Lithium dosing

What is lithium indicated for?

Used as gold standard mood stabiliser for bipolar disorder

What is the mechanism of action of lithium?

Not fully understood, plays a role in mood regulation

Why do we have to be careful when dosing lithium?

It has a narrow therapeutic window

Why would we want to avoid abrupt withdrawal of lithium?

Avoid abrupt withdrawal, increases risk of relapse

True or false: Lithium is the only drug to reduce suicide risk by 80%

true

What are the monitoring requirements for lithium?

Weight/ BMI

ECG - Risk of cardiac problems e.g. bradycardia and QT prolongation in toxicity

FBC

Urea and electrolytes - including calcium

eGFR

Thyroid function test - causes hypothyroidism and hyperparathyroidism (hence calcium levels need to be checked due to increased risk of hypercalcaemia)

Initial lithium starting dose for adults

400mg at night

Initial lithium starting dose for elderly

200mg at night

After initiation of lithium, when would we conduct monitoring?

measure serum levels 4-7 days later to allow lithium to reach steady state

How often would we monitor lithium whilst we wait for lithium to be stable?

weekly

What is the maintenance lithium levels required for prophylaxis of mania

0.4-0.8mmol/l

There are two dosing regimens for lithium, what are they? Which is most common?

• Once daily dosing - taken at night

• Twice daily dosing - taken morning and night

ONCE daily dosing is more common, reduced risk of kidney injury

When monitoring lithium levels, indicate the time in which the blood test should be conducted. Do this for both dosing regimens.

• once daily dosing - measure levels 12 hours post dose e.g. 10pm dose taken, measure no later than 10am the next day

• Twice daily dosing - measure levels immediately before next dose is due

How often is monitoring required once patient is stabilised on current lithium dose?

• weekly until stabilised

• three months for first year

• every 6 months thereafter

When would additional lithium monitoring be required?

• patients taking interacting medicines

• patients who are acutely unwell

• physical illness - e.g. when the patient is dehydrated

this is to check for sub-therapeutic and toxic levels

How is lithium excreted?

Lithium is excreted by the kidneys, unchanged. It behaves like sodium - hence dehydration increases risk of toxicity as increased sodium reabsorption leads to accumulation of lithium in plasma.

What would be classed as lithium toxicity?

Anything greater than 1.0 could be classed as toxicity (1.0mmol/l can be used in acute mania)

1.2mmol / l and over suggests mild toxicity

1.5mmol/l and over suggests moderate toxicity

2.5mmol/l and over suggests severe toxicity and possible need for haemodialysis

3.5mmol/l - life threatening toxicity

What are side effects of lithium?

Lithium can cause tremor, polyuria, polydipsia, hypothyroidism

When would a lithium level of 1.0-1.2mmol/L be most appropriate?

During a manic episode - this is to reduce excitation in manic episode. Once heightened mood subsides we would want range within 0.4-0.8mmol/L for maintenance

What are signs of lithium toxicity?

• Nausea

• Vomiting

• Sedation

• Confusion

• Coarse tremor

• ataxia

What are the long term risks of lithium?

• hypothyroidism - Regular TFTs

• renal impairment - monitor creatinine and GFR

• Hyperparathyroidism - Ca2+ monitoring

  • Reduction in suicide risk will outweigh renal toxicity

Name 3 major interactions with lithium

• NSAIDs - including OTC NSAIDs - Reduce renal perfusion, therefore reducing lithium excretion and as a result leads to accumulation of lithium and possible toxicity.

• Diuretics - thiazide, loops and aldosterone antagonists (spironolactone) BONUS fludrocortisone all reduce excretion of lithium and increase risk of toxicity - thiazide diuretics for example are sodium depletors so the kidney tries to compensate for hyponatraemia by causing increased reabsorption of sodium and as a result, lithium is reabsorbed alongside increasing the risk of toxicity

• ACE inhibitors and Angiotensin II receptor antagonists - reduce renal perfusion and therefore increase the risk of toxicity as less lithium is excreted

• SGLT2s? more of a question of drug disease - theoretical

ANYTHING that causes hyponatraemia would interact with lithium

What are key points when counselling lithium

• patient should have treatment book and alert card

• ensure monitoring appointments are attended

• Drug interactions - including otc NSAIDs, diuretics, ACEi, SGLT2s ALWAYS CHECK

• Seek medical attention if you develop diarrhoea, vomiting (increases risk of dehydration)

• Ensure you maintain fluid intake - a low salt diet is dangerous and you should consult a HCP before commencing

• Seek advice about maybe stopping their lithium if become unwell severely for up to 7 days

• Counsel patients on signs of toxicity e.g. - diarrhoea, vomiting, sedation, confusion, tremor

Why should we caution use of metronidazole and tetracyclines with lithium?

Reduces lithium clearance, increasing plasma concentrations and increased risk of Li toxicity

Why would we be concerned with the use of SSRIs, Tricyclics, SNRIs with lithium?

Increased risk of CNS toxicty: be mindful of signs of toxicty at ‘normal plasma levels"‘

A patient wanting to by sodium citrate for UTI otc on lithium

A patient wanting to but sodium alginate for acid reflux on lithium

• Concurrent use of sodium containing antacids with lithium or other sodium containing products increases risk of reducing lithium levels - can precipitate toxicity when lithium is stopped

Why would we want to avoid medicines which prolong QT interval with lithium, give an example.

E.g. citalopram - additive effects and icnreases risk of fatal arrhythmia including torsades de pointes

True or false - sodium depleting drugs should be cautioned with lithium

True - drugs which cause hyponatraemia should be cautioned with lithium - increase risk of lithium toxicity - Salty can displace dairy toffee - SSRIs, carbamazepine, diuretics, desmopressin, trimethoprim

In this case - bendroflurothiazide increases risk of lithium toxicity due to hyponatraemia and increased diuresis increasing lithium levels by increasing reabsorption

Besides lithium levels, what else are we monitoring?

renal function - creatnine

U&Es

electroyters - also calcium levels due to risk of hypercalcaemia secondary to hyperparathyroidism

thyroid function test - risk of hyperparathyroidism and hypothyroidism

Weight / BMI

ECG - due to risk of QT prolongation

Name 3 reasons for high lithium plasma levels

1) Blood samples taken too early - samples should be taken as close to 12 hours after the previous dose, if blood samples are obtained before 12 hours this could lead to plasma levels being interpreted as high - falsely representing high doses.

2)Dehydration caused by vomiting and diuretics. Vomiting and diarrhoea could be a sign of lithium toxicity. If people become dehydrated, then lithium toxicity is a risk. Lithium is handled like salt in the body. Sodium depletion stimulated lithium reabsorption in PCT and hence increases plasma levels

3) interacting medicines e.g. benfroflumethiazide

What is the problem when lithium levels are higher than 1.4mmol/L?

When lithium levels exceed 1.4mmol/L you get reduced urine output, further reducing lithium excretion which raises serum lithium levels even higher

Lithium levels above 3.5mmol/l =

life threatening - especially if this is caused by gradual increase rather than acute overdose.

If patients serum levels are above 1.0mmol/l and no signs of toxicity - what should we do?

• consider if there is an explanation for higher levels e.g. interacting medicine, poor adherence, timing of levels, brand change. If the levels have been consistently high for some time:

  • Decrease dose by 200-400mg

  • Encourage fluids

  • Re-check levels in 5 days

• If no clear explanation - recheck levels and renal function

Explain lithiums pharmacokinetics in terms of dose reduction and plasma levels

lithiums pharmacokinetics are linear, this means that if you halve dose, you halve lithium plasma concentration - halve dose - halve level

Following lithium toxicity/ change in drug dose/ change in brand of lithium, when would we repeat lithium levels?

4-7 days following initiation of new dose. Steady state concentrations may not be achieved until 4-7 days following initiation therefore, avoid taking levels before this time

WHAT MUST BE WRITTEN ON BOTH COMMUNITY AND HOSPITAL DRUG CHARTS

The brand of lithium - narrow therapeutic window drug so changes in brand may ppt change in plasma concentrations above or below the therapeutic range