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LITHIUM Objectives Develop a plan of lab and clinical monitoring parameters to ensure safety of lithium Know what effects various drugs have on lithium levels Know what are signs of lithium toxicity Be able to predict how changes in diet and new medications effect lithium levels Know the desired li...

LITHIUM Objectives Develop a plan of lab and clinical monitoring parameters to ensure safety of lithium Know what effects various drugs have on lithium levels Know what are signs of lithium toxicity Be able to predict how changes in diet and new medications effect lithium levels Know the desired lithium levels for various disease states Clinical Uses of Lithium First-line agent for acute mania and maintenance treatment of bipolar I and II Shows 78% response rate in aborting an acute manic or hypomanic episode Second-line agent for acute bipolar II depression Shown to reduce suicide risk Mechanism of Action Unknown, but it is thought to modulate neurotransmission at both the neuronal and intracellular levels, and chronic administration may modulate gene expression and have neuroprotective effects. Pharmacokinetics Formulations – Exams Qs Bioavailability Readily and almost completely absorbed from the small intestine by passive diffusion Oral syrup - ~100% Immediate release – 95 to 100% Extended release – 60 to 90% Food does not effect Absorption Complete dissociation to the lithium cation after oral administration Absorption rate varies for salt form and release type Lithium carbonate Regular-release tablets/capsules–Peak concentrations 0.5 to 3 hours Extended-release tablets–peak concentrations 4 to 12 hours Citrate solution Peak concentrations 15 to 60 minutes Food may delay the rate of absorption due to slower gastric emptying but not the extent Distribution Open, two-compartment model Initially distributed in the extracellular space Vd=0.25 to 0.3 L/kg Distributes evenly in total body water space Vd=0.7 to 1.0 L/kg Preferential uptake into: Brain, kidney, thyroid, bone Not protein bound Crosses into placenta breast milk 20 to 30% age-dependent reduction in Vd patients ≥ 65 Elimination Not metabolized by the liver Eliminated as free ion in urine Clearance is largely renal (~95%) Saliva, sweat, feces→<5% Freely filtered across the glomerular membrane 80% reabsorbed via proximal renal tubules along with sodium Clearance is directly proportional to GFR and blood flow to the kidney ~20-25% of CrCl Summary Lithium Pharmacokinetics Tmax IR 0.5-3 hrs; XR 4-12 hrs, Syrup 0.25-1 hr Steady state: 5 days Absorption 100% absorbed Affected by food Metabolism No hepatic metabolism No CYP interference Elimination Plasma t1/2-24 hrs Clearance increases by 50-100% Excretion 90-95% unchanged by kidney Factors Affecting Lithium Levels – exam Qs Situations to Consider Drug Interactions with Lithium Adverse Effects and Warnings Lithium Adverse Effects Lithium Warnings Contraindicated: renal disease, severe cardiovascular disease, history of leukemia, first trimester of pregnancy and hypersensitivity to lithium Precautions: thyroid disease, patients who have sodium depletion, patient who receive diuretics or dehydrated patients Takes 2 weeks to see the full effects of lithium Counseling Points Lithium Counseling Take with or without food. Take with food if medication causes an upset stomach Keep salt in your diet the same. Changes in salt intake can change your lithium drug levels in the body Avoid excessive amounts of caffeine . Caffeine can increase the amount of lithium that is excreted from the body through the kidneys. Avoid becoming dehydrated. Discuss the use of other medications. (ESPECIALLY OTC NSAIDS) Monitor lithium levels Side effects of medication Toxicity: Blurred vision, being sick, diarrhea, muscle weakness, drowsiness, feeling shaky, lack of coordination Pregnancy status? Baseline Labs and Vitals Lithium Baseline CBC Electrolytes Renal function Thyroid function tests Urinalysis EKG pregnancy tests Therapeutic Ranges Lithium is a monovalent cation, due to this, the therapeutic range expressed in mEq/L  The general therapeutic range is 0.6-1.5 mEq/L (not useful in clinical practice!!!) Due ranges changing based on clinical situations you will need to ranges based on individual clinical situations Therapeutic concentration (acute mania) 0.8-1.2 mEq/L Rare but sometimes ranges of 1.2-1.5 mEq/L are needed Therapeutic concentration (maintenance) 0.6-1.0 mEq/L Rare but sometimes ranges of 1.0-1.2 mEq/L are needed Lithium Levels – Exam Qs Increase levels based on plasma levels Therapeutic concentration (acute mania) 0.8-1.2 mEq/L Therapeutic concentration (maintenance) 0.6-1.0 mEq/L Order levels 12 hours post dose for accurate levels Generally, the dose is titrated in 300 mg increments with monitoring of serum levels. Usually results in an increase in the serum lithium level of 0.3 mEq/L at steady states. 300 mg increase=lithium level increase by 0.3 mEq/L Twice weekly until both patient's clinical status and levels are stable, then repeat levels every 1 to 3 months or as clinically indicated Therapeutic Ranges An increase of 300 mg equates to ~0.3 mEq/L in steady state serum concentrations Higher concentrations are sometimes needed in select patients. (1.2-1.5 mEq/L for acute mania) Lithium Levels Therapeutic Ranges are based off steady-state lithium serum concentrations. Order levels12 hours post dose for accurate levels After oral administration, lithium concentrations follow a complex concentration-time curve that is best described using multicompartment models There is a great deal of variability among patients in the time needed for distribution between serum and tissues. Make sure the patient takes all their medicine as instructed 2-3 days before the blood sample is obtained Blood sample need to be drawn 12 ± 0.5 h after the last dose Make sure patients are comfortable tell you and their provider about any discrepancies they had prior to lab draw. This could affect the levels. More frequent monitoring maybe needed with changes in fluid and electrolyte balances, unstable renal function, or if toxicity is a concern Lithium Toxicity Lithium toxicity usually occurs with blood levels greater than 1.5 mEq/L (mmol/L) In elderly patients may experience toxicity at lower levels. Lithium Dosing Lithium Dosing (Adults) Dosing recommendations for Bipolar Disorder: Initial dosing range: 600-900 mg/day in 2 to 3 divided doses depending on the formulation Increase dose based on response and tolerability by 300 to 600 mg every 1 to 5 days to a usual therapeutic range of 900 mg/day to 1.8 g/day. After 5 to 7 days at a stable therapeutic dose, further adjust as needed based on clinical response, tolerability, and serum concentration Dosing recommendations for Bipolar Disorder: Maintenance doses should be adjusted based on the steady-state serum concentration and clinical picture of the patient. IR formulation: 900-2400 mg/day in 2-4 divided doses ER formulation: 900-1800 mg/day in 2 divided doses Steady state reaches at about 5 days; however, it may be prudent to obtain a serum concentration 3 days after dosage changes or initiation Dose Adjustments Generally, the dose is titrated in 300 mg increments with monitoring of serum levels. Usually results in an increase in the serum lithium level of 0.3 mEq/L at steady states. 300 mg increase=lithium level increase by 0.3 mEq/L Dose Prediction Methods - FYI Traditional pharmacokinetic method $D = \frac{\text{Cl}_{\text{Li}}\text{~x~τ~x~}C_{\text{ss}}}{\text{S~X~F}}$ D = dose (mEq) τ = dosing interval (hr) Css = steady state concentration (mEq/L) F = fraction absorbed (1) S = salt form (1) ClLi =clarence of lithium (L/hr) Lithium clearance estimate ClLi=0.2 (CrCl mL/min) In acute mania, lithium clearance is increased by ~50% Lithium Clearance - FYI Clearance is expressed in L/day Conversion used is Cl=0.288*(CrCl) In patients with acute mania clearance increases by ~50% Conversion used is Cl=0.432*(CrCl)

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