Valproic acid action

M. Ki ogh, K. Johansen, F. Tonnesen and K. E. Rasmusen, Solid-phase microexti action for the detemination of the free concentration of valproic acid in human plasma by cap-illai y gas chi omatography , J. Chromatogr. B 673 299-305 (1997). 

Phenobarbitone was the first AED and was introduced in 1912. It was largely replaced in 1932 by phenytoin for the management of tonic-xilonic seizures and partial and secondary epilepsy. Carbamazepine followed, then ethosuximide for absence seizures and valproic acid. These remained, apart from the introduction of the benzodiazepines, the mainstay of therapy until the last decade. They were introduced solely on their ability to control experimentally induced seizures. Their mechanisms of action were unknown and no thought was given to the possibility of NT modification and in fact subsequent research has shown that with the exception of the benzodiazepines none of them work primarily through NT manipulation. They act directly on neuronal excitability. 

Several mechanisms have been suggested for the action of valproic acid, including blockade of voltage-dependent Na+ channel, potentiation of y-aminobutryric acid... 

Valproic acid is a very stable compound. No degradation has been observed by the action of heat, light, and strong aqueous alkali, or acid. 

Of the mood stabilizers, valproic acid (Depakene, Depakote) is the most widely used. Like the other mood stabilizers, its onset of action can be delayed by several days. Valproic acid is a reasonably well tolerated mood stabilizer. It does occasionally cause tremor, and it can on rare occasion lower platelet counts or cause liver problems. For this reason, blood monitoring is required when starting this medication. In addition, valproic acid can irritate the stomach lining, but this problem is largely overcome by using the buffered form sodium divalproex (Depakote or Depakote ER). Finally, valproic acid can also cause hair loss or drowsiness. 

Valproic acid and its salts are a new group of antiepileptic drugs that differs from the known drugs both structurally and in terms of its mechanism of action. It is believed that it acts on the metabolism of the GABA system. Valproic acid has been shown to elevate the level of GABA in the brain by means of competitive inhibition of GABA transaminase and the dehydrogenase of succinic semialdehyde. 

Whether there is any other connection between anticonvulsant activity and camosine s antiaging actions is obviously highly speculative. It may be relevant to note that epileptic seizures and a shortened life span, together with altered protein accumulation, are consequences of PIMT-deficiency in mice, while treatment with valproic acid, an anticonvulsant, partially suppresses these symptoms including effects on life span (Yamamoto et ah, 1998). Conversely, PIMT overexpression can increase life span of Drosophila (Bennet et ah, 2003). Furthermore, the chemistry of some anticonvulsants (ethosuximide) resembles quite closely the structure of the succinimide intermediate formed during both asparagine deamidation and PIMT-mediated repair of isoaspartate residues. One conjectures whether there are any relationships between these... 

Diazepam (Valium, Diastat) [C-IVj [Anxiolytic, Skeletal Muscle Relaxant, Anticonvulsant, Sedative/Hypnotic/ Benzodiazepine] Uses Anxiety, EtOH withdrawal, muscle spasm, status epilepticus, panic disorders, amnesia, preprocedure sedation Action Benzodiazepine Dose Adults. Status epilepticus 5-10 mg IV/IM Anxiety 2-5 mg IM/IV Preprocedure 5-10 mg IV just prior to procedure Peds. Status epilepticus 0.5-2 mg IV/IM Sedation 0.2-0.5 mg/kg IV (onset w/in 5IV and 30 min IM duration about 1 h IV and IM) Caution [D, / -] Contra Coma, CNS depression, resp d es-sion, NAG, severe uncontrolled pain, PRG Disp Tabs 2, 5, 10 mg soln 1, 5 mg/mL inj 5 mg/mL rectal gel 2.5, 5, 10, 20 mg/mL SE Sedation, amnesia, bradycardia, i BP, rash, X resp rate Interactions T Effects W/ antihistamines, azole antifungals, BBs, CNS depressants, cimetidine, ciprofloxin, disulfiram, INH, OCP, omeprazole, phenytoin, valproic acid, verapamil, EtOH, kava kava, valman T effects OF digoxin, diuretics X effects w/ barbiturates, carbamazepine. 

Bismuth Subsalicylate (Pepto-Bismol) [Antidiarrheal/ Adsorbent] [OTC] Uses Indigestion, N, D combo for Rx of H. pylori Infxn Action Antisecretory anti-inflammatory E>o e Adults. 2 tabs or 30 mL PO PRN (max 8 doses/24 h) Feds. 3—6 y 1/3 tab or 5 mL PO PRN (max 8 doses/24 h) 5-9 y 2/3 tab or 10 mL PO PRN (max 8 doses/24 h) 9-72 y 1 tab or 15 mL PO PRN (max 8 doses/24 h) Caution [C, D (3rd tri), -] Avoid w/ renal failure Hx severe GI bleed Contra Influenza or chickenpox (T risk of Reye synd), ASA allergy (see Aspirin) Disp Chew tabs, caplets, Liq, susp SE May turn tongue stools black Interactions T Effects OF ASA, MTX, valproic acid effects OF tetracyclines i effects W/ corticosteroids, probenecid EMS Monitor for hypovolemia and electrolyte disturbances d/t D may darken tongue stool OD Similar to ASA OD V, tinnitus, metabolic acidosis activated charcoal may be effective... 

Flurazepam (Dalmane) [C-IV] [Sedative/Hypnotic/ Benzodiazepine] Uses Insomnia Action Benzodiazepine Dose Adults Beds >15 y. 15-30 mg PO qhs PRN X in elderly Caution [X, /-] Elderly, low albumin, hepatic impair Contra NAG PRG Disp Caps SE Hangover d/t accumulation of metabolites, apnea, anaphylaxis, angioedema, amnesia Interactions T CNS depression W/ antidepressants, antihistamines, opioids, EtOH T effects OF digoxin, phenytoin T effects W/ cimetidine, disulfiram, fluoxetine, iso-niazid, ketoconazole, metoprolol, OCPs, propranolol, SSRIs, valproic acid. 

Vorinostat (Zolinza) [Histone Deacetylase Inhibitor] Uses Rx cutaneous manifestations in cutaneous T-cell lymphoma Action Histone deacetylase inhibitor Dose 400 mg PO daily w/ food if intolerant X 300 mg PO d for X 5 d each wk Caution [D /-] w/ warfarin (t INR) Disp Caps SE NA /D, dehydration, fatigue, anorexia, dysgeusia, DVT, PE, Xplt, anemia, hypoglycemia, QT prolongation Interactions t Risk of thrombocytopenia GI bleed W/HDAC inhibitors (valproic acid) EMS May t QT interval, monitor ECG may t glucose T risk of DVT has been r orted OD Sxs unknown... 

Valproic acid is a fatty acid derivative which is used for the management of absences and the control of generalized tonic-clonic seizures. Multiple mechanisms of action have been proposed. It prolongs Na+ inactivation which could explain its effectiveness against grand mal seizures. However also inhibition of T-Type Ca++ channels has been postulated. 

Type II Multiple actions enhance GABAergic inhibition, reduce T-calcium currents, and possibly block SRF Valproic acid Benzodiazepines Phenobarbital Primidone... 

As with several other AEDs, it is difficult to ascribe a single mechanism of action to valproic acid. This compound has broad anticonvulsant activity, both in experimental studies and in the therapeutic management of human epilepsy. Valproic acid has been shown to block voltage-dependent sodium channels at therapeutically relevant concentrations. In several experimental studies, valproate caused an increase in brain GABA the mechanism was unclear. There is evidence that valproate... 

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