Clinical Clinical PharmacokineticsPharmacokinetics of Lithiumof Lithium

Dr. Muslim Suardi, MSi., Apt. Dr. Muslim Suardi, MSi., Apt. School of Pharmacy, Faculty of ScienceSchool of Pharmacy, Faculty of Science

University of AndalasUniversity of Andalas

20042004

ObjectivesObjectives

• Clinical correlation between Cp levels & toxicity

• Li elimination with renal physiology• Current controversy with overall usefullness

of dialysis.

LiLi

• Monovalent cation (Charge +)• Rapid GI absorption• No protein binding• Small Vd ( 0.66-0.8 L/ kg)• 80% tubular reabsorption.• 20% renally excreted• T 1/2 18h average• Toxicity increased by dehydration • Unit mEq/L = mmol/L

Clinical Use of LithiumClinical Use of Lithium

• Li first-line therapy for treatment of acute mania & long-term prophylaxis

• of bipolar disorder. • It is also used in a variety of other• conditions, such as: • schizoaffective disorder, major, depressive

disorder, schizophrenia, aggression, premenstrual dysphoria, & cluster headaches.

AbsorptionAbsorption

• Oral BA is good for all lithium salts & dosage forms & equals 100%.

• The peak Li concentration occurs 15–30 min after a dose of Li citrate syrup

DistributionDistribution

• Li ion is not plasma protein bound

• Vd equal to 0.9 L/kg

• Li crosses the placenta, & human milk concentrations are 30–100% that of concurrent serum concentrations

• When given orally, Li follows a 2-comp model

DistributionDistribution

• Li is widely distributed into most body tissues 7 fluids.

• However, it is unevenly distributed among

• several tissue compartments, so for instance, the Li concentration is higher in saliva & in the thyroid than in serum.

DistributionDistribution

• Li initially distributes into an apparent volume that is about 25%-40% of BW, & later into a volume that is about 50%-100% of BW The apparent Vd at SS ranges from 0.5 - 1.2 L/kg.

EliminationElimination

• Because Li is eliminated almost exclusively by the kidney, renal dysfunction is the most important disease state that affects Li PKT.

• Li clearance rate decreases in proportion to CrCl

Elimination Elimination

• Li is eliminated almost completely (>95%) unchanged in the urine.

• The ion is filtered freely at the glomerulus, & subsequently 60–80% of the amount filtered is reabsorbed by the proximal tubule of the nephron.

• Li eliminated in the saliva, sweat, & feces accounts for <5% of the administered dose.

EliminationElimination

• Lithium is removed from the body by hemodialysis, peritoneal dialysis, and arteriovenous hemodiafiltration

CaseCase

• 37yo female

• Bipolar

• Had a prescription for Li

• Found confused by sister

• Told her she ingested her month’s worth of meds.

Questions?

Q?Q?

Coingestants?

Time of ingestion?

Other medical disease?

Types of Types of ToxicityToxicity

Acute

Acute on chronic

Chronic

Li Li PPeak eak AAbsorptionbsorption

Immediate release

2-6h

Slow release

6-24h

Li Li TToxicityoxicity ACUTE CHRONIC

GI 42% 20%

CNS Delayed Common > 2.mmol/L

Renal Usually non significant

Universal

ECG Normal QT prolongation usual

Thyroid None Hypothyroidism 20%

Recovery Usual, rapid Disability 10% delayed

Level correlation Poor Good

CChronic hronic TToxicityoxicity SymptomSymptom

Mmol/L Effects

0.5 None

1.0 Mild tremor

1.5 Coarse tremor

2.0 Hyperreflexia, dysarthria

2.5 Myoclonia, ataxia,confusion

> 3.0 Delirium, coma, seizures

DecontaminationDecontamination

Sodium polystyrene sulfonate13 published studies- human case reportsAcute vs chronic dosing?Time of ingestion vs time of treatment?Electrolytic complicationsTheoretically good, practically ?

Bentonite(Ponampalam & Otten, 2002 )

Polyethylene glycol(Smith, 1991)

Tubular Tubular LLithium ithium HHandlingandling

Effect of Effect of FFrruusemidesemide

Li+ Li+ LLoop oop DDiuretics iuretics

Frusemide increases Li Cl in single doses / healthy volunteers

In real world: Li

+ Frusemide / ECFV contraction

+Comorbidity (LV dysfunction, kidney disease)

= Li+ toxicity

Back to Back to CCasease• In ressuscitation area• No Norit given• BP 110/80, HR 115, RR 24 • Nystagmus, truncal ataxia, disoriented.• SMA-7 normal except Cr of 120• ASA, APAP, Et-OH negative.• Normal anion gap• Initial Cp Li 3.0• What next intervention?

PPKK of of LiLi OOverdoseverdose

• 1 case study over 12 days• Calculation of CSF, serum, urine &

dialysate concentration of Li• Urinary excretion of Li not affected by HD

but dependant of renal function• Lack of parallelism of serum & CSF conc =

slow equilibrium between comp• Rebound peaks after HD• HD is effective in redusing cellular pool of

Li

When to When to DDialyse?ialyse?

• Kinetics of 14 patients all with HD• Levels 1.4-9.6mmol/L• Pre HD

– Serum t ½ = 23 h– Total Cl 26 mL/min

• With HD– Serum t ½= 3.6-5.7h

– Cl 63-110 ml/min

• Dependant on type of poisoning, RI• No rigid indication for HD• Decision should be based of first 12h data

HHDD & Li Le& Li Levelsvels

• Most studies were done with chronic poisoning.

• Not based on population PCC study• Physicians tend to react to high Li

levels rather than symptoms or decrease Li excreation

Hd Hd

• Replacement doses of Li during dialysis or hemofiltration should be determined using serum concentration monitoring

Lithium Intoxication Lithium Intoxication

• Li is a complex intoxication• Existence of acute-on-chronic type?• Neurotoxicity occurs with chronic

poisoning• CVVHD works but not as much as HD• HD should be reserved for the most

severe cases.

TREAT THE PATIENT NOT THE LEVEL

CCll

Cl = [Urine Li] x Volume[Plasma Li] x time

Individualized Dose of LiIndividualized Dose of Li

• Pharmacokinetic dosing method

• Literature-based recommended dosing

• Test dose methods

Pharmacokinetic Dosing Pharmacokinetic Dosing MethodMethod

• CL ESTIMATE

• SELECTION OF APPROPRIATE PK MODEL & EQUATIONS

• SS CONCENTRATION SELECTION

ExampleExample

MJ is a 50yo, 70-kg (5 ft 10 in) male with bipolar disease. He is not currently experiencing an episode of acute mania. His Scr is 0.9 mg/dL. Compute an oral Li dose for this patient for maintenance therapy.

1. 1. Estimate CrClEstimate CrCl

• This patient has a stable Scr and is not obese.

• The Cockcroft-Gault equation can be used to estimate CrCl:

• CrClest = [(140−age)BW]/(72*SCr)

= [(140−50y)70kg]/(72*0.9mg/dL) = 7 mL/min

2. 2. Estimate ClearanceEstimate Clearance

• The drug Cl vs CrCl relationship is used to estimate the Li Cl for this patient:

• Cl = 0.288(CrCl)

= 0.288(97 mL/min)= 27.9 L/d

Use average SS concentration Use average SS concentration equation to compute Li MDequation to compute Li MD

For a patient requiring maintenance therapy for bipolar disease the desired Li concentration would be 0.6–0.8 mmol/L. A Scr equal to 0.6 mmol/L will be chosen for this patient, & oral Li2CO3 will be used (F =1,8.12 mmol Li+/300 mg of Li2CO3.

Use average SS (Cont)Use average SS (Cont)

• D/τ = (Css*Cl) / F = (0.6 mmol/L*27.9 L/d) /1 = 16.7 mmol/d

• D/τ = (300-mg Li2CO3/8.12 mmol Li+) 16.7 mmol/d = 617 mg/d, rounded to 600 mg/d of Li2CO3. This dose would be given as 300 mg of Li2CO3 every 12h.