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Sedatives & Hypnotics Sedatives & hypnotics © Oldřich Farsa 2011 Sedatives = „calmative“ compounds Hypnotics = compounds causing a condition less or more similar to the physiologic sleep ●often the same; the difference in their action is only in a dose The sleep in accordance to EEG and other methods: non-REM (non-rapid eye movement) sleep – 70 - 75% REM – the rest; deep sleep which is needed to the organism regeneration (Pre)history ●ethanol ●bromides (KBr, NaBr) Br O Cl OH H O Cl NH Cl OH H3C CH3 NH2 chloral hydrate bromisoval ●used as a mild sedative and hypnotic in childern up to now (suppositories) History O Barbiturates 2 R NH R1= R2 = H barbituric acid 1 O R R1, R2= alkyl, alkenyl, aryl barbiturates N H O H C O 2 O CH3 H H N N O O H C N 2 N H H O O symetric asymmetric ●slow action onset ●usually more lipophilic ●mild activity (sedatives) ●more efficient, faster onset of action ●dlouhé odeznívání long decay of action (hypnotics) ●usage in analgesic mixtures (irrational, addiction) ●treatment of hyperbilirubinemia and kern icterus in neonates till today (probably irrational) ●used on a mass scale approx. 1912 – 1955 ●classification according to duration of action ●up to 50 derivatives ●supress REM-sleep ⇒ the patient is not relaxed Chemical properties of barbiturates: lactam-lactim tautomerism and salts formed by tautomers O O O 2 2 2 R NH R N R N O 1 1 OH 1 OH R R R N N N H H O O HO NaOH O + O O 2 - Na 2 2 R N R N R N - - + 1 O O O Na R 1 + 1 R Na R N N N H H O O HO NaOH O + Na O O 2 - 2 2 R N R N R N - - + 1 O O 1 O + 1 Na R - R - R N + Na Na N + N Na - O O O + Na ●lactam-lactim tautomerism ●dibasic acids ●significant difference of both pK values ⇒ possilbility of monosodium etc. salts well soluble a in water Examples of barbiturates R1 = R2 = C H barbital 2 5 R1 = R2 = allyl allobarbital O R1 = C H ; R2 = C H phenobarbital, syn. luminal 6 5 2 5 2 ●also antiepileptic, treatment of febrile convulsions in babies, R NH till now in neonates yellow-gum (probably irrational; may be connected with enzyme induction) ●GABA receptor agonists A 1 O ● ® R also in mixtures (Bellaspon ) N H O Piperidine-2,6-dione (glutarimide) derivatives O CH3 H O N O N N H H O O O glutethimide thalidomide ●derived from phenobarbital Contergan® ●obsolete sedative and hypnotic ●originally a hypnotic ●withdrawn in 1970th due to tetatogenicity of its S-enantiomer; enantiomers however racemize rapidly; the need of its withdrawal initiated the INN nomenclature introduction ●after 2000 used again: imunosuppresant, antineoplastic, angiogenesis inhibitor; the lead compound of a novel group of anticancer drugs Benzodiazepins 1,4-benzodiazepins H3C O N N - O + N R O R = H nitrazepam – rather sedative R = F flunitrazepam - hypnotic (Rohypnol®) ●only minor effect on the REM sleep AE: amnesia, respiration and circulation attenuation ●tolerance „Z-compounds“ N O N N N N N Cl CH3 N N N N H3C O H O O H3C N N CH3 H C N O N 3 CH3 H3C (±)-(5R,S): zopiclon zolpidem Eanox®, Hypnogen® zaleplon Zopitin ● (+)-(5S): eszopiclon also anticonvulsant activity Sonata®, Zerene® ... GABA -receptor – Cl- channel: the target structure for most sedatives and hypnotics A and many antiepileptics ●alosteric receptor agonists Melatonine receptor agonists („melatonergic“ drugs) ●melatonine is responsible for skin colouring (pigmentation) but also for circadian rhytm ●agonists produce the sleep and „reset circadian pacemaker“ (=“Zeitgeber“) to enable it H N H O O O H H CH3 CH3 NH HN NH O CH3 O O H3C melatonine ramelteon ● tasimelteon administration in the evening ●melatonine receptors MT ⇒ 1 syn. BMS-214778 „re-synchronisation“ and MT agonist 2 ● T too short 1/2 Melatonine receptors ●MT and MT 1 2 ●present in various parts of the brain, important namely in supraschiazmatic nucleus („circadian pacemaker = Zeitgeber“-SCN) ●G-protein-coupled receptors ●binding of melatonine to MT ⇒ „clock resetting“ 2 ●binding to MT ⇒ suppressing of neuronal firing 1 ●MT mediated effect of melatonine causes the sleep mainly by means of the „hypothalamic 1 sleep switch“ which under influence of melatonine suppresses neuronal pathes connected with keeping awake and stimulates those connected with the sleep ●thalamus is also of some importance for sleeping effect of melatonine; MT receptors are present here also, spindles which are characterized by non-REM sleep are formed by influence of 5-aminoindole ●there are also other binding structures or sites for melatonine: quinoreductase 2, nuclear receptors which belong into retinoic acid receptors superfamily, Ca2+ binding proteins: calmoduline, calreticuline and its analogues in nucleus etc. Antiepileptics ●compounds selectively suppresing CNS used for treatment of epilepsy Anticonvulsants ●compounds protecting from convulsions used most frequently (but not only) in epilepsy ●many antiepileptics act as anticonvulsants and vice versa but not all Modes of action of antiepileptics and some of their target structures ●GABA -receptor A ●voltage gated Na+ channels: extending of inactivation decreases the ability of neurons to spread and impulse on higher frequences ●low threshold Ca2+ channels: decrease of the flux of Ca2+ throuh T type channels leads to decrease of the current of the pacemaker which conditions the thalamic rhytm in peaks and waves which is seen in generalized seizures Synaptic vesicular protein 2A (SV2A) ●widely spread in whole CNS; its participation in exocytosis of synaptic vesicles and release of neurotransmitters is assumed ●afinity of levetiracetam and its analogues to SV2A closely correlates with their ability to protect against convulsions induced experimentally in animal models Phenobarbital and its analogues O H H H N N N O O HN O HN O CH3 N CH3 H O O phenytoin 5,5-diphenylhydantoin phenobarbital primidone ●since 1938 Luminal® inj., Liskantin® tbl. ●compared with Pheneamal 0.1®, ●metabolized to phenobarbital phenobarbital nearly „non- Phenaemaletten® ●drug of the 2nd choice: sedative“ ●drug of the 2nd choice: sedation, ataxia, attenuated ●acts on Na+ channel; teratogenic, induction libido prolongs its opened period of hepatic enzymes, Epilan D Gerot® tbl., sedation, depression, Epanutin® inj. irritation in childern ●in fact monobasic acid; and the elderly Na+ salt also used Isosteric analogues of hydantoins – oxazolidine-2,4-diones a succinimides H H O N O N O O O CH3 CH3 H3C H3C ethosuximide Pethinimid® cps. ● dimethadione effective in patients with absences but not in generalized and tonic-clonic seizures ●does not intertact with other drugs ●AE: nausea, vomitting , abdominal pain, headache, alergic rash ... ●block Ca2+ type T channels in thalamic neurons Benzodiazepins 1,4-benzodiazepins H O H C 9 3 O N N 8 1 2 3 7 O + N 5 N 6 4 Cl N - Cl O clonazepam diazepam Rivotril®tbl., gtt. ●also prevention of febrile convulsions in babies Diazepam Desitin®Rectal Tube ●GABA -receptor A Dibenzo[b,f]azepins H2N O H2N O H2N O 6 4 N N 7 N 3 5 8 2 9 10 1 5H-dibenzo[b,f]azepine-5-carboxamide 11 R O O H (prodrug) carbamazepine oxcarbazepine R = H- Carbamazepinum PhEur ® eslicarbazepine ® ® ® Oxkarbazepin Merck , Biston , Neurotop , Tegretol CR … … Mylan®; Trileptal® R = CH CO- ●blocks voltage gated Na+ channels 3 eslicarbazepine and thus hinders uncontroled impulses H2N O spreading acetate Exalief ® tbl., Zebinix N ® tbl. ●also modulate currents mediated by Ca2+ a K+ O (metabolite) carbamazepine-epoxide CH3 OH H3C O valproic acid Acidum valproicum PhEur ●sodium valproate more fraquently used Natrii valproas PhEur ●blocks voltage gated Na+ channels ●amplifies inhibition effect of GABA ●lowers currents through voltage gated low threshold Ca2+-T-channels ●all types of seizures ●teratogenic Absenor ® , Convulex ® (valproic acid), Depakine ® , Orfiril ® … (sodium vaproate) Carbamates O CH3 O O O NH NH NH2 F NH2 O H2N felbamate O ● retigabin an analogue of meprobamate and syn. D 23129 carisoprodole ●developed from the analgesic flupirtine Modes of action: + ● Modes of action: activates K channels of potentiates GABA mediated inhibition Kv7 type + potentiates GABA-induced ● blocks voltage gated Na+ channels ● currents in cortical neurones blocks ion channels of N-methyl-D- ●adjunctive treatment of partial onset aspartate (NMDA) receptors ● seizures with or without secondary treatment of generalized seizures including generalisation in adults aged 18 years and Lennox–Gastaut syndrome (= a difficult-to- above treat form of childhood-onset epilepsy ●risk of QT-interval prolongation and characterized by frequent seizures of various psychiatric problems types and often accompanied by mental Trobalt ® authorized by EMA 28th March retardation) 2011 ●high risk of fatal hepatitis and aplastic anaemia Compounds with a sulphonamide eventually a sulphamic acid fragment O O S O NH2 O H O O S NH2 O O O N S O N H C CH3 3 O O O O H H CH H3C 3 S O H N topiramate 2 2,3:4,5-Di-O-isopropylidene-β-D- sulthiame zonisamide fructopyranose sulfamate ●a sulphanilamide derivative ● blocks voltage gated Topilept® tbl., Topilex® tbl., Topiragis® ●introduced 1961 Na+ channels & Ca2+ tbl.... ● ● carboanhydrase inhibitor channels of T type many structural changes proceeded Ospolot®tbl. ● inhibits but analogues inactive carboanhydrase ●blocks Na+ channels and high voltage Zonegran®tbl. gated Ca2+ channels, attenuates effects of excitation transmitters and amplifies GABA effect; impact of carboanhydrase inhibition on its action is not clear Substitution derivatives of γ-amino butyric acid (GABA) H3C CH3 OH OH NH2 O H2C O O NH2 NH2 OH [1-(aminomethyl)cyclohexyl]acetic acid pregabalin vigabatrin gabapentin ® ® ® ® Lyrica Sabril tbl. Gabagamma tbl., Gabanox tbl. ●6 – 8x more ● GABA-aminotransferase inhibitor … effective than gabapentin ● AE: weight increase ●also for neuropathic pain and generalized anxious disorder ●bind to α2δ subunit of neuronal voltage gated Ca2+ channel and inhibit stream of Ca2+ ●excreted by urine, do not interfere with metabolism of other drugs Some „newer“ antiepileptics with heterocyclic fragments O OH N NH2 H F Cl N N N O Cl N CH N 3 N NH 2 NH2 F CH3 S S tiagabin rufinamide lamotrigin Gabitril®tbl.
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