Exam 2 Drugs: Anti-manics (16)

Question 1

Lithium

Answer 1

• Ion agent (monovalent cation)
• first non-antipsychotic drug useful for manic phase of bipolar disorder (also used in maintenance/prophylactic)
• monotherapy, narrow therapeutic window
• first used to treat gout, then hypertension but too toxic
• pharmacokinetics: peak plasma levels .5-2 hours, no protein binding, some sequestration in bone, slow entry into intracellular compartment
• t1/2: 20 hours, excretion virtually entirely in urine
• mech: not entirely understood. Inhibits inositol signaling (by depletion of intracellular inositol) and glycogen synthase kinase-3 (GSK-3)
• GSK-3 limits neuroprotective abilities
• GSK-3 inhibition indirect because inhibits phosphatase that makes GSK-3 active.
• Can also be direct by inhibiting Mg-ATP by competitive inhibition of Mg
• can sub for Na in generating action potentials, can sub in Na-Na exchange across the membrane (Li inhibits this)
• at therapeutic concentrations Li does not affect Na-Ca or Na-K ATPase
• Inositol phosphate plays a part in many second messenger systems –> IP3, DAG
• Li inhibits IMPase which decreases free inositol and PIP2 (precursor of IP3 and DAG)
• PIP2-dependent pathway activity is increased in an manic episode
• inhibits inositol monophosphate (rate limiting step in inositol recycling)
• inhibits inositol polyphosphate 1-phosphatase (another enzyme in inositol recycling)
• can inhibit NE-sensitive adenylyl cyclase which could relate to its antidepressant and anti-manic effects
• may uncouple receptors from G-proteins.. common side effect polyuria and subclinical hypothyroidism (uncoupling vasopressin and TSH receptors)
• Reasons movement has gone away from Lithium: slow onset of action, often instead supplemented w/ use of other drugs esp for severe mania (antipsychotics or benzodiazapines [maintenance])
• remission from manic phase 80% (lower when hospitalization required)
• success rate for maintenance 60%
• still used in combined treatment in severe cases: antipsychotic can be stopped after mania is gone; can use antidepressants for depressive phase (mixed opinions)
• at therapeutic concentrations, no autonomic blocking effects or activating or sedating effects unlike antipsychotics or antidepressants
• can treat endogenous cyclic depression
• treats schizoaffective disorder in combo with antipsychotics (alone rarely works)
• unipolar depression that does not respond to monotherapy w/ antidepressants (esp. TCAs and SSRIs)
• at lower end of recommended range for manic-depressive illness
• renal clearance reduced 25% by diuretics (thiazides) and newer NSAIDS
• interaction not reported w/ aspirin or acetaminophen
• interactions with all neuroleptics except clozapine and newer atypical antipsychotics b/c it can produce severe extrapyramidal effects
• adverse: tremor most common, choreoathetosis, motor hyperreactivity, ataxia, dysarthia, aphasia
• if new symptom, temporarily stop treatment and monitor serum levels
• thyroid adverse: reversible decreased thyroid function (need serum TSH levels checked every 6-12 months)
• kidney adverse: reversible polydipsia and polyuria common at therapeutic levels, nephrogenic diabetes insipidus (lose response to ADH but respond to amiloride). Long term therapy: chronic interstitial nephritis, nephrotic syndrome (minimal change in glomerulopathy), decreased GFR, no marked azotemia or renal failure
• should avoid dehydration
• edema and weight gain common (not related to edema in 30%).. edema may be related to effect of lithium on sodium retention
• cardiac adverse: brady-tachy syndrome (sick sinus): lithium further depresses the sinus node, T-wave flattening on ECG. Contra to lithium use
• pregnancy: Category D. renal clearance increases during pregnancy, need higher doses. Immediately after birth, dose can be toxic. Lithium transferred through breast milk
• Ebstein’s anomaly incidence may be increased in mother’s taking Lithium, but now think relatively low risk of teratogenic effects
• misc adverse: acne early in treatment, folliculitis, leukocytosis (always present).. direct effect on leukopoiesis (therapeutic in those with low WBC count)
• overdoses usually occur due to accumulation from a change in behavior (lowered serum sodium, use of diuretics, fluct. in renal function)
• peritoneal and hemodialysis (preferred) are effective
• infant overdose: lethargy, cyanosis, poor suck and moro reflexes, hepatomegaly

Question 2

Chlorpromazine

Answer 2

• phenothiazine antipsychotic
• treats bipolar disorder manic phase
• mech: block of D2 receptors&raquo_space; 5HT2a receptors
• effects: alpha-receptor blockade, muscarinic-receptor blockade, H1-receptor blockade, CNS depression (sedation)

Question 3

Aripiprazole

Answer 3

• Atypical antipsychotic
• treats mania, mixed, and maintenance of bipolar disorder
• mech: blockade 5HT2a receptors > blockade D2 receptors
• effects: variable H1-receptor blockade

Question 4

Quetiapine

Answer 4

• Atypical antipsychotic
• treats mania and mixed
• mech: blockade of 5HT2a receptors > blockade D2 receptors
• effects: variable H1-receptor blockade

Question 5

Olanzapine

Answer 5

• Atypical antipsychotic
• treats mania, mixed, and maintenance
• mech: blockade of 5HT2a receptors > blockade D2 receptors
• effects: M-receptor blockade, variable H1-receptor blockade

Question 6

Olanzapine plus Fluoxetine

Answer 6

• Atypical antipsychotic
• treats bipolar DEPRESSION when used together
• mech: blockade of 5HT2a receptors > blockade D2 receptors
• effects: M- receptor blockade, variable H1-receptor blockade

Question 7

Risperidone

Answer 7

• Atypical Antipsychotics
• treats mania, mixed and maintenance
• mech: blockade 5HT2a receptors > blockade D2 receptors
• effects: alpha-receptor blockade, variable H1-receptor blockade

Question 8

Ziprasidone

Answer 8

• Atypical Antipsychotic
• treats mania and mixed
• mech: blockade 5HT2a receptors > blockade D2 receptors
• effects: alpha-receptor blockade, variable H1-receptor blockade

Question 9

Lurasidone

Answer 9

• Atypical Antipsychotic
• treats mixed and depressive bipolar disorder
• mech: blockade 5HT2a receptors > blockade D2 receptors
• effects: variable H1 receptor blockade

Question 10

Asenapine

Answer 10

• Atypical Antipsychotic
• treats mania and mixed
• mech: blockade 5HT2a receptors > blockade D2 receptors
• effects: variable H1-receptor blockade

Question 11

Cabamazepine

Answer 11

• Newer agent
• anti-convulsant used as mood stabilizer
• more widely used than Li
• treats acute mania and prophylaxis in depressive phase (?)
• mech: unclear in bipolar treatment
• no evidence of GSK-3 inhibition but does deplete inositol (alters neuronal morphology)
• can add to antipsychotic in treatment of schizophrenia
• adverse generally no greater (sometimes less) than those for Li
• dose-related diplopia and ataxia
• may be used as a monotherapy
• may be used with Li in refractory patients
• rarely used with valproate
• blood dyscrasias prominent adverse effect when used as anticonvulsant but not major problem when used in bipolar
• overdose –> medical emergency, should be managed like overdose of tricyclics (cardiac monitoring, airway support, gastric lavage.. sodium bicarb administered)
• more info on antiseizure cards!

Question 12

Lamotrigine

Answer 12

• Newer agent
• anticonvulsant used as mood-stabilizer
• treats acute mania and useful in preventing depression that follows manic phase of bipolar disorder (main use)
• mech: unclear in treating bipolar disorder
• adverse: nausea, dizziness, headache
• more info on seizure cards!

Question 13

Valproic Acid/ Valproate

Answer 13

• Newer agent
• Anticonvulsant used as a mood stabilizer
• treats acute mania and prevention of reoccurrence
• increasingly used as a first line agent in acute mania
• mech of action in bipolar disorder unclear but may indirectly reduce GSK-3 activity, upregulate gene expression through inhibition of histone deacetylase, and inhibit inositol signaling through an inositol depletion mechanism (alters neuronal morphology). May also have indirect effects on neurotransmitters and their release
• efficacy equiv to that of Lithium during early weeks of treatment
• effective in some patients with inadequate response to lithium
• can rapidly increase dosage over a few days
• combinations of Valproate w/ other psychotic meds generally well tolerated and likely to be used in management of either phase of bipolar disorder
• many clinicians combine lithium and valproate treatment in those who do not respond fully to either agent alone
• adverse: GI distress, possible weight gain, alopecia (hair loss)
• More in antiseizure cards!

Question 14

Topiramate

Answer 14

• Newer agent
• Anticonvulsant used as a mood stabilizer
• not approved by FDA for treatment of bipolar disorder
• mech: unclear in bipolar treatment
• more in antiseizure cards!

Question 15

Gabapentin

Answer 15

• Newer agent
• Anticonvulsant used as a mood stabilizer
• not approved by FDA for this
• mech: unclear in bipolar treatment
• more in antiseizure cards!

Question 16

Oxcarbazepine

Answer 16

• Newer agent
• Anticonvulsant used as mood stabilizer
• used off label to treat acute mania
• good for small groups of refractory patients but not for maintenance or depression
• mech unclear
• more in antiseziure cards!