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)