Antimanic drugs and its pharmacology

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 ,  benzodiazepine s  (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: Reduce acute episodes of mania to a more manageable level Relieve symptoms such as agitation, inappropriate behaviour, and sleep problems 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: 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. 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. 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

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

19. 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 .

20. 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+.

21. 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.

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

23. 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.

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

25. 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.

26. 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.

27. 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

28. Thank you