Mood Stabilizers

Lithium Brand Names

• Eskalith

• Eskalith CR

• Lithobid

What is the MOA of Lithium?

• no psychotrophic, sedative, depressant, or euphoiant effects

• modulates neurotransmission associated w/ phosphatidyl inositol second messenger system

• alters sodium transport in nerve cells, affecting function

• increase BDNF

What is the PK of Lithium?

• rapid absorption (95-100%)

• Wide distribution

• No protein binding

• No metabolism

• 90-95% eliminated unchanged by the kidneys

What are Li+ adverse effects?

• V/D

• Weight gain

• hypothyroidism

• Tinnitus (ear ringing)

• Tremor, poor muscle control, muscle weakness

• drowsiness

• cardiac dysrhythmias

• reversible leukocytosis (↑ WBC)

• Long term use: Nephrogenic diabetes insipidus

• Rare: thyroid enlargement, nephrotoxicity

What is the Li+ therapeutic range & toxicity range? What effects happens during toxicity?

• 0.6-1.2 (Toxicity >1.5)

• Early signs: N/V/D, Tremor, ataxia

• High toxic: arrhythmia, seizures, stupor, coma, death

What are situations that predispose pts to toxicity?

• sodium restriction

• dehydration

• V/D

• Age (>50)

• HF

• Cirrhosis

• DIs that decrease Li+ CL & activities that increase Na+ loss

What are Li+ Drug Interactions & what does it cause?

• NSAIDs, COX-2 Inhibitors: ↓ GFR & ↓ Li+ elimination

• ACEi/ARBs: ↓ GRF, ↑ proximal reabsorption, ↓ Li+ elimination

• Thiazide/Thiazide-like diuretics: ↑ proximal reabsorption, ↓ Li+ elimination

• ↓ salt intake, Na loss: ↑ proximal reabsorption, ↓ Li+ elimination

• Osmotic diuretics, caffeine, ↑ salt intake: ↑ Li+ elimination

Brand Name of Divalproex Sodium

Depakote

Brand Name of Valproic Acid

Depankene

Brand Name of Valproate sodium

Depacon

MOA of Divalproex/ Valproic acid/ Valproate

• Inhibits voltage-sensitive sodium channels at presynaptic GLU neurons: ↓ action potential, ↓ neuron firing, ↓ GLU release

• antagonizes NMDA (GLU) receptor: ↓ GLU action

• enhancing GABA transmission: ↓ neuronal excitation

• affects second messenger cascades

Valproic Acid PK

• Absorption:

• Protein bound:

• Metabolism:

• CYP:

• rapid & almost completely absorbed

• highly protein bound (>90), saturable

• glucuronidation (VPA-glucuronidation undergoes enterohepatic recirculation)

• Mitchochondrial beta-oxidation

• Minor CYP2C9, but inhibits CYP2C9 & UGT

Adverse Effects of VPA

• N/V, Abdominal pain, indigestion

• HA, Dizziness, excess sleepiness, dose-related tremor

• Diplopia (double vision), blurred vision

• Anorexia, weight gain

• bleeding, other hematopoietic changes

• alopecia

• Mitochondria dysfunction ( hepatotoxicity, increase ammonia, edema in the brain)

Warnings/ CIs of VPA

• Hepatotoxicity (monitor liver function)

• Fetal risk: neural tub defects, cognitive deficits)

• Pancreatitis

• hepatic disease/dysfunction

• mitchondrial disorders

• urea cycle disorders

DIs of VPA

• Inhibits & metabolized by CYP2C9 & UGT

• Carbapenems: ↑ VPA elimination; interferes w/ an enzyme that breakdown glucoronidation & prevent recirculation of VPA

Brand Names of Carbamazepine

• Equetro

• Tegretol

• Epitol

• Tegretol-XR

• Carbatrol

MOA of Carbamazepine

• inhibition of voltage-sensitive sodium channels at presynaptic GLU neurons: ↓ action potential, neuron firing, GLU release

• agonist at GABA receptor ↑ GABA inhibitory action

Carbamazepine PK

• absorption

• metabolism

• CYPs

• slowly but completely absorbed

• metabolized to 10,11-epoxide metabolite (active) 3A4 inhibitor/inducers

• Induces CYP,UGTs, Pgp

• induces its own metabolism

Carbamazepine Adverse Effects

• dizziness, drowsiness, blurred vision

• N/V, dry mouth

• Itching, photosensitivity, rash

• Alopecia

• Increased liver enzymes

• SJS

Carbamazepine Warnings, Contraindications

• risk of developing anemia or agranulocytosis

• dermatological toxicity: HLA-B* 1502 allele at highest risk

MOA of Lamotrigine

• inhibition of voltage-sensitive sodium channels at presynaptic GLU neurons: ↓ action potential, neuron firing, GLU release

• inhibition of voltage-gated calcium channels at presynaptic GLU neurons, ↓ GLU release

Brand Name of Lamotrigine

Lamictal

Lamotrigine PK

• Rapid & complete absorption

• Metabolism:

  • primarily glucuronidation

  • at high doese: UGT saturation (depletion of UDP-glucuronic acid), ↑ CYP pathway & ↑ epoxide

Adverse Effects of Lamotrigine

• Nausea

• HA, Dizziness, drowsiness, tremor, poor muscle control, double vision

• rash, itching

• SJS

Lamotrigine DIs & their effects

• VPA: Inhibits Lamotrigine glucuronidation

• Ethunyl estradiol + progestogen: induces lamotrigine glucuronidation

What fetal effects does Li+, VPA, and carbamazepine have?

• Li: ↑ congenital cardiac malformation & other abnormalities

• VPA: fetal facial dysmorphism, neural tube defects, cognitive deficts

• Carbamazepine: fetal facial dysmorphism