Pharmacology of antimanic drug , mechanism of action, pharmacokinetics, adverse effects and uses of lithium carbonate

1. Antimanic drugs
Pharmacology
KRVS Chaitanya

2. Bipolar affective disorder
• Mood disorder characterized by mood swings from mania
(exaggerated feeling of well-being, stimulation, and
grandiosity in which a person can lose touch with reality) to
depression (overwhelming feelings of sadness, anxiety, and
low self-worth, which can include suicidal thoughts and
suicide attempts).

3. Mania
• Mania is a severe form of emotional disturbance in which a
person is progressively and inappropriately euphoric and
simultaneously hyperactive in speech and locomotor
behaviour.
• This is often accompanied by significant insomnia (inability
to sleep), excessive talking, extreme confidence, and
increased appetite.

4. • As the episode builds, the person experiences racing thoughts,
extreme agitation, and incoherence, frequently replaced
with delusions, hallucinations, and paranoia, and ultimately
may become hostile and violent and may finally collapse.
• In some persons, periods of depression and mania alternate,
giving rise to bipolar disorder.

5. • The most effective antimanic medications, which are used primarily
for bipolar disorder, are the simple salts lithium chloride or lithium
carbonate.
• Although some serious side effects can occur with large doses
of lithium, the ability to monitor blood levels and keep the doses
within modest ranges makes it an effective treatment for manic
episodes, and it can also stabilize the mood swings of the patient
with bipolar disorder.

6. • Lithium has a gradual onset of action, taking effect several weeks
following initiation of treatment. The precise mechanism of its
action is not known.
• If patients take an overdose of lithium, or if their normal salt and
water metabolism becomes unbalanced by intervening infections
that cause anorexia or fluid loss, then loss of coordination,
drowsiness, weakness, slurred speech, and blurred vision, as well as
more serious chaotic cardiac rhythm and brain-wave activity with
seizures may occur.

7. • Because lithium is generally excreted along with sodium in
the urine, rehydration and supportive therapy are all that is required
for treatment.
• Prolonged use of lithium, however, can in fact damage the body’s
ability to respond properly to the hormone vasopressin, which
stimulates the reabsorption of water, thus causing the emergence
of diabetes insipidus, a disorder characterized by extreme thirst and
excessive production of very dilute urine.
• Lithium can also interfere with the response of the thyroid gland to
the thyroxin-stimulating hormone produced in the pituitary gland.

8. • Other compounds used in the treatment of mania include
valproic acid, carbamazepine,
gabapentin, benzodiazepines (e.g., Clonazepam and
lorazepam), haloperidol, and chlorpromazine.
• These substances reduce the transmission of nerve
impulses in the brain and thereby lessen the severity of
manic episodes.

9. • They are important antimanic alternatives to lithium in
instances when lithium does not provide adequate symptom
control, and, with some exceptions, they may be used in
combination with lithium, particularly when rapid control
of acute mania is needed to bridge the delay to onset of action
of lithium therapy.
• Antimanic drug, any drug that stabilizes mood by controlling
symptoms of mania, the abnormal psychological state of
excitement.

10. • Mood stabilizers are used to treat bipolar affective disorder.
• Lithium was the first medication used to treat this disorder
and is sometimes referred to as an anti-mania drug because it
can help control the mania that occurs in bipolar disorder.
• Lithium must be closely monitored with a narrow therapeutic
range.

11. What are Antimanic agents?
• Antimanic agents help to calm episodes of mania in people
with bipolar disorder, and they may be used in other conditions
where people periodically display periods of great excitement or
euphoria, delusions, or over-activity.
• The term mood stabilizer may also be used to describe an antimanic
agent, although technically, antimanic agents are those mood
stabilizers that only treat episodes of mania, not depression.
• Three mood stabilizers that are effective at treating both mania and
depression are lamotrigine, lithium, and quetiapine.

12. • Lithium, some anticonvulsants (such as carbamazepine,
lamotrigine, valproate), and some atypical antipsychotics (for
example, Aripiprazole, olanzapine, quetiapine) are the most
common drugs used for their mood stabilizing effects and in
the control of mania.

13. • Although experts do not fully understand how antimanic
agents work to stabilize episodes of mania, it is believed that
they either influence levels of chemical neurotransmitters in
the brain, such as dopamine, GABA, Norepinephrine, or
serotonin; or, for anticonvulsants, reduce the excitability of
nerve impulses in the brain.
• An effective antimanic agent should:
1. Reduce acute episodes of mania to a more manageable level
2. Relieve symptoms such as agitation, inappropriate behaviour, and
sleep problems
3. Prevent symptom relapses and hospitalization.

14. LITHIUM CARBONATE
• Lithium is a small monovalent cation.
• In 1949,it was found to be sedative in animals and to exert beneficial
effects in manic patients.
• In the 1960s and 1970s the importance of maintaining a narrow range of
serum lithium concentration was realized and unequivocal evidence of its
clinical efficacy was obtained.
• Lithium is a drug of its own kind to suppress mania and to exert a
prophylactic effect in bipolar(manic depressive) disorder at doses which
have no overt CNS effects.
• Lithium is established as the standard antimanic and mood stabilizing drug.
• Over the past 2 decades, several anticonvulsants and atypical antipsychotics
have emerged as alternatives to lithium with comparable efficacy.

15. Mechanism of Antimanic
The following mechanisms have been Proposed:
1. Li+ partly replaces body Na+ and is nearly equally distributed
inside and outside the cells(contrast Na+ and K+ which are
unequally distributed); this may affect ionic fluxes across brain
cells or modify the property of cellular membranes.
• However, relative to Na+ and K+ concentration, the
concentration of Li+ associated with therapeutic effect is very
low

16. 2. Lithium decreases the presynaptic release of NA and
DA in the brain of treated animals without affecting 5-
HT release.
• This may correct any imbalance in the turnover of brain
monoamines

17. 3. The above hypothesis cannot explain why Li+ has no effect
on people not suffering from mania.
• An attractive hypothesis has been put forward based on the
finding that lithium in therapeutic concentration range
inhibits hydrolysis ofinositol-1-phosphate by inositol
monophosphatase.
• As a result, the supply of free inositol for regeneration of
membrane phosphatidyl inositides, which are the source of
IP3 and DAG, is reduced

19. Indications
1. Treatment of manic episodes of bipolar disorder
2. Maintenance treatment for individuals with a diagnosis of bipolar
disorder.
3. Sporadically used in many other recurrent neuropsychiatric illness,
cluster headache and as adjuvant to antidepressants in resistant
nonbipolar major depression.
4. Cancer chemotherapy induced leukopenia and agranulocytosis:
Lithium may hasten the recovery of leukocyte count.
5. Inappropriate ADH secretion syndrome: Lithium tends to
counteract water retention, but is not dependable.

20. Nursing Considerations
• Lithium must be closely monitored with a narrow therapeutic serum range
of 0.8 to 1.2 mEq/L.
• Serum sodium levels should also be monitored for potential hyponatremia.
• The drug is contraindicated in renal or cardiovascular disease, severe
dehydration or sodium depletion, and to patients receiving diuretics
because the risk of lithium toxicity is very high in such patients.
• Lithium can cause fetal harm in pregnant women.
• Safety has not been established for children under 12 and is not
recommended.
• When given to a patient experiencing a manic episode, lithium may
produce a normalization of symptomatology within 1 to 3 weeks.

21. Pharmacokinetics
• Lithium is slowly but well absorbed orally and is neither protein
bound nor metabolized.
• It first distributes in extracellular water, then gradually enters cells
and penetrates into brain, ultimately attaining a rather uniform
distribution in total body water.
• The CSF concentration of Li+ is about half of plasma concentration.
• Apparent volume of distribution at steady-state averages 0.8
L/kg.Lithium is handled by the kidney in muchthe same way as
Na+.

22. • Nearly 80% of the filtered Li+ is reabsorbed in the proximal
convoluted tubule.
• When Na+ is restricted, a larger fraction of filtered Na+ is
reabsorbed, so is Li+.
• After a single dose of Li+, its urinary excretion is rapid for 10–
12 hours, followed by a much slower phase lasting several
days.
• The t½ of the latter phase is 16–30 hours. Renal clearance of
lithium is 1/5 of creatinine clearance.
• On repeated medication, steady-state plasma concentration is
achieved in 5–7 days.
• Levels are higher in older patients and in those with renal
insufficiency.

24. Adverse effects
• Toxicity occurs at levels only marginally higher than
therapeutic levels.
1. Nausea, vomiting and mild diarrhoea occur initially, can be
minimized by starting at lower doses.
2. Thirst and polyuria are experienced by most, some fluid
retention may occur initially, but clears later.
3. Fine tremors are noted even at therapeutic concentrations.

25. 4. CNS toxicity
– Manifests as plasma concentration rises producing coarse
tremors, giddiness, ataxia, motor incoordination, Nystagmus,
mental confusion, slurred speech, hyper-reflexia.
– Overdose symptoms are regularly seen at plasma concentration
above 2 mEq/L.
– In acute intoxication these symptoms progress to muscle
twitchings, drowsiness, delirium, coma and convulsions.
– Vomiting, severe diarrhoea, albuminuria, hypotension and
cardiac arrhythmias are the other features.

26. 5. On long-term use, some patients develop renal diabetes
insipidus. Most patients gain some body weight. Goitre has
been reported in about 4%.
6. Lithium is contraindicated during pregnancy: foetal goitre
and other congenital abnormalities, especially cardiac, can
occur; the newborn is often hypotonic.

27. 7. At therapeutic levels
– Li+ can cause reduction of T-wave amplitude.
– At higher levels, SA node and A-V conduction may be
depressed, but arrhythmias are infrequent.
– Lithium is contraindicated in sick sinus syndrome.
– Lithium can cause dermatitis and worsen Acne.

29. Patient Teaching & Education
• Patients should take medication as directed It is important to
note the antimanic drugs may increase dizziness and
drowsiness.
• Additionally, if individuals have low sodium levels, it may
predispose the patient toxicity.
• Patients should also be advised that weight gain may occur.

30. Class/Subclass
Prototype/
Generic
Administration
Consideration
Therapeutic
Effects
Adverse/Side
Effects
Antimanic lithium
Black Box
Warning:
Monitor for
signs of lithium
toxicity
Monitor serum
lithium and
sodium levels
Contraindicated
in renal and
cardiovascular
disease and in
dehydration
When given
during a manic
episode,
symptoms may
resolve in 1-3
weeks
When given for
maintenance
therapy, it
should reduce
the frequency
and intensity of
manic episodes
Lithium toxicity
Hyponatremia
Tremor
Cardiac
arrhythmia
Polyuria
Thirst

32. Thank you