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
• drugs 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
Endocanabioids
(enkephalins, VIP, subst.P, together with other neurotransmitters)
( NO
(neuronal NOS-1988;  release of neurotransmitters)
nitric oxide)
(neuromodulatory lipids, memory, mood, analgesia...)
Most psychotherapeutics influence processes on
synapse
...influence
neurotransmitters
Mood disorders = affective disorders
Large depressive disorder
Unipolar disorders
Dysthymia
(chronic
depression)
Bipolar disorder
Type I (alternation of mania and
depression)
Type II (hypomania and depression)
Cyklothymia (perzistent mood
instability)
Epizóda
1
2
3
4
Prevalence 5 – 6 %, men and women
One episode may last 4 – 6 months;
risk of suicide 60×
Provoking factors
Bipolar 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, ...)
Symptoms of major depression
• At least 5 of the following symptoms present for at least 2
months, or producing marked functional impairment for at
least 2 weeks:
- depressed mood, loss of interest and
enjoyment of activities, loss of energy, loss of
apetite or weight disturbances, sleep
disturbance, psychomotor change, a sense of
guilt and worthlessness, concentration
difficulties or indecisiveness or thoughts of
death or suicide
Causes of depression
• Are not totally known (more mechanisms):
1. Neurotrophic hypothesis (Changes in the
connectivity between key structures in the
brain that are involved in regulation of mood
and the stress response. In people who are
genetically predisposed can higher
production of stress hormones CRH and
cortizol lead to impaired neuroplasticity.
Antidepressants prevent these changes.)
Causes of depression
2. Monoamine hypothesis (Reduced
monoaminergic neurotransmission in CNS.
Possible higher monoamino oxidase A activity
in CNS. Is complementary to the first theory.
Beginning of effect of antidepressants with
latency – reason not only increase in
monoamines, but also adaptive changes in
serotoninergic and noradrenergic
transmission)
*
RIADIA NAŠE
ŽIVOTY
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 ONLY DUE TO IT
ANTIDEPRESSANTS
•
•
•
•
Symptomatic treatment
Beginning of effect – latency
Adverse effects – soon after beginning of therapy
Drugs with high interindividual variabillity of
effect in different patients and high variabillity of
adverse effects in different group of drugs
ANTIDEPRESSANTS
different divisions
CLASSICAL
NEWER
TCA – tricyclic antidepressants
IMAO – inhibitors of MAO
RIMA
SSRI
SNRI
SARI
NaSSA
NDRI
others
Why we prefer newer AD?
TCA
- More adverse effects
- At overdose cardiac arrhythmias
IMAO
- Interactions with drugs and food
Administered when newer are not effective
Divission according to mechanism of action
• RUI – reuptake inhibitors
• IMHIBITORS OF MONOAMINE OXIDASE
• ANTIDEPRESSIVES WITH OTHER MECHANISMS OF
ACTION
Tricyclic antidepresants (TCA)
Chemical structure - 3 cycles (nomenclature)
→ significantly lipophilic substances
developed from antihistaminics
imipramín
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!
TCA
TCA
imipramine
desimipramine
amitriptyline
nortriptyline
dosulepine
quinupramine
clomipramine
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
• Antidote at overdose with TCA
• Effective at severe cardiotoxicity
– imipramin, amitriptylin, quetiapin,
– sertraline, haloperidol,
– olanzapin, venlafaxin
• i.v. lipid emulsion
• CELEPID, INTRALIPID
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,
IMAO
ADRs:
postural hypotension
CNS stimulation: tremor, excitation, insomnia, spasms
increased 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
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
SSRI
ADRs --- better profile than TCA and IMAO
GIT – nausea, vomitting, abdominal spasms, accelerated peristalsis,
diarrhea
Headache
Sexual dysfunction
Akathisia
Insomnia and fatigue
Sometimes - increased anxiety / agitation at the beginning
of therapy
Serotonin syndrome at intoxications or interactions
SSRI
SSSSRI
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 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....
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)
Alprazolam
• benzodiazepine
• Anxiolytic effectt at generalized anxiety (neurosis) till 20
min.
• Depression – latency of effect 1-6 weeks
• Neuroprotective effect (unlike other benzodiazepines)
SSRE Selective Serotonin Reuptake Enhancer
Reduces effect of serotonin in limbic system
3x / day, effect starts already after 1. week
ADRs: dry mouth, obstipation, nausea
postural. hypotension, tachycardia
insomnia, nightmares, dizziness, collapse
Don´t administer together with IMAO !
? Biogenic amine hypothesis
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
VORTIOXETINE
• Multimodal antidepressant
– A serotonin modulator and stimulator (SMS)
• Antagonises 5HT3(anxiolysis) and 5HT7 (cognition,
depression)
• Agonises – 5HT1A (anxiety,depression,aggressivity, analgesis)
partial 5HT1B ( aggressivity)
• + Inhibition of serotonin transporter SERT
• major depressive disorder
• anxiolysis, older patients, cognitive functions +,
Emsam Patch (Selegiline) – IMAO B:
Standard usage – Parkinson´s disease
From 2006............. depression
Patch – missing first pass – liver, small intestine,
Diet not neccessary (tyramine !!!!)
LEVOMILNACIPRAN
• SNRI
• Ratio serotonin/noradrenaline RUI :
–
–
–
–
–
venlafaxine = 30:1,
duloxetine = 10:1,
desvenlafaxine = 10:1
milnacipran = 1:3
levomilnacipran = 1:2
– If prominent fatigue, loss of energy, emergent
sexual dysfunction
VILAZODON (Viibryd)
RUI as SSRI + parcial agonist 5-HT1A
• No sexual dysfunction
• No weight gain
• ADR – diarrhoea , nausea, cefalea
• Ramelteon (Rozerem)
• First indication – insomnia
• Perspective – bipolar disorder
St. John’s Wort (Hypericum perforatum)
• questionable efficacy (exact dose?)
• high potential for drug-drug interactions
(don´t combine with other antidepressants!!!)
BE HAPPY!
FACTORS IMPORTANT FOR THE CHOICE
OF ANTIDEPRESSANT
• Characteristic of depression
– severity, number of episodes, symptoms, risk of
suicide
• unipolar, bipolar, seasonal, cyclic, psychotic
• 1st, repeated....
• Age, comorbidities
• Drug anamnesis
• Patient´s preferences
BIPOLAR DISORDER
Mania
• Elevated mood that is more usually interspersed with
episodes of depression
• The onset mostly between the ages 15-25 years
• Has a stronger genetic component than depression
• The reasons of onset are not totally understood
• Increased CNS monoamine neurotransmitter activity
(particularly serotonin and dopamine) and reduced
acetylcholine and GABA neurotransmission
• Changes in neuronal function within the prefrontal cortex,
visual association cortex and limbic circuitry
Bipolar affective disorder
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
A. Therapy of mania
Bipolar affective disorder
Goal: influence irritability, agitation, agressivity, impulsivity
Lithium
Selected antiepileptic drugs (valproic acid, carbamazepine,
clonazepan, lamotrigine)
Atypical antipsychotics – olanzapine, risperidone,
quetiapine, aripiprazole
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
•Teratogen
TDM
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
(chlorpromazine)
incisive
(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 Syndrome
ADR 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
(↓ AP ef., ↓ EP ADR
↑ other ADR)
incisive
(↑ AP ef., ↑ EP 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
subtype of receptor and its localisation:
1-benzodiazepine receptor – anxiolytic
sedative effect, highest density in
cerebellum
GABA-B
binding of muscle
2-benzodiazepine receptor – myorelaxant
relaxants
effect, in striatum and spine
(BACLOFEN)
3-benzodiazepine receptor – in kidneys,
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
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)