1. Clinical Pharmacokinetics of Lithium Dr. Muslim Suardi, MSi., Apt. School of Pharmacy, Faculty of Science University of Andalas 2004

2. Objectives Clinical correlation between Cp levels & toxicity Li elimination with renal physiology Current controversy with overall usefullness of dialysis.

3. Li 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

4. Clinical 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.

5. Absorption 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

6. Distribution 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

7. Distribution 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.

8. Distribution 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.

9. Elimination 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

10. 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.

11. Elimination Lithium is removed from the body by hemodialysis, peritoneal dialysis, and arteriovenous hemodiafiltration

12. Case 37yo female Bipolar Had a prescription for Li Found confused by sister Told her she ingested her month’s worth of meds. Questions?

13. Q? Coingestants? Time of ingestion? Other medical disease?

14. Types of Toxicity Acute Acute on chronic Chronic

15. Li Peak Absorption Immediate release 2-6h Slow release 6-24h

16. Li Toxicity ACUTECHRONIC GI 42%20% CNS DelayedCommon > 2.mmol/L Renal Usually non significant Universal ECG NormalQT prolongation usual Thyroid NoneHypothyroidism 20% Recovery Usual, rapidDisability 10% delayed Level correlation PoorGood

17. Chronic Toxicity Symptom Mmol/LEffects 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

18. Decontamination Sodium polystyrene sulfonate 13 published studies- human case reports Acute vs chronic dosing? Time of ingestion vs time of treatment? Electrolytic complications Theoretically good, practically ? Bentonite (Ponampalam & Otten, 2002 ) Polyethylene glycol (Smith, 1991)

19. Tubular Lithium Handling

20. Effect of Frusemide

21. Li+ Loop Diuretics Frusemide increases Li Cl in single doses / healthy volunteers In real world: Li + Frusemide / ECFV contraction + Comorbidity (LV dysfunction, kidney disease) = Li + toxicity

22. Back to Case 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?

23. PK of Li Overdose 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

24. When to Dialyse? 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 – S erum 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

25. HD & Li Levels 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

26. Hd Replacement doses of Li during dialysis or hemofiltration should be determined using serum concentration monitoring

28. 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

29. ClClClCl Cl = [Urine Li] x Volume [Plasma Li] x time

30. Individualized Dose of Li Pharmacokinetic dosing method Literature-based recommended dosing Test dose methods

31. Pharmacokinetic Dosing Method CL ESTIMATE SELECTION OF APPROPRIATE PK MODEL & EQUATIONS SS CONCENTRATION SELECTION

32. Example 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.

33. 1. Estimate 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

34. 2. Estimate 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

35. Use average SS concentration equation 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 Li 2 CO 3 will be used (F =1,8.12 mmol Li + /300 mg of Li 2 CO 3.

36. 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 Li 2 CO 3 /8.12 mmol Li + ) 16.7 mmol/d = 617 mg/d, rounded to 600 mg/d of Li 2 CO 3. This dose would be given as 300 mg of Li 2 CO 3 every 12h.