Transcript Slide 1

Pharmacotherapy of bipolar
disorder
One of the most studied articles
of therapeutic effects of
psychopharmacons is their
influence on neurotrasmitter
synthesis, release and
degradation and on interaction
with their receptors.
Noradrenaline, dopamine,
serotonine, acetylcholine and
others act also in the brain
protected by hematoencephalic
barrier.
Disorder of neurotransmitters is
in connection with CNS disease
incidence.
Psychopharmacons (PPh) – general
properties:
- diferentially affect psychical processes
- many of their specific effects are apparent only in the presence
of psychopathological reactions → such antipsychotic action
has no analogy in mentally healthy people; usually develops
with latency (1-3 weeks)
-Except that PPh have also non-specific sedative or excitable
CNS effects - occur rapidly and among all (mentally ill or
healthy); these non-specific effects have often form of
interference with the central and peripheral receptors and
transmitter systems → very often manifested as ADR
?
?
Research of PPh using animal experiments is extremely
hard; in opposition to somatic diseases, practically don´t
exist animal models for psychiatric disorders
ACETYLCHOLINE
neurotransmitter ensuring motoric action through PPS
and HS, regulates cognitive (intellectual, rational)
functions, it´s sufficiency is necessary to have intact
consciousness and intellectual performance measurable by
intelligence quotient (IQ)
lack of Ach = consciousness disturbance, disorientation,
delirium
chronic lack of ACh = demention, Alzheimer´s disease
(Alz.)
!!! many drugs have anticholinergic effects as
ADR!!!
anticholinergic effect is used also as the main effect
– spasmolytic drugs
if we measure serum anticholinergic activity:
the higher, the higher cognitive deficits
to anticholinergic effect are particularly vulnerable
elderly people
we need to know to distinguish between benign
senescent forgetfulness and Alz. (A. within three
acute  of acetylcholine neurotransmission with
administration of:
FYZOSTIGMINE (inhibitor of AChE)
Indications:
- delirium caused by anticholinergic drugs
- sedation of confused patients whose condition is
worsened by BDZ
- 1-2 mg s.c. we achieve rapid sedation and clear
consciousness
- diagnostic test → share of insufficient ACh
neurotransmission
- for several hours will also help at Alz., but better
are p.o. longer acting inhibitors of AChE
Longer acting inhibitors of AChE:
DONEPEZIL, RIVASTIGMINE, GALANTAMINE
d
Cognitives:
MEMANTINE – normalises function of excitation
AMA (mainly glutamate)
derivates of
fyzostigmine:
NEOSTIGMINE
PYRIDOSTIGMINE
AMBENON
at myasthenia gravis
NOREPINEPHRINE (NE)
regulates psychomotoric action by its acceleration,
increases sympathetic tone(mydriasis,tachycardia,BP)
the highest NE activity in CNS is in locus
coeruleus: maintaining vigilance and mood, and
share on the nyctemeral cycle, attention, clear
consciousness dependent on sufficient activity of
reticular formation, parietal and frontal cortex,
limbic system and hypothalamus
to symptoms of reduced NE activity belong
disorders of attention, working memory
disturbances, slowing down, depression, fatigue
activity of descendent NE pathways in the spinal
cord attenuates pain at the spinal level and
therefore has NE a direct analgesic effect and
antidepressants increasing the concentration of NE
are considered as coanalgetics
increased NE activity
(sympathetic) leads to
anxiety and the
withdrawal syndrome
(abstinence syndrome) at
drug abuse
Vegetative symptoms of withdrawal syndrome we
reduce by betablockers or CLONIDINE
NE acts on betaadrenergic receptors, whose
density is  at depressive disorder, their upregulation is due to the lack of NE
antidepressants increase
the concentration of NE in
synaptic gap, leading to
receptor down-regulation
and that relates to the
withdrawal of depressive
symptomatology
DOPAMINE
initiation of movement, dynamogenia (Prof.
Vondráček), higher activity of the DOP increases
assertiveness and, if enforcement is not controlled
by own will, increases aggressiveness
high activity of DOP in the
limbic system is associated
with the occurrence of
delusions and
hallucinations Schizophrenia
increasing of amphetamine dose (stimulans with
DOPergic effect) leads within a few weeks to a
hallucinogenic paranoid syndrome
dopaminergic structures in the limbic system
belong to the „range of rewards“, activity was
detected at drug abuse
deficiency of DOP in striatum leads to
parkinsonismus
MAO B
Treatment:
MAO B inhibitors
Levodopa – prekursor of dopamine
DOP neurotransmission deficiency in prefrontal
cortex and mesocortical pathways leads to apathy
and abulia - symptoms of depression; we administer
antidepressants with dopaminergic effect
Endocrine regulation of DOP:
inhibits tonic secretion of prolactine
Antipsychotic drugs block D2 receptors
in tuberoinfundibular system, what leads to increased
concentration of prolactine in blood dependent on the
dose; hyperprolactinaemia leads to galaktorea and
mammary abscess
Increased prolactine:
women – anovulation cycles, abnormal. luteal
phase, decreased estrogen, libido, anorgasmia
men – reduction of testosterone concentration,
potency, erection and ejaculation
BROMOKRYPTINE and KATERGOLINE –
indication: prolaktinoma of hypophysis
dopamine increases libido and ability to have
orgasm (sexology)
γ-AMINOBUTIRIC ACID
receptor of GABA-A opens or
closes Cl- channels,
alosterically modulated by
benzodiazepine receptors, and
also by nonbenzodiazepine
hypnotics
GABA-B
subtype of receptor and its localisation:
1-benzodiazepine receptor – anxiolytic
sedative effect, highest density in cerebellum
2-benzodiazepine receptor – myorelaxant
effect, in striatum and spine
3-benzodiazepine receptor – in kidneys,
unknown effect
binding of muscle relaxants
(BAKLOFEN)
benzodiazepines have
hypnotic, anxiolytic,
anticonvulsive, muscle
relaxant, amnestic
effects – difference
according to the site to
which they on receptor
bind
!!! interaction with
s alcohol!!!
antidote of
benzodiazepines specific antagonist
FLUMAZENIL
Benzodiazepines
(max. 4-6 weeks)
stress situation leading
o anxiety is temporary
and removable
rebound phenomenon
if the patient is too
calm, he is loosing
motivation
anticonvulsive and myorelaxant effect, fast incoming
effects of some benzodiazepines (after parenteral
administration) →
→ therapy of emergency conditions! (status epilepticus,
intoxications with spasms)
classically diazepam, recently promoted lorazepam (a
lower risk of recurrence)
SEROTONIN (SER)
seven subtypes of receptor
Major serotoninergic core is
nucleus raphe in the brainstem
projection from nucleus raphe to:
frontal core regulates afectivity
basal ganglions helps control motoric activity and compulsive
behavior
limbic structures regulates anxiety and panic behaviour
hypothalamus regulates apetite and food behaviour
high concentration of SER in the brainstem
regulates sleeping (non-REM)
chemoreceptors 5-HT3 in the brainstem cause
vomitus (area postrema)
SER descendent pathways in spinal cord controlling
medullar reflexes cause ejaculation and orgasm
In small intestine receptors 5-HT3 and 5-HT4
regulate apetite and GIT motility
SER released into the
synapse at stress situation
and its higher
concentration helps to
remove the effects of
chronic stress
on release of SER
involves also NE, but SER
receptor doesn´t release
NE
Clasification of Psychopharmacons:
1.Effect on vigility
+ psychostimulants
- hypnotics
2.Effect on afectivity
+ antidepressants, anxiolytics
- antimanic drugs, thymoprophylactics
3.Effect on mental integration
+ neuroleptics
- halucinogenes
4.Effect on memory
+ nootropics
- amnestics
Interaction of neuromediators
with receptors:
acetylcholine
dopamine
serotonin
first electrostatic attractive force
between the partially positively
charged nitrogen (quaternary) and
anionic center of the receptor
molecules
the rest of the molecule exactly "fits"
to the binding site, often with the
help of other electric forces
mediators have afinity and also inner
activity → are agonists
Typical interaction of psychopharmacons
with receptors (not all):
chlorpromazin
partially (+)-charged nitrogen of the side chain
through electric forces gets closer to (-)
anion receptor center
large non-polar system of nuclei is then bound
to the receptor through hydrophobic forces
imipramine
fluoxetine
→ psychopharmacons have afinity
unlike mediators but don´t have
inner activity → are antagonists
Antagonistic effect also applies to receptors outside of
CNS
→ anticholinergic, antiserotoninergic,
antihistaminic, antiadrenergic,... effects,
often as significant ADR
This type of pharmacodynamics applies particularly to
neuroleptics and antidepressants
chlorpromazine – neuroleptic drug (phenothiazine),
imipramine – AD (group TCA), fluoxetine – AD
(SSRI)
Mood disorders = affective disorders
Large depressive disorder
Unipolar disorders
Dysthymia
(chronic
depression)
Bipolar disorder
Type I (alternation of mania and
depression)
Type II (hypomania and depression)
Cyklothymia (perzistent
mood instability)
Depression
experiments in rats which swim in the tank with
water; have induced a state of helplessness and
if they swim longer, they can develop depression
chronic pain and also depression are connected
with high cortisolemia
after administration of dexamethazone no
cortisol level reduction – dexamethazone
possitive test
Depressive disorder – inability to experience joy,
lasts at least two weeks, drop of the mood or
even despair, loss of interest in all things and all
people, thoughts of death, suicidal thoughts, and
even suicidal attempts, sleep disturbances, loss
of appetite
Causes:
Non-pharmacologic treatment of depression
Pharmacologic treatment of bipolar disorder
Tymoprophylac drugs (lithium, antiepileptic drugs) –
treatment of mania
LITHIUM
•In contrast to other antidepressants effective mainly
in manic phase, used mainly as prophylaxis of bipolar
depression
•Mechanism of action unclear:
-interference with Na+/K+ ATPase
-interference with cAMP formation
-interference with inositol phosphates formation
-numerous and complex effect on neurotransmitter systems
•Very small therapeutic range: 0,5-1,0 mmol/l
•Before treatment needed to exclude cardiopathia and
nephropathia
•ADR:
- at the treatment beginning: GIT problems, tiredness, shaking of fingers
of hand; dissapear in several weeks
- late: polydipsia, polyuria, hypothyreosis, increased weight, cardiopatia,
forgetting, teratogenic effects
•Intoxication: tremor, twitching, apathia, muscle
weekness, convulsions, coma
•Many drug onteractions – e.g. increased lithemia at
simultaneous administration of diuretic and
antirheumatic drugs
ANTIDEPRESSANTS
different divisions
CLASSICAL
NEWER
TCA – tricyclic antidepressants
IMAO – inhibitors of MAO
RIMA
SSRI
SNRI
SARI
NaSSA
NDRI
others
Pharmacologic Treatment of Depression
group
tricyklic (thymoleptics)
II. and III. generation
Inhibitors of MAO
subgroup
examples of antidepressants
aktivating
desipramine, nortriptyline protriptyline,
dibenzepine, dosulepine, lofepramine
sedative, anxiolytic
imipramine, amitriptyline, trimipramine,
clomipramine
II. generation - aktivating
viloxazin, bupropion, buspiron, amineptine,
maprotiline
II. generation - sedative, anxiolytic
mianserine, trazodone, nefazodone,
pirlindol
III. generation - SSRI
citalopram, fluvoxamine, fluoxetine,
sertraline, paroxetine
increasing uptake of 5-HT
tianeptine
nonselective irreversible
selective MAOI-B irreversible
selegiline
selective MAOI-B reversible
selective MAOI-A irreversible
selective MAOI-A reversible
thymoprophylactics
moclobemid, brofaromine, toloxaton,
amiflamine
lithium, carbamazepine, valproic acid,
valpromid, clonazepam
How antidepressants act
SSRI – selective serotonine reuptake inhibitors
PAROXETINE, FLUOXETINE, CITALOPRAM,
SERTRALINE, FLUVOXAMINE, ESCITALOPRAM
Inhibitors of MAO (monoamine oxidase)
in combination with serotoninergic opioids
(petidine, tramadol) can evoke serotonin
syndrome, which may endanger the patient's
life; also combination with SSRI
Serotonin syndrome is manifested by
hyperthermia, muscle rigidity, chills,
hypertension, significant changes of
consciousness and vital functions
MAO A degrades SER, DOP and NE – inhibited is
by moclobemid
MAO B degrades DOP – inhibited is by selegiline
nonspecific (irreversible) IMAO: tranylcypromine,
fenelzine (tyramine reaction)
in the situation of MAO inhibition is on the
periphery in vesicles of the nerve endings more
monoamine „filling“ including NE
→ combination with tyramine (indirect
sympathomimetic) from food strongly increases
responses to sympathicus stimuli
physiologically tyramine from food very quickly
splits MAO, at pharmacological inhibition
(irreversible) with MAO it isn´t possible
tyramine reaction is mainly manifested by
hypertension crisis – strong headache, risk of
cerebral bleeding
→ patients taking IMAO must avoid intake of
tyramine
→ strict dietary regimen!!
main sources of tyramine in food: cheese, bier,
wine, yeast