LITHIUM

v Monovalent cation, referred to as a alkali metal

v Distributed in total body water, half-life is 24 hours

v Cleared by the kidneys

v Narrow therapeutic window ( 0.5 to 1.5 mEq/L) (Steady state concentration lower than 0.8 tend to have more relapses)

v Administered in 1-2 gram quantities

Lithium effects:

1) Inhibits Na/K ATPase pump

2) Affects several neurotransmitter systems:

Serotonin – increases transmission

Dopamine – decreases transmission and release

Norepinephrine – increases turnover in depression

Decreases turnover in mania

Ach – increases synthesis with chronic administration

3) Inhibits cAMP mediated events

Side effects: most side effects are dose related (need to monitor blood levels). The side effects are divided into three groups. The side effect leading to noncompliance the most is cognitive dysruption (memory problems).

1) Side effects appearing at therapeutic ranges:

- fine tremor

- GI upset - nausea

- malaise, dizziness, fatigue

- polydipsia/polyuria

2) Symptoms appearing with elevated lithium levels (begin at about 2.0 mEq/L) These symptoms suggest a need for downward dose adjustment.

- drowsiness, somnolence, ataxia, blurred vision .

3) Signs of serious toxicity

- Acute organic brain syndrome: GI – vomiting and diarrhea (lead to electrolyte and fluid abnormalities which increases retention of lithium and the toxicity gets progressively worse)

- myclonus, seizures, abnormal reflexes

VALPROIC ACID AND CARBAMAZEPINE

v Believed to be related to enhancing GABA transmission in some fashion

v Anti- kindling agents

v Seem to be more effective for patients in whom lithium is less effective

v Also used to treat episodic rage, PTSD, panic, and post head injury syndromes

v Should be used with caution in patients with hepatic disease. Close monitoring is suggested with periodic assessment of CBC, liver enzymes, and plasma concentrations.

VALPROIC ACID

- Branched chain organic acid

- Increases concentration of GABA in the CNS by inhibiting the metabolism of GABA by

GABA- aminotransaminase

- FDA approved for first line treatment of mania but is not approved for prophylaxis but is reported effective in the literature.

- Drug interactions: relatively few. Interactions occur because of competition for a protein-binding site. VPA binds to albumin fatty acid binding site, which also binds most acidic drugs. Especially watch out for agents that interfere with coagulation (warfarin and aspirin) due to thrombocytopenia

Side Effects:

1) CNS: Sedation, tremor

2) GI: nausea, vomiting, diarrhea

3) Coagulopathies

4) Teratogenic in pregnancy

5) Rare: heptatotoxicity, pancreatitis, agranulocytosis

6) Key drug interactions: NSAIDS

7) Valproate is an inhibitor of P-450 enzymes

CARBAMAZEPINE

- Acts at sodium channels

- Drug interactions: induction of the cytochrome p450 system ( isoenzyme 3A4) same one that metabolizes oral contraceptives

inhibitors of 3A4 may lead to CBZ toxicity ( erythromycin, nefazadone, etc.)

Side Effects:

1) CNS: sedation, weakness, ataxia, interference with cognitive function

2) Abnormal eye movements: diplopia, nystagmus

3) Skin rash, exfoliative dermatitis

4) Hematologic: leucopenia, aplastic anemia

5) CNS toxicity in overdose

6) Cardiovascular toxicity in overdose

7) Teratogenic in pregnancy

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