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

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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, deliriumchronic lack of ACh = demention, Alzheimer´s disease (Alz.)

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 months gets worse)

!!! many drugs have anticholinergic effects as ADR!!!

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

 

                                                                                    

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Longer acting inhibitors of AChE:DONEPEZIL, RIVASTIGMINE, GALANTAMINE

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 up-regulation 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

DOPAMINEinitiation 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 inhibitorsLevodopa – 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

binding of muscle relaxants (BAKLOFEN)

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

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

if the patient is too calm, he is loosing

motivation

stress situation leading to anxiety is temporary

and removable

Benzodiazepines(max. 4-6 weeks)

rebound phenomenon

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:

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

acetylcholine

dopamine

serotonin

Typical interaction of psychopharmacons with receptors (not all):

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

→ psychopharmacons have afinity

unlike mediators but don´t have

inner activity → are antagonists

chlorpromazin

imipramine

fluoxetine

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

Unipolar disordersLarge depressive disorder

Dysthymia (chronic depression)

Bipolar disorder

Cyklothymia (perzistent mood instability)

Type II (hypomania and depression)

Type I (alternation of mania and depression)

Depressionexperiments 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 cortisolemiaafter 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

ANTIDEPRESSANTSdifferent divisions

CLASSICAL

TCA – tricyclic antidepressantsIMAO – inhibitors of MAO

NEWER

RIMASSRISNRISARINaSSANDRIothers

Pharmacologic Treatment of Depression

group subgroup examples of antidepressants

tricyklic (thymoleptics) aktivating desipramine, nortriptyline protriptyline, dibenzepine, dosulepine, lofepramine

sedative, anxiolytic imipramine, amitriptyline, trimipramine, clomipramine

II. and III. generation 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

Inhibitors of MAO nonselective irreversible  

selective MAOI-B irreversible selegiline

selective MAOI-B reversible  

selective MAOI-A irreversible  

selective MAOI-A reversible moclobemid, brofaromine, toloxaton, amiflamine

thymoprophylactics   lithium, carbamazepine, valproic acid, valpromid, clonazepam

How antidepressants act

SSRI – selective serotonine reuptake inhibitorsPAROXETINE, 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 possibletyramine 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