Pharmacology set 3
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CLINICAL SYMPTOMS OF SCHIZOPHRENIA .
Psychiatrists have designated many subtypes of schizophrenia depending on the particular symptoms shown. The symptoms of schizophrenia are usually divided into positive and negative characteristics
1. religious, grandiose, or persecutory delusions 2. hallucinations (auditory and/or visual) 3. paranoia, thought disorders, withdrawal – violence to objects, other people and themselves may occur
1. apathy 2. lack of motivation 3. inability to think and communicate clearly 4. lack of energy 5. withdrawal from society
BIOCHEMICAL BASIS OF SCHIZOPHRENIA
A simple molecular model of schizophrenia has suggested that schizophrenia is due to an overproduction of dopamine or oversensitivity of dopamine receptors in the mesolimbic and mesocortical areas of the brain. This model is too simple, but we will use it.
The newer atypical antipsychotics (clozapine, olanzapine and risperidone) appear to block serotonin receptors as well as dopamine2 receptors. The atypical antipsychotics are claimed to be more effective in treating the negative symptoms of schizophrenia than the older drugs and claimed to show fewer extrapyramidal adverse effects. They have also shown some efficacy in treating patients with bipolar disorder, depression (affective disorder) or a combination of schizophrenia and depression (schizoaffective disorder). Most of the atypicals have been approved for used with the manic phase of bipolar disorder and some forms of autism.
- Older antipsychotics
- Many of the side effects are due to the fact that these drugs also blockade other brain receptors: 1. dopamine blockade in striatum results in adverse extrapyramidal effects analogous to Parkinson’s disease 2. blockade of cholinergic, 1, and histamine receptors
Other adverse effects of the older antipsychotics:
Early onset, reversible effects 1. acute dystonia – severe stiffness and spasms of tongue, face, neck, back 2. akathisia – pacing and squirming, profound restlessness 3. neuroleptic malignant syndrome (rare but potentially fatal) – extreme rigidity, high fever, heart dysrhythmias and fluctuations in blood pressure.
Adverse effects which appear later (often after years)
1. tardive dyskinesia develops in long term patients – writhing movements of tongue and face, "fly-catching" motion, lip smacking – progresses into involuntary movement of limbs and trunk. Geriatrics are at particular risk.
(high potency, 2-5 mg) Used for treatment of schizophrenia. Short term use to sedate severe behavior problems. Available orally, IM doses, and IM depot preparations(Long term (2 week) IM depot injections available.
Adverse effects of Haloperidol:
1. frequent extrapyramidal reactions due to blockade of dopamine receptors in striatum. Extrapyramidal symptoms reduced by giving Cogentin, an anticholinergic drug. Blocking both dopamine and acetylcholine receptors in the striatum seem to reduce extrapyramidal symptoms in many patients. 2. anticholinergic effects less than in chlorpromazine 3. tardive dyskinesia 4. neuroleptic malignant syndrome, photophobia, seizures less of a problem than thorazine 5. strong sedative effect; often used for that purpose.
(low potency-30-2000mg/day) Thorazine is no longer used. In general, the older antipsychotics have been replaced by the atypical antipsychotics. They are called atypical because they 5 claimed to have fewer adverse effects than typical antipsychotics. The atypicals have become the first line drugs for treating schizophrenia.
Adverse effects of Chlorpromazine :
1. strong anticholinergic effects – dry mouth, urinary hesitancy, etc. 2. sedation (anti-histamine) 3. anti 1 – orthostatic hypotension and impotence 4. Lesser extrapyramidal effects – dystonia, Parkinsonism, akathisia is lower than Haldol but still significant tardive dyskinesia 5. photochemical sensitivity 6. increased likelihood of seizures
- Atypical antipsychotics are claimed to have fewer adverse side effects than the older drugs and to work better on the negative symptoms of schizophrenia than the positive effects. They are also being prescribed for a wide variety of other conditions: bipolar disorder, anger syndromes, autism, obsessive compulsive disorder, generalized anxiety disorder, post-traumatic syndrome, elderly dementia and agitation and other conditions.
- Atypical antipsychotics block serotonin receptors as well as mesolimbic dopamine D2 receptors. The blockade of the serotonin receptors seems to reduce the adverse symptoms due to dopamine blockade. Hence they produce fewer extrapyramidal effects.
General adverse effects of atypical antipsychotics:
1) Sedation 2) Weight gain(especially olanzapine) average of 15% weight gain in one study 3) Hyperglycemia (type II diabetes)(especially Zyprexa and Seroquel) 4) Increased risk of sudden heart attacks/cardiac death (~ twice that of those not taking antipsychotics), but typical antipsychotics increase risk comparably. 5) Elevated cholesterol and triglycerides 6) Prolonged QT interval 7) Adverse effects due to blockade of 1, histamine and acetylcholine receptors. 8) Tardive dyskinesia
1990) 1. Clzapine was the first of the atypical antipsychotics on the market (1990). The major problem with clozapine is a risk of agranulocytosis (absence of granular leukocytes, a type of white blood cell) in 1-2% of patients taking the drug.Risk of death 1 in 5000 patients on clozapine. Weekly blood testing 6 required and it is rarely prescribed except in cases resistant to all other antipsychotics.
( 1995)(now available as a generic)
1996) weight gain is a particularly common problem. 16% of olanzapine patients gained at least 30 kg (66 pounds). "As of 2009, Lilly has paid $1.2 billion to settle 8,000 lawsuits from people who said they had developed diabetes or other diseases after taking Zyprexa. Thousands more suits are still pending." Lilly also paid 1.42 billion dollars for illegal marketing of off label uses of Zyprexa
)(1997): weight gain and sedation are common problems
)(2002)-less weight gain than other atypicals
)(2000). Adverse effects: somnolence, nausea
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