DRUGS ANTIPSYCHOTICS

View previous topic View next topic Go down

DRUGS ANTIPSYCHOTICS

Post  counselor on Mon Oct 15, 2012 12:10 pm

DRUGS ANTIPSYCHOTICS

Schizophrenia is a chronic disease characterized by positive symptoms such as:
• hallucinations
• delusions
• agitation
and negative symptoms such as:
• anhedonia,
• attention difficulties
• affective flattening
• cognitive disorders
Affects 1% of world population.

Several neurotransmitter systems have been implicated in its pathogenesis:

Dopaminergic hypothesis
• It 's the first that has been proposed (Van Rossum 1966) and remains the most reliable.
• E 'supported by the fact that there is good correlation between the effect of antipsychotic drugs and their affinity for D2 receptors.
• Analysis conducted with PET showed increased number of D2 receptors in the brains of schizophrenics.

Serotonergic hypothesis
It 'supported by the following evidence:
• altered density and altered function of transduction systems of 5-HT2A receptors in the brains of schizophrenic subjects
• Many newer antipsychotic drugs are potent 5-HT2A receptor antagonists.

Glutamatergic hypothesis
It 'supported by the following evidence:
• non-competitive antagonists of the NMDA receptor induce psychotic symptoms
• Haloperidol has been reported to increase the expression of the subunit 1 of the NMDA receptor and reduce the expression of transporters for glutamate.
• The glutamatergic markedly influences the dopaminergic.

GABAergic hypothesis
• Imbalances of GABAergic transmission in the cortex could give an account of changes in dopaminergic subcortical level.
Conventional antipsychotic drugs (TYPICAL)

The conventional antipsychotic drugs include phenothiazines, thioxanthenes, dibenzodiazepine and dibenzoxazepine, butirrofeni,


Pharmacodynamics

The conventional antipsychotic drugs induce:
• Reduction of positive symptoms such as delusions, hallucinations and agitation
• Decrease in aggressive behavior.
• Negative symptoms are not improved, however. Therefore observed reduction in spontaneous movements, reduction of initiative and concern for the environment.
• The unconditional behavior (escape or avoidance responses unconditional) is not inhibited, while the conditioned avoidance is inhibited. This occurs due to impairment of cognitive processes.

Mechanism of Action
The antipsychotic activity correlates very well with the affinity of drugs for dopamine D2.
These receptors are both presynaptic, postsynaptic that
The hypothesis is that conventional antipsychotics act by blocking central dopaminergic mechanisms (action dopaminolitica).

After acute administration
Predominant presynaptic D2 receptor blockade, so you can see:
• Increased frequency of firing of dopaminergic neurons.
• Increased production of metabolites of dopamine (3-methoxytyramine, dihydroxyphenylacetic acid and homovanillic acid).
• Increased conversion of tyrosine to dopamine.

After chronic administration
It is observed reduction in the frequency of discharge of dopaminergic neurons.
Compare block by depolarization of neurons
This effect, together with blockade of postsynaptic dopamine receptor D2, determines action dopaminolitica and subsequent onset of schizophrenia.



Other effects of antipsychotic drugs

On the other hand antipsychotic drugs to block D2 receptors, inducing:
• antiemetic effect. Reduce vomiting induced by drugs that stimulate Chemoreceptor trigger zone (CTZ) in the area postrema level of the medulla oblongata. Decreased by less vomiting by vestibular stimulation, not antagonize emetic agents acting on the gastrointestinal tract.
• Increased secretion of prolactin. Also inhibit the secretion of ADH and GH.

To block adrenergic receptor  1, induce:
• Mild hypotension
• After weeks develops tolerance to the hypotensive effect, but can remain orthostatic hypotension.

To induce blockade of muscarinic receptors:
• Effects on exocrine glands and
• on gastrointestinal function.

Tolerance and Physical Dependence
Phenothiazines do not produce drug dependence.
Days after tolerance develops especially for neurological effects in the basal ganglia. Poor tolerance to the effects of cortical and limbic.
Physical dependence is manifested by difficulty in falling asleep and dyskinesia on abrupt treatment.

PHARMACOKINETICS
• Absorption irregular species when administered orally in tablet form.
• The absorption is decreased by food, by antacids and anticholinergic drugs.
• The maximum plasma concentrations in 2-4 hours you have.
• The bioavailability is 10 times greater for im administration Injectable depot forms (decanoic acid esters) are used for subjects with very low compliance.
• Strong distribution of the brain.
• The drug in the blood is bound to albumin in a high percentage.
• Elimination very slow (t1 / 2 conc. = Plasma 20-40 hours)
• Elimination primarily metabolic by hepatic microsomal enzymes: CYP2D6, CYP2C19, CYP3A4

TOXICITY '
Extrapyramidal neurological effects:
Akathisia: a sense of pain and discomfort in the legs, need to keep moving, even difficulty in controlling movements. Can respond to -blockers
Acute dystonia: contractions of the jaw, tongue protrusion, torticollis, oculogyric crisis. May respond to anticholinergics.
Parkinsonian syndrome: reduction movements, rigidity and tremor at rest. It comes with anticholinergic or dopaminergic receptors.
Neuroleptic malignant syndrome: similar to severe parkinsonism with catatonia, hyperthermia, arrhythmias, unstable pressure. Death in 10% of cases.
Tardive Dyskinesia: Compare in 10-20% of patients. It is manifested by succhiamenti and schiocchii lips, lateral movements of the jaw and tongue flicks. Seems to be due to up-regulation of D2 receptors, resulting in protracted all'suo diantagonisti.

Phenothiazines lower the seizure threshold for seizures access (Caution in epileptics)

Endocrine effects
The increase in prolactin causes gynecomastia in the male, with loss of libido and impotence in the female causes galactorrhea and menstrual disorders.

Effects on SNA
Dry mouth, feeling of blockage of the nose, blurred vision, urinary retention. Feeling cold and sleepy.
orthostatic hypotension and hypothermia

Liver damage
Can be observed liver dysfunction and jaundice

Disorders of blood counts
May occur eosinophilia, leukopenia, agranulocytosis

Skin reactions
Hypersensitivity reactions, photosensitivity and blue-gray pigmentation.


INTERACTIONS WITH OTHER DRUGS
• Phenothiazines potentiate the effects of sedatives, hypnotics, analgesics, ethyl alcohol on the CNS.
• Can exacerbate orthostatic hypotension of various antihypertensive drugs.
• Stabilize the inotropic effect of digitalis.
• interact with drugs that act on receptors for histamine, serotonin, acetylcholine and catecholamines.
• Phenobarbital accelerates the metabolism of phenothiazines.

THERAPEUTIC USE
• Schizophrenia and schizo-affective syndromes
Able to control hyperactivity, hostility,
hallucinations, delirium, tendency to withdrawal.
Not result in improvement of depression, and
cognitive function.
In schizophrenic patients are required to observe at least three weeks antipsychotic. If you stop the therapy has a high likelihood of relapse (50%). Intermittent therapy may be useful.
The optimum dosage should be determined experimentally
• manic phase of bipolar disorder
• senile psychosis
• borderline personality disorders (psychosis, drug abuse, autism, Huntington's disease, Gilles de la Tourette)
• They are used as anti-emetic drugs


ANTIPSYCHOTICS UNCONVENTIONAL or ATYPICAL

The term has been used to indicate antipsychotic presenting:
• lower incidence of extrapyramidal adverse reactions
• more effectively to the negative symptoms of schizophrenia
• minor increase in prolactin

CLOZAPINE
The first member of the class was clozapine.
Clozapine has the following profile of receptor affinity:
D4 =  1> 5-HT2> D1> D2
Compared to haloperidol
D2> D1 = D4> a1> 5-HT2

Olanzapine
Such as clozapine has also affinity for D4 receptors and 5-HT2 receptors in addition to D2 and D1.

RISPERIDONE
The risperidone has not only strong affinity for D2 receptors, but also 5-HT2 receptors. It also has a certain affinity for D4 receptors.

REMOXIPRIDE and raclopride
These two atypical antipsychotics are antagonists of both receptors D2 receptor D3.
And ZIPRASIDONE QUETIAPINE.
Show strong antagonism for 5-HT2 receptors as well as for D2.

ARIPRIPAZOLO
E 'D2 receptor antagonist and partial agonist for the 5-HT1A receptor


TOXICITY '
• Atypical antipsychotics have much lower incidence of extrapyramidal symptoms. Quetiapine and ziprasidone are practically free of these effects.
• However, tardive dyskinesia and neuroleptic malignant syndrome may occur, although less frequently
• Clozapine and to a lesser extent olanzapine may cause agranulocytosis, probably with radical mechanism.
• Increased weight especially after clozapine and olanzapine. The effect appears to be due to antagonism of 5-HT2C receptors and H1.
• Increase then circulating leptin levels. This helps to reduce insulin release and reduces the sensitivity of the tissues in the periphery.
The result is the so-called metabolic syndrome =
insulin resistance, dyslipidemia and obesity
• Even the atypical damage hyperprolactinemia and sexual dysfunction
• Clozapine causes orthostatic hypotension in excess of olanzapine, risperidone and quetiapine.

THERAPEUTIC USE
• Schizophrenia and schizo-affective syndromes
They are able to control not only hyperactivity, hostility,
hallucinations, delirium, but also evoke improvement
depression and cognitive function.
• manic psychosis
• Depression with psychotic features

Are drugs of choice in the treatment of these diseases because compared with conventional antipsychotics are:
• improved handling,
• effectiveness even on negative symptoms.
• more effective on positive symptoms

They have the disadvantage of being much more expensive than typical antipsychotics, however, minor damage frequency of re-hospitalization.


Why do some atypical antipsychotics are?

There have been many assumptions made about the role played by various receptors other than D2:

• E 'was assumed the role of D1 receptors, for which clozapine and quetiapine show good affinity.
But D1-selective agonists are devoid of antipsychotic activity.
• E 'was suggested an important role for D4 receptors which have an affinity for clozapine, olanzapine and risperidone. However, D4-selective agonists have antipsychotic activity.
• Perhaps the most likely hypothesis is that the antagonism of 5-HT2A receptor contributes to atypical dell'antipsicotico.
• The hypothesis that atypical depends on antagonism "combined" for 5-HT2 and D2 receptors (Meltzer, Psychopharmacology 99: S18-S27, 1989) has stimulated the development of compounds with 5-HT2 antagonist.
• E 'was suggested that it is important for the purposes of atypicality if the affinity for the 5-HT2 receptors in the cortex is greater than for D2 in striatum
However, the 5-HT2A receptor antagonism does not seem sufficient for antipsychotic effect.




• E 'has also been proposed that a certain stimulation of 5-HT1A receptors may be responsible for the atypical clozapine and aripiprazole; however, risperidone and olanzapine do not have affinity for this receptor
• E 'was proposed, although no clear evidence, a role for muscarinic receptors,  1-adrenergic, 5-HT2C, 5-HT6, 5-HT7.

On the other hand have been hypothesized explanations of more general meaning, not related to receptors other than dopamine.

1. The atypical might result from the increased release of glutamate in the prefrontal cortex, observed several atypical antipsychotics

2. PET has documented at the level of striatum greater% occupancy of D2 receptors with typical antipsychotics than with atypical. This could be due to different dissociation constant of the various compounds from the D2 receptor.
The need for fewer D2 receptors in the striatum may explain the lower incidence of extrapyramidal disorders.





VOMITING

Coordinate changes of the gastrointestinal and respiratory movements:
1) Inhale and contract your abdominal muscles.
2) Close the epiglottis, soft palate lift.
3) Contraction of the pylorus and the fundus and cardia and esophagus sphincter relax.
4) Eject gastric contents

CENTER OF VOMITING: Located ventrally with respect to the nucleus of the solitary tract in the medulla oblongata. Has close relations with centers of the mouth, breathing and vague.

Excitatory impulses to the vomiting center:
a) Receptors intracranial pressure
b) gastrointestinal receptors sensitive to muscle tension and chemical stimuli.
c) From the vestibular nuclei that receive information source cholinergic
d) receptors in pain
e) From the cerebral cortex (disgusting feelings, conditioned reflexes, emotion)
f) From the CTZ (chemoreceptor trigger zone) by mediating the synaptic dopaminergic (astrocytes to neurons).
avatar
counselor
Admin

Posts : 172
Join date : 2012-09-01
Age : 32

View user profile http://www.myhelpforum.net

Back to top Go down

View previous topic View next topic Back to top


 
Permissions in this forum:
You cannot reply to topics in this forum