Lithium

Amiloride REF: Goodman & Gillman’s 11th edition page 494, 505

“Lithium-induced polyuria is usually reversible. Amiloride is useful for lithium-induced nephrogenic diabetes insipidus because it blocks Li+ transport into the cells of the collecting tubules”

“Paradoxically, thiazide diuretics reduce the polyuria of patients with DI and often are used to treat non-lithium-induced nephrogenic DI”

“While case reports describe the effectiveness of indomethacin in the treatment of nephrogenic DI, other cyclooxygenase inhibitors (e.g., ibuprofen) appear to be less effective”

Cardiac anomaly [Ref: K.D.T. 6/e p. 436; Katzung 11/e p. 503]

• Lithium is a weak teratogen in human.
• The main effects attributable to lithium are increased cardiac malfonnation in the fetus especially “Ebsteins anomaly”.
• Lithium may increase the incidence of Ebstein’s anomaly in fetus but it is not contraindicated during pregnancy. Lithium is not considered a major human teratogen and the risk _.for Ebstein’s anomaly is only .5% for babies whose mother takes lithium during pregnancy.

Therefore lithium is not contraindicated during pregnancy. It is however advisable to perform a “fetal echocardiography” to exclude the possibilities of cardiac anomaly.

Evaluation of studies on lithium in pregnancy shows that lithium therapy throughout pregnancy does not seem to increase the general rate of major anomalies and apparently add only a small risk for cardiovascular defects notably Ebstein’s anomaly.

–  It can be concluded that whenever lithium is the drug of choice in women with bipolar disorder, it may be  continued even in pregnancy.

–Moreover it is advised not to discontinue lithium as it may subsequently lead to replapse of the disorder.

– In addition, pregnancy of lithium treated women should he considered high risk and therefore monitoring during pregnancy has to include “fetal echocardiography”.

-Pregnancy interruption in lithium treated mothers can probably be considered only if severe cardiac anomaly is diagnosed.

According to K.D.T.

• Lithium is contraindicated during pregnancy.
• But all other hooks states that lithium can be administered is during pregnancy.

Lithium

Lithium

Generalized anxiety disorder

Hypothyroidism

Lithium is most commonly used in the treatment of bipolar depression. It has a low toxic : therapeutic ratio.

The therapeutic level of Lithium in serum is 0.8 – 1.2 mEq/L.

Lithium toxicity occur when serum lithium levels exceed 1.5 to 2 mEq/L.

Hence frequent bood tests are done to monitor the drug levels.

Lithium is fully metabilised by the kidney. Hence, dehydration could cause the drug levels to rise.

Ref: Current Medical Diagnosis and Treatment 2013, chapter 38.

Concentrations considered to be effective and acceptably safe are between 0.6 and 1.5 mEq/L. The range of 1.0-1.5 mEq/L is favored for treatment of acutely manic or hypomanic patients. Serum concentrations of Li+ have been found to follow a clear dose-effect relationship between 0.4 and 1.0 mEq/L, but with a corresponding dose-dependent rise in polyuria and tremor as indices of adverse effects.

Lithium is indicated in the treatment of acute mania, acute bipolar disorder, long term treatment of recurrent unipolar depression, conduct disorder such as severe aggression and explosive affect in children and mentally retarded patients, cluster headache and prophylaxis of herpes viral infections.

C i.e. Neuroleptic malignant syndrome

A i.e. Commonest side effect is tremor; C i.e. Amiloride is DOC for Li induced diabetes insipidus

Commonest side effect of lithium is tremorsQ which can be treated by /3-adrenergic antagonist such as propranolol & primidoneQ. Diabetes insipidus induced by lithium can be treated by thiazide or potassium sparing diuretics such as amiloride, spironolactone, triamterene, or amiloride-hydrochlorothiazideQ. Lithium does not bind to plasma proteinsQ and show toxicity at serum levels >1.5 mEq/LQ.

• After oral administration, peak serum concentrations reach in 1 to 1.5 hours with standard /4 to 4.5 hours with slow-controlled released preparations. It does not bind to plasma proteinsQ, is not metabolized, and is excreted through kidneys. Plasma half life is initially 1.3 days and is 2.4 days after more than 1 year of administration. Equilibrium is reached 5-7 days of regular intake.
• Blood brain barrier permits only slow passage of lithium, that is why a single over dose does not necessarily cause toxicity & that is why long term lithium intoxication is slow to resolve.
• Excretion increases during pregnancy but decreases after delivery (especially requiring close monitoring of Li concentration). Adequate hydrate can reduce Li toxicity during labour. Lithium is excreted in breast milk so should be cautiously taken by nursing mother after benefit & risk evaluation. Signs of Li toxicity in infants are lethargy, cyanosis, abnormal reflexes & rarely hepatomegaly. Lithium should not be given to pregnant women in 1^st trimester because birth malformations most commonly involving cardiovascular system, most commonly Ebstein’s anomaly of tricuspid valvesQ. The teratogenic risk of lithium (4-12%) is higher than that of general population, but appears to be lower than that a/w use of valproate and carbamazepine. So when it is taken during pregnancy, the lowest effective dose should be used and with close monitoring (esp after delivery).
• Thyroid and renal concentrations are higher than serum levels. Insignificant amounts are excreted in feaces & sweat. Excessive sodium intake lowers lithium concentration. Conversly too little sodium & /or dehydration (eg excessive perspiration) can cause lithium toxicity.

B i.e. 0.7 – 1.1 meg/Lit

C i.e. Heart block

A i.e. Lithium toxicity 

B i.e. Bipolar MDP prophylaxis 

Ans. is ‘a’ i.e., Lithium

o Not all teratogenic drugs are contraindicated in pregnancy. For example carbamazapine is a teratogenic drug but it is also the DOC for epilepsy in pregnancy. Similarly propylthiouracil is teratogenic but is the DOC for thyrotoxicosis in pregnancy. In these conditions primary management is more important, because if left untreated it may risk the life of pregnant woman and fetus.

o In previous explanations I have given the list of teratogenic drugs, here I am giving the list of drugs that are contraindicated in pregnancy.

Important drugs contraindicated in pregnancy

 o Domperidone            o Lansoprazole                          o Cisapride                   o Morphine

 o Tetracyclines             o Chloramphenical                    o Aminoglycosides          o Astemizole

o Diethylcarbamazine    o Albendazole, mebendazole      o Warfarin                    o Radioactive iodine

o Lithium                     o Cyclophosphamide                     o ACE inhibitors            o AT-II antagonists

Ans. is ‘a’ i.e., Amiloride

o Amiloride is the drug of choice for lithium induced DL

Ans. is ‘c’ i.e., 2.6

Ans. is ‘c’ i.e., 0.8-1.1 mmol/L

Prophylactic level of lithium in bipolar disorder is 0.5-0.8 mEq/L and therapeutic level in acute mania is 0.8-1.2 mEq/L.

Ans. is d  i.e., Hyperthyroidism

• Lithium is known to exacerbate psoriasis and cause acne.
• It is known to cause Ebstein’s anomaly in children.
• It also causes thyroid dysfunction, hypothyroidism and not hyperthyroidism.
• Lithium nephrotoxicity is well known.

Ans. is ‘a’ i.e., Arrythmia

Due to hypokalemia, arrhythmias can occur.

Ans. is ‘a’ i.e., Sodium

• Diuretics (particularly thiazides) decrease the renal excretion of lithium and thus may result in toxicity. This is due to increased reabsorption of Na+ and lithium ions (as a compensatory response to excessive loss of Na+).

Ans. is ‘b’ i.e., Serum creatinine

Pretreatment evaluation for Lithium therapy 

o Serum creatinine (or 24 hour urine creatinine)                         o Thyroid function (T3, T4, TSH)         o ECG

o Electrolytes                                                                        o Complete blood count                    o Pregnancy test

Ans. is ‘c’ i.e., Ebstein’s Anomaly

o Intake of lithium causes Ebstein’s anomaly in fetus.

Ans. is ‘a’ i.e., Hypokalemia

Lithium can cause hypokalemia.

Ans is ‘d’ i.e. Diuretics

Interactions of lithium

1. 1.  Diuretics (thiazide, furosemide) by causing Na+ loss promote proximal tubular reabsorption of Na+ as well as Li – Plasma level of lithium rises.
2. Tetracyclines, NSAIDs and ACE inhibitors cause lithium retention.
3. Lithium tends to enhance insulin/sulphonylurea induced hypoglycemia (lithium has insulin like action on glucose metabolism).
4. Lithium inhibits the action of ADH on distal tubules –> causes nephrogenic DI.
5. Lithium reduce thyroxine synthesis by interfering iodination of tyrosine.

Ans. is ‘a’ i.e., Cardiac malformations

Teratogenic effects of lithium

o Lithium carries the risk of teratogenesis if ingested during pregnancy, especially during first trimester.

o The most commonly reported congenital malformations are cardiac abnormalities particularly Ebstein’s anomaly.

o Other congenital malformations have also been described and include neural tube defect, Talipes, Microtia, thyroid abnormalities.

Ans. is ‘c’ i.e., Lithium

Ans. is ‘a’ i.e., Lithium

Ans. is ‘b’ i.e., Lithium

Ans. is `c’ i.e., Lithium

The etiology of the majority of CHDs is not known.

In less than 10% of cases the cause and effect relationship has been estabilished.

Both environmental and hereditary factors play a role in the etiology of CHDs.

1. Hereditary factors

 A higher incidence of CHD in siblings suggests heredity as an important factor.

 The strongest familial tendency is known in ASD associated with bony abnormalities (Holt oram syndrome).

 Other hereditary conditions have been mentioned in subsequent explanations.

2. Environmental factors

 Those who have an inherited tendency, develop CHD due to unfavorable environmental factors.

 Of these the most well known is high altitude -4 There is higher incidence of PDA and ASD in children born at a high altitude.

 Other important environmental factors are : –

Pulmonary stenosis, Aortic stenosis

• Phenytoin                          Coarctation of aorta, PDA

• Alcohol                             VSD, PDA, ASD, TOF
• Rubella                            PDA, PS, ASD, VSD

Endocardial cushion defect

• Down’s syndrome                 ASD, VSD, TOF

• Infant of a diabetic             GA, VSD, COA, PPHN

Cardiomyopathy mother

• Valproate                          ASD, VSD, AS, PA, COA

D. i.e. All

Ans. A: Lithium

Its main focus is on drugs with a narrow therapeutic index, i.e. drugs that can easily be under- or overdosed. Examples of drugs analysed by therapeutic drug monitoring:

• Aminoglycoside antibiotics (gentamicin)
• Antiepileptics (such as carbamazepine, phenytoin and valproic acid)
• Mood stabilisers, especially lithium citrate
• Antipsychotics (such as pimozide and clozapine)
• Theophylline
• Digoxin
• Antiarrhythmics

Ans. A i.e. Acidification of urine

Ans. A i.e. Renal failure

Ans: A i.e. Lithium

• Dose related side effects of lithium includes polyuria/polydypsia, weight gain, tremor etc.
• Common side effects of clozapine are anticholinergic, antiadrenergic etc. Potentially life threatening side effects includes fatal agranulocytosis, fatal myocarditis, fatal pulmonary embolism etc.
• Side effect of antipsychotic, include sedation, weight gain, extra-pyramidal side effects, postural hypotension etc.

Ans. B i.e. Fine tremors

Ans. A i.e. Pregnancy

Ans. C: Lithium

It has also been used in the treatment of depression with less success.

Lithium needs to be closely monitored by repeated blood levels, as the difference between the therapeutic (0.8-1.2 mEq/ L) and lethal blood levels (more than 2.5-3.0 mEq/1) is not very wide (narrow therapeutic index).

Ans. is ‘a’ i.e., Nephrogenic DM

Lithium associated renal toxicity

• The use of lithium salts for the treatment of manic-depressive illness may have several renal sequelae, the most common of which is nephrogenic diabetes insipidus manifesting as polyuria and polydipsia.
• Lithium accumulates in principal cells of the collecting duct by entering through the epithelial sodium channel (ENaC), where it inhibits glycogen synthase kinase 3 and down- regulates vasopressin-regulated aquaporin water channels.
• Less frequently, chronic tubulointerstitial nephritis develops after prolonged (greater than 10-20 years) lithium use and is most likely to occur in patients that have experienced repeated episodes of toxic lithium levels.

Ans. is ‘a’ i.e., Propranolol

Toxic symptoms of lithium toxicity are frequent at serum level of lithium exceeds 1.5 meq/L and regularly seen at plasma concentration above 2 meq/L.

The most common symptoms of acute lithium intoxication are neurological, i.e., tremer (being the most common). increased tendon reflexes, seizures, drowsiness, delirium, muscle twitching / weakness and coma. Gastrointestinal toxicity may also occur, e.g. Nausea, vomiting, diarrhea, abdominal pain, and metallic taste.

Chronic intoxication can cause hypothyroidism and nephrotoxicity (diabetes insipidus, polyuria, polydipsia, nephrotic syndrome).

Amiloride is the DOC for lithium induced diabetes insipidus.

Propranolol is used to treat lithium induced tremor in adults.

Ans. a. 2 mEq/L

Ans. b. 2

Lithium should be stopped 48 hours, i.e. 2 day before surgery due to its interaction with anesthetic agents.