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PHARM.Psych > Drugs to Treat Bipolar Disorders > Flashcards

Drugs to Treat Bipolar Disorders Flashcards

1
Q

What are the illness phases of bipolar disorder?

A
  • acute mania: bipolar I disorder
  • acute hypomania: bipolar II disorder
  • bipolar depression: bipolar I or II
    • CANNOT treat with only an anti-depressant; could bring pt out of depression and flip them into a maniac episode (need to combo with a mood stabilizer)
  • bipolar maintenance: bipolar I or II
    • neither manic nor depressed
  • in a sense, treating many disorders at once
  • some meds are useful for all of the phases
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2
Q

LITHIUM in the tx of Bipolar Disorder

A
  • first‐line treatment for bipolar disorder
    • first and oldest tx, still one of the most effective
  • effective in all illness phases: acute mania, depression, maintenance tx
    • ​may be better in tx mania tha bipolar depression
    • may be better in preventing relapses of mania than bipolar depression
  • ***only drug proven to reduce risk of suicide in bipolar I patients
    • VERY useful and rare
  • can enhance antidepressant effectiveness in the treatment of major depression
  • may take days to weeks (2-3w) to produce a full therapeutic effect
    • need to make a dosage adjustment
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3
Q

LITHIUM MOA

A
  • Li+ therapeutic action in tx of bipolar disorder is unclear
  • Most accepted MOA involves 2nd messenger enzymes that affect NT action
    • Inositol recycling: Li+ inhibits a number of enzymes involved in inositol recycling
    • Protein kinase C: Li+ may affect specific isozymes of protein kinase C
    • Glycogen synthase kinase‐3 (GSK‐3): Li+ inhibits GSK‐3 synthesis
  • can effect NT and their release
    • may enhance the effects of serotonin
    • may decrease NE & DA turnover (may be relevant to antimanic effects)
    • may augment synthesis of acetylcholine
  • **effects on electrolytes and ion transport (due to similarity to Na+)
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4
Q

LITHIUM PK

A
  • 100% absorbed from the GI tract (peak levels in 0.5‐2 hrs)
  • Blood level monitoring
    • half‐life | 20 hrs; draw 5‐7 days after starting med or med dose change
    • requires trough blood level, draw ~12 hours after last dose of medication
    • narrow therapeutic window (narrowest window for psych meds)
      • acute mania treatment (0.6‐1.2 mEq/L)
      • Bipolar maintenance treatment (0.6‐0.7 mEq/L)
      • Lithium toxicity (>1.5 mEq/L)
  • 0% protein binding; No (hepatic) metabolites
  • Lithium removal is almost entirely by the kidney;
    • Glomerulus: Li+ freely filtered
    • Proximal renal tubule: Li+ mostly reabsorbed in parallel with Na+
    • Collecting duct: Li+ reabsorbed by principal cells epithelial Na+ channel
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5
Q

LITHIUM Drug-Drug Interactions. DIURETICS

A
  • Urinary alkalization (Acetazolamide, dichlorphenamide, methazolamide)
    • Inhibition of proximal tubule reabsorption of HCO3-
      • ​Na+ (Li+) accompanying HCO3- (instead of being reabsorbed)
        • lead to an INCREASE of HCO3 at DCT and some Na+(Li+) reabsorption…but: NET LOSS of Na+ (Li+)
        • DECREASE in Li+ level
  • Osmotic diuretics (Mannitol, Urea); CA-i
    • increase tubular fluid osmolality
      • impaired reabsorption of fluid
      • increased excretion of H2O (some Na+ (Li+) accompanies)
      • overall DECREASE in Li+ level
  • Loop diuretics:
    • inhibits co-transport system of ThickALoH
      • decreases medulla hypertonicity
      • inability to concentrate urine
      • Na+ loss (Li+ loss +/-)…exception to the rule)
        • minor variable effects on Li+ level (+/-/0)
  • Thiazide diuretics:
    • inhibits NaCl reabsoprion in DCT
      • diuresis intially leads to Na+ (Li+) loss
      • BUT compensatory proximal tubular reabsorption of Na+ (Li+) causes and INCREASE in Li+ level
  • K+ sparing diuretics (SPIRONOLACTONE)
    • Antagonize aldosterone receptors in the cortical collecting tubule
      • decrease Na+ (Li+) reabsorption in late DCT
      • INCREASE Li+ levels (compensatory proximal tubular reabsorption?)
  • K+ sparing diuretics (AMILORIDE)
    • Lithium’s action after being absorbed by the collecting tubule’s principal cells is believed to be part of the cause of Li+ induced Nephrogenic Diabetes Insipidus (NDI)
    • Amiloride blocks Na+ (Li+) reabsorption at the collecting tubule and may successfully tx Li+ induced NDI
  • ACE Inhibitors & Angiotensin II receptor antagonists
    • Inhibits Angiotensin II production
    • decreases aldosterone (aldosterone normally increases Na+ resorption at the collecting tubule)
    • decreases Na+ resorption: Na+ loss (Li+ loss)
    • INCREASES Li+ levels (compensatory proximal tubular reabsorption?)
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6
Q

LITHIUM general SE

A

bold=common, star=rare

  • Derm: acne, psoriasis, rashes, alopecia
  • Endocrine: decreased thyroid, increased parathyroid**
    • hypothyroidism-decreased thyroud fxn
      • weight gain, mental slowness, fatigue, depressed mood, constipation, cold intolerance
      • symptoms overap with depression and other Li+ SE (increased weight)
    • common; seen in 10-50% (5W:1M)
  • GI: N/D
  • Heme: increased WBC’s
  • Neuro: fine tremor, decreased conc, sedation (sedation may decrease over time)
  • Other: Edema & weight gain (gradual)
    • initial weight gain: Li acting like Na -> thirst and some water accumulation
    • long-term weight gain: slowly over time, may also be due to decrease in thyroid fxn, may be from increase in eating secondary to depression
    • W>M
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7
Q

LITHIUM severe SE

A
  • Renal issues:
    • Nephrogenic diabetes insipidus (NDI)
      • Commonly effects kidney ability to concentrate urine (polyuria) which leads to fluid intake (polydipsia); this is drug-induced NDI
      • [Not a S-T risk] risk for patients on lithium L-T (10+ ys)
      • A common (L-T) risk; 10%-60% patients on L-T Li+ may develop NDI
      • Episode(s) of Li+ toxicity increase risk
      • Amiloride may treat NDI (see diuretic section)
    • Mild renal insufficiency
      • Glomerular & interstitial changes seen from chronic (yrs) Li+ tx.
      • Slow decrease in fxn—20% of pt’s GFR slowly decreases; progression to ESRD due to Li+ (rare)
    • Patients w/ renal impairment require more cautious (lower) dosing of Li+
  • Cardiac‐rare
    • arrhythmia, severe sinus node dysfunction (bradycardia*,sick sinus syndrome*)
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8
Q

LITHIUm toxicity

A
  • mild: stop Li, restart at lower dose a couple days later
  • moderate: tx like mild, may also need some supportive care
  • severe: dialysis
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9
Q

Managing pts on LITHIUM

A
  • before starting Li+
    • TSH
    • renal fxn
    • ECG-if pt >50 yo
    • weight (BMI)
    • pregnancy test!
  • After starting Li+
    • Li+ level-needs to be therapeutic
  • When stable; every 6-12 mo check the following:
    • TSH
    • renal fxn
    • weight (BMI)
    • Li+ level
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10
Q

ANTI-convulsants (Mood Stabilizers)-KENE vs. KOTE

A
  • Valproic acid (VPA; DepaKENE)=liquid, hard on the stomach; always take with food to decrease N/D
  • Divalproex Sodium (DepaKOTE)
    • 1:1 molar ratio of VPA and sodium valproate
    • white powder that is made into a pill and entericlaly coated
    • enteric coat (“kote”) helps decrease N/D
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11
Q

KENE/KOTE MOA

A
  • GABA reuptake inhibitor
  • influences 2nd msgr enzymes (GSK-3)
  • blockade of voltage-dependent sodium channels
    • blocks sustained high frequency neuronal firing rates (anti-epiliptogenic effect)
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12
Q

KENE/KOTE PK

A
  • 100 absorbed
  • highly (90%) protein bound
    • ​unbound fraction crosses the BBB and exerts pahrmacologic activity
  • therapeutic range: 50-125 ug/mL (monitor blood levels)
  • t1/2=12 hrs
  • DDI
    • protein displacement:
      • displaces other protein bound drugs (Ex: PHENYTOIN-Dilantin…increased PHENYTOIN free fraction=potential toxicity)
        • also: CARBAMAZEPINE, DIAZEPAM
      • may itself be displaced (caffeine, aspirin) from serum proteins=increased free fraction and possible toxicity
    • inhibits hepatic metablism
    • inhibits metabolism of other anti-convulsants=risk of toxicity
    • VPA interaction with LAMOTRIGINE:
      • inhibits phase 2 glucoronidation PW that inactivates and eliminates LAMOTRIGINE (CYP450 system NOT involved)
      • increases LAMOTRIGINE levels (2-3x) leads to an increased risk of LAMOTRIGINE SE
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13
Q

KENE/KOTE SE

A
  • Derm: alopecia*
  • GI: Nausea (avoid by giving with food or use enteric coated Depakote) V/D, mildly increased LFT’s; pancreatitis*
  • Heme: decreased platelets*
  • Neuro: ataxia, headache, dizziness, tremor, sedation
  • x Other: increased ammonia level, weight gain, polycystic ovarian syndrome (PCOS)
  • increased suicide risk*
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14
Q

KENE/KOTE Toxicity

A
  • typically from med OD:
    • CNS depression
    • decreased BP
    • metabolic acidosis
    • abnml electrolytes
  • toxicity can happen from therapeutic use:
    • mild increase in LFTs-very common (lamost 50% pts)
      • reversible with med discontinuation
    • Hepatotoxicity-greatest risk: kids <2 yo who are also treated with other drugs
    • HYPERammonemia:
      • may be dose related; LFTs may be nml
      • if ammonia level high, VPA is discontinued
      • if severe (HYPERammonemic encephalopathy) tx with L-carnitine
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15
Q

Managing Pts on KENE/KOTE

A
  • before starting:
    • LFTs
    • platelet count
    • weight (BMI)
    • pregnancy test!
  • After starting:
    • VPA level needs to be therapeutic
  • When stable, every 6-12 months
    • LFTs
    • platelet count
    • weight (BMI)
    • VPA level
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16
Q

CARBAMAZEPINE (Tegretol) MOA + Indication

A
  • Used to be 2nd line treatment; now 3rd line behind SGA for tx of bipolar mania; bipolar maintenance treatment
  • MOA: not completely clear
    • reduces Na+ influx and depresses synaptic transmission;
    • reduces release of NE and excitatory AA such as glutamate
    • adenosine receptor agonist (caffeine=adenosine receptor ANTagonist)
17
Q

CARBAMAZEPINE (Tegretol) PK

A
  • erratic absorption
  • medium protein binding (70‐80%)
  • structurally similar to TCA’s (tricyclic compound)
  • Therapeutic range: 4-12 ug/mL (monitor blood levels)
    • therapeutic range established for treating seizures
    • therapeutic range for treating a manic episode NOT established (though clinically the range for treating seizure disorders is what is used)
  • **CYP450 effects
    • strong inducer of various CYP450 enzymes (1A2, 2C8, 2C9, 2D6, 3A4) that INCREASE metabolism of many drugs (OCP, warfarin, theophylline, doxycycline, haloperidol, TCA’s, VPAs‐most anticonvulsants, benzodiazepines)
    • carbamazepine levels can be INCREASED by CYP450 3A4 inhibitors (fluoxetine, cimetidine, erythromycin, isoniazid)
    • carbamazepine auto‐induces its own metabolism
      • PRE-auto induction half‐life = 24 hrs
      • POST‐auto‐induction half‐life = 8 hrs
    • carbamazepine levels can be DECREASED by P450 3A4 inductors (phenobarbital, phenytoin, primidone)
  • **hepatic metabolism to 10,11‐epoxide: can cause neurologic side effects
    • ​induces UDP-glucuronosyltransferases
18
Q

CARBAMAZEPINE (Tegretol) SE/Toxic Effects

A
  • Derm: rash (Stevens Johnson Syndrome)*
    • SJS is more common in pts of Asian ancestry who have human leukocyte antigen (HLA) allele HLA‐B*1502
  • GI: N/V, mild increase in LFTs, hepatotoxic**
  • Heme: decreased WBC’s, aplastic anemia**, agranulocytosis** [1/100,000 (0.001%)]
  • Neuro: ataxia, diploplia, dizziness**, tremor, **sedation
  • Other: decreased Na, weight gain; increased suicide risk**
  • Teratogenic: risk of neural tube defects (0.9%)
19
Q

LAMOTRIGINE (Lamictal) MOA + Indication

A
  • (NOT useful in treating acute manic episode)
  • approved for:
    • bipolar long‐term maintenance treatment
    • bipolar depression
  • MOA: not completely clear
    • inhibits release of glutamate (excitatory AA)
    • inhibits voltage sensitive Na+ channels resulting in stabilization of neuronal membranes that mediate PRE-synaptic transmitter release of excitatory AA
20
Q

LAMO-TRIGINE (Lamictal) PK

A
  • low protein binding (55%)
  • metabolized primarily by glucuronidation
  • DDI:
    • Valproate can DBL Lamo-trigine’s plasma levels
    • OCPs can DECREASE lamotrigine’s plasma level by 50%
    • Carbamazepine (Tegretol)‐induced enzymes (i.e. CYP3A4) can:
      • INCREASE metabolism of Lamo-trigine
      • DECREASE Lamo-trigine’s plasma level
  • Lamo-trigine can induce own metabolism
21
Q

LAMO-TRIGINE (Lamictal) SE

A
  • alcohol may INCREASE the SE severity
  • **Derm: rash (benign or SJS*)
    • benign: ~10%
    • SJS: 0.02-0.10 % and happens within 8 wks
  • GI: Nausea, vomiting
  • Neuro: ataxia, HA, dizziness, dbl vision, blurred vision, fatigue
  • Heme: DECREASED WBCs, blood dyscrasias* (agranulocytosis*, aplastic anemia*)
  • Other: insomnia
22
Q

Second Gen ANTI-psychotics (SGA) used in treating Bipolar Disorder

A
  • many approved for treating acute mania (in combo with a mood stabilizer)
    • severe bipolar mania-psychosis, suicidal/homicidal/dangerous behavior
      • these pts also generally require in-pt hospitalization
    • start trial of: Li+ + SGA -or- Depakote + SGA
    • Several are approved for maintenance tx
    • 3 approved for Bipolar depression
23
Q

LITHIUM-Bipolar meds teratogenic risks

A
  • 1st trimester exposure INCREASES risk of Ebstein’s anomaly (congenital cardiac defects)
  • revised risk calculation
    • initial: 400x general pop/2%/1-in-50
    • revised: 0.05 to 0.1% (betwen 1 in 1,000-2,000)
    • general pop risk 0.005% (1-in-20,000)
  • Li+ levels may DECREASE during pregnancy (INCREASED GFR as pregnancy progresses) and are INCREASED after delivery (DECREASED GFR late 3rd trimester)
  • Li+ toxicity in newborns (lethargy, cyanosis, poor suck and Moro refleces, cardia arrhythmias, muscle flaccidity)
24
Q

Pregnancy and Bipolar Meds-General

A
  • Baseline incidents of major fetal malformation in general population is 2‐5%
  • For pregnant women w/ bipolar disorder, risk of a manic episode is INCREASED d/r the pregnancy AND in the post‐partum period
25
Q

***[KENE/KOTE];VPA; Sodium Valproate (Depakote)-Bipolar meds teratogenic risks

A
  • greatest risk of serious birth defects of ALL psychotropic meds
  • risk of neural tube defects: 3-5% (12-16x gen pop rate) […or is it 1-2% (10-20x gen pop]
26
Q

CARBAMAZEPINE (Tegretol)-Bipolar meds teratogenic risks

A

INCREASED risk of neural tube defect (Spina Bifida; about 0.9%) if used during pregnancy–lower thn with Sodium Valproate (Depakote)

27
Q

LAMO-TRIGINE (Lamictal)-Bipolar meds teratogenic risks

A
  • appears least teratogenic risk of mood stabilizers
  • possible risk of cleft palate
28
Q

ANTI-psychotics-Bipolar meds teratogenic risks

A
  • FGA and SGA prental exposure
    • same incidence of major physical malformations as general population

PHARM.Psych (5 decks)

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