focuses on pharmacology of lithium

1. ANTIMANIC AND MOOD
STABILIZING
DRUGS
(Drugs for bipolar disorder)

2. Bipolar disorder (manic-depressive illness) is characterised by
mood changes which swing between mania and depression.
Severe mania
Severe Depression

3. Drugs For Bipolar disorder
• Lithium, an inorganic ion, taken orally as
lithium carbonate.
• Antiepileptic drugs (e.g., valproate,
carbamazepine, lamotrogine)
– - better side effect and safety profile.
• Atypical antipsychotic drugs (e.g. olanzapine,
risperidone, quetiapine, aripiprazole).

4. Lithium
• The psychotropic effect of lithium was
discovered in 1949 by Cade.
• Lithium is a monovalent cation that can mimic
the role of Na+ in excitable tissues.
• Lithium is established as the standard
antimanic and mood stabilizing drug.

5. Contd..
• Over the past 2 decades, several
anticonvulsants and atypical antipsychotics
have emerged as alternatives to lithium with
comparable efficacy.

6. Mechanism of action
1. Altering signal transduction pathways
2. Effect on electrolyte & ion transport
3. Inhibiting NT release.
Inhibiting inositol monophatase Inhibiting GSK3

7. Mechanism of action
• The biochemical effects of lithium are
complex, and it inhibits many enzymes that
participate in signal transduction pathways.
• Lithium is capable of altering G-protein
function.
• They use IP3 & DAG as second messengers.
• IP3 is metabolised to regenerate PIP2

8. Contd..
• Activity of these pathways is postulated to be
markedly increased during manic episodes
• The hyperactive neurons involved in the manic
state may be preferentially affected.
• Lithium inhibits the regeneration of PIP2 by
inhibiting an enzyme inositol monophosphatase
thereby decreasing the activity.

9. Inositol monophosphatase

10. Contd…
• Thus, lithium may ignore normally operating
receptors, but ‘search out’ and selectively,
though indirectly, dampen signal transduction
in the overactive receptors functioning
through phosphatidyl inositol hydrolysis.

11. Contd..
• Inhibition of glycogen synthase kinase 3
(GSK3) isoforms.
• GSK3 isoforms phosphorylate a number of key
enzymes involved in pathways leading to
apoptosis and degradation of BDNF.

12. MOA
2. Effect on electrolyte & ion transport
• Affect ionic fluxes across brain cells or modify
the property of cellular membranes.
3.Lithium decreases the presynaptic release of
NA and DA in the brain of treated animals
without affecting 5-HT release.

13. Other actions
• Lithium inhibits the action of ADH on distal
tubules in the kidney.
• An insulin-like action on glucose metabolism is
exerted
• Lithium inhibits release of thyroid hormones.
• Leukocyte count is increased by lithium
therapy.
Diabetes insipidus

14. Pharmacokinetics
• Well absorbed orally, but slowly.
• Attains uniform distribution in total body water
• The CSF concentration of Li+ is about half of
plasma concentration.
• Nearly 80% of the filtered Li+ is reabsorbed in the
proximal convoluted tubule.
• Initially rapid excretion, then slower in later
phase.
• T1/2 is about 24 Hrs
Next slide

15. Control of therapy
• Since the margin of safety is narrow,
monitoring of serum lithium
concentration(TDM) is essential for optimizing
therapy.
• On repeated medication, steady-state plasma
concentration is achieved in 5–7 days.
• Serum lithium level is measured 12 hours after
the last dose to reflect the steady-state
concentration

16. Contd..
• 0.5–0.8 mEq/L is considered optimum for
maintenance therapy in bipolar disorder
• 0.8–1.1 mEq/L is required for episodes of
acute mania.
• Exceed 1.5 mEq/L.- toxic symptoms

17. Adverse effects
• Gastrointestinal s/e can be seen during initiation of
therapy.
– Fine tremors and polyuira are frequent.
 CNS
– Mental confusion, coarse tremors, ataxia, nystagmus,
seizures etc..
– Occurs mainly when plasma level is high (2mEq/L)
- In acute intoxication these symptoms may progress to
coma and death. In association with hypotension &
cardiac arrhythmias,vomiting & diarrhoea

18. Treatment of acute toxicity
• It is symptomatic. There is no specific
antidote.
• Osmotic diuretics and sod. bicarbonate
infusion promote Li+ excretion.
• Haemodialysis is indicated if serum levels are
> 4 mEq/L.

19. Adverse effect
Renal:
– On long term use Nephrogenic Diabetes
Insipidus.
– Loss of ability of collecting tubules to conserve
water by influence of ADH (G protein).

20. Contd..
3.Cardiac Effects: Sick-sinus syndrome –
contraindicated – flattening of T wave
4. Thyroid Function: Decrease in thyroid
Function – goitre (G protein)
5. Pregnancy – contraindicated
– Foetal goitre, congenital abnormalities (cardiac
Ebstein’s anomaly )

21. Drug interaction
• Diuretics: Lithium clearance is reduced by 25%
with Diuretic e.g. furosemide, Thiazides.
• Tetracyclines, NSAIDs and ACE inhibitors can
also cause lithium retention.
• The neuroleptic action appears to be
potentiated by lithium.
• Lithium tends to enhance insulin/sulfonylurea
induced hypoglycaemia

22. Uses
1. Acute mania:
• lithium is effective in controlling acute mania, but
the effect develops after 1-2 wks.
• Initially with a second generation antipsychotic
such as olazapine/ Risperidone / aripiprazole in
conjuction with or without benzodiazepine.
• Start lithium/valproate after the episode is under
control.
• Maintenance lithium therapy is generally given for
6–12 months to prevent recurrences.

23. 2. Prophylaxis in Bipolar disorder
• Li+ is the mood stabilizer with the most robust
data on suicide reduction in bipolar patients.
• Li can reduce the frequency of manic or
depressive episodes in the bipolar patient and
therefore is considered a mood-stabilizing agent.
• Type I (mania episodes only or both manic and
depressive phases), Type II (cycles of hypomania
alternating with major depression)
• Lithium appear to work best in patients with
classic bipolar 1 disorders.(CMDT 2018)

24. Contd..
• Li+ is also efficacious in unipolar depressive
patients who respond inadequately to
antidepressant therapy.

25. Alternative to Lithium
Sodium Valproate:
– 1st line in acute mania.
• Patients with rapid cycling pattern may
particularly benefit from valproate therapy.
– Lithium resistance cases.
– Lithium + Valproate – resistance to
monotherapy

26. Carbamazepine
• Its efficacy in mania and bipolar disorder has
now been confirmed.
• Carbamazepine is less effective than lithium or
valproate in acute mania.
• It is a valuable alternative/adjunct to lithium.

27. Lamotrigine
• Lamotrigine-Prophylaxis of depression in
bipolar disorder.
• It is now extensively used in the maintenance
therapy of type II bipolar disorder
• Used as monotherapy as well as with Lithium

28. Atypical antipsychotics:
• Olanzapine, risperidone, aripiprazole,
quetiapine, with or without a BZD, are now
preffered drugs for control of acute mania.
• Aripiprazole has recently emerged as the
favoured drug for treatment of mania in
bipolar I disorder

29. MCQs
1.Drug of choice for rapid cyclers in manic –
depressive psychosis is:
A)Carbamazepine
B)Valproate
C)Phenytoin
D) Lithium
Next slide

30. 2.Drugs having proven efficacy in bipolar
depression is:
A)Carbamazepine
B)Valproate
C)Tiagabine
D) Lamotrigine
Next slide

31. Just to remember
• L- leucocytes
• I – Increased
• T – Tremors
• H- Hypothyroidism
• I- Increased
• U- Urine
• M- should be avoided in expectant MOTHER
as it causes Ebstein’s anomaly
Diabetes Insipidus

32. Thank you