Lecture – Autumn 2016
INTRODUCTION to PSYCHOPHARMACOLOGY
Antipsycotics
Alexandra Šulcová, M.D., Ph.D., FCMA, FECNP, FCINP
Professor of Pharmacology
CEITEC (Central European Institute of Technology) MU
WHO nomenclature of NEUROPSYCHOTROPICS
www.ecnp.eu/nomenclature
NEW Neuroscience Based Nomenclature of Psychotropics
ECNP (European College of Neuropsychopharmacology)
and
CINP (International College of Neuropsychopharmacology)
Generic drug name
Class – acording to pharmacological mechanism of action
Indication
Eeffectiveness and side effects
Neurobiological data (preclinical and clinical)
- interactions with neurotransmitters
- physiology
- brain pathways
www.ecnp.eu/nomenclature
NEW NOMENCLATURE OF NEUROPSYCHOTROPICS in axis 1 – 5:
PROPOSED TEMPLATE FOR
A MULTI-AXIAL PSYCHOPHARMACOLOGICAL NOMENCLATURE
Axis 1 Class (primary pharmacological target)
Relevant mechanism
Axis 2 Family (primary neurotransmitter(s)
and relevant mechanism)
Axis 3 Neurobiological activities (Animal, Human)
Neurotransmitter effects
Brain circuits
Physiological
Axis 4 Efficacy and major side effects
Axis 5 Indication(s)
PROPOSED TEMPLATE FOR
A MULTI-AXIAL PSYCHOPHARMACOLOGICAL NOMENCLATURE
Axis 1 . . .
Axis 2 . . .
Axis 3 Neurobiological activities (Animal, Human)
Neurotransmitter effects
Brain circuits
Physiological
Axis 4 . . .
Axis 5 . . .
www.ecnp.eu/nomenclature
NEW NOMENCLATURE OF NEUROPSYCHOTROPICS in axis 1 – 5:
TYPES of SYNAPSES
axodendritic
axoaxonic
dendrodendritic
dendrosomatic
axosomatic
secondary neuron
primary axon terminaldescending
modulating
axon terminal
SYNAPSE
electrical
(“gap junction”) chemical
receptors
neurotransmitter
bidirectional passage of ions and
small molecules through channels
CHEMICAL SYNAPSES
directed synapse nondirected synapse
20 - 30 nm till 400 nm
`
postsynaptic potential
excitatory
or
inhibitory
“RETROGRADE NEUROTRANSMISSON“
e.g.: Synaptic functions of the endocannabinoid system
biodegradation
CHEMICAL SYNAPSE
- ionotropic
- metabotropic
(subtypes)
adenylylcyclase
ATP
cAMP proteinkinase
R
R
phosphorylation
of membrane
proteins
Na+
K+
membrane
depo- or hyperpolarization
adenylylcyclase
ATP cAMP
proteinkinase
inhibition of neurotransmitter synthesis
inorganic phosphates
ion
conductance
GABA Cl Cl
-
membrane hyperpolarization
if CL- channels are opened
inhibiting influence
of GABA
Kjell Fuxe et al., Physiology, 2008, 23: 322-332
Kearn CS et al. Concurrent stimulation of
cannabinoid CB1 and dopamine D2
receptors enhances heterodimer formation:
a mechanism for receptor cross-talk?
Mol. Pharmacol. 2005;67(5):1697-704
.
Eye
světlo
Activity of heterodimers of MT a 5HT2C
receptors
can influence SCN
glandula pienalis
(melatonin
- receptors:
MT1, MT2, MT3)
MT1
(Mel1A)
MT2
(Mel1B)
5HT2C
melatonin
Suprachiasmatic Nuclei (SCN) = circadian clock
Agomelatin
(VALDOXAN, Servier)
agonist
antagonist
agonist
Guardiola-Lemaitre B at al. Br J Pharmacol. 2014; 171(15): 3604–3619
axon
transmitter I
transmitter Itransmitter II
A
B
C
C
D
A - postsynaptic receptor
B - autoreceptor (presynaptic)
C - homoreceptor
D - heteroreceptor
postsynaptic
neuron
Potential targets for transmitter
release from nerve terminal
“up-regulation”
of receptors
“down-regulaction”
of receptors
chronic effect of antagonists
chronic effect of agonists
stimulation
frequency
CO-TRANSMISSION
     
    
   
     
    
   
     
    
   
     
    
   
 co-transmitters stored in the same vesicles;
convey different messages to different receptors
at the same time
 co-transmitters stored in the differential vesicles;
released preferentially in response to different
frequency nerve impulses
Co-transmission
Exogenic influences affecting just one transmitter
cannot simulate the physiological synaptic effects
Other neurotransmitters, co-transmitters, neurohormones
endogenic opioids ( enkefaline, endorphine, dynorphine )  euforia
 anhedonia
angiotensine
gastrine
neurokinines
neuropeptide Y
neurotensin
substance P
bradykinine
somatostatin
. . . . . . .
. . . . . . . . . . .
cholecystokinine ( CCK )  satiety, panic disorder
 hunger
NEUROHORMONES
e.g.:
oxytocine vasopressin,
gonadotropin, corticotropin . . .
neurotransmitters released by nerve cells into blood circulation
NEUROMODULATORS (e.g. opioids, anandamide, NO ... )
biologically active in small amounts,
released on synapses, however, also by e.g. glial cells,
have impact on receptor activity either directly
or through interaction with neurotransmitter
www.ecnp.eu/nomenclature
NEW NOMENCLATURE OF NEUROPSYCHOTROPICS
PROPOSED TEMPLATE FOR
A MULTI-AXIAL PSYCHOPHARMACOLOGICAL NOMENCLATURE
Axis 1 . . .
Axis 2 Family (primary neurotransmitter(s)
and relevant mechanism)
Axis 3 . . .
Axis 4 . . .
Axis 5 . . .
MAO
synthesis
A - reuptake blockade
( antidepressants)
B - inhibition
( antidepressants - IMAO )
C - transmitter depletion
D - precursorsE - fals neurotransmitter
precursor
G - agonists
H - antagonists
CH - agonists/antagonists
Sites of drug action at the synapse DIRECT - G, H, CH
F – interference with
vesicle discharge
INDIRECT - A, B, C, D, E, F
R R`R
E E
A AB B
A
B
= agonist
= antagonist
ANTAGONISMUS
competitive
and
specific noncompetitive
ANTAGONISM
noncompetitive
nonspecific
allosteric change
of receptor
partial
agonist
agonist
antagonist
partial
inverse
agonist
inverse
agonist
LIGANDS of RECEPTORS
Stephen M. Stahl
TYPES of RECEPTOR LIGANDS
agonist
partial agonists (competitive dualist)
antagonist ▬ competitive
▬ noncompetitive
▪ specific
▪ nonspecific
inverse agonist
partial inverse agonist
AGONISTIC LIGANDS EFFECTS
agonist . . . . . . . . . . . . . . . . . . maximal receptor activation
partial agonist . . . . . . . . . . none full activation
inverse agonist . . . . . . . . . . . inactivation of receptors
constitutively active
ANTAGONISTS EFFECTS
competitive. . . . . . . . . . . . reversibile receptor blockade
noncompetitive . . . . . . . . . . irreversibile receptor blockade
(specific)
noncompetitive . . . . . . . . . . reversibile or irreversibile
(nonspecific, binding to different binding site
allosteric) closely to receptor active site
CB1 cannabinoid receptors …. rimonabant
µ opioid receptors …. naloxon
5HT receptors …chlorpromazine, risperidone, mirtazapine
Psychotropics
with inverse agonistic receptor mechanism of action,
e.g.:
Effects of benzodiazepine receptor ligands
agonist partial antagonist partial inverse
agonist inverse agonist
agonist
anxiolytic anxiolytic žádný klinický promnestický promnest
sedative/ anxiogenní anxio
hypnotic
myorelaxant prokonvulsivní
antikonvulsive
amnestic
dependence
Catecholaminergic
pathways
Noradrenergic from:
Locus coeruleus
Catecholamines
dopamine ( basal ganglia, limbic system . . . )
noradrenaline ( hypothalamus, cortex, cerebellum )
adrenaline
synthesis tyrosine  tyrosine hydroxylase  DOPA  decarboxylase
 dopamine  hydroxylasea  noradrenaline 
N-methyltransferase  adrenaline
storage - in vesicles ( with ATP - 4 : 1 )
- free in cytoplasmic fluid
breakdowb - re-uptake !!
- diffusion
- intracellularly - MAOA (A a Na ) + MAOB ( DA )
extracellularly - MAOB + COMT
receptors
DA r. - partly sensitive to A a Na, too
D1 , 5 - coupled to adenylylcyclase  ↑ cAMP – excitation
D2, 3, 4 - coupled to phosphodiesterase (cAMP degradation) - cAMP - inhibition
Catecholamines continuation
adrenergic r. (in the CNS in neurons; on vessels )
- 
1 - stimulation of phosphatidylinositol metabolism
2 -  cAMP
 K+ channel
 Ca 2+ channel
- β1, 2, 3 -  cAMP
regulated by G-protein
 DA + cholecystokinin ( CCK )
 DA + neurotensin
 DA + galanin
 DA + dynorphin
 DA + Met-enkephalin
 DA + Leu-enkephalin
 DA + GH-RH ( hormon uvolňující růstový hormon )
Known co-transmissions with
DOPAMINE
www.ecnp.eu/nomenclature
NOVÁ NOMENKLATURA NEUROPSYCHOTROPIK
PROPOSED TEMPLATE FOR
A MULTI-AXIAL PSYCHOPHARMACOLOGICAL NOMENCLATURE
Axis 1 . . .
Axis 2 . . .
Axis 3 . . .
Axis 4 . . .
Axis 5 Indication
PSYCHOSIS
• a person's capacity, affective response to recognize
reality, communicate, and relate to others is impaired
 schizophrenia,
 mania,
 depression,
 Alzheimer's dementia
 cognitive disorders
hallucinations (auditory, visual, olfactory, gustatory, tactile)
delusions (misinterpretations of perceptions or experiences)
Stephen M. Stahl, 2000
negative
symptoms
anxiety /
/ depresssion
aggressive
symptoms cognitive
symptoms
posittive
symptoms
Stephen M. Stahl, 2000
negative
symptoms
anxiety /
/ depresssion
aggressive
symptoms cognitive
symptoms
posittive
symptomsPOSITIVE SYMPTOMS
delusions
hallucinations
disorganised speech
disorganized behaviour
catatonic behaviour
improved
cognitive
functions
low EPS
acceptable
price
low occurence of
long-term changes
in total health state
impact on both
positive and
negative sympt.
Ideal antipsychotic drug effects
mood
stabilization
improved
quality of live
Ideal
antipsychotic
no
weight
changes
www.ecnp.eu/nomenclature
NOVÁ NOMENKLATURA NEUROPSYCHOTROPIK
PROPOSED TEMPLATE FOR
A MULTI-AXIAL PSYCHOPHARMACOLOGICAL NOMENCLATURE
Axis 1 . . .
Axis 2 . . .
Axis 3 Neurobiological activities
Animal Human Neurotransmitter effects
Brain circuits Physiological
Axis 4 . . .
Axis 5 . . .











D2 antagonist
Blocking of postsynaptic dopamine receptors D2
SUPPRESSION
OF POSITIVE
SYMPTOMS
in psychosis
"Dopaminergic hypothesis of schizophrenia"
Dopamine receptor subtypes
DA r. – partly sensitive to Adrenaline and Noradrenaline, too
Family D1:
D 1, 5 - coupled to adenylylcyclase  ↑ cAMP – excitatory
influence
Family D2:
D 2, 3, 4 - coupled to phosphodiesterase (cAMP degradation)
  cAMP - inhibitory influence
Dopaminergic neurotransmision
Dopamine receptors
Possible modulation of dopaminergic transmistter functions
NIGROSTRIATAL (subt. nigra – basal ganglia)
control of movements
MESOLIMBIC (midbrain VTA – ncl. accumbens)
positive symptoms, euphoria
MESOCORTICAL (midbrain – limbic cortex)
negative symptoms,
cognitive side effects
TUBEROINFUNDIBULAR
(hypothalamus – anterior pituitary gland)
control of prolactine secretion
4 DAergic brain pathways
POSITIVE SYMPTOMS
delusions
hallucinations
disorganised speech
disorganized behaviour
catatonic behaviour
MAIN SYMPTOMS OF SCHIZOPHRENIA
POSITIVE SYMPTOMS
delusions
hallucinations
disorganised speech
disorganized behaviour
catatonic behaviour
NEGATIVE SYMPTOMS
affective flattening (restriction
of emotional expression)
alogia
avolition (general lack of desire,
motivation, difficulty, or inability
to initiate and persist in
goal-directed behaviour )
anhedonia (lack of pleasure)
attention impairment
MAIN SYMPTOMS OF SCHIZOPHRENIA
mesocortical pathway
? ? Couses of hypoactivity of mesocortical DAergic pathway ??
________________________






5-HT2A
receptor
5-HT
Secondary deficit
of dopamine








D2 antagonist
Blockade
of D2 receptors
 dopamine
Primary defficit
of dopamine
Bazální
ganglia
Nigrostriatal
extrapyramidal effects
Mesolimbická
Mesokortikální
Tuberoinfundibulární
nigrostriatal pathway → DA inhibits Ach activity
blockade of DA function → Ach hyperactive
DA
Ach
antipsych.
anti-Ach
consolidation of Ach hyperactivity






5-HT2A
receptory
5-HT
Sekundární deficit
dopaminu








D2 antagonist
Blockade of D2 recept.
in nigrostriatal
pathway
 dopamin
Primární deficit
dopaminu
D2 receptor up-regulation
EPS Tardive dyskinesia
Stephen M. Stahl, 2000
Bazální
ganglia
Nigrostriatální
Mesolimbická
Mesokortikální
Tuberoinfundibular
endocrinological efects











D2 antagonist
Tuberoinfundibular dopaminergic pathway
HyperprolactinemiaBlockade of D2 receptors
Dopamine-Serotonin
system stabiliser
1930 ’40 ’50 ’60 ’70 ’80 ’90 ’00 ’05
TCA
chlorpromazine
tioridazine
trifluoperazine
flufenazine
perfenazine
haloperidol
Typical
antipsychotics
Atypical
antipsychotics
clozapine
risperidone
olanzapine
quetiapine
ziprasidon
Development of antipsychotics
a
r
i
p
i
p
r
a
z
o
l
e
ANTIPSYCHOTICS (neuroleptics)
Typical (I. generation)
Basic (sedative): (lower efficacy - doses in hundreds of mg)
chlorpromazine, levomepromazine, chlorprothixen,
thioridazine, clopenthixol
Incisive: (higher efficacy - doses in mg or tens of mg)
prochloperazine, phluphenazine, perphenazine, pimozide,
haloperidol, flupenthixole
DEPOT (1x /1 – 3 weeks) – penfluridole, fluphenazine
TYPICAL
A N T I P S Y CH O T I C S
H1
α1
D2
M1
D2 blockade = antipsychotic effects
M1 blockade = dry mouth, diplopia,
constipation
α1 blockade =  BP, dizziness
H1 blockade = drowsiness, weight gain
Stephen M. Stahl, 2000
ANTIPSYCHOTICS (neuroleptics)
Typical (I. generation)
Basic (sedative): (lower efficacy - doses in hundreds of mg)
chlorpromazine, levomepromazine, chlorprothixen,
thioridazine, clopenthixol
Incisive: (higher efficacy - doses in mg or tens of mg)
prochloperazine, phluphenazine, perphenazine, pimozide,
haloperidol, flupenthixole
DEPOT (1x /1 – 3 weeks) – penfluridole, fluphenazine
Adverse effects: EPS, tardive dyskinesia, prolactinemia,
malignant neuroleptic syndrom
Neuroleptic Malignant Syndrom
idiosyncratic response (20-30% mortality; in 1-2% treated patients)
5-10 day persistence after the withdrawal of p.o. treatment,
(3-30 days after injections)
HYPERTERMIA; EPS (rigidity, dysartria, dysforia, tremor),
VEGETATIVE SY. (tachycardia,  BP, tachypnoe, urinary incontinence);
DISORDERS OF BEHAVIOUR & CONSCIOUSNESS (delirium, somnolence, comma,
epileptic paroxysms);
leukocytosis, homeostatic disturbance, hemocoagulation ….
ANTIPSYCHOTICS (neuroleptics) ... cont.
Atypical (II. generation)
(without EPS, tardive dyskinesia, prolactinemia,
malignant neuroleptic syndrom)
• MARTA (Multi-Acting Receptor Targeted Agents)
clozapine, olanzapine, quetiapine
• SDA (Serotonin-Dopamine Antagonist)
risperidone, ziprasidone, sertindole
• D2/D3 antagonists
sulpiride, amisulpride
• DSSS (Dopamine-Serotonin System Stabilizers)
aripiprazole
TYPICAL
A N T I P S Y CH O T I C S
ATYPICAL
(MARTA)
H1
α1
D2
M1
M1
H1
α1
D2
D1
D3
D4
More selective for mesolimbic pathways
less EPS
therapeutic efects side effects
D1,2,3,4 α1, α2, M1 , H1
5-HT2A
D2 blockade = antipsychotic effects
M1 blockade = dry mouth, diplopia,
constipation
α1 blockade =  BP, dizziness
H1 blockade = drowsiness, weight gain
Stephen M. Stahl, 2000
α2
ANTIPSYCHOTICS (neuroleptics) ... cont.
Atypical (II. generation)
(without EPS, tardive dyskinesia, prolactinemia,
malignant neuroleptic syndrom)
• MARTA (Multi-Acting Receptor Targeted Agents)
clozapine, olanzapine, quetiapine
• SDA (Serotonin-Dopamine Antagonist)
risperidone, ziprasidone, sertindole
• D2/D3 antagonists
sulpiride, amisulpride
• DSSS (Dopamine-Serotonin System Stabilizers)
aripiprazole
5-HT2A D2
SDA
SDA (Serotonin-Dopamin Antagonist)
risperidone, olanzapine, sertindol, seroquel
better effect on negative symptoms,
less of EPS (especially at lower dosage)
DA
5-HT SDA
5-HT → inhibition of DA realease
5-HT r. blockade →  release of DA
= suppression of
impact of D2 blockade
Stephen M. Stahl, 2000
ANTIPSYCHOTIC RECEPTOR BINDING











blockade of D2, 3 postsynaptic receptors
D2/D3 antagonists
SUPPRESSION
OF POSITIVE
SYMPTOMS
in psychosis
Selective blockade of D3/D2 autoreceptors in the limbic region
Activation in the
cortex
Suppression of
negative
(cognitive)
symptoms
DA autoreceptors
blockade
Suppression of
anhedonia
FRONTAL CORTEX
NUCL. ACCUMBENS
D3
D3
D2
D1
DA
D2
LIMBIC REGION
D2
D3
VTA
D2/D3 antagonists
CEITEC
Masaryk University
Brno, Czech Republic
Sulcova A.E.
Aripiprazole  partial agonist of D2 receptors
blocks D2 receptors in regions
with high DAergic activity
stimulates D2 receptors in regions
with low DAergic activity
aripiprazol "normalizes" dopaminergic activity
Ozdemir et al., 2002
heteroreceptor 5-HT2A
receptor 5-HT1A
receptor D2
presynaptic postsynaptic
DA
5-HT
aripiprazole
dopamine (DA)
serotonin (5-HT)
receptor 5-HT1A
r. 5-HT1A
- partial agonist at D2 autoreceptors and 5-HT1A somatodendritic receptors
- antagonist at 5-HT2A heteroreceptors of dopaminergic neurons
(Burris at al., 2002; Jordan et al., 2002)
DSSS (Dopamine-Serotonin System Stabilizers)
ARIPIPRAZOLE suggested mechanisms of action:
heteroreceptor 5-HT2A
receptor 5-HT1A
receptor D2
presynaptic postsynaptic
DA
5-HT
aripiprazole
dopamine (DA)
serotonin (5-HT)
receptor 5-HT1A
r. 5-HT1A
- partial agonist at D2 autoreceptors and 5-HT1A somatodendritic receptors
- antagonist at 5-HT2A heteroreceptors of dopaminergic neurons
(Burris at al., 2002; Jordan et al., 2002)
- partial agonist at D2 autoreceptors  inbibition of DA release
- partial agonist at 5-HT1A somatodendritic receptors
 augmentation of serotonin transmission (antianxiety, antidepressant
effects)
 inbibition of DA release
DSSS (Dopamine-Serotonin System Stabilizers)
ARIPIPRAZOLE suggested mechanisms of action:
heteroreceptor 5-HT2A
receptor 5-HT1A
receptor D2
presynaptic postsynaptic
DA
5-HT
aripiprazole
dopamine (DA)
serotonin (5-HT)
receptor 5-HT1A
r. 5-HT1A
- partial agonist at D2 autoreceptors and 5-HT1A somatodendritic receptors
- antagonist at 5-HT2A heteroreceptors of dopaminergic neurons
(Burris at al., 2002; Jordan et al., 2002)
- antagonist at 5-HT2A heteroreceptors of dopaminergic neurons
 desinhibition of DA neurons (nigrostriatum, mesocortical region)
 suppression of negative symptoms of schizophrenia
DSSS (Dopamine-Serotonin System Stabilizers)
ARIPIPRAZOLE suggested mechanisms of action:
Kantrowitz J.T., Citrome L. From MedscapeCME Psychiatry & Mental Health
Antipsychotics A-Z, 2010, www.medscape.org/viewarticle/718207
ARIPIPRAZOLE - main indications:
]
1. Schizophrenia in adults and adolescents
(age 13-17)
2. Acute manic or mixed episodes of
bipolar disorder I.
(as monotherapy or with valproate in adults or
adolescents of age 10-17)
3. Adjunctive therapy in major depression
4. Irritability associated with autistic disorder in
pediatric patients (age 6-17)
5. Acute agitation associated with schizophrenia or
bipolar disorder (intramuscularly)
INDICATIONS FOR ANTIPSYCHOTICS
• psychoses
• nausea, vomitus
• sleeping disorders
• anxiety
• Huntington disease
• Tourett's syndrome
• anesthesiology / neuroleptanalgesia
Antipsychotic Drugs: Side effects
SEDATION Greater with CLOZAPINE, OLANZAPINE, QUETIAPINE
HEADACHE
SUBJECTIVE BURDEN
 Loss of energy/drive Greater with classic
 Dysphoria Greater with classic
 Problems with memory and concentration
SLEEP DISTURBANCE
 Night sleep pattern
 Difficulty waking/daytime sleepiness
 Insomnia Greater with ARIPIPRAZOLE
Sedation may be Related to Affinity of Medications
for the Histamine H1 Receptor
*Presented at 102 × 1/Ki (nM)
**Data with cloned human receptors
Bymaster FP et al. Neuropsychopharmacology 1996;14:87–96;
0 2 4 6 8 10 12 14 16 18
Clozapine
Olanzapine
Quetiapine
Risperidone
Ziprasidone
Aripiprazole
Haloperidol
Affinity*
Increasingsedation
CARDIOVASCULAR
 Palpitations/tachycardia ? Greater with QUETIAPINE
 Postural hypotension Greater with CLOZAPINE, LEVOMEPROMAZINE
 ECG abnormalities
 QT prolongation Greater with SERTINDOLE, ZIPRASIDONE
GASTROINTESTINAL
 Nausea/vomiting, constipation, diarrhoea
ENDOCRINE
 Weight gain Greater with CLOZAPINE and OLANZAPINE
 Diabetes Greater with CLOZAPINE and OLANZAPINE
 Decreased T3 Greater with QUETIAPINE
HEPATIC DYSFUNCTION
 Increased transaminases ? Greater with OLANZAPINE
 Cholestatic jaundice
Antipsychotic Drugs: Side effects
NNH = number needed to harm
Abilify® (aripiprazole) US PI, October 2006. Geodon® (ziprazidone) US PI, August 2004. Risperdal® (risperidone) US PI, November 2006.
Seroquel® (quetiapine fumarate) US PI, July 2007. Zyprexa® (olanzapine) US PI, March 2002.
Clinically Significant Weight Gain (7%)Incidence(%)
0
5
10
15
20
25
30
35
New antipsychotics vs placebo
NNH 1720 11 6 4
HYPERSALIVATION Greater with CLOZAPINE
ANTICHOLINERGIC EFFECTS
 Dry mouth / Blurred vision / Urinary hesitancy
NOCTURNAL ENURESIS Greater with RISPERIDONE
SEXUAL SIDE-EFFECTS Greater with RISPERIDONE, AMISULPRIDE
 Loss of libido
 Females: Anorgasmia/Change in menstruation
 Males: Erectile dysfunction/Ejaculatory disturbance
? Reduced ejaculatory volume with SERTINDOLE
PROLACTIN ELEVATION Dose-related with RISPERIDONE,
AMISULPRIDE
Antipsychotic Drugs: Side effects
CNS
 Emergence of disorientation/clouding of consciousness
 Seizures Greater with CLOZAPINE,? Classic antipsychotics
 Neuroleptic malignant syndrome Classic
OPHTHALMOLOGICAL
 Glaucoma
 Corneo-lenticular opacities/pigmentary lesions
CUTANEOUS REACTIONS
 Photosensitive skin rash
 Pigmentation
HAEMATOLOGICAL
 Blood dyscrasias Greater with CLOZAPINE
Antipsychotic Drugs: Side effects
ANTIPSYCHOTIC-INDUCED
MOVEMENT DISORDER
Early onset
Parkinsonism (Classic potent D2)
Acute akathisia (Classic, aripiprazole)
Acute dystonia (Classic potent D2,
risperidone dose dependant)
Late onset
Chronic akathisia ?
Tardive dystonia ?
Tardive dyskinesia (Classic)
Negative
symptoms in
schizofrenia
Hypoactivity in
frontal. cortex
Hyperactivity of
limbic sytem
Pozitive
symptoms
Iin schizophrenia
Hypoactivity
of mesolimbic
pathways
Anhedonia,
depression
www.drugabuse.gov
prefrontal
cortex
Dopaminergic “reward pathway“
- activation (food, sex, drug of abuse …)  EUPHORIA
In case of hypoactvity  ANHEDONIA, DEPRESSION
Serotonin ( 5-HT )
synthesis tryptophan  hydroxylase  5-hydroxytryptophan 
decarboxylase  5-hydroxytryptamine ( 5-HT )
storage - in vesicles ( with ATP ) in presynaptic terminals
- in a mobile extravesicular cytoplasmic pool
breakdown - re-uptake ! !
- MAOA ( cytoplasmic )
receptors 5-HT1 A, B, C, D -  cAMP
5-HT2A, B, C - stimulation of phosphoinositol metabolism
5-HT4 -  cAMP
5-HT5A, B = metabotropic receptors
5-HT6, 7
5-HT3 - stimulation of ion channels ( = ionotropic receptor)
Serotonergic
pathways
Serotonin ( 5-HT )
synthesis tryptophan  hydroxylase  5-hydroxytryptophan 
decarboxylase  5-hydroxytryptamine ( 5-HT )
storage - in vesicules (with ATP )
- in cytoplasma
breakdown - re-uptake !
- MAOA ( in cytoplasma )
receptors 5-HT1 A, B, D, E, F
5-HT2A, B, C
5-HT4 5-HT5A, B = metabotropic receptors
5-HT6, 7
5-HT3 - stimulation of cation channels ( = ionotropic receptor)
Serotonin = neurotransmitter: 1954, John Welsh (UK)
Serotonergics
↓ 5-HT → deregulations of other neurotransmitters
Regulation of stress response
and behaviour (anxiety, depression, psychosis)
5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B , 5-HT2C , 5-HT3
5-HT receptor subtypes
autoreceptors
heteroreceptors
neuron of
different neurotransmitter
serotonergic neuron
http://inovace-mbb.upol.cz/files/vyukovy-portal/bunecna_biologie_2/kbb-bb2_07.pdf
ANTIDEPRESSIVE DRUGS
http://inovace-mbb.upol.cz/files/vyukovy-portal/bunecna_biologie_2/kbb-bb2_07.pdf
ANTIDEPRESSIVE DRUGS
- stimulation of 5-HT reuptake
- increase of extracellular DA concentration in nucleus accumbens
http://inovace-mbb.upol.cz/files/vyukovy-portal/bunecna_biologie_2/kbb-bb2_07.pdf
ANTIDEPRESSIVE DRUGS
• older generation – tricyclic antidepressants - Imipramin, Amitryptilin …
GABA ( gama-aminobutyric acid )
synthesis glutamic acid    decarboxylase  GABA
storage in neurones, in glial cells
beakdown - re-uptake
- GABA-transaminase (in neurones, in glial cells]
receptors GABAA , GABAC - part of Cl- channel structure,
(postsynaptic)
GABAB -  cAMP
 K+ kanálu
 Ca 2+ kanálu,
(presynaptic)
GABA 
( sleep )
GABA 
( anxiety )
GABAergic synapse
gama-aminobutyric acid (GABA)
R
glutamine
glutamine
glutamate
GABA
GABA
receptor
complex
Excitatory amino acids - glutamate, aspartate
receptors
ionotropic:
- NMDA r ( NR1-3) - ( N-methyl-D-aspartate, glutamate)
- AMPA r. (GluR1-4 ) – ( alfa-amino-3-hydroxy-5- methyl-4isoxazolepropionic
acid )
- kainate-ergic r. (GluR5-7, KA1, K2)
metabotropic, G-protein coupled:
mGluR1-8 inhibition of glutamate release from presynaptic terminal or
Increase of phosphatidylinositol turnover
memory functions, learning processes
Activation of NMDA receptors can induce changes in the activity
of a larger number of AMPA receptors (LEARNING mechanismus ?)
Glutamatergic receptors
+ neuromuscular junctions
Ach-ergic pathways
Acetylcholine
synthesis choline  cholinacetyltransferase ( acetyl ko-enzym A )
 Ach  acetylcholinesterase  choline + acetate
storage in synaptic vesicles
breakdown ( very fast )
specific cholinesterase – in neurones and neuroeffector junction
pseudocholinesterase( butyrylcholinesterase ) – throughout the body,
including body fluids
re-uptake choline
1921 – Otto Loewi (Germany) – 1936 Nobel price
Acetylcholine continuation
Ach  IQ ( learning, memory, attention, emotions, nociception, sleep . . . )
Ach  demention, delirium
receptors M1-5 ( muscarinic ) - stimulation has slower and more sustained
action, G-protein coupled
N ( nicotinic ) - stimulation has rapid and short action,
part of receptor mediated Cl- channels ,
often occurring as heteroreceptors (increase of
neurotransmitter release)
Cholinergic synapse - acetylcholin (Ach)
Ac CoA
+
cholin
Ach
R
N rec.
Ach
DA activity
“up-regulation”
of N receptors
vareniklin
partial agonist of
nicotinic receptors
Inhibition of nicotine
binding to receptors
and
increase of DA release
dopaminergic
drug
anticholinergic
drug
DA
Ach
normální parkinsonismus treatment
treatment
ANTIPARKINSONIC AGENTS
beta-amyloid gene mutation
(fragment of neuron membrane
protein precursor)
extracellular plaques
neurofibrillary tangles
of abnormally
phosphorylated tau-protein
+
deficit of Ach-ergic activity
+
excitotoxicity
Alzheimer's disease
. . .
Other neurotransmitters, co-transmitters, neurohormones
endogenic opioids ( enkefaline, endorphine, dynorphine )  euforia
 anhedonia
angiotensine
gastrine
neurokinines
neuropeptide Y
neurotensin
substance P
bradykinine
somatostatin
. . . . . . .
. . . . . . . . . . .
cholecystokinine ( CCK )  satiety, panic disorder
 hunger
. . .
. . .