Nervous System- Anti-Psychotics By Schriefer

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Nervous System- Anti-psychotics by Schriefer

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Nervous System- Anti-psychotics by Schriefer

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Schizophrenia

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a disorder in which thought processes diverge from reality. Patients may manifest disorders of perception, thinking, speech, emotion or physical activity. The symptoms have been divided into 2 broad categories

Positive symptoms – delusions, hallucinations, disorganized speech and catatonic behavior.
Negative symptoms – flattened affect, lack of motivation, withdrawal, and poor speech.

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Biological Theories

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Antipsychotics block dopamine receptors, so increased and unregulated dopamine activity causes psychosis

Recent studies suggest that nicotinic receptors may be involved in the pathophysiology of schizophrenia

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Typical Anti-psychotics

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*Chlorpromazine (Thorazine)
*Thioridazine (Mellaril)
Fluphenazine (Prolixin)
Perphenazine (Trilafon)
Thiothixene (Navane)
*Haloperidol (Haldol)
Loxapine (Loxitane)

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Atypical Anti-psychotics

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Clozapine (Clozaril)
Risperidone (Risperdal) Paliperidone (Invega)
Olanzapine (Zyprexa)
Quetiapine (Seroquel)
Ziprasidone (Geodon)
Aripiprazole (Abilify)
Asenapine (Safris)
Iloperidone (Fanapt)

newer, different receptor binding profiles.

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Receptor interactions of antipsychotic drugs

what do all do to some extent?

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All antipsychotics block D2 receptors but the importance of this in relation to other receptor actions varies from drug to drug. Many receptors are involved in antipsychotic effects. The receptor binding profiles of three antipsychotics illustrates this point

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Receptor Binding Profiles

haloperidol, clozapine, olanzapine

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haloperidol : D2 > D1 = D4 > a1 > 5 HT2
Clozapine : D4 = a1 > 5 HT2 > D2 = D1
Olanzapine : 5HT2A>H1>D4>D2>α1>D1

bind to receptors to block them!

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Pharmacological Properties

D2 blocking does what?
D4, 5HT2 blocking does what?

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“Atypical” antipsychotics have different receptor binding profiles, but they all tend to be less potent at D2 receptors than chlorpromazine or halperidol and more potent at 5HT2 and D4 receptors.

Aripiprazole is a partial agonist at DA2 and 5HT1a receptors, claimed to represent a “new generation” of antipsychotics.

Glutamate receptors latest target.

Blocking D2 receptors alleviates positive symptoms of schizophrenia (tension, hostility, hyperactivity, combativeness, hallucinations, delusions, insomnia, and anorexia.

Blocking D4 and 5HT2 receptors may alleviate negative symptoms (apathy, withdrawal, unresponsiveness).

both attack positive sx, but atypicals attack negative sx better.

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CNS effects

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CNS effects:
Cortex – little known; EEG changes; antipsychotic effects
Limbic system – antipsychotic effects. Combine with cortical effects to produce psychomotor slowing and affective indifference (emotional quieting and sedation).
Basal ganglia – antidopaminergic action appears to be responsible for Parkinson-like extrapyramidal effects.
Hypothalamus – increased prolactin secretion; temperature regulations
Medullary chemoreceptor trigger zone (CTZ) – antiemetic action DMV – increased eating

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Mesolimbic
Mesocortical
Migrostriatal
Tuberoinfundibular

Pathways

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1. Mesolimbic- overactivity causes the positive sxs
2. Mesocortical- decreased activity causes negative sxs
3. Nigrostriatal- blocking this causes extrapyramidal (parkinson) sx
4. Tuberoinfundibular- inhibition here causes increase prolactin release

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Peripheral effects
ANS
Endocrine
CV

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Peripheral effects:
Autonomic nervous system – peripheral cholinergic block, a-adrenergic block

Endocrine – alterations in the secretion of many hormones

Cardiovascular system – direct depressant effect on heart, direct vasodilation plus indirect effects due to ANS effects

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Disposition: absorption, distribution, metabolization, elimination

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Absorption after oral administration varies from drug to drug; can be as low as 25%.

Distribution – highly lipid soluble so sequestered.

Metabolized by oxidation and glucuronide conjugation. Some active metabolites formed. It is thought that an active metabolite of clozapine, norclozapine, is responsible for the serious side effect of clozapine.

Elimination T ½ - 10-20 hours. Biological effects last 24 hours or more

Multiple daily doses needed at beginning; single daily dose for maintenance.

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Adverse reactions

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CV, endocrine, central and autonomic are most important. Other dangerous effects include seizures, agranulocytosis and pigmentary degeneration of retina.

Neurologic – Alteration of extrapyramidal system (EPS) associated with high D2 potency (eg haloperidol) and less likely with atypicals (eg clozapine)

Early onset – Parkinson syndrome, akathisia, and acute dystonic reactions

Late onset - tardive dyskinesia, perioral tremor

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Neurological Side Effects of Antipsychotic Drugs:
Acute dystonia

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Features: Spasm of muscles of tongue, face, neck, back; may mimic seizures; not hysteria

Time of max risk: 1 to 5 days

Tx: Many treatments can alter, but effects of antimuscarinic agents are diagnostic and curative.*

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Neurological Side Effects of Antipsychotic Drugs:
Akathisia

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Features: Motor restlessness: not anxiety or “agitation”

Time of max risk: 5 to 60 days

Tx: Reduce dose or change drug; antimuscarinic agents, dephenhydramine, benzodiazepines, or propranolol ++ may help

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Neurological Side Effects of Antipsychotic Drugs:
Parkinsonism

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Features: Bradykinesia, rigidity, variable tremor, mask facies, shuffling gait

Time of max risk: 5 to 30 days

Mechanism: antagonism of dopamine

Tx: antimuscarinic agents helpful

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Neurological Side Effects of Antipsychotic Drugs:
Neuroleptic Malignant syndrome

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Features :catatonia, stupor, fever, unstable blood presure, myoglobinemia; can be fatal

Time of max risk:weeks; can persist for days after stopping neuroleptic

Mechanism: antagonism of dopamine may contribute

Tx: stop antipsychotic immediately; dantrolene or bromocriptine may help§; antimuscarinic agents not effective

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Neurological Side Effects of Antipsychotic Drugs:
Perioral tremor (“rabbit” syndrome)

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Features: perioral tremor (may be a late variant of parkinsonism)

Time of max risk: after months or years of treatment

Mechanism: unknown

Tx: Antimuscarininic agents often help+

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Neurological Side Effects of Antipsychotic Drugs:
*Tardive dyskinesia

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Features: oral-facial dyskinesia; widespread choreoathetosis or dystonia

Time of max risk: after months or years of treatment (worse on withdrawal)

Mechanism: up regulation of striatal D2 receptors

Tx: prevention crucial; clozapine or olanzapine may help

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Cardiovascular and cerbrovascular effects

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Orthostatic hypotension – peripheral a blockade
QT prolongation (thioridazine, ziprasidone, others)
Increased risk of stroke in elderly (risperidone, olanzapine)

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Neurologic side fx

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seizures with clozapine

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major side effects of typicals are extrapyramidal sxs. what's the big side effect(s) of atypicals?

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weight gain and type 2 diabetes

especially with

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Weight gain and metabolic effects –

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Prominent with clozapine and olanzapine. Uncommon with ziprasidone and aripiprazole. Can increase risk of Type 2 diabetes.

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Blood disorders.. clozapine causes WHAT?!

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Bone marrow suppression or agranulocytosis with clozapine.

need to take CBCs often. it's a 3rd line drug bc of the side effects

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which drug is most likely to give you a QT prolongation?

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ziprasidone

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Drug interactions

Therapeutic Uses

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Drug interactions:
potentiate the effects of opioids, barbiturates, and ethanol

Therapeutic uses:
Psychoses – All agents improve positive symptoms. Atypicals also improve negative symptoms. CATIE Trial (NEJM 9/22/05) suggests atypicals may not be much better than less expensive typicals, just different.
Risperidone recently approved for use in children and teens. Also approved for autism.
-Nausea and vomiting (prochlorperazine – Compazine)
-Hiccough

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Other neuropsychiatric diseases

black box warning for what when you use atypicals?

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Tourette’s syndrome – Haloperidol, risperidone, olanzapine or pimozide (Orap). Pimozide last resort.

Agitation associated with Alzheimers and other dementias. Careful with using atypicals to treat dementia in the elderly (“Black Box” warning)!

Bipolar disorder.

Aripiprazole approved for major depressive disorder