What makes an antipsychotic drug atypical?
Atypical drugs generally have greater 5-HT2 than D2 receptor occupancy.
The discovery of these drugs is relatively recent and new atypical drugs are produced each year since no two drugs have the same receptor blockade.
The first atypical antipsychotic drug introduced into medicine.
It is the only antipsychotic drug that is effective in treating schizophrenics who are unresponsive to other medications.
The effects produced by this drug surpass those of traditional antipsychotics since it alleviates much of the negative symptoms with minimal EPS.
It is less of a cognitive inhibitor than previously used drugs.
There is evidence that this drug may actually improve core deficit schizophrenia by improving:
A phenomenon known as “waking” is observed in schizophrenics under clozapine therapy.
It has also shown marked improvement in patients with Parkinson’s disease.
Clozapine Induced Agranulocytosis:
In 1975, several schizophrenic patients under clozapine treatment died of agranulocytosis, a disease characterized by the loss of white blood cells in the blood stream. Consequently clozapine was taken off of the market.
Clozapine was reexamined later reexamined since agranulocytosis was discovered to be a reversible condition and the drug was found to be therapeutically beneficial to schizophrenic patients.
One particular study was conducted using 318 severely psychotic patients and found a 30% improvement rate in those who were unresponsive to other drugs.
In the same study, only 1 to 2 % of patients developed agranulocytosis.
This percentage of mortality among patients is almost negligible in comparison to the 10% of schizophrenics that commit suicide when they are left untreated.
The pharmacokinetics of clozapine varies extensively among patients.
It is well absorbed orally and most of the metabolism occurs when the drug reaches the plasma and enters the liver, prior to its distribution throughout the body.
The drug peaks in one to four hours.
Clozapine is metabolized in the liver into two major metabolites, which are both pharmacologically benign.
The half life of the drug is 9 to 30 hours
The optimum plasma level of clozapine is 200 to 350ng/mL and therefore monitoring blood levels may aid in treatment. Blood is also monitored for WBC count.
Clozapine has a high binding affinity for dopamine4, serotonin1C, serotonin2, alpha1, muscarinic, and histamine receptors. In addition, a moderate affinity is seen for many other receptor types
What makes clozapine unique is that it is a mixed but weak D1/D2 antagonist. It has been speculated that synergism between D1 and D2 receptors may allow therapeutic effects to occur below the level needed to elicit unwanted motor side effects.
Clozapine has a low rate of binding to D2 receptors and has a greater 5-HT2 blockade at therapeutic doses. This binding ratio defines an atypical antipsychotic drug.
Side Effects and Cost:
Unfortunately, clozapine yields a myriad of side effects that range from mild to severe.
Some side effects include sedation, weight gain, withdrawal, constipation, agranulocytosis, urinary incontinence, hypotension, esophagitis, seizures, and excessive drooling.
Withdrawal from clozapine is associated with delusions, hallucinations, hostility and paranoia.
At times, olanzapine has been used to block the withdrawal symptoms of clozapine.
Clozapine therapy is much more expensive than that of other conventional of atypical antipsychotic drugs.
Those taking the drug must have their blood monitored at regular intervals to screen for potential agranulocytosis.
Currently, the annual cost of clozapine therapy is estimated at $6,000 per year.
This drug was first marketed in 1993 and acts as a potent inhibitor of D2 and 5-HT2 receptors.
Risperidone is a serotonin antagonist and its action can result in decreased incidence of psychotic symptoms with minimal EPS.
Risperidone is well absorbed when taken orally and is highly bound to plasma proteins.
It is metabolized by 9-hydroxy-risperidone, which serves as an active intermediate.
The rate of metabolism varies according to genetic differences.
The half-life of Risperidone is three hours.
Many studies have concluded that Risperidone is as effective as haloperidol in reducing the positive symptoms associated with schizophrenia without EPS.
Risperidone is equivalent to clozapine in relieving negative symptoms but not as effective in relieving the positive symptoms.
This is considered a first line agent in treating schizophrenia due to its efficacy and favorable safety profile.
Few cognitive deficits and extrapyramidal side effects are noticed at moderate therapeutic dosages.
Side effects of Risperidone include sedation, agitation, anxiety, insomnia, headaches, and nausea.
The likelihood of EPS increases with doses above 8 mg/day.
In schizophrenics with no previous exposure to antipsychotic drugs the EPS that occurred were identical to those produced by haloperidol, even at low doses.
This led researchers to believe that risperidone is not the ideal medication for newly diagnosed schizophrenics without any prior exposure to antipsychotic medications.
This drug is structurally related to clozapine and is capable of blocking dopamine and serotonin receptors.
The greater serotonin blockade is responsible for the low incidence of EPS.
Improvements in both positive and negative symptoms have been observed in studies and minimal EPS were noticed.
Olanzapine may be more effective in less severely psychotic schizophrenics.
There is a considerable source of bias associated with the studies that show a favorable outcome for olanzapine.
Sedation, dizziness, dry mouth, hypotension, and weigh gain were the major side effects noted and cognitive function is only minimally impaired in individuals taking this drug.
This drug is seen to be as effective traditional antipsychotic drugs in alleviating the symptoms associated with schizophrenia.
Very few instances of EPS were seen in schizophrenic patients undergoing this treatment.
This drug is absorbed poorly when taken orally but the amount that is absorbed is efficiently metabolized into inactive byproducts.
The half-life for ziprasidone is only six hours.
What makes this drug unique is its receptor actions, in addition to blocking 5-HT2 and D2 receptors, it acts as an agonist at 5-HT1A receptors.
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