Exam 2 ( Antipsychotics)

Question 1

A9 nigrostriatal DA neurons

Answer 1

originate in substantia nigra pars compacta dendrites extend into pars reticulata.

axons innervate corpus striatum

DA release in striatum essential for normal extrapyramidal motor function

Question 2

A10 mesolimbic DA neurons

Answer 2

originate in midbrain ventral tegmental area (VTA)

axons innervate limbic portions of striatum (nucleus accumbens) and cortex

DA release from these neurons important for normal affect, orderly thinking, “drive” states, pleasure and reward

Question 3

D1 vs D2 receptor

Answer 3

D1 = short 3rd intracellular loop, long carboxyl tail

D2 = long 3rd intracellular loop, short carboxyl tail

Question 4

Epidemiology of schizophrenia

Answer 4

1st presents between ages 16 - 20 yr old

1-3% pop overall

genetic predisposition, genetic component probably affected by multiple genes

both neurochemical (nature) and environmental factors (nurture) likely to contribute to development of disease

Question 5

Organic psychoses

Answer 5

cause is known, due to impaired cerebral tissue function; cognitive and intellectual decline

can be secondary to drug abuse, metabolic or toxic insult, trauma, infections, or structural disease of the nervous system

Question 6

Dopamine theory of schizophrenia

Answer 6

cause is postulated to be excessive DA transmission, especially within the limbic striatum and limbic cortical areas innervated by A10 DA neurons (mesolimbic and mesocortical DA pathways)

Question 7

Idiopathic psychoses

Answer 7

cause not known, may have a genetic component.

schizophrenia denotes a form of idiopathic psychosis

Question 8

Positive symptoms

Answer 8

hallucinations, usually auditory (voices talking to patient) delusions (false beliefs), grandiosity, paranoia
disorganized thinking, speech; tangential thinking, “word salad” bizarre behavior, catatonia

Question 9

Negative symptoms

Answer 9

affective (emotional) flattening withdrawal, depersonalization, asociality poverty of speech and thought anhedonia, loss of motivation

Question 10

Cognitive symptoms

Answer 10

impaired attention, deficits in learning and memory

Question 11

D2 like family

Answer 11

D2, D3, D4

Question 12

D1 like family

Answer 12

D1 and D5

Question 13

D1 receptors

Answer 13

lead to stimulation of adenylate cyclase and increase cAMP

Affinity for phenothiazines > butyrophenones

Question 14

D2 receptor

Answer 14

not associated with stimulation of adenylate cyclase and may inhibit it.

Affinity for butyrophenones > phenothiazines

Question 15

Typical

Answer 15

blockade at D2 receptors > 5-HT2A receptors; antipsychotic potency correlates strongly with D2 receptor blockade

Phenothiazine derivatives
Thioxanthene derivatives
Butyrophenone derivatives
Miscellaneous “typical” antipsychotic drugs

Question 16

Atypical

Answer 16

blockade at 5-HT2A receptors > D2 receptors

Loxapine
Clozapine
Risperidone
Quetiapine
Olanzapine
Ziprasidone 
Aripiprazole

Question 17

Manifestation:
Loss of accommodation, dry mouth, difficulty urinating,
constipation

Answer 17

Mechanism:
Muscarinic cholinoreceptor blockade

ANS

Question 18

Manifestation:

Parkinson’s syndrome, akathisia, dystonias

Answer 18

Mechanism:
Dopamine-receptor blockade

CNS

Question 19

Manifestation:

Tardive dyskinesia

Answer 19

Mechanism:
Supersensitivity of dopamine receptors

CNS

Question 20

Manifestation:

Orthostatic hypotension, impotence, failure to ejaculate

Answer 20

Mechanism:
α-Adrenoceptor blockade

ANS

Question 21

Manifestation:

Toxic-confusional state

Answer 21

Mechanism:
Muscarinic blockade

CNS

Question 22

Manifestation:

Amenorrhea-galactorrhea, infertility, impotence

Answer 22

Mechanism:
Dopamine-receptor blockade resilient in hyperprolactinemia

Endocrine System

Question 23

Manifestation:

Weight Gain

Answer 23

Mechanism:

Possibly combined H1 and 5-HT2 blockade

Question 24

Clozapine (dibenzodiazepine)

Answer 24

1st effective antipsychotic without extrapyramidal side-effects

may suppress tardive dyskinesia due to other agents

reduces positive and negative symptoms

blocks many receptors

most serious side effect: agranulocytosis

other side effects:
hypercholesterolemia, weight gain, diabetes

Question 25

Risperidone (Benzisoxazole)

Answer 25

D2 and 5-HT2 receptor blocking properties no blood toxicity of clozapine lower incidence of extrapyramidal side effects and tar dive dyskinesia than classical antipsychotics not as effective in drug resistance cases as clozapine

Question 26

Olanzapine (Thienobenzodiazepine)

Answer 26

effective treating both positive and negative symptoms low incidence of extrapyramidal effects main side-effects = weight gain and associated with metabolic disorders...diabetes, hypertension, hyperlipidemia

Question 27

Quetiapine (Dibenzothiazepine)

Answer 27

one of most widely used D2> 5-HT2a low incidence of extrapyramidal side effects lesser chance of weight gain effective positive and negative symptoms

Question 28

Ziprasidone (dihydroindolone)

Answer 28

injectable form for acute treatment of very agitated or violent patients may cause QTc segment prolongation and serious cardiac arrhythmias (ventricular tachycardia and sudden death)

Question 29

Aripiprazole (Dihydrocarbostyril)

Answer 29

most widely prescribed 1st antipsychotic with partial agonist activity at D2 termed DA stabilizer due to blocking D2 receptor but also stimulating D2 considered 3rd gen antipsychotic lower weight gain, little effect on prolactin levels, no extrapyramidal side effects

Question 30

Asenapine

Answer 30

used for schizophrenia and acute manic episode associated with bipolar disorder sublingual admin limited weight gain, no hyperlipidemia, no change in prolactin minor extrapyramidal effects

Question 31

Lurasidone

Answer 31

schizophrenia, depressive episodes associated with bipolar minimal weight gain extrapyramidal effects may occur; especially akathisia

Question 32

CNS effects and side effects of antipsychotic

Answer 32

sedation mild anti anxiety neuroleptic syndrome

Question 33

Neuroleptic syndrome

Answer 33

common with typical antipsychotics cause loss of pleasure and reward

Question 34

Endocrine effects and side effects

Answer 34

increased prolactin secretion increased female, decreased male libido increase appetite

Question 35

increased prolactin secretion

Answer 35

"typical" cause prominent prolactin elevating effects "atypical" have minimal effects on prolactin release

Question 36

Antiemetic effect

Answer 36

due to blockade of DA receptors at chemoreceptor trigger zone (CRTZ) in medulla

Question 37

Other clinical uses of DA receptor antagonists

Answer 37

Treating Huntington's Disease Treatment of Gilles de la Tourette's syndrome As an antiemetic In anesthesiology to produce neurolepanalgesia treatment of intractable hiccoughs

Question 38

Parkinson syndrome (EPS)

Answer 38

onset 5-30 days, bradykinesia, rigidity, tremor. Treatable with anticholinergic drugs and amantidine

Question 39

Acute dystonic reactions (EPS)

Answer 39

onset 1-5 days, spasm of tongue, neck, face, back muscles. Treatable with anticholinergic drugs

Question 40

Akathisia

Answer 40

Onset 5-6 days, motor restlessness and desire to be in constant motion Treatable by reducing antipsychotic drug dose.

Question 41

Neuroleptic malignant syndorme

Answer 41

Onset weeks, can persist for days after stopping, characterized by fever, unstable blood pressure, stupor, can be fatal Treat by stop antipsychotic immediately

Question 42

Tardive dyskinesia

Answer 42

late occurring movement disorder (Months to years) characterized by repeated involuntary movements of mouth, tongue, lips, jaws No effective therapy, crucial to use lowest effective dose to prevent development Mechanism: chronic blockade of Da receptors causes increase in D2 like receptors in striatum....supersensitivity?

Question 43

Skin Reactions

Answer 43

Especially with phenothiazines hypersensitivity reactions - urticaria, itching Contact dermatitis - those who handle drug photosensitivity - resembles sunburn, use sun screen Abnormal skin pigmentation - grey/blue patches

Question 44

Problem with Dopamine Theory

Answer 44

1. no evidence for increased DA cell activity or DA release, no increase in DA levels or metabolites in brain or CSF of schizophrenics 2. Poor temporal correlation between DA receptor block and antipsychotic effect 3. correlation may not imply causation: DA receptor blocking property of anti-psychotic drugs does not necessarily indicate a causative role of DA in psychosis 4. other transmitter systems and brain areas are also likely involved in etiology of schizophrenia

Question 45

Psychosis

Answer 45

Characterized by impaired behavior with inability to think coherently and comprehend reality

Question 46

Support for DA theory

Answer 46

Drugs that block DA receptors reduce psychotic symptoms Drugs that increase synaptic DA levels can cause psychotic symptoms PET scans show increase D2 like receptors in caudate nucleus of untreated schizophrenics, suggest D@ up regulator is feature of disease Strong correlation between D2-like receptor blockade and antipsychotic drug potency