Antidepressants
• often life-saving drugs
Possible classification of antidepressants
1. Non-selective monoamines reuptake inhibitors (tricyclic and tetracyclic
antidepressants)
2. Monoaminooxidases (MAO) inhibitors
2.1 Non-selective MAO inhibitors
2.2 Selective MAO A inhibitors
3. Selective serotonine and noradrenaline reuptake inhibitors (SSNRI)
4. Selective serotonine reuptake inhibitors (SSRI)
5. Dual-serotoninergic antidepressants
6. Selective noradrenaline reuptake inhibitors (SNRI)
7. Alkaline metals salts
© Oldřich Farsa 2011
Amines involved in effects of antidepressants
OH
OH
H NH2
OH
4-[(1R)-2-amino-1-hydroxyethyl]benzene-1,2-diol
noradrenaline (norepinephrine)
OH
OH
NH2
4-(2-aminoethyl)benzene-1,2-diol
dopamine
N
H
NH2
OH
3-(2-aminoethyl)-1H-indol-5-ol
serotonine
1. Non-selective monoamines reuptake inhibitors (tricyclic antidepressants)
● inhibit reuptake of serotonine and noradrenaline
Genesis (derivation) of tricyclic antidepressants
C
H2
N
N
CH3 CH3
N
S
CH2
N
CH3 CH3
N
CH2
N
CH3
CH3
imipraminepromazine
antipsychoticsantihistamines
N
N
CH3
R
1
R
2
R
3
N
CH3
R
1
R1
=-CH3
R2
=R3
=-H imipramine
Tofranil®
R1
= R2
=R3
=-H desipramine
R1
= R2
=-H R3
=-Cl clomipramine
Anafranil®
R1
= R2
=-CH3
R3
=-H trimipramine
Surmontil®
R1
=-CH3
amitriptyline
Elavil®, Endep®
R1
=-H nortriptyline
Pamelor®
1st
and 2nd
generations of tricyclic antidepressants
•act innhibitory also on M, H1
, α1
, α2
, 5-HT2
receptors
•2nd
gen. increases more amount of NA than 5-HT in synapsis, 1st
gen. reversely
1st
generation of tricyclic antidepressants
O
N
S
N
cidoxepin [INN]
syn. doxepin [USAN]
dosulepin [INN]
syn. dothiepin [USAN]
Prothiaden ® 25
Mechanism of action:
- Inhibition of neurotransmitters reuptake
- Immediate effect = >↑ NA and 5-HT in synapsis.
- After longer period treatment (2 - 4 weeks) = >
↓ of activity β and ↓5-HT2 rp.
↓ of release and return of NA
↓ NA-stimulated cAMP level in the brain
↑ sensitivity of 5-HT receptors
* „Adaptive responses“ *
● as long as 4 weeks of treatment are needed for full activity
Unwanted effects of tricyclic antidepressants due to antagonist action on various
receptors:
•M(uscarine) rp. - dry in the mouth, bad accomodation, tachycardia, problems with
emiction, forgeting
•H1
rp. - sedation, increase of body weight
•5-HT2
- increase of appetite and body weight
•α1
- orthostatic hypotension, reflex tachycardia
Tetracyclic antidepressants
(or „thymoleptics of 2nd
generation“)
N
N
CH3
N
H
CH3
N N
N
CH3
mianserin maprotiline
inhibits reuptake of
noradrenaline mainly
•moderate anicholinergic
effects, significant
antihistamine ones
(sedative)
Ludiomil ®
mirtazapine
•minimal activity on monoamines reuptake
from synapses, quite selective antagonists
of α2
-adrenergic receptors which inhibit
noradrenaline release
•inhibits also α1
-rp. ⇒
↓ blood pressure
Lerivon ® , Miabene ®
Esprital ® , Mirtazapin ® firm
2. Monoaminooxidases (MAO) inhibitors – also thymoeretics
• MAOs = enzymes oxidatively degrading catecholamines
– discovered in 1950th
– potent but less used due to their lower security
(interactions, unwanted effects)
– frequent occurence of drug interactions
– most frequently used if other treatment methods failed
– AE: orthosthasis, sedation, sexual dysfunctions, body
weight increase
– type A (MAO-A) decomposes mainly serotonine and less
also noradrenaline
– typ B (MAO-B) decomposes various phenylethylamine
including dopamine
2.1 Non-selective MAO inhibitors
NH
NH2
NH2
NH
NH
N
O
CH3
CH3
NH
NH
ON
O CH3
1-(2-phenylethyl)hydrazine
phenelzine
trans-2-
phenylcyklopylamin
tranylcypromine
isonicotinic acid N´-
isopropylhydrazide
iproniazid
4-methylisoxazole-3karboxylic
acid N´-
benzylhydrazide
isocarboxazid
•dangerous interaction with „exciting amines“ in food (maturing cheeses, red
wines) especially tyramine ⇒↑ blood pressure to hypertension crisis
NH2OH
tyramine
2.2 Selective MAO A inhibitors
• MAO A decomposes mainly endogenous noradrenaline (NA) and serotonine
(5HT)
moclobemide
N-(2-morfolinoethyl)-4-
chlorobenzamide
Aurorix ®
toloxatone amiflamine
Cl
N
H
O
N
O N
CH3
H
OH
O
O
N
CH3
CH3
H
CH3
NH2
CH3
3. Serotonine and noradrenaline reuptake inhibitors (SNRI)
•indirect central agonists of both adrenergic and 5HT receptors
venlafaxine
Argofan ® , Apo-Venlafaxin ® , Velaxin ® ...
(3S)-1-methylamino-3-(1-naphtyloxy)-3-
(thiophene-2-yl)propane
duloxetine
Cymbalta ® , Xeristar ®
N
CH3
O
CH3
CH3
OH
1-[2-(dimethylamino)-1-(4-methoxyphenyl)
ethyl]cyclohexanol
S
O
NCH3
H
4. Selective serotonine reuptake inhibitors (SSRI)
O
N
F
N
CH3
CH3
O
N
F
N
CH3
CH3
citalopram
Citalex®
escitalopram
(S)-citalopram
Depresinal ® , Elicea ®
F
F
F O
NCH3
H
3-(4-trifluorophenoxy)-3-phenyl-
1-methylaminopropane
fluoxetin
Deprex®
, Floxet®
, Fluocim®
,
Fluval®
…
N CH3H
Cl
Cl
H
H
(1S,4S)-4-(3,4-dichlorophenyl)-1-methylamino-
1,2,3,4-tetrahydronaphtalene
sertralin
Asentra®
, Serlift®
, Setralex®
, Zoloft®
…
•slightly activates, can disturb
the sleep if administered in the
evening, increase of tension
and anxiety possible, long half
time – no problems with an
omission of a single dose
paroxetine
Arketis ® , Parolex ®
fluvoxamine
O
N
H
F
O
O
CH3
O
CF3
N
O
NH2
•attenuating effects,
administration in the
evening, suitable for
inquiet patients,
inhibition of suicidal
turns
Fevarin ®
5. Dual-serotoninergic antidepressants
N
N
Cl
N
N
O
N
N
N
Cl
N
N
N
O
O
trazodone nefazodone
•serotonine reuptake inhibitors and
simultaneously 5-HT2
receptor antagonists
•also inhibits NA reuptake
•markedly sedative
Trittico AC ®
6. Selective noradrenaline reuptake inhibitors (SNRI)
reboxetine
•R,R
viloxazine
•racemate atomoxetine
•R
Strattera ®
NH
OO
O
H
CH3
NH
OO
O
H
CH3
NH
CH3
CH3
O
H
•effective in motivation and interest stimulation
•enhance effect of sympathomimetics
•AE : tachycardia, tremor
7. Alkaline metals salts
Li+
•mostly often Li2
CO3
•treatment of bipolar illness (formerly manio-depressive syndrome)
•high toxicity, low difference between therapeutic and toxic doses, plasmatic levels
monitoring necessary
Rb+
•total amount in the body 400 – 900 mg
•potentiates noradrenergic and dopaminergic transmission of nervous impulses in
CNS
•evidences of antidepressant effects