Drugs are used for

treatment of affective
disorders
Affective disorders are mania, depression and
bipolar affective disorders - maniac-depressive
psychosis.
 Mania (greek mania-madness) is expressed by unusual high
mood and is accompanied by the below mentioned symptoms
combination: self-confidence, overestimation of own abilities,
high psychological activity, impulsive behavior, fastening of
associative thinking, excessive speech, in some cases
overexcitation and aggressive behavior, hallucinations.
 Depression (latin` depression- pressure, inhibition)is
described by emotional disorders, characterized by
pathologically lowered mood (hypotimia), unmotivatied
melancholy, apathy, pessimism, low self- esteem, loss of
motivation etc.
 Somatic symptoms are also revealed: psychomotor inhibition,
loss of sexual activity, loss of appetite, sleepiness. Usually if
from the above-mentioned symptoms are existed, in the
patient we can diagnose depression.
 Monoamine theory of affective
disorders
On the basis of this hypothesis the origin of
depressions is related to the decline of
function of amine neuromediators:
noradrenaline (NA), dopamine (DA),
serotonine (5-HT) in the certain parts of
cerebrum and vice versa, the increase of
functions of these mediators is instrumental
in the origin of the maniac state. The most
important mediator for mood is 5-HT, which
is mediator of ”high mood “.
 Antidepressants
Antidepressants are used for the treatment of
depression. Nowadays all antidepressants can
increase mediators amount in the synaptic
cleft by the different ways and by this way
improves the pathological changed mood in
patients.
Classification of antidepressants
 1. Inhibitors of the neuronal reuptake of
monoamines
 Tricyclic antidepressants (TCA), non selective

inhibitors of neuronal reuptake of monoamines

(mainly inhibiting the reuptake of 5-НТ and
NA)Amitriptyline, Imipramine, Clomipramine,
Doxepin
 Inhibitors of neuronal reuptake of mainly 5-НТ

(5-НТ>NА): Fluoxetine. Fluvoxamine

 Inhibitors of neuronal reuptake of mainly NA

(NА>5- HT):Maprotiline
Classification of antidepressants
 2. Inhibitors of monoaminoxidase (MAO)
 Non selective inhibitors of MAO (both MAO-A

and MAO-B): Nialamid (irreversible inhibitor )

 Selective inhibitors of MAO-A: Moclobemide

(reversible inhibitors)
 Selective inhibitors of MAO-B: Selegiline
 3. Atypical antidepressants:Mianserin,

Тrazodone, Мirtazapine
 Tricyclic antidepressants
Pharmacodynamics of tricyclic antidepressants
 Tricyclic antidepressants are non selective
inhibitors of neuronal reuptake of
monoamines, which competitively bind and
inhibit transport systems of presynaptic
membrane (transport systems of NA, 5-HT).
As a result of which the reuptake of
noradrenaline and serotonine is disturbed. It
results in the accumulation of these
mediators in synaptic cleft, leading to
activation of adrenergic and serotoninergic
neurotransmission .
 Tricyclic antidepressants
Pharmacodynamics of tricyclic antidepressants
 It is necessary to mark that the antidepressive effect
appears not immediately, and after 2-3 weeks. At
depression, in the conditions of deficit of mediators,
there is an increase of amount and sensitiveness of
receptors (up regulation) on a postsynaptic
membrane by compensative mechanism, the changes
of level of receptors affect also presynaptic
membrane. At the action of tricyclic antidepressants,
the amount of mediators is increased in a synaptic
cleft, that gradually leads to reverse process –
diminishing of amount and sensitiveness of receptors
(down regulation). It takes 2-3 weeks.
 Tricyclic antidepressants
Pharmacodynamics of tricyclic antidepressants
 The antidepressant effect can be potentiated
also by properties of tricyclic antidepressants
to block presynaptic α2-adrenoreceptors,
which brings to increased secretion of
noradrenaline from presynaptic membrane.
 Beside the main mechanisms, TCA have also

M-, α- and H1- lytic effects, which define

drugs` action and more side effects.
 Other effects
 Sedative effect. Bring to the general calming,
diminishing of anxiety. These effects are conditioned
by properties of tricyclic antidepressants to block
central M-cholino, α-adreno-, histamine Н1
receptors. Sedative effect shows up a few hours
after adopting antidepressant. To the sedative effect
tolerance is developed as a rule.
 Psychostimulant action. Shows up the revival of
psychomotor activity, renewal of motivations,
increase in mental and physical capacity. It is
conditioned by the strengthening of the adrenergic
neurotransmission.
 Other effects
 Not all tricyclic antidepressants have sedative and
psychostimulant effects at the same degree. So for
Amitriptiline the sedative effect is more expressed, and
Imipramine possesses a potent psychostimulant action, while
a sedative effect and property to block M-cholinoreceptors is
expressed in a less degree. Modulating action is characteristic
for Imipramine, it means that the expressiveness of one or
another action depends on the state of patient.
 Analgesic action. It is related to property of tricyclic
antidepressants to activate the antinociceptive system, and
also to activate opioid receptors and inhibit the nociceptive
system.
 Tricyclic antidepressants have also hypothermic and
antivomiting actions.
 Pharmacokinetics of tricyclic
antidepressants
 Tricyclic antidepressants can be used both
parenterally and orally. At oral rout of
administration absorption is very rapid, firmly
binds with plasma albumins. Have expressed
affinity to tissue proteins and large volume of
distribution. Metabolism takes place mainly in the
liver, with formation of possibly active metabolites,
also possessing the antidepressant action.
 For the people of senile age elimination of
antidepressants is prolonged even more, that is
dangerous from point of cumulating of
preparations and connecting with it side effects.
Side effects of tricyclic antidepressants:
 A- type side effects are mainly connected with the blockage of
different types of receptors: α –adreno, M-cholino, histamine Н1
receptors.
 1. CNS: Expressed sedation: weakness, sense of fatigue,
deceleration of thought, somnolence.
 2. Eye: mydriasis, increase of intraocular pressure, paralysis of
accommodation, inhibition of secretory function of tear glands.
 3. Cardiovascular system: orthostatic hypotension, tachycardia,
cardiotoxic action, arrhythmias, different degrees of
atrioventricular blockages and inhibition of intraventricular
conductivity.
 4. Gastrointestinal tract: dryness of mouth, difficulties in
swallowing, inhibition of secretory function of the digestive
glands, constipation, billiary stasis during long-term treatment,
hepatotoxic action.
Side effects of tricyclic antidepressants:
 5. Increase of appetite and increase of mass
of the body (blockage of the central
histamine Н1 receptors)
 6. Urinary tract: delay of urination, different

types of sexual dysfunctions

 7. B-type side effects: Allergic reactions,

agranulocytosis, thrombocytopenia (rarely)

 Selective inhibitors of neuronal
reuptake of serotonine (SIONRS)
 Fluoxetine, Fluvoxamine
 Parmacodynamics SIONRS selectively bind

with the specific transporter of serotonine,

block them, and bring to the accumulation of
serotonine in the synaptic cleft strengthening
serotoninergic neurotransmission. During
usage of these drugs also receptor changes
can occur and antidepressant action develops
after 3 weeks of administration.
 Parmacodynamics
 It is known that in the conditions of deficiency of
serotonine (depressions of the different origin)
postsynaptic as well as presynaptic 5-НТ receptors
are exposed to the changes on the principle of up
regulation. During the treatment with SIONRS
increased level of serotonine brings to the process
of down regulation of 5-HT receptors. Diminishing
of reception to the normal level (in 2-3 weeks)
results in the clinical manifestation of the
antidepressant (timoleptic) action of SIONRS.
 High doses of SIONRS can also block the
transporter of noradrenaline.
 Parmacodynamics
 The distinctive feature of this group of
preparations is an absence of properties to
block M-cholinoreceptors and insignificant
influence on α-adreno and histamine Н1-
receptors.
 They are safer from the point of overdose.
 As compared to other SIONRS Fluoxetine

possesses the most expressed

psychostimulating effect, it is also an agonist
of 5-HT receptors.
 Pharmacokinetics of SIONRS
 SIONRS are used orally. They are lipophylic,
well absorbed from GIT. Bioavailability varies ,
well bind to the plasma proteins 95-98%,
have high volume of distribution up to,
biotransformation takes place in the liver,
with the formation of active metabolites.
 A-type side effects
 1. CNS: state of excitation, anxiety, alarm, insomnia,
aggression, cruelty, suicide ideas.
 2. Hormonal sphere: inhibition of secretion of ADH
and hyponatriemia.
 3. “Serotonine syndrome”: anxiety, rigidity and
spastic constriction of muscles, hyper reflection,
promoted perspiration, hyperthermia, tremor, cramps
and coma. arises up at combination of SIONRS with
inhibitors of MAO, that results in the excessive
increase of amount of serotonine in synapse.
 4. Gastrointestinal tract: the dyspeptic disorders are
expressed by nausea, vomiting
 A-type side effects
 5. Disturbances in sexual sphere
 6. Fluoxetine inhibits Cytochrome P-450

isoenzymes, leading to decrease and/ or

increase in some drugs` metabolism (other
antidepressants, neuroleptics, barbiturates,
antiepileptic drugs, β-adrenoblockers, some
antibiotics).
 Selective inhibitors of neuronal reuptake of
noradrenaline
Maprotiline
 Selective inhibitors of neuronal reuptake of
noradrenaline bind mainly with the transporter
of noradrenaline and depress its activity. As a
result the amount of noradrenaline in the
synaptic cleft is increased and adrenergic
neurotransmission is activated.
 By other pharmacological features selective
inhibitors of neuronal reuptake of noradrenaline
are like tricyclic antidepressants. Property to
block M-cholino, αadreno - and the histamine
Н1 receptors, for them is expressed moderately.
 Inhibitors of monoaminooxidase (IMAO)
Classification of MAO-inhibitors
 1. Non selective MAO-inhibitors (MAO-A and
MAO-B): Nialamid (irreversible inhibitor )
 2. Selective inhibitors of MAO-A:

Moclobemide (reversible inhibitor)

 3. Selective inhibitors of MAO-B: Selegiline
 Pharmacodynamics of IMAO
 IMAO inhibiting MAO, block inactivation of
noradrenaline, serotonine, dopamine, leading to
increase of the amount of these mediators in the brain.
Exactly the same changes are marked in periphery also:
heart, liver, intestine, substantially the concentration of
monoamines rises also in plasma.
 As a result increase of the amount of mediators in
axoplasma of presynaptic part, in the synaptic cleft
interact with the proper receptors on the postsynaptic
membrane, leading to activation of the following types
of neurotransmission adrenergic, serotoninergic,
dopaminergic (though the last one changes in less
degree, than the first two ones).
 Pharmacodynamics of IMAO
 Inhibition of MAO comes immediately after
taking these drugs, however the
antidepressant action is developed in 2-4
weeks (changes in sensitivity).
 Non selective IMAO irreversibly inhibit MAO.
 Selective IMAO bind with an enzyme

reversibly. Moclobemid possesses a

psychostimulating effect.
 In the modern medicine is mainly used MAO-

A reversible inhibitor Moclobemide.

 A- type side effects
 Excessive excitation (during overdoses):
agitation, maniac state, insomnia, fear, panic,
hallucinations etc.
 Cardiovascular system:hypotension up to an

orthostatic collapse.
 Eye and GIT:as a result of blockade of

Mcholinoreceptors
 Violation of sexual function –decrease of

libido etc.
 A- type side effects
 “Cheese crisis” or “thyramine syndrome” is mainly
typical for non selective IMAO and for selective ones is
not characteristic practically. Normally thyramine, which
enters the organism with food (cheese, bananas,
chocolate, wine, beer) and can be formed in intestines,
is inactivated under influence of MAO of the intestine
and liver. In conditions of MAO inhibition thyramine is
not inactivated and enters to blood stream. Being
indirect adrenomimetic, it leads to the increased
noradrenaline release to the synaptic cleft. Clinical
manifestations are arterial hypertension, tachycardia,
arrhythmias etc.
 Increase of appetite and mass of body.
 Atypical antidepressants
 The antidepressant action of preparations of this group
is mainly conditioned by their influence on different
receptors.
 Мirtazapine (Mianserine derivative) Increases the amount
of NE and 5HT, blocks α2 and 5-HT receptors as a result
diminishes probability of development of violations of
sexual functions and anxiety. Blocks also H1 receptors
and can cause sedation , increase of bodymass.
 Тrazodone selectively blocks the neuronal reuptake of
5HT, blocks 5-HT receptors, sedation, anxiety, sexual
disturbances are less expressed.
 Venlafaxine has dose–depending property to block the
neuronal reuptake of serotonine and less noradrenaline.
Thank you