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
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
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+)
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
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
-
Na+ (Li+) accompanying HCO3- (instead of being reabsorbed)
- Inhibition of proximal tubule reabsorption of HCO3-
- 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
- increase tubular fluid osmolality
- 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)
- inhibits co-transport system of ThickALoH
- 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
- inhibits NaCl reabsoprion in DCT
- 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?)
- Antagonize aldosterone receptors in the cortical collecting tubule
- 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?)
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)
- hypothyroidism-decreased thyroud fxn
- 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
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+
-
Nephrogenic diabetes insipidus (NDI)
-
Cardiac‐rare
- arrhythmia, severe sinus node dysfunction (bradycardia*,sick sinus syndrome*)
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
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
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
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)
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
- displaces other protein bound drugs (Ex: PHENYTOIN-Dilantin…increased PHENYTOIN free fraction=potential 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
-
protein displacement:
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*
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
-
mild increase in LFTs-very common (lamost 50% pts)
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
