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  • Drugs influencing CNS psychoterapeutic drugs (antipsychotics, antidepressants, mood-stabilzing drugs) psychoterapeutic drugs (antipsychotics, antidepressants, mood-stabilzing drugs) anxiolytics, hypnotics anxiolytics, hypnotics antiepileptics antiepileptics local and general anesthetics local and general anesthetics opioid analgesics and antagonists opioid analgesics and antagonists drugs for neurodegenerative diseases drugs for neurodegenerative diseases drugs of abuse drugs of abuse
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  • Neurotransmitters faciliate transmission of impulses Norepinephrine (locus coeruleus allertness, attention, consciousness; depression) Acetylcholine (attention, learning, memory; demention, stimulate at Alzheimers disease) Dopamine (motoric activity, reward system; Parkinsons disease, depression, schizophrenia) Serotonin (mood, anxiety, agressivity; Parkinsons disease, schizophrenia) GABA (inhibitory-Cl - ; benzodiazepines; anxiolytic, sedative) Glutamate (NMDA receptors; learning, memory, cell death, inhibit: Alzheimers 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)
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  • Most psychotherapeutics influence processes on synapse...influence neurotransmitters
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  • Mood disorders = affective disorders Unipolar disorders Large depressive disorder Dysthymia (chronic depression)
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  • Bipolar disorder Cyklothymia (perzistent mood instability) Type II (hypomania and depression) Type I (alternation of mania and depression)
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  • Prevalence 5 6 %, men and women One episode may last 4 6 months; risk of suicide 60 Epizda 1 2 3 4
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  • Provoking factors Bipolar mood disorder
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  • Non-pharmacologic Approaches to the Treatment of Depression (e.g. psychotherapy, electroconvulsive therapy, repetitive trancranial magnetic stimulation, if disturbances in biorhythms light, sleep deprivation,...)
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  • Therapy of Depression mechanism of action of antidepressant drugs generally not fully understood... most antidepressants have effect on synthesis, release and degradation of neurotransmitters and their interaction with receptors biogenic amine hypothesis (mood disorders result from abnormalities in serotonin, norepinephrine, or dopamine neurotransmission) NOT VALID
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  • ANTIDEPRESSANTS different divisions CLASSICAL TCA tricyclic antidepressants IMAO inhibitors of MAO NEWER RIMA SSRI SNRI SARI NaSSA NDRI others
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  • Tricyclic antidepresants (TCA) Chemical structure - 3 cycles (nomenclature) significantly lipophilic substances developed from antihistaminics Mechanism of action: Block reuptake of norepinephrine (NE) and serotonin (5-HT) Dopamine neurotranssion is less influenced Most TCA block following receptors responsible for ADR: H 1 -receptors, -adrenoreceptors, muscarinic-receptors also outside of CNS! imipramn
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  • TCA
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  • imipraminedosulepine desimipraminequinupramine amitriptylineclomipramine nortriptylinepropizepine pharmacokinetics: p.o. administration, first pass effect, low variable bioavailability, strong binding to plasma proteins metabolised in liver, active metabolites CYP450 polymorfism, interactions
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  • TCA Adverse drug reaction Muscarinic receptor blockade (atropine-like, anticholinergic) dry mouth, blurred vision acomodation inability, obstipation, retention of urine, palpitations, tachycardia -adrenergic receptor blockade (in older age) postural (orthostatic) hypotension + reflex tachycardia H 1 -receptor blockade (amitriptyline) sedation, drowsiness, impaired concentration Sexual dysfunction, cardiac arrhythmias
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  • Monoamine oxidase inhibitors (IMAO) Decrease degradation of monoamines MAO is responsible for degradation of the biogenic amine neurotransmitters (norepinephrine, serotonin, dopamine) tranylcypromine nonspecific irreversible inhibitor of MAO; tyramine reaction selegiline treatment of Parkinsons disease inhibitor of MAO B (MAO B degrades DOP) increase activity euphoria + excitation
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  • 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 isnt possible patients taking IMAO must avoid intake of tyramine strict dietary regimen!! main sources of tyramine in food: cheese, bier, wine, yeast
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  • IMAO ADRs: postural hypotension CNS stimulation: tremor, excitation, insomnia, spasms increased apetite Tox.: hepatotoxicity
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  • RIMA - reversible inhibitors of MAO A moclobemid MAO A degrades SER, DOP and NE
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  • Selective Serotonin Reuptake Inhibitors - SSRI Indications: antidepressants anxiety disorders, OCD bulimia, gambling Fluoxetine Fluvoxamine Paroxetine Sertaline Citalopram Escitalopram pharmacokinetics: p.o. administration Polymorfism of metab. in liver (2D6, 2C19) Long T 1/2 (50 h) Interactions biding to plasma proteins: TCA, betablockers, benzodiazepines
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  • SSRI ADRs --- better profile than TCA and IMAO GIT nausea, vomitting, abdominal spasms, accelerated peristalsis, diarrhea Headache Sexua dysfunction Akathisia Insomnia and fatigue Sometimes - increased anxiety / agitation at the beginning of therapy Serotonin syndrome at intoxications or interactions
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  • Serotonin syndrome 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
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  • Serotonin syndrome 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....
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  • 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 5HT 1A,5HT 1B )
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  • Agomelatine Receptors for melatonine (subtype MT 1 and MT 2, nucleus suprachiasmaticus) and serotonin (5HT 2C - frontal cortex, hipocampus) in CNS Efect similar to melatonine Resynchronises cirkadian rhythms
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  • Alprazolam benzodiazepine Anxiolytic effectt at generalized anxiety (neurosis) till 20 min. Depression latency of effect 1-6 weeks Neuroprotective effect (unlike other benzodiazepines)
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  • Therapy of Bipolar Disorder mood stabilizing drugs Acute treatment - 2 months - manage mania depression Stabilizing treatment - 6 months prevention of recurrence Prophylactic treatment- 12 months..... long-term prophylaxy Bipolar affective disorder
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  • A.Therapy of mania Goal: influence irritability, agitation, agressivity, impulsivity Lithium Selected antiepileptic drugs (valproic acid, carbamazepine, clonazepan, lamotrigine) Atypical antipsychotics olanzapine, risperidone, quetiapine, aripiprazole Bipolar affective disorder
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  • B. Therapy of bipolar depression Goal: no depressive symptomatology ATTENTION reoccurence of mania in (20-40%!) Lithium Antidepressants (TCA, SSRI) Lamotrigine, quetiapine Bipolar affective disorder
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  • 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
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  • 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
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  • Drug Induced Psychia

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