Lithium: indications, side effects, overdose, interactions

1. Clinical pharmacology of
lithium
Domina Petric, MD

2. Bipolar affective disorder (BAD)
I.
Katzung, Masters, Trevor.
Basic and clinical

3. Bipolar affective disorder (BAD)
• Smaller percentage of bipolar patients
now recieve lithium because lithium has a
slow onset of action.
• The overall success rate for achieving
remission from the manic phase of BAD
can be as high as 80%, but lower among
patients who require hospitalization.
Katzung, Masters, Trevor.
Basic and clinical

4. Bipolar affective disorder (BAD)
• Maintenance treatment is about 60% effective
overall, but less in severely ill patients.
• Increased use of combined treatment in
severe cases!
• After mania is controlled, the antipsychotic
drug may be stopped and benzodiazepines
and lithium continued as maintenance
therapy.
Katzung, Masters, Trevor.
Basic and clinical

5. Bipolar affective disorder (BAD)
• The depressive phase of BAD often requires
concurrent use of an antidepressant drug.
• Tricyclic antidepressant agents have been linked
to precipitation of mania, with more rapid
cycling of mood swings.
• Selective serotonin reuptake inhibitors (SSRIs)
are less likely to induce mania, but may have
limited efficacy.
Katzung, Masters, Trevor.
Basic and clinical

6. Bipolar affective disorder (BAD)
• Bupropion may be efficacious, but it may
induce mania at higher doses.
• The anticonvulsant lamotrigine is
effective for many patients with bipolar
depression.
• Quetiapine and the combination of
olanzapine and fluoxetine has been
approved for use in bipolar depression.
Katzung, Masters, Trevor.
Basic and clinical

7. Bipolar affective disorder (BAD)
• Lithium ion at therapeutic
concentrations is devoid of autonomic
blocking effects and of activating or
sedating effects.
• Lithium can produce nausea and tremor.
• Prophylactic use of lithium can prevent
both mania nad depression.
Katzung, Masters, Trevor.
Basic and clinical

8. Bipolar affective disorder (BAD)
Antipsychotics
Used in the manic phase:
aripiprazole, olanzapine,
quetiapine, risperidone…
Lithium
Treatment of BAD, especially
in the manic phase.
Bipolar depression
Lamotrigine,
bupropion, SSRIs
Prophylactic use of Li
Prevention of both mania
and depression
Combination
Combined treatment in severe
cases: lithium and antipsychotics
Antipsychotics
Li + Lamotrigine
Li
Katzung, Masters, Trevor.
Basic and clinical

9. Other applications
II.
Katzung, Masters, Trevor.
Basic and clinical

10. Other applications
Recurrent endogenous depression
Recurrent endogenous
depression with a cyclic
pattern is controlled by
either lithium or imipramine.
Katzung, Masters, Trevor.
Basic and clinical

11. Other applications
Schizoaffective disorder
• Schizoaffective disorder is characterized by a
mixture of schizophrenic symptoms and
depression or excitement.
• It is treated with antipsychotic drugs alone or
combined with lithium.
• Various antidepressants are added if
depression is present.
Katzung, Masters, Trevor.
Basic and clinical

12. Other applications
Schizophrenia
• Lithium alone is rarely successful in treating
schizophrenia.
• Adding the lithium to an antipsychotic may
salvage an otherwise treatment-resistant
patient.
• Carbamazepine may work equally well when
added to an antipsychotic drug.
Katzung, Masters, Trevor.
Basic and clinical

13. Other applications
Unipolar depression
• Lithium may be added to tricyclic
antidepressants or SSRIs in patients with
unipolar depression who do not respond fully
to monotherapy with the antidepressant.
• For this indication, concentrations of lithium
at the lower end of the recommended range
for BAD are adequate.
Katzung, Masters, Trevor.
Basic and clinical

14. Monitoring treatment
III.
Katzung, Masters, Trevor.
Basic and clinical

15. Monitoring treatment
• An initial determination of serum lithium
concentration should be obtained about 5 days
after the start of treatment.
If the clinical response suggests a change in
dosage, simple arithmetic should produce the
desired level:
• New dose=
𝑷𝒓𝒆𝒔𝒆𝒏𝒕 𝒅𝒐𝒔𝒆 𝑿 𝑫𝒆𝒔𝒊𝒓𝒆𝒅 𝒃𝒍𝒐𝒐𝒅 𝒍𝒆𝒗𝒆𝒍
𝑷𝒓𝒆𝒔𝒆𝒏𝒕 𝒃𝒍𝒐𝒐𝒅 𝒍𝒆𝒗𝒆𝒍
Katzung, Masters, Trevor.
Basic and clinical

16. Monitoring treatment
• The serum concentration attained with
the adjusted dosage can be checked after
another 5 days.
• Once the desired concentration has been
achieved, levels can be measured at
increasing intervals unless the schedule is
influenced by intercurrent illness or the
introduction of a new drug.
Katzung, Masters, Trevor.
Basic and clinical

17. Maintenance treatment
IV.
Katzung, Masters, Trevor.
Basic and clinical

18. Maintenance treatment
The decision to use lithium as prophylactic
treatment depends on:
• FREQUENCY and SEVERITY of previous
episodes
• CRESCENDO pattern of appearance
• DEGREE to which the patient is willing to
follow a program of indefinite
maintenance therapy
Katzung, Masters, Trevor.
Basic and clinical

19. Maintenance treatment
• If the present attack was the patient´s
first or if the patient is unreliable, one
might prefer to terminate treatment after
the episode has subsided.
• Patients who have one or more episodes
of illness per year are candidates for
maintenance treatment.
Katzung, Masters, Trevor.
Basic and clinical

20. Maintenance treatment
Some patients can be maintained with
serum levels as low as 0,6 mEq/L.
The best results have been obtained
with higher levels, such as 0,9 mEq/L.
Katzung, Masters, Trevor.
Basic and clinical

21. Drug interactions
V.
Katzung, Masters, Trevor.
Basic and clinical

22. Drug interactions
• Renal clearance of lithium is reduced about
25% by diuretics (eg, thiazides): doses may
need to be reduced by a smiliar amount.
• A similar reduction in lithium clearance has
been noted with several of the newer
NSAIDs that block synthesis of prostaglandis,
but not with aspirin and acetaminophen.
Katzung, Masters, Trevor.
Basic and clinical

23. Drug interactions
Many neuroleptics, except of
clozapine and the newer atypical
antipsychotics, may produce more
severe extrapyramidal syndromes
when combined with lithium.
Katzung, Masters, Trevor.
Basic and clinical

24. Adverse effects and complications
VI.
Katzung, Masters, Trevor.
Basic and clinical

25. Neurologic and psychiatric adverse
effects
Tremor is one of the most common adverse
effects of lithium treatment.
It occurs with therapeutic doses.
Propranolol and atenolol alleviate lithium-
induced tremor.
Katzung, Masters, Trevor.
Basic and clinical

26. Neurologic and psychiatric adverse
effects
Other neurologic abnormalities are:
• choreoathetosis
• motor hyperactivity
• ataxia
• dysarthria
• aphasia
Katzung, Masters, Trevor.
Basic and clinical

27. Neurologic and psychiatric adverse
effects
• Psychiatric disturbances at toxic
concentrations are generally marked by
mental confusion and withdrawal.
• Appearance of any new neurologic or
psychiatric symptoms or signs is a clear
indication for temporarily stopping
treatment with lithium and for close
monitoring of serum levels.
Katzung, Masters, Trevor.
Basic and clinical

28. Decreased thyroid function
• Lithium probably decreases thyroid function in
most patients exposed to the drug: reversible
and nonprogressive effect.
• Few patients develop frank thyroid
enlargement.
• Fewer show symptoms of hypothyroidism.
• Obtaining a serum TSH concentration
every 6-12 months is recommended.
Katzung, Masters, Trevor.
Basic and clinical

29. Nephrogenic diabetes insipidus
• Polydipsia and polyuria are common, but
reversible concomitants of lithium
treatment, occuring at therapeutic serum
concentrations.
• The principal physiologic lesion involved is
loss of responsiveness to antidiuretic
hormone (nDI).
• Lithium-induced nDI is resistant to
vasopressin, but responds to amiloride.
Katzung, Masters, Trevor.
Basic and clinical

30. Other renal adverse effects
Chronic interstitial nephritis
Minimal-change glomerulopathy with
nephrotic syndrome
Decreased glomerular filtration rate
Katzung, Masters, Trevor.
Basic and clinical

31. Warning!
Patients receiving lithium should avoid
dehydration and the associated increased
concentration of lithium in urine.
Periodic tests of renal concentrating ability
should be performed to detect changes.
Katzung, Masters, Trevor.
Basic and clinical

32. Edema
Edema is common adverse
effect of lithium treatment.
It may be related to some effect
of lithium on sodium retention.
Katzung, Masters, Trevor.
Basic and clinical

33. Cardiac adverse effects
• The bradycardia-tachycardia (sick-
sinus) syndrome is a definite
contraindication to the use of lithium
because this ion further depresses
the sinus node.
• T-wave flattening is often observed
on the ECG.
Katzung, Masters, Trevor.
Basic and clinical

34. Katzung, Masters, Trevor.
Basic and clinical
Lifeinthefastlane.com

35. Use during pregnancy
• Renal clearance of lithium increases during
pregnancy and reverts to lower levels
immediately after delivery.
• A patient whose serum lithium concentration is
in a good therapeutic range during pregnancy
may develop toxic levels after delivery.
• Lithium is transferred to nursing infants through
breast milk, in which it has a concentration
about one third to one half that of serum.
Katzung, Masters, Trevor.
Basic and clinical

36. Use during pregnancy
Lithium toxicity in newborns:
• LETHARGY
• CYANOSIS
• POOR SUCK REFLEX
• POOR MORO REFLEX
• HEPATOMEGALY
Katzung, Masters, Trevor.
Basic and clinical

37. Miscellaneous
• Transient acneiform eruptions: early in lithium
treatment, some of them subside with
temporary discontinuance of treatment and do
not recur with its resumption.
• Folliculitis: less dramatic, more frequently.
• Leukocytosis: always present during lithium
treatment, therapeutic effect in patients with
low leukocyte counts.
Katzung, Masters, Trevor.
Basic and clinical

38. Overdose
VII.
Katzung, Masters, Trevor.
Basic and clinical

39. Overdose
• Therapeutic ovedoses are due to accumulation
of lithium resulting from changes in the
patient´s status: diminished serum sodium, use
of diuretics, fluctuating renal function.
• Any value over 2 mEq/L must be considered as
indicating likely toxicity.
• Lithium is a small ion and it is dialyzed readily:
peritoneal dialysis, hemodialysis.
Katzung, Masters, Trevor.
Basic and clinical

40. Literature
• Katzung, Masters, Trevor.
Basic and clinical
pharmacology.
• Lifeinthefastlane.com
Katzung, Masters, Trevor.
Basic and clinical