Bez nadpisu

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ANTIPSYCHOTIC DRUGS
Martin terba, PharmD., PhD. 2008
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• Psychotic disorders (psychosis)
• are severe mental disorders that cause abnormal
  thinking and perceptions.
• Classification of psychotic disorders
• Schizophrenia see below
• Schizoaffective disorder disorder of both
  thought and mood
• Delusional disorder incl. paranoid psychosis
• Substance-induced psychotic disorder
  use/withdrawal of amphetamines, cocaine, alcohol,
  LSD
• Psychotic disorder due to a medical condition
  (organic psychosis) - disturbances caused by head
  injury or tumor
• others

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Schizophrenia

• Definition Chronic (relapsing and remitting)
  disorder of though characterized by acute
  psychotic episodes bridged by periods showing
  impaired psychosocial functionality and residual
  symptoms
• Typical feature is a loss of touch with reality
• Life-time prevalence 1 of population
• Onset in adolescence/early adulthood
• Ethiology unclear
• significant genetic component
• neurodevelopmental theory aberrant intrauterine
  brain development (infections, hypoxia?) ?
  abnormal neuronal shape, position and connections
• Highly disabling strong medical, social and
  economical implications

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Schizophrenia - pathophysiology

• Morphological changes brain asymmetry with
  decreased cortical/hippocampal size and increased
  ventricular size
• Neurotransmitter changes
• The theories were largely derived from
  observations of pharmacological observations,
  unfortunately not on detail understanding to the
  neurochemistry of particular neutronasmitter
  system
• Dopamine theory central and most important one,
  it will be discussed further in detail
• Glutamate theory comes from psychotic symptoms
  induced by administrations of NMDA-antagonists
  (ketamine and phencyclidine), together with
  observations from post-mortem examination
• It was proposed that reduced glutamatergic and
  increased dopaminergic neurotransmissions may
  impair the gating function of GABA-ergic neurons
  projecting themselves into the thalamus which
  cause deteriorations of the SENSORY GATE.
• Serotonine theory schizophrenia-like symptoms
  induced by LSD, many atypical antipsychotics
  block also 5-HT receptors

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Dopamine theorydopaminergic systems in CNS
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Dopamine theorydopaminergic systems in CNS

• Schema of dopamine pathways in the brain
• Please se Rang-Dale p. 495 (Fig. 34.3)

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Dopamine theory of schizophrenia

• Symptoms of schizophrenia arise from
  hyperactivity of dopaminergic pathways in
  mesolimbic/mesocortical system
• It was based on observation that psychotic
  symptoms and related behavioural changes can be
• Induced by
• Drugs causing dopamine release e.g.,
  amphetamines
• D-agonists (e.g., bromocryptine) and dopamine
  precursors (like L-DOPA)
• Inhibited by
• Drugs blocking dopamine storage (e.g., reserpine)
• D-antagonists
• Dopamine receptors D1 type (D1 and D5) and
  D2-type (D2, D3, D4)
• D2-receptors
• Are evidently involved
• There is a strong correlation between
  D2-antagonistic effects and antipsychotic action
• Clinical response is reached when 80 of D2
  receptors is occupied
• Involvement of other D-receptors ??? D4
  specific antagonists are ineffective
• Some theories suggest that the key issue may be
  the overactivation of D2 receptors in subsortical
  regions (positive symptoms) while activation of
  D1 receptors can be deficient (negative symptoms)

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Symptom clusters of schizophrenia

• Positive symptoms
• Delusions (fixed false beliefs, often
  paranoid/conspirative in nature)
• Hallucinations (usually hearing of voices,
  typically spurring)
• Incoherent thought disconnection - loosing of
  associations, inability of logical analysis of
  the situation, ambivalence contradictory
  thoughts
• Suspiciousness, hostility and potentially
  agressvity
• Disorganised speech
• Stereotype/abnormal movements
• Negative symptomes
• Affective flattening poor emotional experience
• Anhedonia loss of the capacity to experience
  pleasure
• Avolition - lack of desire, drive, or motivation
  to pursue goals
• Withdrawal from social contacts
• Cognitive symptomes
• Impaired attention, working memory and executive
  function
• Clinical picture may vary considerably,
  especially according to the positive/negative
  symptoms balance

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Goals and means of treatment

• Goals
• To suppress any acute psychotic episode
• To prevent relapses and progression of the
  disease
• To restore/keep the psychosocial functionality
  (family, job and social networks)
• Therapy
• should be complex
• Is not causual
• Pharmacologic the mainstay of the treatment
• Common mechanism of action D2-antagonism
• Additional mechanisms antagonism on a1, M, H1,
  5-HT2A/C
• Adverse effects
• Therapeutic effects
• Nonpharmacologic rather complementary
  (psychotherapy, psychosocial rehabilitation),
  electroconvulsive therapy

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Pharmacotherapy of Schisophreniageneral aspects

• Response in 70 of patients (30 are treatment
  resistant forms big clinical issue)
• Negative symptoms respond much less than positive
  symptoms (improved in atypical drugs)
• The full antipsychotic effect deserve several
  weeks (3-4 weeks) to be reached. Only
  non-specific sedative and agressivity controlling
  effects can be induced immediately
• Monotherapy is preferable, combinations only in
  resistant forms
• In acute psychotic episode with strong
  agressivity and agitation typical antipsychotics
  might be useful (sedative effects, injectable
  forms are available)
• Long-term treatment is usually initiated with
  newer atypical drugs
• Compliance often big issue, i.m. injection
  (acute episode) or depot i.m. forms (to avoid
  chronic non-compliance)
• Dose is usually gradually titrated, adverse
  effects should be closely monitored

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• Pharmacokinetics of antipsychotics
• Most drugs can be given orally or by i.m.
  injection, once or
• twice a day.
• generally highly lipophilic drugs
• highly bound on plasma proteins
• large distribution into the tissues (high Vd),
  risk of
• accumulation
• t1/2 of most antipsychotics is long (15-30
  hours)
• CL depends entirely on hepatic biotransformation
• - mostly CYP 450-dependent (exception
  ziprasidone)
• genetic polymorphisms (e.g., in CYP 2D6 -
  substrates risperidon)
• Slow- release (depot) preparations
• are available, for several drugs. In these the
  active drug is esterified with heptanoic or
  decanoic acid and dissolved in oil. Given as an
  i.m. inj., the drug acts for 2-4 weeks.
• e.g. Flupentixol decanoat, fluphenazine decanoat

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Classification of antipsychotic drugs I.
typical antipsychotics a) basal (sedative)
- chlorpromazine (typical example, a
phenothiazine structure) - chlorprotixene,
thioridazine b) incisive - haloperidol
(typical example, a butyrophenone structure)
- fluphenazine, flupenthixol, clopenthixol
II. atypical antipsychotics a) Multi Acting
Receptor Targeted Antipsychotics (MARTA) -
olanzapine, zotepin, quetiapine, clozapine
D1/2, a, H1, M and 5-HT2 receptor antagonists
b) Dopamine and serotonin receptor antagonists -
risperidone, ziprasidon c) D2-selective
antagonists - sulpiride, amisulpiride
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Classification of antipsychotics

• Incisive vs. sedative (typical) antipsychotics
• Incisive antipsychotics are more potent and
  selective D2-antagonits than sedative (basal)
  drugs
• Incisive drugs are more effective, however, they
  induce significant problems with extrapyramidal
  adverse effects
• Sedative drugs are weaker D2-antagonists but
  block also H1, a1, M (which explain sedative
  effects as well as some adverse effects)
• Atypical vs. typical antipsychotics
• Atypical drugs
• Cause less extrapyramidal complications
• Have improved efficacy against negative symptoms
  
• Might be useful in treatment-resistant group of
  patients (especially clozapine)
• Difference in overal efficacy ?

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Adverse effects A- type(predictable, dose
dependent)

• I. Extrapyramidal motor disturbances
• - result from D2 receptor blockade in the
  nigrostriatal pathways
• - more frequent in typical (especially
  incisive) antipsychotics
• Acute (reversible)
• Parkinson-like symptoms (further details on next
  seminar)
• Tremor
• Rigidity
• Bradykinesia/akinesia
• Acute dystonias - sever muscle spasms, very
  painful (occur within initial 24-96h)
• Orofacial muscles (e.g., blepharospasm - eye lid
  spasm, oculogyric crisis turning of eye bulbi
  upward),
• Neck muscle spasms (torticollis wry neck)
• Tongue protrusion
• Can be life-threatening pharyngeal-laryngeal
  forms
• Akathasia
• motor restlessness (restless leg syndrome)
• inner restlessness
• Treatment benzodiazepines, beta-blockers

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Mechanisms of EPS
Dopamine (-)
cholinergic pathway ()
S. NIGRA
CORPUS STRIATUM
GABA (-)
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Adverse effects A -type
II. Decreased seizure threshold - in predisposed
persons may induce seizures (convulsions) -
mainly in high doses III. Sedation and cognitive
deficit - occurs with many antipsychotics
- antihistamine (H1) activity significantly
contributes to this effects (especially
sedative typical drugs but also others) IV.
Antimuscarinic activity - blurring of
vision - increased intraocular pressure
(glaucoma!) - dry mouth and eyes
- constipation - urinary
retention V. Cardiovascular adverse reactions
- Orthostatic hypotension - a-adrenoreceptors
blockade - Drug induced QT syndrome
(e.g., thioridazine) VI. Weight gain - probably
related to 5-HT antagonism
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Adverse effects B typeunpredictable

• - neuroleptic malignant syndrome
• Muscle rigidity is accompanied by a rapid
  rise in body temperature and
• mental confusion. It is usually reversible,
  but death from renal or
• cardiovascular failure occurs in 10-20 of
  cases. Discontinuation of therapy
• and supportive care is essential (cooling!).
  It is more frequent with typical
• antipsychotics.
• - jaundice (with older drugs, mainly
  phenothiazines) - usually mild cholestatic
  hepatitis (obstructive origin), disappears
  quickly when the drug is stopped
• - leukopenia and agranulocytosis
• - rare but potentially fatal complication
  ocuring in clozapine its
• use requires regular monitoring of
  blood cell counts.
• - urticarial skin reactions (mainly
  phenothiazines)
• Depositions
• - in skin (in complex with melanine, gray
  discolouristion of skin) and
• excessive sensitivity to UV
  light.
• - in cornea/lens (vision distubances)