Pharmacotherapy of bipolar disorder

1. Pharmacotherapy of bipolar disorder

2. 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.

3. 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.

4. Psychopharmacons (PPh) – general properties: - diferentially affect psychical processes - many of their specific effects are apparent only in the presence of psychopathological reactions → such antipsychoticaction 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

5. ? ? Research of PPh using animal experiments is extremely   hard; in opposition to somatic diseases, practically don´t exist animal models for psychiatric disorders

6. 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.)

7. !!! many drugs have anticholinergic effects as ADR!!! anticholinergic effect is used also as the main effect – spasmolytic drugs ifwe 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)

8. 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

9. Longer acting inhibitors of AChE: DONEPEZIL, RIVASTIGMINE, GALANTAMINE d Cognitives: MEMANTINE – normalises function of excitation AMA (mainly glutamate)

10. derivates of fyzostigmine: NEOSTIGMINE PYRIDOSTIGMINE AMBENON at myasthenia gravis

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. deficiency of DOP in striatum leads to parkinsonismus MAO B

18. Treatment: MAO B inhibitors Levodopa – prekursor of dopamine

19. DOP neurotransmission deficiency in prefrontal cortex and mesocortical pathways leads to apathy and abulia - symptoms of depression; we administer antidepressants with dopaminergic effect

20. Endocrine regulation of DOP: inhibits tonic secretion of prolactine Antipsychotic drugsblock 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

21. 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)

22. 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

23. benzodiazepines have hypnotic, anxiolytic, anticonvulsive, muscle relaxant, amnestic effects – difference according to the site to which they on receptor bind !!! interaction with salcohol!!! antidote of benzodiazepines - specific antagonist FLUMAZENIL

24. Benzodiazepines (max. 4-6 weeks) stress situation leading to anxiety is temporary and removable rebound phenomenon if the patient is too calm, he is loosing motivation

25. 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)

26. SEROTONIN (SER) seven subtypes of receptor

27. 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

28. 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

29. 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

30. Clasification of Psychopharmacons: • Effect on vigility • + psychostimulants • - hypnotics • Effect on afectivity • + antidepressants, anxiolytics • - antimanic drugs, thymoprophylactics • Effect on mental integration • + neuroleptics • - halucinogenes • Effect on memory • + nootropics • - amnestics

31. acetylcholine 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 inneractivity → are agonists dopamine serotonin

32. 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

33. Antagonistic effect also applies to receptorsoutside ofCNS → 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)

34. Mood disorders = affective disorders Large depressive disorder Unipolar disorders Dysthymia (chronic depression)

35. Type I (alternation of mania and depression) Bipolar disorder Type II (hypomania and depression) Cyklothymia (perzistent mood instability)

36. 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

37. 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:

38. Non-pharmacologic treatment of depression

39. Pharmacologic treatment of bipolar disorder Tymoprophylac drugs (lithium, antiepileptic drugs) – treatment of mania

40. 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

41. 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

42. ANTIDEPRESSANTS different divisions NEWER RIMA SSRISNRI SARI NaSSA NDRI others CLASSICAL TCA – tricyclic antidepressants IMAO – inhibitors of MAO

43. 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 Pharmacologic Treatment of Depression

44. How antidepressants act

47. SSRI – selective serotonine reuptake inhibitors PAROXETINE, FLUOXETINE, CITALOPRAM, SERTRALINE, FLUVOXAMINE, ESCITALOPRAM

49. Inhibitors of MAO (monoamine oxidase) in combination with serotoninergic opioids (petidine, tramadol) can evoke serotoninsyndrome, 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

50. 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