Pharm of psychoses Flashcards
Explain the dopamine theory of schizophrenia
Abnormality of brain function in schizophrenics is due to overactivity in brain dopaminergic pathways, especially in the mesolimbic pathway.
chlorpromazine*
typical antipsychotic, D2 block, increased EPSE
haloperidol*
typical antipsychotic D2 block, increased EPSE
clozapine*
atypical antipsychotic, reduced EPSE, poor D2 block, good 5HT2a block, hypersalivation, Agranulocytosis
risperidone
atypical antipsychotic, reduced EPSE, poor D2 block, good 5HT2a block
olanzapine
atypical antipsychotic, reduced EPSE, poor D2 block, good 5HT2a block
aripiprazole
atypical antipsychotic, reduced EPSE, poor D2 block, good 5HT2a block
Describe the relationship between receptor blocking potency-selectivity (esp. 5HT vs DA), efficacy in schizophrenia, and side effect profile for typical and atypical antipsychotic agents.
typical have more D2 block, atypical have more 5HT2a block. less EPSE in atypicals but clozapine does have a couple (agranulocytosis, hypersalivation)
Describe the catecholamine hypothesis of depression and its limitations and how it may relate to the neurodegenerative hypothesis of depression.
Initial observation: Reserpine depleted brain NE and 5HT induced depression
Additional support: Effective antidepressant drugs share property to enhance NE-5HT-(DA) availability in synapse
BUT – does not totally explain etiology of depression
Effect on amines immediate – mood elevating effect delayed 2-3 weeks
Direct evidence in support largely lacking
Dysregulation of pre-and post-synaptic control of NE-5HT neurotransmission
Synaptic changes produced by antidepressants then lead to alterations of gene expression
Time frame for these changes correlates with onset of mood changes
amitriptyline*
TCAD, blocks SERT and NET, high sedation and antimuscarinic
imipramine
TCAD, blocks SERT and NET, med. sedation and antimuscarinic
desipramine
TCAD, only blocks NET, little sedation, little antiM
fluoxetine*
SSRI, blocks SERT
paroxetine*
SSRI, blocks SERT
sertraline
SSRI, blocks SERT
bupropion*
NDRI, blocks NET and DAT
venlafaxine*
SNRI along with duloxetine blocks SERT and NET
trazodone*, S/E
blocks SERT, high sedation used as sleeping med
Drowsiness
Dizziness, nausea, agitation
“Black Box Warning” for liver failure with nefazodone
phenelzine*
(MAOI) antidepressant and anxiolytic. non-selective MAOI
electroconvulsive therapy
Most rapid and effective (70-90%) treatment for severe acute depression
Can be life-saving if patient is suicidal
Usually 6-12 treatments at a frequency of 2-3 per week
Adverse effects
Medical cardiopulmonary events, fractures, orodental injuries, headache
Cognitive acute confusion, retrograde and anterograde amnesia
lithium*
mood stabilizer, used to augment antidepressants, narrow therapeutic window Slow onset (10-21 d) – necessary to accumulate Li+ in cell
Effects greatest on cells with highest level of activity (use-dependence)
Enhance 5HT action and/or diminish NE and DA effect – most favored MOA:
Interference with PIP recycling (Gq protein: IP3 and DAG)
S/E
In thyroid anti-TSH hypothyroidism
In kidney anti-ADH polyuria-polydipsia
Competes with Na+ for reabsorption
increase dietary Na+ decreaseLi+ plasma levels
Na+ restriction increases Li+ plasma levels
valproic acid
anti convulsants
carbamazepine
Carbamazepine (Tegretol)
primarily in the treatment of epilepsy and neuropathic pain.
not effective for absence seizures or myoclonic seizures. may be used in schizophrenia along with other medications and as a second line agent in bipolar disorder.
Explain the limitations of the dopamine theory of schizophrenia
- Block of D2 receptors immediate – onset of psychoses improvement 3-6 wks
- Clozapine weak D2 blocker but extremely effective antipsychotic
- If DA system completely responsible, D2 blockers would be more effective
- Evidence exists for role of glutamate and serotonin and acetylcholine systems
describe the mechanism of antipsychotic drug action
Virtually all antipsychotic drugs block dopamine D2 receptors. Drugs that increase dopaminergic activity produce or aggravate psychosis
Mesolimbic pathway
Subserve the integration of sensory input and motor responses with affective or emotional data
+++++++
Mesocortical pathway
Involved in communication and social abilities
———-
Nigrostriatal pathway
Part of basal ganglia (aka extrapyramidal tract) plays a central role in planned, coordinated movement
Tuberoinfinduibular pathway
Hypothalamic neurons release DA in pituitary to inhibit prolactin release
Serotonin Hypothesis
Glutamate Hypofunction Hypothesis
mesocortical and mesolimbic
Cortical Glu neurons activate cortical GABA neurons to produce a tonic inhibition of cortical Glu excitation of mesolimbic DA neurons
Hypofunction in cortical NMDA-Glu neurons remove GABA inhibition activate DA Neurons positive symptoms of schizophrenia
Cortical Glu neurons activate GABA to inhibit cortical Glu to inhibit VTA GABA to produce a tonic excitation of mesocortical DA neurons
Hypofunction in cortical NMDA-Glu neurons remove inhibition of VTA GABA inhibit mesocortical DA negative symptoms of schizophrenia
Positive symptoms of schizophrenia (delusions, hallucinations) are believed to result from:
Overactivity of dopamine neurons in the mesolimbic system
Underactivity of glutamate neurons in the prefrontal cortex
Quetiapine*
atypical antipsychotic, reduced EPSE, poor D2 block, good 5HT2a block
Atypical antipsychotic agents such as clozapine (Clozaril) or olanzapine (Zyprexa) are distinguished from typical agents such as haloperidol (Haldol) because they are associated with a lower incidence of:
Extrapyramidal side effects
side effects of D2 block
tardive dyskinesia in elderly females (involuntary orofacial mvts)
Pseudoparkinsons- treat with anticholinergics
Antipsychotic agents exert both therapeutic actions and side effects as a result of dopaminergic receptor blocking activities in various brain regions. Appetite increase, weight gain and diabetes are common side effects of antipsychotic use that result from block of dopamine receptors at which site?
hypothalamus
Agranulocytosis (low white blood cell count) can predispose patients to infections. Which of the following agents used in the pharmacotherapy of mental illnesses is associated with the highest incidence of agranulocytosis as a side effect?
clozapine
*Which of the following therapeutic actions or side effects of antipsychotic agents does NOT result from blockade of dopamine receptors?
Orthostatic hypotension
Monoamine Theory of Depression
Dysregulation of pre-and post-synaptic control of NE-5HT neurotransmission
Synaptic changes produced by antidepressants then lead to alterations of gene expression
Time frame for these changes correlates with onset of mood changes
SSRI S/E
Nausea-diarrhea [5HT3] (increased serotonin effects in GI tract)
Activation-insomnia (commonly)
Restlessness [5HT2] (akathisia), somnolence possible
Weight gain
!Sexual dysfunction [5HT3]
Cognitive blunting
Very low likelihood of fatalities in overdose
Withdrawal (discontinuation) symptoms
Flu-like or neurologic symptoms severity related to half-life (shorter > longer [paroxetine > fluoxetine])
SNRI side effects
Venlafaxine - Duloxetine
Hypertension, anxiety, nausea, somnolence, sweating, dizziness, sexual dysfxn!!
More rapid appearance of withdrawal symptoms than with SSRIs
Norepinephrine Dopamine Reuptake Inhibitors (NDRIs) S/E
Bupropion
Dizziness, dry mouth, tremor, insomnia, anxiety, aggravation of psychosis
Potential for seizures at high doses
TCAD S/E
Sedation: Lassitude, fatigue, sleepiness [Amitriptyline
Antimuscarinic Effects:
Blurred vision, constipation, dry mouth, urinary hesitancy, fuzzy thinking
Higher doses-aggravation of narrow angle glaucoma, paralytic ileus, urinary retention, delirium
Orthostatic hypotension (α1 blockade)
EKG abnormalities arrhythmias sudden death in overdose
Neurologic: Tremor, paresthesias, can see seizures in overdose
Monoamine Oxidase Inhibitors S/E
Postural hypotension via chronic increase in false neurotransmitter formation
Seizures, shock, hyperthermia in overdose
what drug class do u worry about a Tyramine reaction (hypertensive crisis)?
beer wine cheese fava beans, MAOI
Which of the following statements concerning the side effects and toxicities of antidepressant drug use is FALSE?
A Concomitant use of SSRIs and MAOIs may result in a serotonin syndrome.
B SSRIs (e.g., fluoxetine) can induce hypomania in patients with bipolar disorder.
C Tricyclic antidepressants (e.g., amitriptyline) have a higher incidence of anticholinergic side effects than SSRIs.
D Inhibitors of dopamine and norepinephrine reuptake (e.g., bupropion) have been observed to cause anxiety and restlessness due to their mild stimulant action.
E None of the above (All are TRUE).
B
serotonin syndrome
SSRIs + MAOIs serotonin syndrome
Hyperthermia, muscle rigidity, myoclonus
Rapid changes in mental status (confusion / agitation) and vital signs (hypertension and tachycardia)
Also SSRIs + opioids: analgesics [meperidine-tramadol] and antitussive [ dextromethorphan]
Which of the following statements concerning the treatment of bipolar disorder with lithium is accurate (TRUE)?
A Lithium will alleviate the manic phase of bipolar disorder within 24 hours.
B Excessive intake of sodium chloride will decrease lithium plasma levels.
C Lithium dosage may need to be decreased in patients taking thiazide diuretics.
D Lithium does not cross the blood brain barrier.
E Lithium does not cross the placental barrier.
F Lithium is a safe drug with a wide therapeutic index.
Excessive intake of sodium chloride will decrease lithium plasma levels.
Lithium dosage may need to be decreased in patients taking thiazide diuretics.
