Antipsychotic _Neuroleptic_ Drugs

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					Antipsychotic (Neuroleptic)
• Psychosis is a thought disorder characterized by
  disturbances of reality and perception, impaired cognitive
  functioning, and inappropriate or diminished affect (mood).

 • Psychosis denotes many mental disorders.

• Schizophrenia is a particular kind of psychosis
  characterized mainly by:
     • a clear sensorium
     • a marked thinking disturbance.
•   Pathogenesis is unknown.
•   Onset of schizophrenia is in the late teens early twenties.
•   Genetic predisposition -- Familial incidence.
•   Multiple genes are involved.

• Afflicts 1% of the population worldwide.
Positive Symptoms.

• Symptoms that most individuals do not normally experience.

• They include:
   – delusions
   – auditory hallucinations
   – thought disorder

• are typically regarded as manifestations of psychosis.
Negative Symptoms.

• considered to be the loss or absence of normal traits or

• Include features such as:
   – flat or blunted affect and emotion
   – poverty of speech (alogia)
   – inability to experience pleasure (anhedonia)
   – lack of motivation (avolition)

•   These symptoms are progressive and non-responsive to
Disorganization syndrome includes:
 chaotic speech, thought, and behavior
•   Drugs currently used in the prevention of psychosis.
•   They have also been termed neuroleptics, because
    they suppress motor activity and emotionality.

        ** These drugs are not a cure **

•   Schizophrenics must be treated with medications
    indefinitely, in as much as the disease in lifelong and
    it is preferable to prevent the psychotic episodes than
    to treat them.
 Antipsychotic treatments


   There is no remission
• All currently available antipsychotic drugs
  that alleviate symptoms of schizophrenia
  decrease dopaminergic and/or
  serotonergic neurotransmission.
A. Classification

1. Typical (conventional) antipsychotic drugs:
  – Often subclassified according to their oral potency
    (high potency or low potency).

     a. High-potency drugs
         – piperazine phenothiazines, e.g., fluphenazine
         – butyrophenones e.g., haloperidol
         – more likely to produce extrapyramidal
a. Low-potency drugs
   • aliphatic phenothiazines, e.g.,triflupromazine
   • piperidine phenothiazines, e.g., thioridazine
– are less likely to produce acute extrapyramidal
– more likely to produce sedation and postural
2.    Atypical antipsychotic drugs
     – e.g., Clozapine, risperidone, olanzapine
     – have generally replaced the conventional drugs for
        initial treatment of first-episode patients.
     – Clozapine is reserved for treatment-resistant

3.     Other typical heterocyclic antipsychotic drugs
     –    e.g., loxapine and molindone
     – intermediate potency
     – have no clear advantage over other conventional
B. Mechanism of therapeutic action

1. The therapeutic action of          Tyrosine
                                                 Dopamine Synapse
   the typical antipsychotic
   drugs is correlated best
   with antagonist activity      DA

   at postjunctional
   dopamine D2-
   receptors, where
   dopamine normally
   inhibits adenylyl cyclase
2. The therapeutic action of the atypical
   antipsychotic drugs is correlated with
   antagonist activity at both:
     • 5-HT2-receptors
     • Dopamine D2- or D4-receptors.

•   Aripiprazole is a partial agonist at dopamine
•   Aripiprazole and ziprasidone, also stimulates
    serotonin 5-HT1A-receptors.
3. The therapeutic action is best correlated with
   the actions of these drugs in the mesolimbic
   and mesocortical areas of the CNS.
C. Pharmacologic properties
1. Most of these drugs show little correlation between
   plasma levels and therapeutic action. Plasma levels are
   monitored primarily for compliance and toxicity.

2. Most antipsychotic drugs are highly lipophilic and have
   long half-lives (10—20 h).

•   They are metabolized by liver microsomal oxidation
    and conjugation.
3.   Esterification of fluphenazine and haloperidol
     (fluphenazine decanoate, haloperidol decanoate)
     results in long-acting depot forms (2- to 3-week
     duration of action) that can be used to manage
     compliance issues.

•    Plasma esterases convert the parent compound to
     the active drug when the ester diffuses into the
D. Therapeutic uses

1. Schizophrenia

a. Their antipsychotic effects, including
  – decreasing the positive symptoms:
    symptoms of thought disorders, paranoid
    features, delusions, hostility, hallucinations
  – to a lesser degree decreasing the negative
       –   decreased withdrawal
       –   apathy
       –   blunted affect.
• Atypical antipsychotic drugs, particularly
  clozapine, have a seemingly greater effect on
  negative symptoms than the conventional

b. These drugs curb acute psychotic attacks and
   delay subsequent relapses.
2. Other selected therapeutic uses:

a. Acute mania in bipolar disorder
b. Atypical psychotic disorders (e.g., following surgery or
   myocardial infarction)
c. Depression with psychotic manifestations
d. Tourette's syndrome (haloperidol or pimozide), to
   suppress severe tics and vocalization
e.   Severe nausea or vomiting:

•    Conventional antipsychotics have strong antiemetic
     activity due to dopamine D2-receptor blockade in the
     chemoreceptor trigger zone of the medulla.

      •   Prochlorperazine: most commonly used
      •   Promethazine
E.     Adverse effects and contraindications

•    The adverse effects of antipsychotic agents are due to
     their antagonist actions at receptors

 in the CNS
  – dopamine D2-receptors
  – histamine H1-receptors
  – (and possibly serotonin receptors)

 in the periphery

     – muscarinic cholinoceptors
     – α-adrenoceptors
       1. Central nervous system

A. Extrapyramidal syndromes

  1. These adverse effects are related to a dopamine-
     receptor blockade in the basal ganglia (and
     elsewhere in the CNS) that leads to an imbalance in
     dopamine and acetylcholine actions in the
     nigrostriatal pathway.

  2. These effects are a major cause of
3. Extrapyramidal effects are:
   • most likely to occur with high-potency
     conventional antipsychotic drugs that have a
     high affinity for postjunctional dopamine D2-
     receptors in the basal ganglia.
   • occur with few atypical drugs like risperidone.
4. These effects can sometimes spontaneously remit.
Extrapyramidal syndromes include the following:

1.       Acute dystonia: sustained muscle contractions cause twisting
         and repetitive movements or abnormal postures
     –     This condition is often elicited during the first week
           of therapy.
2.       Akathisia is the irresistible compulsion to be in motion.
     –      This condition can develop as early as the first 2 weeks of
            treatment or as late as 60 days into therapy.
3.       Parkinsonian-like syndrome
     •      Parkinsonian-like syndrome is characterized by tremors,
            bradykinesia, rigidity, and other signs of parkinsonism.
     •      This syndrome can develop from 5 days to weeks into
Acute dystonia
b.     Tardive dyskinesia (10—20%)

•     CNS disorder characterized by:
     • twitching of the face and tongue
     • involuntary motor movements of the trunk and limbs

•     More likely with conventional antipsychotic agents.

•     Tardive dyskinesia generally occurs after months to
      years of drug exposure; it may be exacerbated or
      precipitated by the discontinuation of therapy.
                   Orofacial movements

Dystonic posture
• Tardive dyskinesia is often irreversible.

• more likely to occur in the elderly or in institutionalized
  patients who receive long-term, high-dose therapy.

• The only effective treatment for tardive dyskinesia is the
  discontinuation of treatment.
c.     Neuroleptic malignant syndrome

•    Due to excessively rapid blockade of postsynaptic
     dopamine receptors.

•    This syndrome is characterized by:
     – altered blood pressure and heart rate.
     – muscle rigidity
     – diaphoresis
     – profound hyperthermia
     – myoglobinemia

•    This condition occurs, often explosively, in 1% of
     patients; it is associated with a 20% mortality rate.
• This condition is treated by:
   1. discontinuing drug therapy
   2. initiating supportive measures, including the use of
      bromocriptine to overcome the dopamine receptor
   3. muscle relaxants such as dantrolene and diazepam
      to reduce muscle rigidity.
d.    Sedation

•    More likely with low-potency antipsychotic agents
     and with the atypical agents, are due to a central
     histamine H1-receptor blockade.
•    These effects may be mild to severe.
•    The elderly are particularly at risk.
•    May be temporary
e. Confusional state with memory impairment.

  –   This effect is likely with antipsychotic agents with
      pronounced antimuscarinic activity.

f. Seizures

      •   Seizures are especially common with
          chlorpromazine and clozapine.

      •    This effect is due to a lowering of the seizure
          threshold; antipsychotic drugs may precipitate or
          unmask epilepsy.
    2. Autonomic Nervous system
1. α-Adrenoceptor blockade
 More likely to occur with:
    – conventional low-potency
    – atypical antipsychotic agents.

•    Postural hypotension- phenothiazines
     when a person moves to a more vertical position: from sitting to
     standing or from lying down to sitting or standing.
•    Orthostatic hypotention – atypical drugs
     symptoms: dizziness, faintness or lightheadedness which appear only
     on standing, and which are caused by low blood pressure.
• Failure to ejaculate -phenothiazines
b. Muscarinic cholinoceptor blockade

•   More common with:
     conventional low-potency antipsychotic agents
     atypical agent clozapine.

•   Muscarinic receptor blockade, atropine-like effects (dry
    mouth, constipation, urinary retention, and visual

•   Elderly patients are more at risk
•   The effects may be temporary.
    3.   Endocrine and metabolic disturbances

•    Most likely with
     – most conventional antipsychotic agents
     – atypical agent risperidone

•    Due to dopamine (D2)-receptor antagonist activity in the
     pituitary, resulting in hyperprolactinemia.


 Anterior Pituitary PRL

           PRL (+)

    In women, these disturbances include:
     galactorrhea
     loss of libido
     delayed ovulation and menstruation or amenorrhea.

    In men, these disturbances include:
     gynecomastia
     impotence.
    Weight gain, which is likely with:
     most conventional
     atypical antipsychotic agents, except aripiprazole
       and ziprasidone, may be due in part to histamine
       H1-receptor antagonist activity.
4. Other adverse effects
a. Withdrawal-like syndrome
  1. Symptoms: nausea, vomiting, insomnia, and
    •   in 30% of patients, especially those receiving low-potency
        antipsychotic drugs.
  2. Symptoms may persist for up to 2 weeks.
  3. Symptoms can be minimized with a tapered
     reduction of drug dosage.
b. Cardiac arrhythmias

•   More likely with thioridazine and ziprasidone, which
•   Can prolong the Q-T interval and lead to conduction
    block and sudden death.
c. Blood dyscrasias
 – rare, except in the case of clozapine, which may
   induce agranulocytosis (severe neutropenia) in up to
   3% of patients and, therefore, is used only when
   other drug groups prove ineffective.
c. Cholestatic jaundice, which is caused primarily
         by chlorpromazine

d. Photosensitivity
1.       The effect is specific to chlorpromazine
     –     it includes dermatitis (5%), rash, sunburn, and pigmentation,
           and it may be irreversible.
2.       Chlorpromazine and high-dose thioridazine also
         produce retinitis pigmentosa
f. Overdose.
•   rarely fatal, except when caused by thioridazine or
    mesoridazine (and possibly ziprasidone), which may
    result in drowsiness, agitation, coma, ventricular
    arrhythmias, heart block, or sudden death.
g.   Drug Interactions

•    Additive effects with sedatives.
•    Additive effects with anticholinergics.
•    Additive effects with antihistaminergics.
•    Additive effects with -AR blocking drugs.
•    Additive effects with drugs with quinidine-like action

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