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Nervous System IV > Pharmacology of Mood Disorders & Psychosis > Flashcards

Pharmacology of Mood Disorders & Psychosis Flashcards

1
Q

Absorbption, distribution, and metabolism of anti-psychotics

A

Oral absorption is incomplete with significant first-pass effect

Highly lipid solubility leads to concentration in the CNS, which extends clinical half-life beyond plasma half-life; crosses placenta

Metabolized to polar substance for excretion by hepatic CYP450; can be excreted in breast milk

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2
Q

Dosage formulations for antipsychotics

A

Oral - immediate release for chronic dosing, 1-2x/day

IM - for rapid treatment of acute psychosis or for patients who can’t take oral meds

IM depot - improves adherence to maintenance therapy; administered every 2-4 weeks

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3
Q

Typical antipsychotics - Mechanism

A

High D2/5HT2A blocking ratio

Good D2 block is associated with high efficacy against positive symptoms AND high incidence of extrapyramidal side effects

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4
Q

Typical antipsychotics - agents

A

Haloperidol - High clinical potency due to greater D2 blocking activity; effective in lower doses but higher risk of EPS

Chlorpromazine - Lower clinical potency due to lesser D2 blocking activity; less risk of EPS but higher doses produce other side effects including antimuscarinic (dry mouth, tachycardia, urinary retention, constipation), alpha-1 blockade (hypotension) and antihistamine (sedation)

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5
Q

Atypical antipsychotics - Mechanism

A

Low D2/5HT2A blocking ratio - associated with better efficacy against negative symptoms and increased efficacy in treatment-resistant individuals

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6
Q

Atypical antipsychotics - Agents

A

Clozapine
Risperidone
Olanzapine
Aripiprazole

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7
Q

Clozapine

A

Atypical antipsychotic effective in patients who are refractory to other drugs

Reserved for this indication due to 1-2% incidence of agranulocytosis

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8
Q

Extrapyramidal symptoms

A

Caused by dopaminergic blockade; high with Haloperidol

Acute dystonia - treated with antimuscarinic agents

Akathisia - motor restlessness, inability to sit still

Pseudoparkinsonism (tremor, bradykinesia, rigidity) - treated with anticholinergic agents or Amantadine

Tardive dyskinesias

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9
Q

Tardive dyskinesias

A

Extrapyramidal symptom with onset 3-6 months; characterized by involuntary, repetitive movement of lips and tongue with chorea of arms and legs

May worsen with withdrawal of the antipsychotic drug and is usually irreversible; overall incidence 20-40% with chronic treatment

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10
Q

Other side effects of antipsychotic agents

A

Metabolic effects via block of hypothalamic DA receptors - Type 2 DM, weight gain, hypertension, hyperglycemia, hypercholesterolemia; more common with atypical agents

Altered thermoregulation via block of hypothalamic DA

Lowered seizure threshold

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11
Q

Tricyclic antidepressants - Agents

A

Amitriptyline
Imipramine
Desipramine

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12
Q

SSRIs - Agents

A

Fluoxetine
Paroxetine
Sertraline
Citalopram

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13
Q

Buproprion - Mechanism & Side effects

A

NE and DA reuptake inhibitor (NDRI)

Side effects: anxiety, insomnia, higher seizure risk; contraindicated in patients with eating disorders or history of seizures

No sexual side effects, weight neutral

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14
Q

Venlafaxine - Mechanism & Side effects

A

5HT and NE reuptake inhibitor (SNRI)

Side effects: 
Diastolic hypertension
Sweating
Sexual side effects
Withdrawal syndrome with "electric shock" sensation
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15
Q

Trazodone - Mechanism

A

Serotonin antagonist / reuptake inhibitor (SARI)

Weak antidepressant, mainly used for insomnia

Side effects: drowsiness, dizziness

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16
Q

TCADs - Mechanism

A

Blocks reuptake of NE, 5HT and DA (at high doses)

Also blocks H1 histaminic, muscarnic cholinergic, and alpha-1 receptors

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17
Q

SSRIs - Side effects

A

Acute (diminish over time): Nausea, diarrhea, insomnia, dry mouth

Chronic: Weight gain, sexual dysfunction, cognitive blunting

Flu-like withdrawal syndrome

DDIs with MAOIs & inhibitors of CYP450

18
Q

TCADs - Side effects

A

Anticholinergic effects (blurred vision, constipation, dry mouth, urinary retention, glaucoma)
Orthostasis
Weight gain
Sexual side effects

Fatal in overdose due to seizure and cardiac arrhythmia

19
Q

MAOIs - Mechanism

A

Blocks degradation pathway for NE and 5HT, allowing greater release into the synapse; inhibition is irreversible and persists after drug is no longer detectable in the plasma

Effective in non-responsive patients, especially atypical depression

20
Q

MAOIs - Adverse Effects

A

Anti-cholinergic (dry mouth, constipation, urinary retention)
Sexual side effects
Weight gain
Overdose causing seizures, shock, hyperthermia

21
Q

MAOI DDIs

A

Interaction with foods high in tyramine (liver/beer/wine/cheese); tyramine displaces NE from storage vesicles causing excessive NE release leading to hypertensive crisis

Interaction with SSRIs/SNRIs, Medperdine (Demerol), and Dextromethorphan (cough suppressant) causing serotonin syndrome

22
Q

Serotonin syndrome

A

Increased serotonin in the CNS causes over-stimulation of 5HT2A receptors

Presents as tremor, tachycardia, hypertension, sweating, dilated pupils, hyperreflexia, clonus, and hyperthermia causing metabolic acidosis, rhabdomyolysis, seizures, renal failure, and DIC

23
Q

Mirtazapine - Mechanism, Uses, and Side effects

A

Mechanism: Blocks a-2 receptors on serotonergic and adrenergic neurons, enhancing release of 5HT and NE; does NOT affect reuptake systems

Useful due to additional anti-insomnia and anti-anxiety effects; low incidence of sexual side effects

Side effects: Daytime somnolence, weight gain

24
Q

Benefits of Lithium

A

Best studied, best proven drug for bipolar disorder

Effective anti-manic, reasonable preventative agent, some antidepressant and anti-suicidal properties

Neuro-regenerative

Cheap

25
Q

Lithium - Adverse Effects, and DDIs

A

GI upset, tremor, metallic taste, cognitive dulling

Decreased urine concentration / diabetes insipidus, due to decreased ADH secretion (20-30%)

Hypothyroidism (5-10%); can cause weight gain

Narrow therapeutic window; toxicity/overdose causes confusion, seizures, stupor, coma

DDIs: Diuretics decrease renal clearance up to 25% causing increased Li+ plasma levels

26
Q

MAOIs - Agents

A

Phenelzine, Selegeline

27
Q

SSRI Indications

A 
Major depressive disorder
Generalized anxiety disorder
Social anxiety
Panic 
OCD 
PTSD 
PMDD
28
Q

Mania - Pharmacologic Treatment Options

A

Lithium
All atypical antipsychotics
Divalproex Sodium (Depakote)

29
Q

Bipolar Depression - Pharmacologic Treatment Options

A

Olanzapine-Fluoxetine
Quetiapine

Possibly Lithium, Lamotrigine

30
Q

Bipolar Maintenance - Pharmacologic Treatment Options

A

Lamotrigine

Aripiprazole

31
Q

Bipolar Relapse Prevention - Pharmacologic Treatment Options

A

Lithium

Olanzapine

32
Q

What is the overall response and remission rate of antidepressants?

A

67% overall response rate within 8 weeks; 40% of patients do not respond until week 8, thus 8-14 weeks is considered an adequate trial

SSRIs have a 33% rate of remission; all FDA approved antidepressants have comparable rates

33
Q

Benzodiazepines - Mechanism

A

Bind to the GABA channel gamma subunit, facilitating channel opening and Cl- influx; does NOT directly initiate Cl- current and requires presence of GABA

No effect on excitatory neurotransmitters - graded, dose-dependent CNS depression with ceiling affect below the level of anesthesia

34
Q

Barbituates - Mechanism

A

Prolong the effect of GABA on its receptor (presence of GABA is required); at high doses, interact directly with the GABA receptor

Also depresses excitatory glutamate transmission - capable of inducing surgical anesthesia

35
Q

Zolpidem - Mechanism & Uses

A

Selectively interacts with alpha-1 GABA channels in the cortex

Produces hypnosis (sleep) without anxiolysis; less potential for abuse
Also used as an anti-convulsant

Side effects: Amnesia, additive CNS depression

36
Q

Flumazenil

A

Benzodiazepine binding site antagonist; reverses CNS effects of benzodiazepines in overdose or following surgical use

37
Q

GABA receptor variants - a1 and a2/a5

A

GABA receptors with a1 subunits are expressed in the cortex; mediate sleep, anticonvulsant, and amnesia effects

GABA receptors with a2/a5 subunits are expressed in the limbic system and brain stem; mediate muscle relaxation, motor impairing, anxiolytic, and alcohol-potentiating effects as well as tolerance, dependence, and withdrawal

38
Q

Benzodiazepines - Metabolism

A

Metabolized by CYP450 prior to elimination in urine

Metabolites of some agents are active, with longer half lives than the parent comopounds leading to accumulation effects such as daytime sedation

Lorazepam and Oxazepam are metabolized directly to inactive compounds; better choice in elderly patients or patients with hepatic dysfunction

39
Q

Benzodiazepines - Adverse Effects

A

Extension effects: More likely with high doses, longer half life agents, elderly patients, patients with hepatic dysfunction

Sedation
Performance impairment (drowsiness, incoordination, decreased concentration, cognitive deficits)
Anterograde amnesia

Physical / Psychologic Dependence
Withdrawal syndrome

40
Q

Barbituates - DDIs

A

Barbituates are inducers of CYP450 enzymes; major source of clinically significant DDIs leading to declining use

41
Q

Buspirone

A

Partial agonist of 5HT1A, located pre-synaptically on nerve terminals

Anxiolytic effect only; NO sedation, anticonvulsant, or myorelaxant action

Requires 2 weeks for onset of effect and 4-6 weeks for maximal efficacy; must be administered daily (not prn); useful in chronic anxiety

42
Q

Treatment of GAD

A
  1. Antidepressants - SSRIs, SNRIs
  2. Benzodiazepines - Alprazolam/Lorazepam/Oxazepam (shorter acting) vs. Diazepam (longer acting) if both hypnotic and daytime anxiolysis are desired

Nervous System IV (10 decks)

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