Let's go on to the classical drug, lithium. Lithium is a very
old drug. It was used as much as 200 years ago. The clinical uses
of lithium include the manic phase of bipolar disease, acute
phase illness with psychotic diseases and to prevent recurrent
manic and depressive episodes in mania. The pharmacokinetics
of lithium is what makes it so important for us as pharmacologist
and practising physician. It is rapidly absorbed. It has a
half time of about 20 hours, so it stays in the body a long time.
When you talk about clearance, it's cleared at 20% of the rate
of creatinine clearance. So we have to monitor plasma levels
for 4 weeks when we initiate therapy or when we change the dose.
Lithium will cause dehydration. It can interact with diuretics.
It can interact with ACE inhibitors and using these medications
at the same time as lithium can cause lithium toxicity.
Caffeine and theophylline increase the clearance of lithium.
So heavy coffee drinkers can actually have their lithium levels
lower to the point where their disease gets worst. How does
lithium work? Lithium has a complex reaction and interplay
with the cell membrane and some of the important molecules in
the cell membrane. It reduces phosphatidylinositol bisphosphate
levels or PIP2 levels. This ends up resulting in a reduction
in IP3 or inositol triphosphate levels. There you have it there
and this causes a reduced synaptic release of amines. So uses
in clinical medicine include bipolar disorder and we often use
it in combination with antidepressants in these syndromes.
Remember that antidepressants can also precipitate mania
which is why we like to use these medications in combination.
In terms of toxicity, lithium is very complicated. It can cause
tremor, ataxia, aphasia. It can cause something called
nephrogenic diabetes insipidus. Now my medical students
always get confused when I use the term diabetes insipidus.
Diabetes means pee, right. So insipidus means weak. So it's
weak urine. Diabetes insipidus, weak urine; diabetes mellitus,
sweet urine. So lithium promotes the excretion of almost
free water in the urine. It causes a lot of peripheral edema
and can cause acne. Leukocytosis is almost always present.
And in fact I have received referrals for leukocytosis and I
take a look at their drug list and find, oh they are on lithium
don't worry about it. If given in pregnancy, the fetus can
develop a condition called Ebstein's anomaly which is a
congenital abnormality of the heart. And in terms of
breastfeeding it is contraindicated because it is secreted
heavily in breast milk. Let's take a look at the novel agents
used for bipolar disease. Those novel agents include drugs like
carbamazepine, clonazepam, olanzapine and valproic acid or
valproate. Let's take a look at them in more detail.
Now let's talk first about carbamazepine. Carbamazepine is an
antiseizure medication and I have mentioned it before
and will mention it again. Antimanic and acute illness is
treatable with carbamazepine. And we also use it as prophylaxis
during the depressive stage of manic disease. Lamotrigine is
one of the newer drugs and it is extensively used in patients
with manic disease. It is also an antiseizure medication and
used in the same or similar circumstances. It also can be used
for prophylaxis. Valproic acid or valproate is
a well known medication that is used extensively in the
treatment of seizure disorders. Antimanic and acute illnesses
can also be treated with valproic acid. Also it is used for
prophylaxis during the depressive state. It is often used when
lithium fails. Now that doesn't mean you can't use it in
combination with lithium and in fact sometimes we combine
valproic acid and lithium together. And finally the newer
drugs, olanzapine and quetiapine are antipsychotic
medications which are approved for monotherapy in milder
bipolar disease and more severe psychotic disease. So there
you have it there. Have a look at this chart and understand
how the drugs are a little bit different
but mostly similar to each other.