Transcript 4-Antimanic (edited)..

Anti-manic drugs
Anti-manic drugs
Anti-manic drugs or mood stabilizers are
medications used suppress swings between
mania and depression
They are effective in treating mania and
mood cycling, but are not effective in
treating depression
Normal people have euthymic mood.
Bipolar oscillate between mania and depression
Anti-manic drugs
1- Lithium
2- Anticonvulsants
– Valproic acid [Depakote]
– Carbamazepine [Tegretol]
– Lamotrigine [Lamictal]
Classes of Anti-manic drugs
3- Atypical antipsychotics
– Clozapine
– Olanzapine
– Risperidone
4- Benzodiazepines
Lithium
 Lithium ion, Li+, is the oldest and
best known mood stabilizing drug
 Lithium salts (carbonate, citrate)
are the most commonly prescribed
 60-80% success in reducing acute
manic and hypomanic states
It reduces the risk of suicide
related to bipolar disorder
Lithium: Therapeutic uses
1- Prophylaxis and treatment of mania
2- Prophylaxis of and maintenance treatment of
bipolar
disorders
(in
combination
with
antidepressants)
3-Lithium augmentation (prophylaxis of recurrent
depression) in unipolar depression and schizophrenic
patients who don't respond to treatment (i.e. used in
patients who don’t have mania)
*** it can take up to a week for lithium to
have an effect because it has a slow onset
of action (3-4 days to act) so sedative
drugs such as diazepam should be given
Pharmacokinetics
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Completely absorbed from the GIT
Peak plasma levels within 30 min to 2 hrs
Long plasma half-life (20 hr)
Not bound to plasma proteins
Not metabolized in the body
Distributed in all body fluids
Slow entry into intracellular compartment
Its concentration can be detected in plasma, saliva,
and urine.
• Narrow therapeutic index – requires
monitoring.
Lithium: Mechanism of Action
• Lithium has multiple actions and complex
effects as it stabilizes neuronal activities:
• Lithium is a monovalent cation that can mimic
the role of Na+ in excitable tissues, being able
to permeate the voltage-gated Na+ channels
that are responsible for action potential
generation
• Lithium readjusts balances between excitatory
& inhibitory neurotransmitters, and
decreases glutamate activity
Lithium: Mechanism of Action
 Lithium alters the cellular
concentration of the second
messenger (IP3) by inhibiting
inositol monophosphatase
 Lithium adjusts signaling
activities regulating transcription
factors and gene expression
at nuclear receptors
Lithium: Precautions
• Lithium salts have a narrow therapeutic / toxic
ratio. Patients should know that:
1- Plasma level monitoring is important. Doses
are adjusted to achieve plasma concentrations of
0.4 to 1 mmol Li+/liter
2- Patients should know the early symptoms of
toxicity; nausea, vomiting, diarrhea, ataxia,
confusion, delirium
3- Monitoring of thyroid function
4- NSAIDs decrease lithium clearance
in the kidney
Lithium: Precautions
5- As lithium interferes with the regulation of
sodium and water levels in the body it can cause
dehydration. Patients must avoid dehydration and
heat ,take plenty of fluids.
6- Concurrent use of thiazides that inhibit the
uptake of sodium by the distal tubule should be
avoided. In mild cases, withdrawal of Li+ and
administration of large amounts of sodium and
fluid will reverse the toxicity
7- Contraindicated during pregnancy
affects fetal heart development
Lithium: Toxicity
Usually
with
serum
lithium
concentrations of over 1.5 mmol/L
1- GIT: anorexia, N & V, diarrhea
**Earliest symptoms of toxicity
2-Neurological:
tremors, ataxia, dysarthria,
nystagmus and convulsions
3- Renal impairment: polydipsia and polyuria
(nephrogenic diabetes insipidus)
4- Psychotic effect: Mental confusion
Lithium: Toxicity
5- Changes in heart
rhythm
“sick sinus syndrome”
6-Thyrotoxicosis Enlargement of
thyroid gland with decreased
function (hypothyroidism)
7-Skin: acne, hair loss, psoriasis
8- Teratogenic effect
Atypical Antipsychotics
Some atypical antipsychotics
have mood stabilizing effects and
are thus commonly prescribed even
when psychotic symptoms are
absent
• They affect glucose and lipid
levels and cause weight gain.
Atypical Antipsychotics
• Risperidone, clozapine, and olanzapine are used
as mood stabilizers
• Risperidone is approved for the treatment of
bipolar disease
• Olanzapine is approved for acute mania
associated with bipolar disorder
• Clozapine is effective but have potential
serious side effects
** Still lithium is superior in treatment of
mania and hypomania
Anticonvulsant
Mood Stabilizers
• It is unclear how anticonvulsants work to
stabilize mood
• However, some theories indicate that
these drugs work in the same way that
they act to control seizure activity
• The only difference is that they work
on different parts of the brain
Anticonvulsant
Mood Stabilizers
• Carbamazepine, Tegretol
• Valproic acid, Depakote
• Lamotrigine, Lamictal
Carbamazepine
Therapeutic uses
• As mood stabilizer, carbamazepine is
superior to Li+ for rapid-cycling
(bipolar)
• Second-line treatment for mania
• Drug of choice in partial seizures &
Tonic-clonic seizures (also called grandmal epilepsy)
Carbamazepine:
mechanism of action
Blockade of voltage-dependent
sodium channels (↓cell excitability,
suppresses neuronal firing)
Attenuates glutamate (excitatory)
Carbamazepine:
Side effects
• GIT upset, sedation, ataxia
• Induction of hepatic P450 :  efficacy of
other drugs e.g. failure of oral
contraceptive pills, oral anticoagulants
“warfarin”
• Severe bone marrow depression
(agranulocytosis , aplastic anemia) so
contraindicated with clozapine
• Therapeutic drug monitoring is required
because of narrow safety margin
Valproate sodium
Therapeutic uses
– Acute mania
– Maintenance / prophylaxis of bipolar
disease
– More effective than lithium in rapid
cycling and mixed bipolar states
– Adjuvant treatment in schizophrenia
– It is effective for all forms of epilepsy
Valproate sodium:
Mechanism of action
It acts by several mechanisms
 Blockade of Na+ channels
 Potentiation of GABA (increasing
synthesis and release)
 Blocks T-type Ca2+ channels
Valproate sodium:
Side effects
1. Valproate is teratogenic, causing
spina bifida and other neural tube
defects
2. Transient hair loss
3. Hepatotoxicity
4. Inhibition of P450 leading to
interactions with other
antiepileptic drugs
Lamotrigine
Lamotrigine is effective in
bipolar depression
 MoA: Blocks Na+ channels
(like carbamazepine )
 Inhibits the release of the
excitatory amino acid “glutamate”
Benzodiazepines:
in acute mania
• In state of extreme mood elevation
• Give rapid sedation
• Useful until the effects of Lithium
take place
Ex: Diazepam – long acting (~ 2 days)
MOA: potentiate GABA-A receptors and
open Cl- channels → improve
neuronal firing impulses