Professional Documents
Culture Documents
Antipsychotics
Antipsychotics
Thioxanthenes: flupenthixol,thiothixene
Butyrophenones: haloperidol, trifluperidol Dihydroindolones: molindone
Dibenzoxazepine: loxapine
Phenothiazines: three structural groups
OLDER DRUGS
clozapine
risperidone olanzapine
Quetiapine
Aripiprazole Ziprasidone amisulpirde
Block dopamine receptors in the brain (limbic system, basal ganglia)areas associated with emotion, cognitive function, motor function Dopamine levels in the CNS are decreased
Result: tranquilizing effect in psychotic patients
The newer, atypical antipsychotics also block specific serotonin receptors (serotonin-2 [5HT2] receptors).
This is responsible for their improved efficacy and safety profiles.
Antipsychotics/Neuroleptics
It appears that the specific interaction of antipsychotic drugs with D2 receptors is important to their therapeutic action.
The affinities of most older classical agents for the D2 receptors correlate with their clinical potencies as antipsychotics.
Antipsychotics/Neuroleptics
Both D1 and D2 receptors are found in high concentrations in the striatum and the nucleus accumbens. Clozapine has a higher affinity for the D4 receptors than for D2. Recently it has been found that most antipsychotic drugs may also bind D3 receptors (therefore, they are non-selective).
Antipsychotics/Neuroleptics
hyperprolactinemia
Antipsychotics/Neuroleptics
The acute effects of antipsychotics do not explain why their therapeutic effects are not evident until 4-8 weeks of treatment. Blockade of D2 receptors
Firing rate and activity of nigrostriatal and mesolimbic DA neurons. DA synthesis, DA metabolism, DA release
Antipsychotics/Neuroleptics
Presynaptic Effects Blockade of D2 receptors Compensatory Effects
Firing rate and activity of nigrostriatal and mesolimbic DA neurons. DA synthesis, DA metabolism, DA release.
Receptor Supersensitivity
Antianxiety effects
Pharmacokinetics
Absorption and Distribution
Slow elimination.
**Duration of action longer than expected, metabolites are present and relapse occurs, weeks after discontinuation of drug.**
Pharmacokinetics Metabolism
Most antipsychotics are almost completely metabolized. Most have active metabolites, although not important in therapeutic effect, with one exception. The metabolite of thioridazine, mesoridazine, is more potent than the parent compound and accounts for most of the therapeutic effect.
Pharmacokinetics Excretion
Antipsychotics are almost completely metabolized and thus, very little is eliminated unchanged.
Antipsychotic/Neuroleptics
Butyrophenone
Phenothiazine
Thioxanthene
[Drug dose]
Antipsychotic/Neuroleptics
Chlorpromazine: 1 = 5-HT2= D2>D1 >M>2
Haloperidol: D2>D1= D4>1>5-HT2 >H1>M = 2 Clozapine: D4 = 1>5-HT2 = M>D2 = D1 = 2;H1 Quetiapine: 5-HT2 = D2 = 1 = 2; H1 Risperidone: 5-HT2 >>1 >H1 >D2 >2>>D1
Sertindole: 5-HT2>D2=1
Schizophrenia Schizoaffective disorders Acute control of mania Tourettes syndrome Huntingtons chorea and ballism Intractable hiccups
Antipsychotic/Neuroleptics
Clinical Problems with antipsychotic drugs:
1) 2)
a) b) c) d) e)
3)
Poor Concentration
CNS Cardiovascular
Sedation, delirium, drowsiness Orthostatic hypotension, syncope, dizziness, ECG changes Photosensitivity, skin rash, hyperpigmentation, pruritis
Dermatologic
High Potency
GI GU Hematologic Metabolic/endocrine
Dry mouth,constipation Urinary hesitancy or retention, impaired erection Leukopenia and agranulocytosis Galactorrhea, irregular menses increased appetite, polydipsia
Antipsychotic/Neuroleptics
Neuroleptic Malignant Syndrome
Occurs in pts. hypersensitive to the Ex.Py. effects of antipsychotics. Due to excessively rapid blockade of postsynaptic dopamine receptors. The syndrome begins with marked muscle rigidity. If sweating is impaired, a fever may ensue. The stress leukocytosis and high fever associated with this syndrome may be mistaken for an infection.
Autonomic instability with altered blood pressure and heart rate is another midbrain manifestation.
Creatine kinase isozymes are usually elevated, reflecting muscle damage.
Antipsychotic/Neuroleptics
Neuroleptic Malignant Syndrome
Treatment
Vigorous treatment with antiparkinsonian drugs is recommended as soon as possible. Muscle relaxants such as diazepam, dantrolene or bromocriptine may be helpful.
Antipsychotic/Neuroleptics
Drug Interactions
Can substitute for sodium in generating action potentials may affect ionic fluxes May decrease norepineprine and dopamine turnover Inhibits inositol monophosphatase -Inhibits the conversion of IP2 to IP1 leads to depletion of PIP2 reduced IP3 and DAG -effects of transmitter on the cell diminished
Pharmacokinetics:
well absorbed orally Initially distributed extracellularly, not metabolised Excreted mostly in urine. found in saliva and sweat. Plasma concentration:0.6-1.25 mEq/L
Indications:
bipolar affective disorder Acute manic episode Adjunct to antidepressants in severe recurrent depression Schizoaffective disorders Cancer chemotherapy induced leucopenia SIADH
Adverse effect:
a)neurologic: tremor , Choreoathetosis, ataxia
b)thyroid function: benign, diffuse,nontender thyroid enlargement c)renal: polyuria,polydipsia-loss of ability of kidney to concentrate urine nephrogenic diabetes insipidus long term use chronic interstitial nephritis d)Edema, increase in polymorphonuclear leukocytes
g)misc:nausea,diarrhea,sedation,acneiform eruptions.
Acute intoxication: vomiting, profuse diarrhea, coarse tremor, convulsions, Cardiac arrhythmia, hypotension
Treatment: supportive
Osmotic diuretics and sodium bicarbonate Hemodialysis
Interactions:
1.Diuretics decreased renal clearance 2.insulin/sulphonylureas Sodium valproate: efficacy equivalent to that of lithium Carbamazepine: reasonable alternative to lithium