Drugs influencing CNSDrugs influencing CNS
• psychoterapeutic drugs (antipsychotics, psychoterapeutic drugs (antipsychotics, antidepressants, mood-stabilzing drugs)antidepressants, mood-stabilzing drugs)
• anxiolytics, hypnoticsanxiolytics, hypnotics
• antiepilepticsantiepileptics
• local and general anestheticslocal and general anesthetics
• opioid analgesics and antagonistsopioid analgesics and antagonists
• drugs for neurodegenerative diseasesdrugs for neurodegenerative diseases
• drugs of abusedrugs of abuse
Neurotransmitters – faciliate transmission of impulses
Norepinephrine (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)
Most psychotherapeutics influence processes on synapse
...influenceneurotransmitters
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)
Prevalence 5 – 6 %, men and women
One episode may last 4 – 6 months; risk of suicide 60×
Epizóda 1 2 3 4
Provoking factorsBipolar mood disorder
Non-pharmacologic Approaches to the Treatment of Depression(e.g. psychotherapy, electroconvulsive therapy, repetitive trancranial magnetic stimulation,if disturbances in biorhythms – light, sleep deprivation, ...)
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
ANTIDEPRESSANTSdifferent divisions
CLASSICAL
TCA – tricyclic antidepressantsIMAO – inhibitors of MAO
NEWER
RIMASSRISNRISARINaSSANDRIothers
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:H1-receptors, -adrenoreceptors, muscarinic-receptors
also outside of CNS!
imipramín
TCA
TCA
imipramine dosulepine desimipramine quinupramine amitriptyline clomipramine nortriptyline propizepine
pharmacokinetics: p.o. administration, first pass effect, low variable bioavailability, strong binding to plasma proteins
metabolised in liver, active metabolites CYP450 polymorfism, interactions
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 H1-receptor blockade (amitriptyline)
sedation, drowsiness, impaired concentration Sexual dysfunction, cardiac arrhythmias
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 Parkinson´s disease – inhibitor of MAO B (MAO B degrades DOP)
„increase activity“ – euphoria + excitation
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
IMAO
ADRs:
postural hypotensionCNS stimulation: tremor, excitation, insomnia, spasmsincreased apetite
Tox.: hepatotoxicity
RIMA - reversible inhibitors of MAO A
moclobemid –– MAO A degrades SER, DOP and NE
Selective Serotonin Reuptake Inhibitors - SSRI
Indications: antidepressants anxiety disorders, OCD bulimia, gambling
FluoxetineFluvoxamineParoxetineSertalineCitalopramEscitalopram
pharmacokinetics: p.o. administrationPolymorfism of metab. in liver (2D6, 2C19)Long T1/2 (50 h)
Interactions – biding to plasma proteins: TCA, betablockers, benzodiazepines
SSRI
ADRs --- better profile than TCA and IMAOGIT – nausea, vomitting, abdominal spasms, accelerated peristalsis,
diarrhea
HeadacheSexua dysfunctionAkathisiaInsomnia and fatigue Sometimes - increased anxiety / agitation at the beginning
of therapy
Serotonin syndrome at intoxications or interactions
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
Serotonin syndromeRISK – COMBINATION OF DRUGS
SSRI + inhibitors of CYP 450SSRI + serotoninergic AD (trazodone, clomipramine,
venlafaxine)SSRI + IMAOSSRI + lithiumSSRI + analgetics (tramadol, fentanyl, pentazocine), SSRI + antiemetics (metoclopramide), antimigraine drugs
(sumatriptan)SSRI + antibiotics (linezolid), others: ritonavir,
dextromethorphan, LSD....
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)
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
Alprazolam
• benzodiazepine
• Anxiolytic effectt at generalized anxiety (neurosis) till 20 min.
• Depression – latency of effect 1-6 weeks
• Neuroprotective effect (unlike other benzodiazepines)
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
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
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
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
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
Drug Induced Psychiatric Disorders
Other Selected Drugs
Antipsychotics (Neuroleptics)
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)
Contraindications:
intoxiction with substances depressing CNS, neuroleptic malignant syndrome history, Parkinson´s syndrome, be carefull at patients with kidney and liver problems
Antipsychotics (Neuroleptics)
Mechanism of action:
All antipsychotic drugs tend to block D2 receptors in the dopamine pathways of 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.
Antipsychotics (Neuroleptics)
Antipsychotics
(classical) typical atypical (clozapine, risperidone)
basal incisive (chlorpromazine) (haloperidol)
I. Typical (1st generation) neuroleptics
• a) basal (sedative): - chlorpromazine (model drug, phenothiazine structure)
- levomepromazine - chlorprothixene, thioridazine
• b) incisive: - haloperidol (model drug, butyrophenone structure)
- fluphenazine, flupenthixol, clopenthixol
II. Atypical (2nd generation) neuroleptics
• „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
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
Extrapyramidal ADRs ADRs type A
• 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 ADRs ADRs type A
• Late (often irreversible) – Tardive dyskinesia
» Uncontrolled movements of face/tongue and limbs
» 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?
Neuroleptic Malignant SyndromeADR type B
– 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
Antipsychotics
classical (typical) atypical (↑ AP ef., ↓ EP ADR, ↓ other ADR)
basal incisive (↓ AP ef., ↓ EP ADR (↑ AP ef., ↑ EP ADR
↑ other ADR) ↓ other ADR)
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
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
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, 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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