Drugs for Bipolar Disorders & Migraine Headache

1. Drugs for Bipolar Disorders & Migraine Headache Kaukab Azim, MBBS, PhD DR.Farooq DR.Haneen

2. Drug List

3. Lithium Drug • Lithium is a small monovalent cation (MW: 6.9). Main mechanisms of action • Li+ is classified as a mood-stabilizing drug because it can reduce both manic and depressive symptoms of bipolar disorder. • The precise mechanism of its therapeutic effect is unknown but is likely related to inhibition of two signal transduction pathways: 1) Inositolsignaling Li+ inhibits inositol monophosphatase, the rate-limiting enzyme involved in inositol recycling. This leads to: Depletion of phosphatidylinositol-4,5-bisphosphate ( PIP2) which is the precursor of IP3 and DAG Inhibition of the synthesis of IP3 and DAG Inhibition of the activity of many receptors that are IP3/DAG linked. This is the major current working hypothesis for lithium therapeutic mechanism of action

4. Lithium Effect of lithium on the IP3 (inositol trisphosphate) and DAG (diacylglycerol) second-messenger system. The schematic diagram shows the synaptic membrane of a neuron. (PIP2, phosphatidylinositol-4,5-bisphosphate; PLC, phospholipase-C; G, coupling protein; Effects, activation of protein kinase C, mobilization of intracellular Ca2+, etc.) Lithium, by inhibiting the recycling of inositol substrates, may cause depletion of the second-messenger source PIP2 and therefore reduce the release of IP3 and DAG. Lithium may also act by other mechanisms. (Katzung 2011)

5. Lithium 2) Glycogen synthase kinase-3 signaling • Li+ inhibits glycogen synthase kinase-3, a protein-kinase that regulate signal pathways involved in apoptosis. • suppression of the expression of pro-apoptotic genes and increase expression of anti-apoptotic genes. • The ultimate effect is neuroprotection which could underlie long term mood stabilization (increased neurogenesis has been found in the hippocampus after lithium treatment)

6. Lithium Additional mechanisms of action • Actions on other second messenger systems • Li+ inhibits norepinephrine-sensitive adenylyl cyclase, which results in a decrease of cAMP. • Li+ enhances GABAergic activity and reduces glutamatergic activity • Actions on electrolytes and ion transport • Li+ can mimic the role of Na+ in excitable tissues. • It goes across cell membranes withsodium in action potential. • It is not pumped out by Na+/K+ ATPase and therefore it tends to accumulate inside the cells, displacing Na+. • Ca++/Na+ exchanger is not significantly affected at therapeutic concentration

7. Lithium Pharmacological effects CNS effects • At therapeutic doses Li+ has no mental effects on normal individual. • The calming effect in manic patients develops slowly (several day or weeks). Cardiovascular effects • Depression of the SA node • T wave depression or inversion (likely due to intracellular myocardial K+ depletion by displacement with Li+). Renal effects • Inhibition of vasopressin action on the kidney (likely due to inhibition ofadenylylcyclase)

8. Lithium Endocrine and metabolic effects • Inhibition of thyroid hormone synthesis (TSH-induced production of cAMPin thyroid cells is inhibited, due to inhibition of adenylyl cyclase) • ECF expansion (during the first days of therapy. Li+ tends to accumulate inside the cells, displacing NA+). Pharmacokinetics • Oral bioavailability: 100% • Distribution in total body water (Vd . 45 L) • No metabolism • Excretion:97% in the urine (80% is reabsorbed in the proximal tubule, some is reabsorbed in the collecting duct). • Half -life:20 hours (Accumulation can be a problem due to the long half life)

9. Lithium Adverse effects CNS • Fine hand tremor (up to 50%. Beta-blockers can be useful) • Memory impairment, mentalconfusion, poorconcentration (up tp 40%) • Muscle weakness, lethargy (up tp 30%) • Motor hyperactivity, ataxia, aphasia, seizures (with high doses). Metabolic/Endocrinesystem • Hypothyroidism (5-8%) • Weight gain (up to 30%) Urinary system • Polyuria, polydipsia (up to 70%) • Nephrogenicdiabetes insipidus (12% after long term treatment). Gastrointestinal system • Nausea, epigastricbloating, diarrhea (6-20%).

10. Lithium Adverse effects Cardiovascular system • Edema, frequent during the first 5-7 days of therapy (likely due to increased NA+ in the ECF). • Hypotension, arrhythmias sinus bradycardia, SA / AV block Other systems • Leukocytosis (very frequent) • Acneiform skin eruptions Overdosage • Li+ has a narrow therapeutic index (about 2-3) and Li+ plasma levels must always be monitored. • Symptoms of overdosage include lethargy, apathy, unsteady gait, mental confusion, muscle twitches, seizures, stupor, coma and cardiovascular collapse. Pregnancy • Disagreement exists about the importance of teratogenic effects of Li+ • However the drug is rated pregnancy category Dby FDA • Ebstein’sanomaly of the tricuspid valve is the main teratogenic effect.

11. Lithium

12. Lithium Therapeutic uses Main uses • Manic phase of bipolar disorders (often with concurrent use of antipsychotics or benzodiazepines during the first few days) • Maintenance treatment of bipolar disorder (maintenance treatment can prevents or diminishes the intensity of subsequent episodes of both mania and depression. Treatment must be continued for at least 6-9 months; in severe cases even for life). • Schizoaffective disorder (together with antipsychotic drugs). • Depressive disorder (augmenting agent for antidepressants). Unlabeled/Investigational uses • Aggression, post-traumatic stress disorder, conduct disorder in children

13. Anticonvulsants for Bipolar Disorder Drugs • Valproate, lamotigrine and carbamazepine are the main anticonvulsant drugs with mood stabilizing properties. Mechanism of action • Still uncertain. Actions similar to those of Li+, which seems to mediate the mood stabilizing properties include: • Inhibition of adenylyl cyclase • Reduction of inositol generation in the inositol signaling pathway • Activation of neuroprotective genes Pharmacological and adverse effects (these are discussed under antiseizure drugs) Therapeutic uses in bipolar disorders • As monotherapy in acute mania or mixed states • As monotherapy in acute bipolar depression • As maintenance therapy

14. Atypical Neuroleptics for Bipolar Disorder Drugs • Aripiprazole, olanzapine, quetiapine, risperidone. Mechanism of action, pharmacological and adverse effects • (these are discussed under neuroleptic drugs) Therapeutic uses in bipolar disorders • As monotherapy or adjunctive therapy in acute mania or mixed states • As adjunctive therapy in acute bipolar depression (risperidone, olanzapine)

15. Therapy for Bipolar Disorder

16. Therapy for Bipolar Disorder

17. Migraine Headache Migraine • Severe, throbbing, vascular headache • Recurrent unilateral head pain • Combined with neurologic and GI disturbances • 90% of migraine sufferers report nausea. • Sensitivity to light, sound, and stimulation are also common.

18. Initial Treatment Identifying and eliminating triggers Ex: red wine, caffeine, certain foods, bright lights If attacks are still frequent, drug therapy may be indicated

19. Prophylactic Therapy Attempts to prevent or reduce recurrence Abortive Therapy Treats acute migraine attacks Taken after headache occurs, at first sign of a headache

20. Prophylactic Therapy • Anticonvulsants • Beta blockers • Calcium channel blockers • Estrogen • NASAIDs • SSRIs • Tricyclic antidepressants

21. Abortive therapy Triptans—Selective 5-HT Receptor Agonists • almotriptan • eletriptan • frovatriptan • naratriptan • rizatriptan • sumatriptan • zolmitriptan

22. sumatriptan • Binds to serotonin receptors causing vasoconstriction of blood vessels in the dura • Use at first sign of headache • Available in injection, nasal spray, and tablet • Rizatriptan • Sublingual tablet, quickly absorbed • Has most rapid onset of action of all oral migraine therapies

23. Ergot Preparations (vasoconstictors, but can induce vomiting) dihydroergotamine ergotamine ergotamine-caffeine (Cafergot) Antiemetic Agents e.g. metoclopramide Reduces nausea and vomiting Enhances absorption of other antimigraine products Metoclopramide and aspirin have been prescribed together instead of using sumatriptan

25. butorphanol tramadol High success rate when given with NSAIDs (ibuprofen) Has slow onset of action Is not a controlled substance, but has shown potential for addiction • Nasal spray is used more commonly than injection • Has analgesic properties for moderate-to-severe pain • Can be addictive and is abused

26. Drug combination • Combination of analgesic, sedative, and vasoconstrictor may be used. • Has fewer side effects than ergotamines, but may be less effective.