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30 Cards in this Set

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History and general characteristics of antipsychotic drugs?
Neuroleptic; affecting the nervous system

Introduced in early 1950s – chlorpromazine is the prototype

Not specific for schizophrenia, but rather used to treat psychosis of any etiology

Share central anti-dopaminergic properties
What are the typical antipsychotic drugs?
Chlorpromazine

Haloperidol
Chlorpromazine potency and mechanism?
Low potency

D2 antagonist
Haloperidol potency and mechanism?
High potency

D2 antagonist
What are the atypical antipsychotic drugs?
Clozapine

Risperidone

Olanzepine

Quetiapine

Aripiprazole

Ziprasidone
Clozapine MOA?
D2/5-HT2 antagonist
Risperidone MOA?
D2/5-HT2 antagonist
Olanzapine MOA?
D2/5-HT2 antagonist
Aripiprazole MOA?
D2 partial agonist/5-HT2 antagonist
What is the criteria for the atypical neuroleptic?
Clinical
1. antipsychotic efficacy
2. low likelihood of extrapyramidal side effects
3. no tardive dyskinesias (long-term)
4. no to small increase in plasma prolactin
5. efficacy on negative symptoms

Pre-Clinical
1. greater potency at blocking 5-HT2 serotonin than D2 dopamine receptors

Works on both positive and negative symptoms
Positive symptoms of schizophrenia?
Hallucinations

Delusions

Conceptual disorganization in speech and behavior

Agitation
Negative symptoms of schizophrenia?
Social and emotional withdrawal

Blunted affect

Poverty of speech

Anhedonia (lack of pleasure)

Avolition (lack of initiating goal-directed behavior)
Autonomic side effects of typical antipsychotics?
1. antiadrenergic (mostly α1 and α2)
-- sedation
-- orthostatic hypotension

2. anticholinergic
-- dry mouth, blurred vision
-- urinary retention, sinus tachycardia
-- constipation

3. antihistamine
-- sedation
-- weight gain

4. general toxicity
-- skin reactions (photosensitivity)
-- jaundice
-- ventricular arrhythmias
-- agranulocytosis
Neuroendocrine side effects of typical antipsychotics?
Dopamine antagonism in hypothalamic/pituitary tract

Increased prolactin can lead to
-- gynecomastia
-- galactorrhea
-- amenorrhea
-- weight gain
Neurologic/extrapyramidal side effects (EPS)?
Treatment involves use of anticholinergic drugs such as benztropine

1. acute dystonia
-- muscle spasms

2. pseudoparkinsonism
-- rigidity
-- tremor
-- shuffling gait

3. akasthesia
-- motor restlessness

4. tardive dyskinesias
-- oral facial dyskinesias
-- late onset
-- not always reversible
What is the rationale for selection of typical antipsychotics?
Low potency drugs
-- more anticholinergic
-- more sedative
-- more likely to produce orthostatic hypotension
-- CHLORPROMAZINE

High potency drugs
-- more likely to produce EPS
-- much less likely to produce autonomic side effects
-- HALOPERIDOL
What is the side-effect profile of atypical antipsychotics?
Relatively similar antiandrenergic, anticholinergic and antihistamine profile as the typical antipsychotics except

1. Risperidone and Quetiapine are not anticholinergic
2. Olanzapine is very antihistaminic

NEUROLOGIC/EXTRAPYRAMIDAL(EPS)

NEUROENDOCRINE S/Es due to increased prolactin
1. not seen w/ clozapine, olanzapine, quetiapine
2. possible w/ risperidone

Greater weight gain with many of the atypicals than the typical antipsychotics

Development of Type II DM and hyperlipidemia

Neuroleptic malignant syndrome
What are the extrapyramidal S/E's of atypical antipsychotics?
1. in general, much less incidence
2. no reports of dystonia, some of akathesia
3. Risperidone: inicidence of EPS is dose-related; at 4-6mg/day, EPS is low
4. no incidence of tardive dyskinesia
-- CLOZAPINE can actually decrease tardive dyskinesias in pts who develop TD w/ typical neuroleptic use
Describe the neuroleptic malignant syndrome?
Clinical features
1. hyperthermia
2. severe EPS
3. autonomic dyxfxn
4. characteristic signs
-- clouded consciousness: delirium, mutism, stupor, coma
-- leukocytosis: WBC > 15,000
-- elevated CPK: >300 (myoglobinuria, eventually renal failure)

Mortality: estimated as high as 30%
-- respiratory arrest
-- myoglobinuria w/ acute renal failure
-- cardiovascular collapse

Treatment
-- DANTROLENE (↓ hypertherm) + Bromocriptine (stim D2 in brain)
-- hydration
How does dantrolene decrease hyperthermia?
↓Ca2+ release from SR to decrease contraction
What is the most important side effect of clozapine?
Induced granulocytopenia and/or agranulocytosis

NOT dose related

1. Overall incidence has been claimed to be 1-3% (10-30times higher than with typical drugs) but may actually be about 0.6%
2. Approximately 80% of cases occur w/in the first 18wks
3. Fall in WBC may be abrupt or gradual
4. If total WBC <2000, discontinue
What is a treatment for bipolar disorder?
LITHIUM (usually a later choice)

1. remains standard treatment for bipolar illness
-- effective as antimanic agent; may take days to begin to work
-- effective for “prophylaxis” of bipolar disorder
-- reduces the severity and frequency of mood swings from mania or hypomania to depression
-- many patients do not respond (35-50%)

2. typically given as lithium carbonate
-- doses range of 300mg to 3000mg as needed to achieve appropriate plasma level about 1mM
-- therapeutic range often cited as 0.5-1.4mM
Lithium excretion?
Excreted by kidneys w/ a half life of about 24 hours
Lithium renal, endocrine and pregnancy side effects?
RENAL
-- polyuria, due to impaired concentrating ability (interferes w/ action of ADH) and polydipsia. Very common

ENDOCRINE
-- direct antithyroid effects
-- can cause hypothyroidism and goiter

PREGNANCY AND NURSING
-- increased incidence of CV abnormalities in fetus—avoid use in first trimester of pregnancy; secreted in breast milk
Lithium cardiovascular, weight, and CNS effects?
CARDIOVASCULAR
-- non-specific T wave changes, dysrhythmias, SA block, tachycardia

WEIGHT GAIN
-- leads to patient non-compliance

CNS EFFECTS
-- tremor, fatigue, drowsiness, ataxia, and cognitive deficits (slowing, confusion)
-- hallucinations, encephalopathy
-- worsens myasthenia gravis, delirium, coma
What should you warn patients about regarding lithium and sodium intake?
Inverse relationship between either restricting sodium intake or excessive sodium loss and serum lithium concentrations
Anticonvulsants?
Carbamazepine

Oxcarbazepine

Valproate
Effectiveness of anticonvulsants on mania?
Comparable effectiveness in mania to Li, w/ similar time course of action

Less information is available about effectiveness of these drugs in prophylaxis of bipolar disorder in comparison w that of Li, but existing info indicated compatibility
Carbamazepine interactions?
Potential for drug-drug interactions as it induces liver enzymes
MOA of mood stabilizing agents?
Common effect of Li: to inhibit or dampen processes that are overactive but can cause different behavioral effects
-- overactive excitatory pathways
-- overactive inhibitory pathways

Inhibits coupling of G-protein coupled receptors to G-proteins.
-- seen w/ carbamazepine treatment also
-- Li competes w/ Mg ions for low affinity in Mg sites on G-proteins essential for guanine nucleotide exchange

Inhibits some enzymes through competition for a Mg++ binding site
-- several inositol phosphates so as to decrease agonist-stimulated phosphatidylinositol turnover
-- uncompetitive inhibition produces effects that depend on the concentration of enzyme substrate
-- thus the greater the receptor stmulation to produce more IP, the greater will be the inhibitory effect of Li+. May account for SELECTIVE effects of Li+ on overactive pathways
-- glycogen synthasse kinase-3 (GSK-3)

Inhibits agonist-mediated activation of adenyl cyclase to cause less stimulation of cyclic AMP