Term 2 Pharm - Manic Drugs/Mood Stabilizers Flashcards
What are mood stabilizers?
Mood stabilizers are medications used to prevent the extreme mood swings between mania and depression typically seen in bipolar disorder.
Types of Mood stabilizers
Classic Mood Stabilizer:
- Lithium***
Anti-convulsants:
- Valproic Acid,
- Carbamazepine
- Lamotrigine,
- Oxcarbazepine
Anti-psychotic:
- Olanzapine
Lithium carbonate
“classic” mood stabilizer
- Therapeutic drug monitoring required as the therapeutic range is very narrow
- Volume of distribution (Vd) for lithium is approximately equal to body water therefore anything that changes body water can cause a toxic increase in circulating lithium levels, e.g. thiazide diuretic use, intense exercise, diarrhea.
- If a dose is missed take it at earliest convenience. NEVER DOUBLE UP ON A DOSE OF LITHIUM.
- Signs and symptoms of toxicity include nausea, vomiting, diarrhea, and ATAXIA (the loss of full control of bodily movements)
- Most common side effects are lethargy and weight gain.
- The less common side-effects of using lithium are blurred vision, slight tremble in the hands, and a feeling of being mildly ill.
- Reversible nephrogenic diabetes insipidus also sometimes seen (In general, these side-effects occur in the first few weeks after commencing lithium treatment. These symptoms can often be improved by lowering the dose)
Lithium
Eskalith, Eskalith CR, Lithobid slow-release tablets, Lithostat tablets ®
Drug class: pharmacologic class—Anti-mania, mood stabilizer, headache prophylaxis esp. cluster HA
Pharmacodynamics: MOA is still unknown. It may alter sodium transport in nerve and muscle cells or inhibit the recycling of neuronal membrane phosphoinositides involved in generation of second messengers, or inhibition of glycogen synthase kinase 3, inositol phosphatases, or modulating glutamate receptors.
Pharmacokinetics: urine 95% (100% unchanged), feces 1.5 mEq/L (adult/child), > 0.8 mEq/L (elderly)
BLACK BOX WARNING
Lithium Toxicity
Lithium toxicity closely related to serum lithium levels and can occur at doses close to therapeutic levels; start tx only if facility available for prompt accurate serum lithium determinations
Lithium alternatives
- Anti-convulsant drugs Valproic acid, Carbamazepine, Oxcarbazepine and Lamotrigine are also effective in treating mania.
- Antipsychotic agents (Olanzapine) and/or benzodiazepines (Lorazepam) are used to relieve mania and anxiety symptoms at the beginning of treatment with lithium or valproic acid as their long half-lives (Li=20-24hr, VA=5-20hr) mean it can take days to start getting an effect (Steady state levels are reached in 4-5 half lives)
- Olanzapine and quetiapine (atypical anti-psychotics) are also FDA approved as monotherapies for acute mania.
Valproic acid (Depakene, Depakote)
Drug class: pharmacologic class—Anti-convulsant, partial and absence seizures, mood stabilizer, headache prophylaxis
Pharmacodynamics: MOA is still unknown. Increases GABA effects, may inhibit glutamate/NMDA receptor-mediated neuronal excitation, can block the voltage-gated sodium channels and T-type calcium channels, is an inhibitor of the enzyme histone deacetylase 1 (HDAC1)
Pharmacokinetics: liver; CYP450: 2A6, 2B6, 2C9 substrate; 2C9 inhibitor; UGT: 1A6, 1A9, 2B7 substrate; 1A9, 2B7, 2B15 inhibitor; Info: metabolism is 50% UGT, 40% beta-oxidation, 10% CYP450; dissociates to valproate ion in GI tract; urine (
Carbamazepine (Carbatrol, Tegretol)
Drug class: pharmacologic class—for focal and secondarily generalized seizures, less effective for primary generalized seizures. Mood stabilizer for bipolar disorder. Works well also for neuropathic pain and trigeminal neuralgia.
Pharmacodynamics: Sodium channel blocker in neuronal membranes, slows repetitive firing and stops seizures
Pharmacokinetics: Only has oral preparation. ½ life 12 hours. Hepatic metabolism. Hepatic enzyme inducer. Levels increased by Calcium channel blockers, and macrolide antibiotics, P450 inducer CYP3A4 CYP2C8 CYP1A2 (newer drugs less likely to induce P450s)
Toxicity: drowsiness, headaches and migraines, motor coordination impairment, and/or upset stomach, decreased a alcohol tolerance, weight gain, aplastic anemia
Interactions: diuretics, NSAID , ACE inhibitors, calcium channel blockers
Special considerations: pregnancy risk factor D, CAUTION for hypersens. to drug/class, Brugada syndrome, elderly pts., renal impairment, volume depletion, cardiovascular disease, thyroid disorder, concurrent CNS depressant use, alcohol use
Monitor: perform baseline and periodic hematological testing; if low or decr. WBC or platelet counts monitor closely, consider D/C TX if evidence of significant bone marrow depression
BLACK BOX WARNING
Appropriate Use: can increase toxic potential or decrease activity of other drugs
Serious Dermatologic Rxns and HLA-B*1502 Allele (Allele most common in Asian communities) - Aplastic Anemia/Agranulocytosis risk 5-8x greater than that of general public
Lamotrigine (Lamictal)
Drug class: pharmacologic class—Anticonvulsant, mood stabilizer,
Pharmacodynamics: unclear, blocks sodium channels and blocks release of glutamate, same class as Carbamazepine but unlike other sodium channel blocking anticonvulsants it is also effective in treatment of the depressed phase of bipolar disorder
Pharmacokinetics: metabolized by glucuronidation, half-life 13.5 hrs. and Vd=1.36 L/kg,
Toxicity: rash, fever, and fatigue can be serious, as they may indicate incipient Stevens–Johnson syndrome, toxic epidermal necrolysis, DRESS syndrome or aseptic meningitis, 5-10% get a rash but in only 0.1% will develop a serious rash, nausea/vomiting, dizziness/vertigo, visual disturbance, somnolence, ataxia, pruritus/rash, headache
Interactions: has fewer interactions than many anticonvulsants, other antiepileptic drugs that induce hepatic drug-metabolizing enzymes reduce effect
Special considerations: pregnancy risk factor C
Monitor: Cr at baseline; ophthal. exams if prolonged TX; sx suicidality, clinical worsening if bipolar disorder, and/or unusual behavior changes
Black Box Warning: SERIOUS SKIN RASHES- requiring hospitalization and D/C TX incl. Stevens-Johnson syndrome, rare cases of toxic epidermal necrolysis, and rash-related deaths; incidence w/ adjunctive epilepsy TX 0.8% in 2-16 yo and 0.3% in adults, bipolar and other mood disorder incidence 0.08% as initial monotherapy and 0.13% as adjunctive TX;……
Oxcarbazepine (Trileptal)
Drug class: pharmacologic class—Anticonvulsant, mood stabilizer,
Pharmacodynamics: exact MOA unknown; blocks voltage-sensitive Na channels (like Carbamazepine with fewer side effects), stabilizes neural membranes, inhibits repetitive firing, and decr. synaptic impulse propagation
Pharmacokinetics: urine 95% (
Olanzapine (Zyprexa)
Drug class: pharmacologic class—Atypical anti-psychotic, mood stabilizer
Pharmacodynamics: blocks 5HT2A and D2 receptors similar to clozapine
Pharmacokinetics: liver extensively; CYP450: 1A2, 2D6 (minor), 2C19 substrate; urine 57% (7% unchanged), feces 30%; Half-life: 21-54h
Toxicity: drowsiness, flu syndrome, weight gain, salivation, tardive dyskinesia, QTc prolongation (all anti-psychotics) and rarely neuroleptic malignant syndrome.
Special considerations: pregnancy risk factor C (preferred bipolar med. for pregnancy) p450 inducers,
Indications and dose/route: p.o. IM
Monitor: fasting glucose and lipid panel at baseline, then periodically; AST/ALT if significant hepatic dz; CBC frequently during initial TX if pre-existing leukopenia or if drug-induced leukopenia/neutropenia hx; weight; s/sx orthostatic hypotension (IM use)
Dementia-Related Psychosis
Not approved for dementia-related psychosis; incr. mortality risk in elderly dementia pts. on conventional or atypical antipsychotics; most deaths due to cardiovascular or infectious events; extent to which incr. mortality attributed to antipsychotic vs. some pt. characteristic(s) not clear
Clinical management of patient during period of mania
Short term vs. Long term treatment:
- treatment that will rapidly reduce hyperactivity, sleeplessness, irritability, and psychotic features = e.g. Olanzapine-rapidly dissolves reducing non-compliance
a mood stabilizer to manage the condition long- term = lithium/valproate/lamotrigine etc.
Clinical management of patient during period of mania
Efficacy
Trials have proved that a combination of an atypical antipsychotic with lithium provides better prophylaxis than does lithium monotherapy, however the weight gain and sedation is prohibitory for many.
Usually it is best to taper off the atypical antipsychotic once the incidence of mania had decreased and an effective and safe blood level of the mood stabilizer has been achieved.
Balancing Bipolar Medications: Mood stabilizers and anti-depressants
- Monotherapy with anti-depressants can precipitate mania in bipolar patients
- For some patients anti-depressants (e.g. Fluoxetine/Prozac) are combined with the mood stabilizer.
- For a subset of patients (10-20%) antidepressant monotherapy can trigger manic episodes and increase cycling. However, many people take a mood stabilizer/anti-depressant combination (e.g. Olanzapine/fluoxetine combination Symbyax).
- Lamotrigine monotherapy has been shown to act as a mood stabilizer and an anti-depressant and can also be added to lithium treatment. Olanzapine and quetiapine can also work in this way, however due to their weight gain profile they are less popular for long-term prophylaxis.
Which 2 factors below can potentially cause toxic levels of lithium?
A Excess intake of sodium chloride. B Running a marathon. C High intake of grapefruit juice. D Diuretic given for hypertension. E. Pregnancy.
Correct answers B and D, both can decrease body water levels and therefore increase circulating lithium levels
Excess intake of sodium chloride would decrease circulating lithium levels.
Lithium is not metabolized by CYP450 system so grapefruits inhibition of cytochrome P450 CYP3A4 is not relevant.
Lithium should not be used during pregnancy.
Which of the following drugs would be most useful for the rapid management of an acutely manic patient?
A Lithium. B Valproic acid. C Bupropion. D Olanzapine. E. Fluoxetine.
Correct answer is D. Olanzapine has a rapid onset of action essential to calm manic symptoms especially if patient likely to harm themselves or others.
Lithium and valproic acid are also mood stabilizers but due to long half-lives steady state levels take days to achieve.
Bupropion and Fluoxetine are antidepressants so are not indicated for manic episodes.
