Pharmacology: Antipsychotics

Front 1

What are the positive symptoms of psychosis?

Back 1

delusions, hallucinations, disorganized speech, disorganized behavior, and catatonia
= symptoms not normally present

Front 2

What are the negative symptoms of psychosis?

Back 2

flat affect, suppressed speech, incoherence, and inhibited thinking
= normal behavior that are missing in schizophrenia

Front 3

What type of antipsychotic drugs (typical or atypical) are better at controlling positive symptoms?

Back 3

typical

Front 4

What is the D1 receptor coupled to? What receptors are subfamilies of D1 receptors?

Back 4

coupled to adenylate cyclase
D5 is in subfamily

Front 5

What is the D2 is coupled to? What receptors are subfamilies of D2 receptors?

Back 5

not coupled to or negatively coupled with adenylate cyclase
D2, D3, D4 are in subfamily

Front 6

What is the mechanism of action of classical antipsychotics?

Back 6

D2 receptor antagonists

Front 7

What is the net effect of classical antipsychotics?

Back 7

combination of postsynaptic D2 blockade and reduced release of DA results in a net decrease in DA function in the CNS → responsible for the major pharmacological and therapeutic effects of antipsychotic agents
blockade of DA receptors in corticolimbic system → antipsychotic action of drugs
blockade of DA receptors in neostriatal and hypothalamic regions → extrapyramidal and hyperprolactinemia side effects

Front 8

What is the “dopamine hypothesis of schizophrenia”?

Back 8

excessive activity of DA neuron activity in the mesocorticolimbic areas of the brain is responsible for schizophrenia

Front 9

What abnormalities of brain anatomy and physiology are found in schizophrenics?

Back 9

Absence of degenerative gliosis. Cortical atrophy beginning in adolescence. Non-specific ventricular enlargement. Reduction in dendritic spine density. Decreased cerebral blood flow (CBF) in frontal cortical regions at rest. Failure to increase CBF and cerebral glucose metabolism in dorsolateral prefrontal cortex in response to cognitive challenge tasks

Front 10

What are some extrapyramideal symptoms (EPS) of psychosis?

Back 10

Dystonia - involuntary tonic contractions of skeletal muscles characterized by abnormal activity of facial muscles, neck muscles, bizarre limb movements, etc. These dyskinesias respond to anticholinergic drugs. Akathisia - subjective experience of motor restlessness - the “jitters”. Parkinsonism-like tremors, rigidity, and akinesia.

Front 11

What causes extrapyramideal symptoms (EPS)? How does pharmacology (antipsychotics, anticholinergics) affects this?

Back 11

results from a disturbance of the DA-cholinergic balance in the basal ganglia. Antipsychotics block (inhibitory) DA receptors on cholinergic neurons - result in hyperactivity of the cholinergic activity. Anticholinergics (e.g. benztropine) reduce EPS, but have other side-effects. Better to reduce dose.

Front 12

What is Tardive dyskinesia (TD)?

Back 12

Orofacial dyskinesia is probably the most common characteristic of extrapyramideal symptoms in psychosis. variable mixture of orofacial dyskinesia, chorea, dystonia, and tics. Involuntary movements of extremities may also occur. These symptoms arise during or after discontinuation of neuroleptic therapy. May or may not be reversible, and they are not blocked by anticholinergics.

Front 13

How do you diagnose Tardive dyskinesia (TD)?

Back 13

Diagnostic criteria require that patients have at least 3 months of neuroleptic exposure and that the movements persist for at least 4 weeks.

Front 14

Contrast extrapyramideal symptoms with tardive dyskinesia.

Back 14

In contrast to EPS, TD is characterized by overactive DA activity in the neo-striatum (upregulation of blocked DA receptors). This results in an excessive inhibition of the neostriatal cholinergic interneurons, which in turn leads to the symptoms of TD. That is why anticholinergics are ineffective (and can exacerbate TD symptoms).

Front 15

How do you treat Tardive dyskinesia (TD)?

Back 15

Amine depletors. DA antagonists. DA synthesis inhibitors. Cholinergic agents: Choline, lecithin, physostigmine. DRUGS THAT WORSEN TARDIVE DYSKINESIA: Anticholinergic drugs. DA agonists.

Front 16

What is neuroleptic malignant syndrome (NMS) and what are the signs/symptoms? How do you treat it?

Back 16

Incidence usually less than 1 percent. Hyperthermia, mainly above 40o C. Muscle rigidity often precedes high fever <br /> Requires immediate withdrawal of drug, possibly treat with dopaminergic agonists or skeletal muscle relaxants: Dantrolene, bromocriptine and benzodiazepines used to treat NMS.

Front 17

What are inappropriate uses of antipsychotics?

Back 17

Wandering in dementia. Restlessness, anxiety, fidgeting. Uncooperativeness. Low level agitation. Poor self-care, poor memory. Insomnia

Front 18

What are the atypical psychotics?

Back 18

clozapine, risperidone, olanzapine, quetiapine, ziprasidone

Front 19

What are the typical psychotics?

Back 19

clorpromazine, thioridazine, perphenazine, thiothixene, trifluoperazine, fluphenazine, haloperidol

Front 20

What is special about clozapine? What does it bind to? Side-effects?

Back 20

second line agent
binds D1/4, 5HT2/3, a-1, a-2, ACh, H1, weak D2
sedation, OH, constipation, seizures, sialorrhea, weight, rare DM, agranulocytosis

Front 21

What is special about risperidone? What does it bind to? Side effects?

Back 21

superior for treating negative symptoms
dose dependent EPS
least sedating
hyperprolactinemia
Hi affinity D2/5HT2

Front 22

What is special about olanzapine? What does it bind to? Side effects?

Back 22

superior to typical agents for postive and negative symptoms
less EPS and less likely to cause TD
SE: sedation, OH, weight, hyperglycemia
Hi affinity for D1-4, 5HT2/3/6, a-1, M1, H1

Front 23

What is special about quetiapine? What does it bind to? Side effects?

Back 23

Efficacy like typical agents
lowest risk for EPS, likely low risk for TD, no PRL elevation
more sedating
Hi affinity for a-1/M1/H1
Lo affinity for D1/D2/5HT1A/5HT2A

Front 24

What is special about ziprasidone? What does it bind to? Side effects?

Back 24

good EPS, limited weight gain, no PRL, QT prolonged minimally
Hi affinity for D2-3, 5HT2A/2C/1D, H1, a-1n
5HT1A agonist
serotonin/NE reuptake inhibitor

Front 25

What are the low potency conventional antipsychotics?

Back 25

chlorpromazine, thioridazine

Front 26

What two conventional antipsychotics have CV side effects? What are these side effects?

Back 26

Chlorpromazine & Thioridazine
tachycardia, OH, intraventricular conduction delay

Front 27

In addition to CV side effects, what can happen at high doses of thioridazine?

Back 27

pigmentary retinopathy

Front 28

Can you administer conventional and atypical antipsychotics during pregnancy?

Back 28

no evidence for tetratogenicity with conventional or atypical agents

Front 29

What are some side effects of blocking D2 in the pituitary (i.e. side effects of antipsychotic dopamine receptor blockers)?

Back 29

hyperprolactinemia
gynecomastia, glactorrhea, amenorrhea