Anxiolytic used to treat post-traumatic stress disorder, phobias, panic disorders, obsessive compulsive disorder (OCD). These are link to many neurotransmitters. But gama-aminobutyric acid (GABA), norepi, 5HT are consider as having major influence on these disorders. Benzodiazepines Allosteric modulation of the GABA-GABA A receptor interaction which controls chloride ion channels. (Positive effect) SAR A ring X is electronegative (increase activity) 6,8, and 9 positions should not be substituted.

B ring 5 position phenyl increase activity Saturation of 4,5 double bond or shift decrease activity. Alkyl substitution at the 3- decrease activity (hydroxy does not) Hydroxyl group (short half-life because glucuronide) Carbonyl and nitrogen 2 and 1 positions are needed. R must be a small alkyl C ring Electron withdrawing group at orthro (2’) and diorthro (2’,6’) increase activity 4’ substitution decreases activity. SAR (Continue)

Metabolism of Benzodiazepines

Benzodiazepines Valium (Diazepam) Metabolism N-dealkylation, hydroxylation, glucuronidation Uses: Anticonvulsant, preop. Anxiety. Centrax (Prazepam) Metabolism: N-dealkylation, hydroxylation, glucuronida- tion. Uses: Anxiety Paxipam (Halazepam) Metabolism: Same as Diazepam Uses: Anxiety

Tranxene (Clorazepate) A prodrug Metabolism: Decarboxylation to Norazepam Use: Anxiety Serax (Oxazepam) Short half-life Metabolism: Glucuronidation Use: Anxiety Ativan (Lorazepam) Metabolism: Glu. Use: Anxiety

Klonopin (Clonazepam) Nitro group Metabolism: hydroxylation glucuronidation Librax, Librium and Libritabs (Chlorodiazepoxide) Metabolism: N-dealkylation, hydroxylsis (lactam) reduction, hydroxylation and conjugation

Xanax (Alprazolam) Triazole ring Short half-life Metabolism: hydroxylation of methyl and conjugation Use: anxiety Halcion (Triazolam) Triazole ring Versed (Midazolam) Imidazole ring

Sleep Aids S-enantiomer in U.S. Rapid onset and short Duration (6 hours) Demethylation and oxidation Metabolites in urine Imidazopyridine Weak anticonvulsant Stronger Sedative effect Shorten sleep latency and prolong sleep time (No effect stages of sleep)

Romazicon (Flumazenil) Imidazole ring Competitive benzodiazepine antagonist Ester hydrolysis and glucuronidation Use benzodiazepine overdose Partial inverse agonist receptor is frozen in the inactive state thus chloride channel close and conductance is decrease

Miscellaneous use Selective Serotonin Reuptake Inhibitors (SSRI)

Anticonvulsant and Antiepileptic Anticonvulsant is drug or agent that blocks seizures. Antiepileptic is a drug or agent that controls epilepsies. Types of seizures Generalized (entire brain) Unilateral (one side of the brain) Partial (or focal) Erratic (new born) Unclassified (high mortality) Generalized seizure tonic-clonic seizure (grand mal) nonconvulsive seizure or absence (petit mal)

First anticonvulsant Potassium Bromide (KBr) 1857 Replaced with phenobarbital 1912 still used to infants Phenytoin was discovered as anticonvulsant 1937 Approximately 60% patients with seizure are on monotherapy (Tegretol, Klonopin, diazepam, Zarontin, Dilantin) 20% patients are taking two drug combinations. Other 20% patients take more than two drugs with little benefits Cross interaction among anticonvulsant and other drugs. Increase of dose for children because of metabolism History of Anticonvulsant

Anticonvulsant Mechanism of Action Allosteric modulation of GABA A receptors (Benzodiazepine) Blocking voltage-gated sodium channel (Phenobarbital, phenyl succinimide and hydantoins). Blocking calcium T channel (5,5-dialkyl members of barbiturates, oxazolidine-2,4-diones and succinimide )

Valium (Diazepam) IV for rapid response (Status epilepticus) Klonopin (Clonazepam) Use for many types of seizure except grand mal

Ativan (Lorazepam) Rapid response (Status Epilepticus) IV or IM Use combination with Dilantin Tranxene (Clorazepate dipotassium) Prodrug (decarboxylation) Use in combination for partial seizures

General SARs for Anticonvulsants R and R’ are hydrocarbon. If R and R’ are lower alkyl, tendency is to active against petit mal seizures. If R or R’ is a phenyl, activity tend to be against grand mal seizures and partial seizures.

Barbiturates (sedative-hypnotic) Phenobarbital Use for grand mal and partial seizures Less effective than phenytoin and Tegretol Adminster IV as sodium salt May be in combination with a benzodiazepine Metabolism p-hydroxylation followed by conjugation (glu or sulf). Block sodium channels and GABA A receptors Mephobarbital Use for grand mal and partial seizures Metabolism N-demethylation (active metabolite), also p-hydroxylation follow by conjugation Same mechanism of action

Mysoline (Primidone) 2-deoxy of barbiturates Use for all types of seizure except petit mal Less effective than Dilantin Associated with sedation Overall safe

Hydantoins Relatives of barbiturates but lack 6-oxo group. Weaker acid than barbiturates therefore forms strong basic salts. Phenyl ring indicates active against grand mal seizure Dilantin (Phenytoin and Phenytoin sodium) Block Sodium channel (decrease presynaptic glutamic acid release) Activity against all seizures except petit mal. Metabolism involves p-hydroxylation and conjugation. Cerebyx (Fosphenytoin) Disodium phospate ester prodrug of Dilantin IV or IM (phenytoin sodium has poor water solubility Indication same as Dilantin Side effect include severe bradycardia

Peganone (Ethotoin) Use grand mal and complex Partial seizures Less active than Dilantin and More sedating Use in combination therapy Oxazolidinediones Replacement of NH of hydantoin to oxygen yields oxazolidine-2,4- dione. Oldest drugs used to treat Petit mal seizures (1940s) Tridione (Trimethadione) Prodrug undergoes N-demethylation To active metabolite (water soluble) Use Petit mal Blocks Calcium T-channel

Succinimides Due to toxicity of oxazolidinediones, these drugs were develop for treatment of petit mal seizure (1950s). CH 2 replaces the O of oxazolidine-2,4-dione Milontin (Phensuximide) Primarily use for petit mal seizure Phenyl group indicates some activity against grand mal seizure N-demethylation to yield active metabolite which is deactivated by p-hydroxylation and conjugation Turn urine to pink or red color Less active than Zarontin Zarontin (Ethosuximide) Use for petit mal seizure (worsen grand mal seizure) Block calcium T channel Toxicity involves skin and blood. Metabolism oxidation (hydroxyl) of ethyl group

Celontin (Methsuximide) Use for petit mal and complex partial seizures (does not worsen grand mal seizure) Metabolism in p-hydroxylation and conjugation

Ureas and Monoacylureas Tegretol (CBZ, Carbamazepine) Block sodium channel Use for grand mal and partial seizures Hematological toxicity ( rare aplastic anemia) Metabolism involve epoxidation at double bond convert to Trans diol It is one of the safest and effective anti- convulsant alone with Dilantin. Tricyclic structure similar imipramine Trileptal (Oxcarbazepine) Block sodium channel Use partial seizures Metabolism involve reduction of ketone to active metabolite.

Miscellaneous Agents Depakene (Valproic Acid) Block sodium channel and increase GABA Active as anion available as sodium salts (IV) Metabolism involves conjugation of carboxylic acid and oxidation of hydrocarbon chains. Side effects are mild, but potentially fatal fulminate hepatitis. Lamictal (Lamotrigine) Blocks sodium channels and release of glutamate Use for refractory partial seizures Clinical trial for amyotrophic lateral sclerosis (ALS)

Neurotin (Gabapentin) Design to mimetic GABA May alter metabolism or release of GABA Bind to calcium channels? Use grand mal, partial seizures as single drug therapy Gabitril (Tiagabine) Pipiderine 3-carboxylic acid Know to inhibit GABA uptake Binding GABA transporter GAT1 Blocks GABA reuptake Use partial seizures

Keppra (S-(-)Levetiracetam) Use partial, grand mal and Myoclonic seizures. Felbatol (Felbamate) Dicarbamate Blocks NMDA receptor Blocks sodium channel. Interact with GABA A receptor Side effects aplastic anemia.

Blockage of sodium channels Blockage of voltage-gate calcium channels Diamox (Acetazolamide) Carbonic acid anhydrase inhibitor