NEUROLEPTICS

Psychopharmacologicals

                         Psychotropic drugs – the drugs with the action on the CNS

                                       Classification of Psychotropic drugs

         1) Psycholeptics ( inhibit CNS)

                    -    Neuroleptics

-        Sedatives

-       Tranquilisators

-       Lithium

2)    Psychoanaleptics (activate CNS)

-       Antidepressants

-       Nootropes

-       Psychostimulants

-       Tonisants

-       Adaptogenes

3)    Psychodyslepics Psychosomimetics

Psychotomimetics are able to elicit psychic changes like those manifested in the course of a psychosis, such as illusionary distortion of perception and hallucinations. This experience may be of dreamlike character; its emotional or intellectual transposition appears inadequate to the outsider.

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Neuroleptics (antipsychotics)

Therapy of Schizophrenia

Schizophrenia is an endogenous psychosis of episodic character. Its chief symptoms reflect a thought disorder (i.e., distracted, incoherent, illogical thinking; impoverished intellectual content; blockage of ideation; abrupt breaking of a train of thought: claims of being subject to outside agencies that control the patient’s thoughts), and a disturbance of affect (mood inappropriate to the situation) and of psychomotor drive. In addition, patients exhibit delusional paranoia (persecution mania) or hallucinations (fearfulness hearing of voices). Contrasting these “positive” symptoms, the so-called “negative” symptoms, viz., poverty of thought, social withdrawal, and anhedonia, assume

added importance in determining the severity of the disease. The drugs used in the schizophrenia’s treatment are neuropeltics.

Classification

Typical antipsychotics ( Cause unwanted motor side-effects)

A.    Phenothiazines     - chlorpromazine                  - levomepromazine

-       Fluphenazine                   - perphenazine

B.    Butyrophenones   - haloperidol               - trifluperidol

-       droperidol

C.    Thioxanthenes

-       chlothixen

-       thiothixene

D.    Dyphenylbutylpiperidines

-       Fluspirilen              -  pimozid                - fenfluridol

Atypical antipsychotics

   A Dybenzodiazepines

                - clozapin

   B Benzamides

                - sulpiride

   C Alkaloids of Rauwolfia

               - rezerpine

After administration of a neuroleptic, there is at first only psychomotor dampening. Tormenting paranoid ideas and hallucinations lose their subjective importance; however, the psychotic processes still persist. In the course of weeks, psychic processes gradually normalize; the psychotic episode wanes, although complete normalization often cannot be achieved because of the persistence of negative symptoms. Nonetheless, these changes are significant because the patient experiences relief from the torment of psychotic personality changes; care of the patient is made easier and return to a familiar community environment is accelerated.

The dopamine hypothesis of psychosis proposes that the disorder is caused by a relative excess of functional activity of the neurotransmitter dopamine in specific neuronal tracts in the brain.

Mechanism of action:

     1. Many antipsychotics block brain dopamine receptors

2. All antipsychotics are antagonist of dopamine
3. Antipsychotics potency generally runs parallel to activity on D₂

       receptors.

The antipsychotic effect is probably due to an antagonistic action at dopamine receptors. Aside from their main antipsychotic action, neuroleptics display additional actions owing to their antagonism at

– muscarinic acetylcholine receptors - atropine-like effects;

– α-adrenoceptors for norepinephrine - disturbances of blood pressure regulation;

– dopamine receptors in the nigrostriatal system - extrapyramidal motor disturbances; in the area postrema - antiemetic action, and in the pituitary gland -increased secretion of prolactin;

– histamine receptors in the cerebral cortex - possible cause of sedation.

These ancillary effects are also elicited in healthy subjects and vary in intensity among individual substances.

Effects:    -antidopaminic              -antipsychotic

              -  antihistaminic               - sedative

-       a adrenoblocker              -

-       anti-GABA

-       antiserotonic

-       M cholinoblocker

Spectrum of action:

               -   antipsychotics

-       sedative

-       analgesic potency, hypnotic effects

-       increasing of alcohol’s effects

-       antivomiting

-       muscle relaxation

-       vegetative effects

-       endocrine effects ( increase of melanotrop and prolactine hormones)

-        decreasing of synthesis of adenohypofise hormones  

-       hypotension and tachycardia

-       hypothermia

  Indication: Schizophrenia including hyperactivity, bizarre ideation, delusions and hallucinations.

-       treatment of mania

-       psychotic syndrome

-       schizoaffective disorder

-       toxic psychoses caused by overdosage of certain CNS stimulants

-       sometimes they are used as antiemetics, antipruritics

Other indications. Acutely, there is sedation with anxiolysis after neuroleptization has been started. This effect can be utilized for: “psychosomatic uncoupling” in disorders with a prominent

psychogenic component; neuroleptanalgesia  by means of the butyrophenone droperidol in combination with an opioid; tranquilization of overexcited, agitated patients; treatment of delirium tremens with haloperidol; as well as the control of mania. It should be pointed out that neuroleptics

do not exert an anticonvulsant action, on the contrary, they may lower seizure thershold.

Because they inhibit the thermoregulatory center, neuroleptics can be employed for controlled hypothermia

Adverse Effects. Clinically most important and therapy-limiting are extrapyramidal disturbances; these result from dopamine receptor blockade. Acute dystonias occur immediately after neuroleptization and are manifested by motor impairments, particularly in the head, neck, and shoulder region. After several days to months, a parkinsonian syndrome (pseudoparkinsonism)

or akathisia (motor restlessness) may develop. All these disturbances can be treated by administration of antiparkinson drugs of the anticholinergic type, such as biperiden (i.e., in acute dystonia). As a rule, these disturbances disappear after withdrawal of neuroleptic medication. Tardive dyskinesia may become evident after chronic neuroleptization for several years, particularly

when the drug is discontinued. It is due to hypersensitivity of the dopamine receptor system and can be exacerbated by administration of anticholinergics. Chronic use of neuroleptics can, on occasion, give rise to hepatic damage associated with cholestasis. A very rare, but dramatic, adverse effect is the malignant neuroleptic syndrome (skeletal muscle rigidity, hyperthermia, stupor) that can end fatally in the absence of intensive countermeasures.

Side effects:

-       extrapyramidal disturbances        -constipation

-       dry month                                       - urinary retention

-       hypotension                                    - theratogenic effect

-       agranulocytosis                              - anemia

-       allergy                                            -  hepatotoxic effect

-       leucopoenia                                      - nefrotoxic effect

-       endocrine disturbances

-       sedation

-       hypothermia

                   -   increased intraocular pressure

Neuroleptic activity profiles. The marked differences in action spectra of the phenothiazines, their derivatives and analogues, which may partially resemble those of butyrophenones, are important in determining therapeutic uses of neuroleptics. Relevant parameters include: antipsychotic efficacy

(symbolized by the arrow); the extent of sedation; and the ability to induce extrapyramidal adverse effects. The latter depends on relative differences in antagonism towards dopamine and acetylcholine, respectively. Thus, the butyrophenones carry an increased risk of adverse motor reactions because they lack anticholinergic activity and, hence, are prone to upset the balance between striatal cholinergic and dopaminergic activity. Derivatives bearing a piperazine moiety (e.g., trifluperazine, fluphenazine) have greater antipsychotic potency than do drugs containing an aliphatic side chain (e.g., chlorpromazine, triflupromazine). However, their antipsychotic effects are qualitatively indistinguishable. As structural analogues of the phenothiazines, thioxanthenes (e.g.,

chlorprothixene, flupentixol) possess a central nucleus in which the N atom is replaced by a carbon linked via a double bond to the side chain. Unlike the phenothiazines, they display an added thymoleptic activity. Clozapine is the prototype of the so-called atypical neuroleptics, a group

that combines a relative lack of extrapyramidal adverse effects with superior efficacy in alleviating negative symptoms.

Newer members of this class include risperidone, olanzapine, and sertindole. Two distinguishing features of these atypical agents are a higher affinity for 5-HT2 (or 5-HT6) receptors than for dopamine D2 receptors and relative selectivity for mesolimbic, as opposed to nigrostriatal, dopamine neurons. Clozapine also exhibits high affinity for dopamine receptors of the D4 subtype,

in addition to H1 histamine and muscarinic acetylcholine receptors. Clozapine may cause dose–dependent seizures and agranulocytosis, necessitating close hematological monitoring. It is strongly

sedating. When esterified with a fatty acid, both fluphenazine and haloperidol can be applied intramuscularly as depot preparations.

Tranquilisators

modify affective responses to sensory perceptions; specifically, they render a subject indifferent

towards anxiogenic stimuli, i.e., anxiolytic action.

                                Classification

I .. Major                                                     II  Minor

A Benzodiazepines:                                          proroxane

-       Diazepam                       fenybut

-       Fenazepam                     propranolol

-       Oxazepam                      mebicar

-       Nitrazepam                     meprobamat

B. Non benzodiazepines                                    pyracetam

-       benzoclidine

-       trimetozine

-       lonetyl

C Compound drugs

-       amixid

-       librax

-       antares 120

D. Antidepressants

-       alrazolam

-       opipramol

Furthermore, benzodiazepines exert sedating, anticonvulsant, and muscle-relaxant myotonolytic,) effects. All these actions result from augmenting the activity of inhibitory neurons and are mediated by specific benzodiazepine receptors that form an integral part of the GABAA receptor-

chloride channel complex. The inhibitory transmitter GABA acts to open the membrane chloride channels. Increased chloride conductance of the neuronal membrane effectively shortcircuits

responses to depolarizing inputs. Benzodiazepine receptor agonists increase the affinity of GABA to its receptor. At a given concentration of GABA, binding to the receptors will, therefore, be increased, resulting in an augmented response. Excitability of the neurons is diminished.

Effects:                                                                                   Indications:

Anxyolytic                                                                  Fears(anxiety), aggression, insomnia,

Sedative                                                                   convulsions, neurosis,

Activator                                                                   enuresis, pain

Hypnotic                                                                 pre and postoperation, stress

Anticonvulsant                                                      reactions , neurodermitis.

Muscle relaxation

Therapeutic indications for benzodiazepines include anxiety states associated with neurotic, phobic, and depressive disorders, or myocardial infarction (decrease in cardiac stimulation

due to anxiety); insomnia; preanesthetic (preoperative) medication; epileptic seizures; and hypertonia of skeletal musculature (spasticity, rigidity).

Since GABA-ergic synapses are confined to neural tissues, specific inhibition of central nervous functions can be achieved; for instance, there is little change in blood pressure, heart rate, and body temperature. The therapeutic index of benzodiazepines, calculated with reference to the toxic dose producing respiratory depression, is greater than 100 and thus exceeds that of barbiturates and other sedative-hypnotics by more than tenfold. Benzodiazepine intoxication can be treated with a specific

antidote (see below). Since benzodiazepines depress responsivity to external stimuli, automotive driving skills and other tasks requiring precise sensorimotor coordination will be impaired.

Triazolam (t1/2 of elimination ~1.5–5.5 h) is especially likely to impair memory (anterograde amnesia) and to cause rebound anxiety or insomnia and daytime confusion. The severity of these

and other adverse reactions (e.g., rage, violent hostility, hallucinations), and their increased frequency in the elderly, has led to curtailed or suspended use of triazolam in some countries (UK).

Although benzodiazepines are well tolerated, the possibility of personality changes (nonchalance, paradoxical excitement) and the risk of physical dependence with chronic use must not be overlooked. Conceivably, benzodiazepine dependence results from a kind of habituation, the functional counterparts of which become manifest during abstinence as restlessness and anxiety; even seizures may occur. These symptoms reinforce chronic ingestion of benzodiazepines.

Side effects: somnolence, vertigo, depressions, Rebound effect, dependence, accumulation, tolerance, confusion, amnesia, agranulocytosis, allergy, and prolonged sleep

Benzodiazepine antagonists, such as flumazenil, possess affinity for benzodiazepine receptors, but they lack intrinsic activity. Flumazenil is an effective antidote in the treatment of benzodiazepine

overdosage or can be used postoperatively to arouse patients sedated with a benzodiazepine.

Whereas benzodiazepines possessing agonist activity indirectly augment chloride permeability, inverse agonists exert an opposite action. These substances give rise to pronounced restlessness,

excitement, anxiety, and convulsive seizures. There is, as yet, no therapeutic indication for their use.

Flumazenil is antagonist of anxiolytics .

Sedatives drugs

Drugs used to inhibit agitation, stress, and insomnia

            Classification:

1)    Natural drugs: T-rae Valerian

                                                             T-rae Leonur

2)    Synthetics

                                Bromides (Na, K)

3) Barbiturates        Phenobarbital, pentobarbital

4) Compound          Corvalol

 

Mechanism of action: This drugs activate the inhibited  reactions in the brain, by interacting  with serotonine and dopamine

Indications: neurosis, agitations, insomnia etc…

Side effects: somnolence, vertigo, bromism (nausea, vomiting, tremor, vertigo),                       accumulation.

Lithium

 Lithium carbonate

Mechanism of action: is not well defined. The drug inhibits the recycling of neuronal membrane phosphoinositides involved in the generation of inositol triphosphate and diacylglycerol. This second messengers are important in amin neurotransmission, including that mediated by central adreno and muscarinoreceptors.

Indications: treatment of bipolar affective disorder (maniacal-depressive disease).

Therapy with lithium decreases manic behavior and reduces both the frequency and the magnitude of mood swings.

Manic-depressive illness connotes a psychotic disorder of affect that occurs episodically without external cause. In endogenous depression (melancholia), mood is persistently low. Mania refers to the opposite condition . Patients may oscillate between these two extremes with interludes of normal mood. Depending on the type of disorder, mood swings may alternate between the two directions (bipolar depression, cyclothymia) or occur in only one direction (unipolar depression).

Side effects: tremor, sedation, headache, diarrhea, polyuria, hyponatriemia, ataxia, edema, leukocytosis, skin eruptions, congenital cardiac anomalies (Ebstein’s malformations)

This drug is used in prophylaxis of maniacal-depressive activation.No effects on acute mania. !

Lithium is clinically effective at a plasma concentration of 0,5-1 mmol/l and above 1,5 mmol/l it produces a variety of toxic effects.