Lithium

1
Lithium

• Presented By
• Cory Bradley
• Claire Evangelista
• Nicole Goff
• Ayla Johnson
• Robert Leontyev
• Phung Nguyen
• Roy Pfund
• Daniel Sabin
• Sean Toyooka
• Micah Walter
• Brian Zacker

2
Bipolar Disorder

• Manic depressive illness characterized by
  dramatic mood swings, episodes of mania and
  depression
• Affects 5.7 million adults (2.8 of the
  population) have bipolar
• One more fun bipolar fact to fill up this
  slide

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Symptoms

• Mania symptoms increased energy, euphoric mood,
  extreme irritability, racing thoughts, little
  sleep needed, aggressive behavior, and delusion
  of grandeur
• Depression Symptoms decreased energy, empty
  mood, hopelessness, restlessness, feelings of
  guilt, thoughts of suicide, loss of interests,
  and change in appetite
• Causes of Bipolar are unknown

4
Treatments

• Anticonvulsants Valproate and carbamazepine,
• Lamotrigine, Gabapentin, and Topiramate are
  still being studied for the treatment of bipolar
• Atypical Antipsychotics Clozapine, Olanzapine,
  Risperidone, Quetiapine, and Ziprasidone are
  still being studied for the treatment of bipolar
• Psychosocial treatment helpful in providing
  support, education, and guidance for the patients
  and family
• Antidepressants can be used during depressive
  stage
• Other treatments Electroconvulsive therapy,
  herbal or natural supplements (St. Johns wort)
  and omega-3 fatty acids
• Lithium Most often prescribed and most effective

5
Pharmacology

• Mechanism not well understood
• Alters sodium transport, may interfere with ion
  exchange/nerve conduction
• Enhances uptake of NE, 5HT into the synaptosomes,
  ? their action
• ?release of NE from synaptic vesicles and
  inhibits prod. of cAMP
• May produce a transitory diuresis (?in Na, K
  excretion)
• Other possible mechanisms to help to regulate
  mood
• alteration of gene expression and the
• non-competitive inhibition of Inositol
  Monophosphatase
• Lithium ion deactivates the GSK-3B enzyme.
• Glutamate is the key factor in understanding how
  lithium works

6
Dose and Cost comparison

• Prices are from drugstore.com
• Average medication cost .80 per day or 24 per
  month for a dose
• of 900mg/day

7
Most common Li side effects

• Postabsorbtive SE
• GI discomfort
• Nausea
• Vertigo
• Muscle weakness
• A dazed feeling
• Common and persistent SE (May not justify a
  decrease in dose)
• Fine tremor of the hands
• Fatigue
• Thirst
• Polyuria
• Nephrogenic Diabetes Insipidus

Lacy CF, Armstrong LL, Goldman MP, Lance LL. 
Drug Information Handbook, 13th ed.  Hudson,
Ohio, Lexi-Comp, Inc. 2005  902-903.
http//www.mentalhealth.com/drug/p30-l02.htmlHea
d_
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General Li cautions

• Li toxicity is closely related to serum lithium
  concentrations.
• Dont exceed 1.5 mmol/L to avoid serious adverse
  reactions and lithium intoxication.
• Mild SE can present even when serum lithium
  concentrations are below 1 mmol/L, right near the
  blank of therapeutic range.
• Patients might experience lithium accumulation
  during initial therapy which can increase to
  toxic concentrations quickly.
• Watch the geriatric patients. They might have
  lower renal clearance and are more susceptible
  to adverse effects even when lithium levels are
  in therapeutic range.

http//www.mentalhealth.com/drug/p30-l02.htmlHead
_
9
Progression from dose to toxicity

• In patients with normal renal clearance the toxic
  manifestations occur in a fairly predictable
  sequence related to serum lithium concentrations.
  
• The usually transient gastrointestinal symptoms
  are the earliest side effects to occur. A mild
  degree of fine tremor of the hands may present
  throughout therapy. Development of a rough tremor
  should be a warning sign.
• Thirst and polyuria may be followed by increased
  drowsiness, ataxia, tinnitus and blurred vision,
  indicating early intoxication.
• As intoxication progresses the following
  manifestations may be encountered confusion,
  increasing disorientation, muscle twitchings,
  hyperreflexia, nystagmus, seizures, diarrhea,
  vomiting, and eventually coma and death.

http//www.rxlist.com/cgi/generic/lithium.htm http
//www.mentalhealth.com/drug/p30-l02.htmlHead_
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Li side effects

• Common side effects
  Involuntary
  quivering
  Excessive thirst
  
  
• Nausea
  
• Diarrhea
  
• Problems with bladder control
  
• Frequent Urination
  
• Infrequent side effects
• Abnormal heart rhythm
• Feeling faint
• Weight gain
• Trouble breathing
• Increase in WBC
• Acne
  
• Rash
• Bloating

• Rare side effects
• Depression
• Pseudotumor cerebri
• Hair loss
• Dry skin
• Pain in digits, hands or feet.
• Any disturbance of the senses
• affecting the limbs.
• Edema in hands, feet or limbs in general.
• Hoarseness
• Over Excitement

www.Rxlist.com/drugs/drug-1448-LithiumCarbonateM
isc.aspx?drugid1448drugnameLithiumCarbonateMi
scpagenumber6 http//www.revoptom.com/HANDBOOK/S
ECT53a.HTM Lacy CF, Armstrong LL, Goldman MP,
Lance LL.  Drug Information Handbook, 13th ed. 
Hudson, Ohio, Lexi-Comp, Inc. 2005 
902-903 http//www.mentalhealth.com/drug/p30-l02.h
tmlHead_
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Li side effects During Pregnancy

• Pregnancy Risk Factor D (1st and 2nd trimesters)
• Cardiac Malformations (Ebsteins anomaly)
• Still used, but only at lowest doses possible
  with monitoring.
• ?Clr and ?distribution into RBC can lead to
  subtheraputic levels if dose not increased.
• Condition reverses upon childbirth, results in
  toxicity if dose not decreased.

Lacy CF, Armstrong LL, Goldman MP, Lance LL. 
Drug Information Handbook, 13th ed.  Hudson,
Ohio, Lexi-Comp, Inc. 2005  902-903.
http//www.mentalhealth.com/drug/p30-l02.htmlHea
d_ www.mayoclinic.org/.../ebsteins-anomaly-lg.jpg
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Drug Interactions

• Diuretics ? Li clearance. ? Li blood
  concentrations
• Distal tubule
  Hydrochlorothiazide
• Proximal tubule Acetazolamide
  
• Loop diuretics such as
  furosemide and bumetanide have mixed reports
• NSAIDs ? Li clearance, ? blood Li
  concentrations
• Ibuprofen, naproxen
• ACE Inhibitors May ? the risk of developing
  lithium toxicity
• ? LI clearance ? Li
  blood concentrations
• Enalapril, Lisinopril
• Angiotensin Receptor Blockers Inhibits
  elimination
• Losartan, Valsartan
• SSRI ? the amount of lithium that is lost into
  the urine
• serotonergic hyperarousal syndrome. Fluoxetine,
  sertraline, and fluvoxamine
• Caffeine appears to reduce serum lithium
  concentrations

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Pharmacokinetics

• ABSORPTION
• Lithium is absorbed 100 in all forms and
  therefore has a bioavailability of 1.
• Total absorption occurs over a period of 6-8
  hours to peak concentration at 2-3 hours.
• DISTRIBUTION
• Lithium follows a 2 compartment model
• The distribution occurs over 6-10 hours
• Do not sample during this time
• Lithium is not protein bound

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Pharmacokinetics

• METABOLISM
• There is none
• EXRETION
• Lithium is almost completely eliminated renally
  and excreted in urine
• More then 95
• If clearance is reduced from renal dysfunction,
  dosing should be reduced.
• During acute onset of mania, clearance may
  increase by up to 50
• The t1/2 is 24 hours and testing for levels in
  the blood should be taken after this time.

15
How to determine dosing?

• First find Clearance (L/day)
• Normal Cl 0.288 (CrCl)
• Acute mania Cl 0.432 (CrCl)
• Target Css is between 0.6-0.8 mEq/L
• In acute mania, target can go up to 0.8-1.2 mEq/L

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Dosing

• Dose/interval (in mmol/day) Css Cl/F
• Css target conc.
• Cl calculated from last slide.
• F always 1
• Will come out in mmol/day
• Must convert by multiplying in 300mg/8.12 mmol
  Li

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How to determine initial dosing?

• Test using Perry Method.
• Using a dose of 600-1500mg
• Test serum concentration at 12 and 36 hours
• Find the k value
• K (ln C 12hr ln C 36hr) / 24
• Using the k find the accumulation ratio R
• R 1/ (1 e k(tau) )

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Test dosing-Perry Method, cont

• Css R C12 hours
• Using the new concentration at steady state at
  time t12, find new dose
• Dnew Cssnew Dold/ Cssold

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Equations Summary

• Cl 0.288 (CrCl)
• Cl 0.432 (CrCl)
• Dose/interval Css Cl/F
• K (ln C 12hr ln C 36hr) / 24
• R 1/ (1 e k(tau)
• Css R C12 hours
• Dnew Cssnew Dold/ Cssold

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Example Kinetic Problems

• Patient Parameters
• Age, weight, height, CrCl lt- whatever we need
• Then Link to excel sheet and input these
  parameters

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Sources

• Bauer, Larry A. Applied Clinical
  Pharmacokinetics. 2001. pg 658
• Brunton, Laurence L. Goodman Gilmans The
  Pharmacological Basis of Therapeutics 11th Ed.
  2006.Pg 488

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• References
• Geddes, John Burgess, Sally et al. Long-term
  Lithium Therapy for Bi-polar Disorder Systematic
  Review and Meta-Analysis of Randomized Controlled
  Trials. Amer. Jour. Of Psych. 2004, 1612, pp
  217-222
• http//www.biopsychiatry.com/lithobid.jpg-site of
  lithobid pic