Pharmacology I: CNS VIII - Anti-psychotics and Lithium

…: denotes a variety of mental disorders; disturbances of reality and perception, impaired cognitive functioning and disturbances of mood

Psychosis

Psychotic disorders may have an … or may be …

organic basis, idiopathic

…: a particular kind of psychosis characterized mainly by a clear sensorium but a marked thinking disturbance

schizophrenia

Positive symptoms of schizophrenia: … (4)

delusions, hallucinations, reality distortions, agitated behaviors

Negative symptoms of schizophrenia: … (4)

flattened affect, emotional withdrawl, social withdrawl, anhedonia

Schizophrenia patients experience cognitive impairments of: … (2)

attention, memory

There is decreased activity in the … pathways → negative symptoms, anergia, apathy, etc. 

mesocortical

There is increased activity in the … pathways → positive symptoms, delusions, hallucinations

mesolimbic

There is decreased activity in the … pathway → extrapyramidal symptoms, dystonia, akathisia, parkinsonism, tardive dyskinesia

nigrostriatal

There is decreased activity in the … pathway → increased prolactin, decreased libido, sexual dysfunction, galactorrhea, gynecomastia

tuberoinfundibular

Changes in the mesolimbic pathway … are associated with positive symptoms

increased D2 activity

Changes in the mesocortical pathway … associated with negative and cognitive impairment symptoms

decreased D1 activity

… activation produces neuronal inhibition (through decreased neuronal excitability), increase DA in the mesolimbic pathway, decrease DA in the mesocortical pathways

5-HT2a

In the nigrostriatal pathway 5-HT2a receptor activation → … (extrapyramidal effects)

inhibitory effect on DA release

Schizophrenia may result from disruption of glutamatergic neurotransmission → a reduction in the function of …

NMDA receptors

NMDA receptor hypofunction is thought to enhance activity in the mesolimbic dopaminergic pathway → … of mesolimbic dopaminergic neurons → increased DA → positive symptoms

reduced GABAergic inhibition

NMDA receptor hypofunction reduces the level of activity of in … neurons → decreased DA → negative symptoms

mesocortical dopaminergic

Two classes of anti-psychotic drugs: … (2)

typical, atypical

Typical antipsychotics: … (3)

haloperidol, chlorpromazine, thiothixene

Atypical antipsychotics: … (4)

clozapine, olanzapine, risperidone, aripiprazole

Typical anti-psychotic drugs block brain … in the mesolimbic pathway and some block … receptors too

DA receptors, 5-HT2A

… are dose-dependent with typical anti-psychotics

extrapyramidal effects

Acute neurological side effects of typical anti-psychotics: … (3)

extrapyramidal effects, acute dystonia’s, Parkinson-like syndrome

Typical antipsychotics are more closely associated with …, they are reversible with deceasing dosage and use of anti-muscarinic agents, most frequently with …

extrapyramidal effects, haloperidol

Use of … with typical anti-psychotics and decreasing the dosage helps decrease the adverse effects (parkinsonism like symptoms)

antimuscarinic drugs

…: associated with long-term uses of typical anti-psychotics, involuntary movements of face and tongue, disabling and often irreversible, often worsens on stopping treatment, more frequently seen in typical

tardive dyskinesia

Atypical anti-psychotics have affinity … (3) receptors and might interact with muscarinic, histamine H1, and a receptors)

5-HT2a>D2>D1

Atypical anti-psychotics are … of HT2A receptor (block the constitutive activity of these receptors)

inverse agonists

Drugs with 5-HT2A antagonist properties … in the striatum by reducing the inhibitory effect of 5-HT

enhance DA release

Typical anti-psychotics have an effect on …, and are the first line of treatment due to their low cost

decreasing positive symptoms

Atypical anti-psychotics have an effect on …, used in patients unresponsive to, or intolerant of, typical antipsychotic drugs

decreasing positive and negative symptoms

Antipsychotics can also be used in: … (5)

acute delirium, mania, bipolar disorder, schizoaffective disorder, tourette’s syndrome

Adverse autonomic effects of anti-psychotics result from blockade of … (2)

peripheral muscarinic, a adrenoceptors

Adverse autonomic effects of anti-psychotics: … due to a blockade

postural hypotension (chlorpromazine)

adverse endocrine and metabolic effects of anti-psychotics: … (6)

hyperprolactinemia (risperidone), gynecomastia, infertility, D2 receptor blockade in pituitary, weight gain, hyperglycemia (diabetogenic action of atypical agents, clozapine)

Clozapine treatment has caused …, need to monitor WBC and absolute neutrophil counts

severe neutropenia

All anti-psychotics cause …, risk for arrythmias

QT prolongation

…: sensitivity to the extrapyramidal effects can lead to development of a malignant hyperthermic syndrome (muscle rigidity, impairment of sweating, hyperpyrexia)

neuroleptic malignant syndrome

Management of neuroleptic malignant syndrome: … (3)

dantrolene, diazepam, bromocriptine

Treatments of bipolar disorder: … (3)

lithium, valproic acid, carbamazepine

lithium has a … of treatment

slow onset

Maintenance treatment regimen for Bipolar: … (3)

lithium, anti-psychotics, anti-depressants

Lithium inhibits several enzymes involved in recycling of neuronal membrane … → second messengers are important in amine neurotransmission

phosphoinositide (decreased PIP2 → decreased IP3 and DAG

Adverse effects of lithium: … (8)

tremor (propranolol), ataxia, aphasia, sedation, GI distress, thyroid enlargement, edema, reversible nephrogenic diabetes insipidus

…: loss of responsiveness to antidiuretic hormones, → polydipsia and polyuria

reversible nephrogenic diabetes insipidus