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)
OH
OH
Cl
Cl
Cl
H
CH3 CH3
Br
NH
NH2
O
O
chloral hydrate
●used as a mild sedative and hypnotic
in childern up to now (suppositories)
bromisoval
History
Barbiturates
NH
N
H
O
O
O
R
1
R
2
N
H
N
H
O
O
O
CH3
N
H
N
H
O
O
O
CH2
CH2
R1
= R2
= H barbituric acid
R1
, R2
= alkyl, alkenyl, aryl barbiturates
symetric
●slow action onset
●mild activity (sedatives)
●dlouhé odeznívání long decay of action
●usage in analgesic mixtures (irrational, addiction)
asymmetric
●usually more lipophilic
●more efficient, faster onset of action
(hypnotics)
●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
NH
N
H
O
O
O
R
1
R
2
N
N
H
O
O
OH
R
1
R
2
N
N
OH
O
OH
R
1
R
2
N
-
N
H
O
O
O
R
1
R
2
N
N
H
O
O
O
-
R
1
R
2
N
N
OH
O
O
-
R
1
R
2
N
-
N
-
O
O
O
R
1
R
2
N
N
-
O
O
O
-
R
1
R
2
N
N
O
-
O
O
-
R
1
R
2
NaOH
NaOH
Na
+
Na
+
Na
+
Na
+
Na
+ Na
+
Na
+
Na
+
Na
+
●lactam-lactim tautomerism
●dibasic acids
●significant difference of both pKa
values ⇒ possilbility of monosodium etc. salts well soluble
in water
Examples of barbiturates
NH
N
H
O
O
O
R
1
R
2
R1
= R2
= C2
H5
barbital
R1
= R2
= allyl allobarbital
R1
= C6
H5
; R2
= C2
H5
phenobarbital, syn. luminal
●also antiepileptic, treatment of febrile convulsions in babies,
till now in neonates yellow-gum (probably irrational; may be
connected with enzyme induction)
●GABAA
receptor agonists
●
also in mixtures (Bellaspon®
)
N
H
N
H
O
OO
O
N
H
O
O
CH3
Piperidine-2,6-dione (glutarimide) derivatives
glutethimide
●derived from phenobarbital
●obsolete sedative and hypnotic
thalidomide
Contergan®
●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withdrawn in 1970th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
R
N
N
N
+
O
O
-
OCH3
R = H nitrazepam – rather sedative
R = F flunitrazepam - hypnotic
(Rohypnol®
)
●only minor effect on the REM sleep
AE: amnesia, respiration and circulation attenuation
●tolerance
N
ClN
N
N
H
O
O
N
N
CH3
O
CH3
N
N
CH3
N CH3
CH3
O
N
N
CH3
O
CH3
N
N
N
(±)-(5R,S): zopiclon
Zopitin®
(+)-(5S): eszopiclon
„Z-compounds“
zolpidem
Eanox®
, Hypnogen® zaleplon
●also anticonvulsant activity
Sonata®
, Zerene®
...
GABAA
-receptor – Clchannel:
the target structure for most sedatives and hypnotics
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
N
H
NH
CH3
O
O
CH3
O
H
NH
CH3
O
H
NH
O
CH3
H
O
ramelteon
●melatonine receptors MT1
and MT2
agonist
tasimelteon
syn. BMS-214778
melatonine
●administration in the evening
⇒ „re-synchronisation“
● T1/2
too short
Melatonine receptors
●MT1
and MT2
●present in various parts of the brain, important namely in supraschiazmatic nucleus
(„circadian pacemaker = Zeitgeber“-SCN)
●G-protein-coupled receptors
●binding of melatonine to MT2
⇒ „clock resetting“
●binding to MT1
⇒ suppressing of neuronal firing
●MT1
mediated effect of melatonine causes the sleep mainly by means of the „hypothalamic
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
●GABAA
-receptor
●
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
NH
N
H
O
O
CH3
O
N
H
NH
O
O
CH3
N
H
N
H
O O
phenobarbital
Luminal®
inj.,
Pheneamal 0.1®
,
Phenaemaletten®
●
drug of the 2nd
choice:
teratogenic, induction
of hepatic enzymes,
sedation, depression,
irritation in childern
and the elderly
primidone
Liskantin®
tbl.
●metabolized to phenobarbital
●
drug of the 2nd
choice:
sedation, ataxia, attenuated
libido
phenytoin
5,5-diphenylhydantoin
●since 1938
●compared with
phenobarbital nearly „non-
sedative“
●
acts on Na+
channel;
prolongs its opened period
Epilan D Gerot®
tbl.,
Epanutin®
inj.
●in fact monobasic acid;
Na+
salt also used
N
H
O
O
O
CH3
CH3
O N
H
CH3
CH3
O
dimethadione
ethosuximide
Pethinimid®
cps.
●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 ...
Isosteric analogues of hydantoins – oxazolidine-2,4-diones a succinimides
●
block Ca2+
type T channels in thalamic neurons
Benzodiazepins
1,4-benzodiazepins
N
CH3
N
O
Cl
5
Cl
N
4
3
2
N
H
1
9
8
7
6
N
+O
O
-
O
diazepam
●also prevention of febrile
convulsions in babies
Diazepam Desitin®
Rectal Tube
clonazepam
Rivotril®
tbl., gtt.
●GABAA
-receptor
Dibenzo[b,f]azepins
N
NH2 O
N
5
1
2
3
4
11
10
6
7
8
9
NH2 O
O
NH2 O
N
H
OR
N
NH2 O
O
(prodrug)
(metabolite)
5H-dibenzo[b,f]azepine-5-carboxamide
carbamazepine
Carbamazepinum PhEur
Biston®
, Neurotop®
, Tegretol®
CR …
●
blocks voltage gated Na+
channels
and thus hinders uncontroled impulses
spreading
oxcarbazepine
Oxkarbazepin Merck®
,
… Mylan®
; Trileptal®
R = H-
eslicarbazepine
R = CH3
CO-
eslicarbazepine
acetate
Exalief ® tbl., Zebinix
® tbl.
●also modulate
currents mediated by
Ca2+
a K+
carbamazepine-epoxide
CH3
OH
O
CH3
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)
NH
F
NH
O
CH3O
NH2
O
NH2
O
O
NH2
O
retigabin
syn. D 23129
●developed from the analgesic flupirtine
Modes of action: activates K+
channels of
Kv7 type + potentiates GABA-induced
currents in cortical neurones
●adjunctive treatment of partial onset
seizures with or without secondary
generalisation in adults aged 18 years and
above
●risk of QT-interval prolongation and
psychiatric problems
Trobalt ® authorized by EMA 28th
March
2011
felbamate
●an analogue of meprobamate and
carisoprodole
Modes of action:
● potentiates GABA mediated inhibition
●
blocks voltage gated Na+
channels
● blocks ion channels of N-methyl-Daspartate
(NMDA) receptors
●treatment of generalized seizures including
Lennox–Gastaut syndrome (= a difficult-totreat
form of childhood-onset epilepsy
characterized by frequent seizures of various
types and often accompanied by mental
retardation)
●high risk of fatal hepatitis and aplastic
anaemia
Carbamates
topiramate
2,3:4,5-Di-O-isopropylidene-β-Dfructopyranose
sulfamate
Topilept®
tbl., Topilex®
tbl., Topiragis®
tbl....
●many structural changes proceeded
but analogues inactive
●
blocks Na+
channels and high voltage
gated Ca2+
channels, attenuates
effects of excitation transmitters and
amplifies GABA effect; impact of
carboanhydrase inhibition on its action
is not clear
O
HH
H
O
O
CH3
CH3
O
O
CH3
CH3
O
S
NH2
O O
N
S
O
O
S
NH2
O
O N
O
S
NH2
O
O
sulthiame
●a sulphanilamide derivative
●introduced 1961
●carboanhydrase inhibitor
Ospolot®
tbl.
zonisamide
● blocks voltage gated
Na+
channels & Ca2+
channels of T type
● inhibits
carboanhydrase
Zonegran®
tbl.
Compounds with a sulphonamide eventually a sulphamic acid fragment
gabapentin
Gabagamma®
tbl., Gabanox®
tbl.
…
●AE: weight increase
Substitution derivatives of γ-amino butyric acid (GABA)
OH
O
NH2
CH3CH3
OH
O
NH2
OH
O
NH2
CH2
[1-(aminomethyl)cyclohexyl]acetic
acid
pregabalin
Lyrica®
●6 – 8x more
effective than
gabapentin
●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
vigabatrin
Sabril®
tbl.
● GABA-aminotransferase inhibitor
lamotrigin
Epimil®
tbl., Lamictal®
tbl. …
●
Na+
channels blocker
●can also trigger myoclonic
seizures
●
embryotoxicity: ↑ risk of
cleft of lip and palate
Cl
Cl
N
NH2N
N
NH2
F
F
N N
N
O
NH2
N
H
OHO
S
CH3
S
CH3
rufinamide
●
modulation of Na+
channels –
keeps their inactive state
●AE heart: shortening of QT
interval
Inovelon®
tbl.
tiagabin
Gabitril®
tbl.
●inhibits GABA reuptake in
neurones and glias ⇒ ↑
availability of GABA for
inbibition of postsynaptic
neurones
Some „newer“ antiepileptics with heterocyclic fragments
NO
NH2
O
N
O
NHO
CH3 CH3
NO
NH2
O
CH3
H
NO
NH2
O
CH3
H
NO
NH2
O
CH3
H
F
F
H
etiracetam
NO
NH2
O
CH3
H
CH3
H
N
N
O
H
S
O
O
F
N
N
O
O
piracetam levetiracetam
brivaracetam
seletracetamnefiracetam
klasická nootropika, posilovače kognitivních funkcí "neklasická" antiepileptika, agonisté synaptického
vezikulového proteinu 2A (SV2A)
unifiram sunifiram
„Geneaology“ of racetams
classical nootropics, cognitive
functions enhancers
„non-classical antiepileptics, synaptic
vesicular protein 2A (SV2A) antagonists
Antiepileptic racetams
●interact with SV2A
●
probably also inhibit high voltage activated (HVA) Ca2+
channels (like topiramate)
NH2
CH3
O
H
N
O
NH2
CH3
O
H
N
O
R
H
levetiracetam
Keppra® (2S), (4R)
●10x higher afinity to SV2A than
levetiracetam
R = C3
H7
brivaracetam
●EMA has authorized clinical studies for
treatment of epilepsy in childern and febrile
convulsions in neonates
●
inhibits also Na+
channels
R = CH=CF2
seletracetam
Vomitics
●induce vomiting e.g. in intoxications
●an obsolete group
H
N
H
H
H
O
CH3
O
CH3
NH
CH3
OCH3 O
CH3
emetine
●alcaloid from the roots of Cephaëlis ipecacuanha, Rubiaceae
●emetic (central: medulla oblongata), antiprotozoal, anthelmintic effects
●
formerly also used as „caugh modulator“ - combined with codein – Kodynal®
(50
mg codeine + 5 mg emetine)
Antivomitics (= antiemetics), antikinetics
●parasympatolytics: tropane alkaloids
●H1
-antihistamines
●antipsychotics: phenothiazine derivatives
●compounds enhancing intestinal perislalsis
●setrons
●NK-1 antagonists
R = H moxastine theoclate
syn. mephenhydrinate
Kinedryl®
R = CH3
dimenhydrinát
= diphenhydramine + 8-chlorotheophylline
●molecular complexes
●motion sickenesses, gravidity nausea
●AE: sedation
N
Cl
N
H
O
N
CH3
N
CH3
O
O
N CH3
CH3
R
H1
-antihistamines used as antiemetics and antikinetics
Setrons
●suppress nausea and vomitting by inhibition of serotonine 5-HT3
receptors on
periphery
●treatment of serious nausea accompanying cancer chemotherapy
●also in general anaesthesia
CH3
N
N
N
CH3
O
H
O
N
H
N
ondansetrone
Emeset®
, Zofran®
...
palonosetrone
●the most modern
Aloxi®
inj.
granisetron
●isosteric
Emegar, Granegis ...
H
H
HO
O
N
H
N
CH3
H
H
HNH
O
N
N
H
N
CH3
H
H
H
O
N
O
O
N
H
tropisetron
●effective for 24 hours
●fully metabilized in liver
dolasetron
Setrons – derivatives of indole and isosteric heterocycles
Neurokinine receptor 1 (NK1
) antagonists
●substance P (SP) was isolated in 1931, it was purified and its sequence
was determined in 1970th
: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-
Met-NH2
●belongs to family of small peptides – mammal tachykinins (TK)
●3 types of receptors for TK have been cloned: neurokinines NK1
, NK2
,
NK3
●SP is predominantly an agonist of NK1
receptor
●1984: administration of SP induced vomitting in dogs
●1993: resiniferatoxin acts antiemetic in ferrets by competiton with SP
●1993: the first non-peptide „pure“ NK1
antagonist permeating through
blood-brain barrier (BBB) was prepared: CP-96,345 CH3
S
H
NH
O
H
CH3
CH3
NH
O
NH
O
H
NH
O
H
NH
O
H
NH2
O
NH
O
H
NH2 O
NH
O
H
N
O
H
NH2
NH
OH
N
O
H
NH2
NH
NH2
NH
NH2
O
substance P
Neurokinine receptor 1 (NK1
) antagonists
H
O
O
H
CH3
O
H
O O
O
CH3
OH
OH
O
CH3
H
CH3
CH2
CH3
O
NH
H
N
H
resiniferatoxin
●a terpene from latex of Euphorbia
genus (E. poisonii, E. resinifera)
●also vaniloid (capsaicine)
receptors agonist
●emetic/antiemetic in dependence
on the mode of application
CP-96,345
CH3 H
O
H
O
N
N
O
NH
N
H
H
F
F
F
F
F
F
F
CH3H
N
CH3
O
N
H
H
CH3
F
N
N
CH3
O
F
F
F
F
F
F
aprepitant
●1st
NK1
antagonist available in clinic
Emend®
cps., Ivemend®
plv. inf.
casopitant
syn. GW679769
●phase 3 of clinical evaluation has been finished
Neurokinine receptor 1 (NK1
) antagonists