against their concentration gradient (heart...) Proton pump - H+/K+ ATPase – transports hydrogen and potassium ions (gastric mucosa cells) TRANSPORT PROTEINS Specific transporters Permeates the cell membrane and facilitates transport of neuromediators Allows noradrenaline, serotonin and dopamine reuptake Allows right function, controls, how long neuromediators remains in synapse NA+/K+ ATPASE Pump transports sodium ions from cell (against their concentration gradient) Cardiac glycosides Blocks active transport of sodium and potassium ions – decrease of membrane potential, accumulation of calcium in cell – increase of cardiac muscle contraction force CARDIAC GLYCOSIDES Digoxin, digitoxin Originally isolated from herb Digitalis Lanata or Purpurea By binding to NA/K ATPase inhibits these ions transport Narrow therapeutic range Changes in potassium levels can affect their action In low levels is affinity to receptors higher – carefully during diuretic therapy PROTON PUMP Localized on luminal side of gastric mucosa Transports hydrogen ions against their concentration gradient to gastric fluid Increase of HCl production PROTON PUMP PROTON PUMP INHIBITORS Drugs for gastric protection Intestinal absorption, blood transport to parietal cell – activation Use on an empty stomach, half an hour before meal (but meal is necessary to activation) Omeprazole, esomeprazole, pantoprazole SPECIFIC TRANSPONTERS Neuromediator re-uptake from the synapse Termination of mediator action, storage of mediator into vesicles in neuronal ending Antidepressants Tricyclic Selective re-uptake inhibitors Other drugs effects to re-uptake Cocaine, amphethamines ANTIDEPRESSANTS Depression Affective disorder, mood disorder Monoamine theory – lack of neuromediators Therapy – increase of neuromediators levels, prolong their effects Symptoms Emotional – depressive mood, reduction of interests Somatic – food intake reduction, insomnia, tiredness ANTIDEPRESSANTS Tricyclic drugs Older group Increase levels of all monoamine(dopamine, serotonin, noradrenaline) Re-uptake inhibition Effect after 2-4 weeks Imipramine, clomipramine, dosulepine, amitriptylin ANTIDEPRESSANTS Selective monoamine re-uptake inhibitors Serotonin (SSRI) Effect after 2-4 weeks Fluoxetine (Prozac), citalopram, sertraline (Zoloft), escitalopram, paroxetine Serotonin and noradrrenaline (SNRI) Venlafaxine, duloxetine Noradrenaline and Bupropion dopamine (NDRI) – nicotin and other stimulant addiction withdrawal symptoms OTHER DRUGS EFFECTING RE-UPTAKE Stimulant drugs Cocaine, amphethamines Cocaine blocks serotonin, dopamine and noradrenaline re-uptake with same affinity Amphetamines block dopamine and noradrenaline reuptake with higher affinity, than serotonin re-uptake Amphethamines also block metabolism of monoamines and increase monoamine release THANK YOU FOR YOUR ATTENTION
