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Pharmacotherapy of Bipolar Disorder

Pharmacotherapy of Bipolar Disorder. Drugs influencing CNS. psychoterapeutic drugs ( antipsychotics , antidepressants , mood - stabilzing drugs ) anxiolytics , hypnotics antiepileptics local and general anesthetics opioid analgesics and antagonists drugs for neurodegenerative diseases

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Pharmacotherapy of Bipolar Disorder

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  1. PharmacotherapyofBipolar Disorder

  2. DrugsinfluencingCNS • psychoterapeuticdrugs (antipsychotics, antidepressants, mood-stabilzingdrugs) • anxiolytics, hypnotics • antiepileptics • localandgeneralanesthetics • opioidanalgesicsandantagonists • drugsforneurodegenerativediseases • drugsof abuse

  3. Neurotransmitters – faciliate transmission of impulsesNorepinephrine(locus coeruleus – allertness, attention, consciousness;  depression) Acetylcholine(attention, learning, memory;  demention, stimulate at Alzheimer´s disease) Dopamine(motoric activity, reward system;  Parkinson´s disease, depression,  schizophrenia)Serotonin(mood, anxiety, agressivity;  Parkinson´s disease, schizophrenia) GABA(inhibitory-Cl-; benzodiazepines; anxiolytic, sedative) Glutamate(NMDA receptors; learning, memory, „cell death“ , inhibit: Alzheimer´s disease) Glycine(inhibitory-Cl-; the most common receptor in CNS) Neuropeptides (enkephalins, VIP, subst.P, together with other neurotransmitters)Endocanabioids (neuromodulatory lipids, memory, mood, analgesia...) ( NO nitric oxide) (neuronal NOS-1988;  release of neurotransmitters)

  4. Most psychotherapeutics influence processes on synapse...influenceneurotransmitters

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

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

  7. Epizóda 1 2 3 4 Prevalence 5 – 6 %, men and women Oneepisodemaylast 4 – 6 months; risk ofsuicide 60×

  8. Bipolarmooddisorder Provokingfactors

  9. Non-pharmacologic Approaches to the Treatment of Depression (e.g. psychotherapy, electroconvulsive therapy, repetitive trancranial magnetic stimulation, if disturbances in biorhythms – light, sleep deprivation, ...)

  10. TherapyofDepressionmechanismofactionofantidepressantdrugs ÷ generallynotfullyunderstood ...most antidepressantshaveeffect on synthesis, release and degradationofneurotransmitters and theirinteractionwithreceptorsbiogenicaminehypothesis(mooddisordersresultfromabnormalities in serotonin, norepinephrine, or dopamineneurotransmission) NOTVALID

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

  12. Tricyclicantidepresants (TCA) • Chemicalstructure - 3 cycles (nomenclature) → significantlylipophilicsubstances • developedfromantihistaminics • Mechanismofaction: • Blockreuptakeofnorepinephrine (NE) and serotonin (5-HT)Dopamineneurotranssionislessinfluenced • Most TCAblockfollowingreceptorsresponsibleforADR: • H1-receptors, -adrenoreceptors, muscarinic-receptors • alsooutsideofCNS! imipramín

  13. TCA

  14. TCA imipraminedosulepine desimipraminequinupramine amitriptylineclomipramine nortriptylinepropizepine pharmacokinetics: p.o. administration, first pass effect, lowvariablebioavailability, strongbinding to plasma proteins metabolised in liver, activemetabolitesCYP450polymorfism, interactions

  15. TCA • Adversedrugreaction • Muscarinic receptor blockade • („atropine-like“, anticholinergic) • drymouth, blurredvision – acomodationinability, obstipation, retentionofurine, palpitations, tachycardia • -adrenergic receptor blockade(in olderage) • postural (orthostatic) hypotension + reflextachycardia • H1-receptorblockade(amitriptyline) • sedation, drowsiness, impairedconcentrationSexualdysfunction, cardiacarrhythmias

  16. Monoamineoxidaseinhibitors (IMAO) Decreasedegradationofmonoamines MAOisresponsiblefordegradationofthebiogenicamineneurotransmitters (norepinephrine, serotonin, dopamine) tranylcypromine – nonspecificirreversibleinhibitorof MAO; tyraminereaction selegiline – treatmentofParkinson´sdisease – inhibitorof MAO B (MAO B degrades DOP) „increaseactivity“ – euphoria + excitation

  17. IMAO tyramine reaction→ combination with tyramine (indirect sympathomimetic) from food strongly increases responses to sympathicus stimuli It is mainly manifested by hypertension crisis – strong headache, risk of cerebral bleeding physiologically tyramine from food very quickly splits MAO, at pharmacological inhibition (irreversible) with MAO it isn´t possible → patients taking IMAO must avoid intake of tyramine → strict dietary regimen!! main sources of tyramine in food: cheese, bier, wine, yeast

  18. IMAO ADRs: posturalhypotension CNSstimulation: tremor, excitation, insomnia, spasms increasedapetite Tox.: hepatotoxicity

  19. RIMA - reversible inhibitors of MAO A moclobemid–– MAO A degrades SER, DOP and NE

  20. SelectiveSerotoninReuptakeInhibitors - SSRI Indications: antidepressants anxietydisorders, OCD bulimia, gambling Fluoxetine Fluvoxamine Paroxetine Sertaline Citalopram Escitalopram pharmacokinetics: p.o. administration Polymorfism of metab. in liver (2D6, 2C19) Long T1/2 (50 h) Interactions – biding to plasma proteins: TCA, betablockers, benzodiazepines

  21. SSRI • ADRs --- better profile thanTCA and IMAO • GIT – nausea, vomitting, abdominalspasms, acceleratedperistalsis, diarrhea • Headache • Sexuadysfunction • Akathisia • Insomnia and fatigue • Sometimes - increasedanxiety / agitationatthebeginning • oftherapy • Serotoninsyndromeatintoxications or interactions

  22. Also after 1 dose of SSRI ! Symptoms – soon, till 6 hours Neuromuscular: akathisia, tremor, hyperreflexia, myoclonus, hypertonicity Change in mental status: agitation, delirium Autonomic hyperactivity: tachycardia, midriasis, sweatting, increased motility of GIT, hyperthermia Serotonin syndrome

  23. RISK – COMBINATION OF DRUGS SSRI + inhibitors of CYP 450 SSRI + serotoninergic AD (trazodone, clomipramine, venlafaxine) SSRI + IMAO SSRI + lithium SSRI + analgetics (tramadol, fentanyl, pentazocine), SSRI + antiemetics (metoclopramide), antimigraine drugs (sumatriptan) SSRI + antibiotics (linezolid), others: ritonavir, dextromethorphan, LSD.... Serotonin syndrome

  24. Selective Serotonin and Norepinephrine Reuptake Inhibitors (SNRI): venlafaxin • Selective Serotonin Norepinephrine ane Dopamine Reuptake Inhibitors (NDRI): bupropion • Selective Norepinephrine Reuptake Inhibitors (NaRI): reboxetine • Serotonin Antagonists and Reuptake Inhibitors(SARI): trazodone • Noradrenergic and Specific Serotonergic Antidepressant (NaSSA): mirtazapine (increases noradrenergic and • serotonin transmission; influence on receptors: • 1,2, a 5HT1A ,5HT1B)

  25. Tianeptine SSRESelectiveSerotoninReuptakeEnhancer Reduceseffectofserotonin in limbicsystem 3x / day, effectstartsalreadyafter 1. week ADRs: drymouth, obstipation, nausea postural. hypotension, tachycardia insomnia, nightmares, dizziness, collapse Don´tadministertogetherwithIMAO ! ? Biogenicaminehypothesis

  26. Agomelatine Receptors for melatonine (subtype – MT1 and MT2, nucleus suprachiasmaticus) and serotonin (5HT2C- frontal cortex, hipocampus) in CNS Efect similar to melatonine Resynchronises cirkadian rhythms

  27. benzodiazepine Anxiolytic effectt at generalized anxiety (neurosis) till 20 min. Depression – latency of effect 1-6 weeks Neuroprotective effect (unlike other benzodiazepines) Alprazolam

  28. Bipolaraffectivedisorder TherapyofBipolarDisorder– moodstabilizingdrugs Acutetreatment- 2 months - managemania ÷ depression  Stabilizingtreatment- 6 months – preventionofrecurrence  Prophylactictreatment- 12 months..... – long-termprophylaxy

  29. Therapyofmania • Goal: influenceirritability, agitation, agressivity, impulsivity • Lithium • Selectedantiepilepticdrugs (valproicacid, carbamazepine, clonazepan, lamotrigine) • Atypicalantipsychotics– olanzapine, risperidone, quetiapine, aripiprazole Bipolaraffectivedisorder

  30. B. Therapyofbipolardepression Goal: no depressivesymptomatology ATTENTIONreoccurenceofmania in (20-40%!) Lithium Antidepressants (TCA, SSRI) Lamotrigine, quetiapine Bipolaraffectivedisorder

  31. 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

  32. Lithium • 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

  33. Drug Induced Psychiatric Disorders

  34. Other Selected Drugs

  35. Indications: Psychiatric Psychoses – including delusions, hallucinations, disordered thoughts (particularly in shizophrenia and bipolar disorder) At conditions of acute patologic agressivity and agitation (chlorpromazine, levopromazine, haloperidol) Nonpsychiatric Antiemetic effect – already at low doses (e.g. thiethylperazine – suppositories, injections) Neuroleptanalgezie – droperidol + fentanyl Antipsychotics (Neuroleptics)

  36. Contraindications: intoxiction with substances depressing CNS, neuroleptic malignant syndrome history, Parkinson´s syndrome, be carefull at patients with kidney and liver problems Antipsychotics (Neuroleptics)

  37. Antipsychotics (Neuroleptics) Mechanism of action: All antipsychotic drugs tend to block D2 receptors in the dopamine pathwaysof the brain.This means that dopamine released in these pathways has less effect. Excess release of dopamine in the mesolimbic pathway has been linked to psychotic experiences. Typical antipsychotics are not particularly selective and also block dopamine receptors in the mesocortical pathway, tuberoinfundibular pathway, and the nigrostriatal pathway – ADR. Atypical antipsychotic drugs have a similar blocking effect on D2 receptors. Some also block or partially block serotonin receptors (particularly 5HT2A, C and 5HT1A receptors) – can influence the "negative symptoms" of schizophrenia.

  38. Antipsychotics (Neuroleptics) Antipsychotics (classical) typicalatypical (clozapine, risperidone) basalincisive (chlorpromazine) (haloperidol)

  39. a) basal (sedative): - chlorpromazine (model drug, phenothiazine structure) - levomepromazine - chlorprothixene,thioridazine b) incisive: - haloperidol (model drug, butyrophenone structure) - fluphenazine, flupenthixol, clopenthixol I. Typical (1st generation) neuroleptics

  40. „Multi Acting Receptor Targeted Antipsychotics“(MARTA) olanzapine, zotepine, quetiapine, clozapine Blokujú D1/2, α, H1, M a 5-HT2 receptory „Serotonin and Dopamin receptor antagonists“ (SDA) risperidone, ziprasidone D2-selektívne antagonisty sulpiride, amisulpiride II. Atypical (2nd generation) neuroleptics

  41. Antipsychotics (Neuroleptics) - ADRs blockade of dopamine receptors – extrapyramidal side effects, hyperprolactinaemia anticholinergic – sinus tachycardia, obstipation, retention of urine, dry mucosas, mouth, disturbances of acomodations, increased intraoccular pressure, etc. antiadrenergic – ortosthatic hypotension, impotence, etc. antihistaminic – sedation, weight gain, etc. Neuroleptic malignant syndrome

  42. D2 blockade in striatum more frequent after typical incisive neuroleptics Acute (reversible) Parkinson´s syndrome: tremor, muscle rigidity, hypokinesia/akinesia: Acute dystonia – painful muscle spasms, till 24-96hours Orofacial muscles– e.g. blepharospasmus(eye lashes), oculogyric crisis – upward deviation of the eyes… Neck muscles (torticollis) Protrusion of the tongue Pharyngo-laryngeal muscles – life-threatening Akathisia– Interanl sence of motor restlessness („restless leg syndrome“) . Treatment: benzodiazepines, beta-blockers. Extrapyramidal ADRsADRstype A

  43. Late (often irreversible) Tardivedyskinesia Uncontrolled movements of face/tongue andlimbs Development after months even years of treatment Bizarre movements of tongue, chewing, „rabbit lip syndrome“ – problems with speaking and eating, facial grimaces … Choreiform movements of limbs up-regulation of D-receptors in striatum? Extrapyramidal ADRsADRstype A

  44. All neuroleptics – (potent D2-blockers probably more) Rare (incidence 0.07-0.2%) Potentially life-threatening condition (mortality cca 5-12%) Clinical symptoms severe muscle rigidity, hyperthermia (>38ºC), profuse sweating, tachycardia, tremor, altered mental functions Mechanism – excessive blockade of D2 in striatum and hypothalamus? Treatment Cooling of the body ! + antipyretics D2-agonists – bromocryptine, amantadine + D-precursors (L-DOPA) Dantrolen – blocks Ca2+ release – controversial Neuroleptic Malignant SyndromeADR type B

  45. Antipsychotics classical (typical) atypical (↑ AP ef., ↓ EP ADR, ↓ other ADR) basalincisive (↓ AP ef., ↓ EP ADR (↑ AP ef., ↑ EP ADR ↑ other ADR)↓ other ADR)

  46. 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

  47. 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 (BACLOFEN) 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

  48. 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

  49. anticonvulsive and myorelaxant effect, rapid onset of effect 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)

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