Med Org Lec L4.2 PDF: Anti-Seizures and Antidepressants

# Anti-Seizures ## Old and New Agents - **Epilepsy** is a disorder where there are recurrent seizures unprovoked by identifiable causes. **Seizure** is a symptom for disturbed electrical activity in the brain. - **3 Generalized seizures:** - **Absence** (petit mal) - brief loss of awareness (b...

# Anti-Seizures ## Old and New Agents - **Epilepsy** is a disorder where there are recurrent seizures unprovoked by identifiable causes. **Seizure** is a symptom for disturbed electrical activity in the brain. - **3 Generalized seizures:** - **Absence** (petit mal) - brief loss of awareness (blank stare), postseizure amnesia but with no loss of motor activity. - **Myoclonic seizures** - no loss of consciousness and involves short seizure duration. - **Tonic-Clonic** (grand mal) - bilateral muscular jerking, loss of consciousness, tonic-clonic spasms. - **2 Partial seizures:** - **Simple** - affects an entire hemisphere or a lobe within a hemisphere of the brain. - **Complex** - temporal/psychomotor seizures, mistaken for psychotic behavior. ## MOA Anti-seizure drugs alter ion channel or receptor function to promote synaptic inhibition or modulate synaptic excitation. ## Sites of action for anti-seizure drugs ### Glutamate presynaptic neuron - **Lamotrigine** - **Ezogabine** - **Ethosuximide** - **Valproate** - **Zonisamide** - **Benzodiazepines** - **Carbamazepine** - **Lamotrigine** - **Lacosamide** - **Oxcarbazepine** - **Phenobarbital** - **Phenytoin** - **Rufinamide** - **Topiramate** - **Valproate** - **Zonisamide** ### GABA presynaptic neuron - **SSAH** - **GAD** - **GABA-T** - **Vigabatrin** - **Benzodiazepines** - **Phenobarbital** - **Topiramate** - **Valproate** - **Tiagabine** - **Topiramate** - **Felbamate** ### Partial and generalized tonic-clonic seizures - **Benzodiazepines** - **Carbamazepine** - **Ezogabine** - **Lacosamide** - **Felbamate** - **Oxcarbazepine** - **Phenobarbital** - **Phenytoin** - **Pregabalin** - **Primidone** - **Rufinamide** - **Tiagabine** - **Topiramate** - **Vigabatrin** ### Myoclonic seizures - **Felbamate** - **Lamotrigine** - **Levetiracetam** - **Valproate** - **Zonisamide** - **Gabapentin** - **Clonazepam** - **Topiramate** ### Absence seizures - **Ethosuximide** - **Methosuximide** - **Trimethadione** ## Anti-seizures: Old Agents - **Ureides** are class of drugs and their derivatives with a similar pharmacophore. - The class includes: **hydantoins**, **barbiturates**, **oxazolidinediones**, and **succinimides**. ### Hydantoins (Phenytoin & Fosphenytoin) - **SAR:** - Bulky C5 is optimal for activity (at least 1); Phenytoin has a 5,5-diphenyl giving it maximal activity. - Fosphenytoin is a disodium phosphate ester of phenytoin = water soluble, better stability for parenteral administration. - Used for generalized seizures, partial seizures, status epilepticus - **METABOLISM:** CYP 2C9 catalyzed aromatic hydroxylation, glucuronidation, and sulfation ### Oxazolidinedione (Trimethadione) - **SAR:** - Has no bulky C5 groups eliminates activity for grand mal, but increases activity for petit mal (absence seizure) - High toxicity limits therapeutic applications. ### Succinimide (Ethosuximide) - Drug of choice for absence seizure (petit mal). - **SAR:** - Has no C5 bulky group - Replaced the -O- (in oxazolidinedione) with -CH2 = safer with retained activity. - **METABOLISM:** ~20% excreted unchanged, CYP 3A4 and 2E1 ### Valproic acid - It is a 2-propylpentanoic acid and is used for both grand and petit mal. - 2 rare side effects that limits its use: hepatotoxicity and teratogenicity - **MOA:** - Promotes GABA transmission by inhibiting GABA metabolism. - Blocks VGSC, decreasing excessive neuronal firing. ## Anti-seizures: New Agents ### Iminostilbene (Carbamazepine) - **CBZs** are derivatives of **TCAs** (tricyclic antidepressant). - **SAR:** - 2 phenyl groups are essential for activity - Keto, hydroxy, or acetate ester can be substituted at C10 = less potent but active. - **MOA:** blocks VGSC resulting to inactivation of excessive neuronal firing. ### GABA Analogs (Gabapentin and Pregabalin) - **SAR:** - Both agents are analogs of **GABA** (inhibitory neurotransmitter) - **MOA:** modulates Ca+2 influx by regulating VGCC resulting activation of glutamic acid decarboxylase (GAD) resulting to glutaminergic neurotransmission inhibition. - **METABOLISM:** minimal* ### Phenyltriazine (Lamotrigine) - Useful for both grand mal, petit mal, and partial seizures for adults - **MOA:** blocks both VGSC and VGCC, stabilizing presynaptic neuronal membranes, inhibiting glutamate release producing no excitatory response. - **METABOLISM:** Glucuronidation ### Dicarbamate (Felbamate) - It is very potent and widely used agent but has very toxic severe side effects: aplastic anemia and hepatic failures. - **MOA:** interacts with NMDA decreasing glutamate transmission resulting to decreased neuronal excitation. - **METABOLISM:** ester hydrolysis and oxidation. # CNS Stimulants ## Methylxanthines and Anti-depressants ## Methylxanthines - Xanthine derivatives found in plants acts as CNS stimulants. - **MOA:** competitive inhibition of phosphodiesterase and antagonism of adenosine receptors | Methylxanthine | CNS Stimulation | Respiratory Stimulation | Skeletal Muscle Stimulation | Diuresis | Coronary Dilation | Cardiac Stimulation | |---|---|---|---|---|---|---| | Caffeine | 1 | 1 | 1 | 3 | 3 | 3 | | Theophylline | 2 | 2 | 2 | 1 | 1 | 1 | | Theobromine | 3 | 3 | 3 | 2 | 2 | 2 | *Ranking of different Methylxanthines: 1 - most potent* - **METABOLISM:** liver CYP, xanthine oxidase (into uric acid) ## Antidepressants - Depression as a condition has been hypothesized to be based on the balanced relationship between 5-HT, NE and DA neurotransmitters. ### Example of Drugs: - **TCAs (SNRI/NSRI)** - **SSRIs** - **MAOIs**, MAO inhibitor - **5HT2 Antagonist/SRM** #### Neurotransmitter deficiency syndrome: - Serotonin: anxiety, panic, phobia, obsessive-compulsive disorder, depressed mood, food craving, bulemia. - Dopamine: decreased attention, psychomotor retardation, cognitive slowing, hypersomnia, anhedonia. - Norepinephrine: decreased concentration, decreased working memory, decreased information processing, fatigue. ### MOA Options - **Agonize 5HT receptors** - **Agonize NE receptors** - **Block 5HT reuptake** - **Block NE reuptake** - **Block metabolism by MAO** - **Or any combination** ## Antidepressants - **TCAs** (SNRIs/NSRIs), **SSRIs**, **NDRI**, and **SARI** - These agents target a transporter protein: **SERT**, **NET**, and **DAT**. ### MOA: - Blocks transporter proteins preventing inactivation of NTs, allowing NTs to function. - Increased levels of 5-HT, NE, and DA relieves the signs of NT deficiency - antidepressant activity. ## Antidepressants - Selective Norepinephrine Reuptake Inhibitor (SNRIs) and Norepinephrine/Serotonin Reuptake Inhibitors (NSRIs) ### MOA: - SNRI - selectively blocks NET - NSRI - blocks NET and SERT (binding is dependent on NE:5HT potency ratio) - TCAs are known to produce “anti-HAM” effect like phenothiazines. #### Anti-HAM: - **H**: Histaminic (sedation). - **A**: Adrenergic (orthostatic hypotension). - **M**: Muscarinic (dry mouth, constipation, blurred vision, urinary retention). ## Antidepressants ### SAR: - 2° N is essential for SNRI selectivity - C3-X = increases activity and affinity for NET & SERT - B-ring side chain must be 3C long ending with an amine, branching side chain decreases affinity for NET & SERT - Replacement of Ring N with propylene = max potency - C10-C11 double bond = increase activity - O-replacement in C10-C11 leads to an E/Z mixture resulting to preferential NET/SERT binding ### METABOLISM: - N-demethylation (SNRI = inactivation, NSRI = leads to NET inhibitors) - Aromatic hydroxylation (Atomoxetine, Duloxetine) - CYP 2D6 hydroxylation (SNRI at C10; Clomipramine at C8) - CYP 2D6 demethylation (Clomipramine, Venlafaxine, Doxepin) - Glucuronidation ## Antidepressants ### Dibenzazepines TCAs - “-PRAMINE” - **Desipramine:** SNRI agent, NET blocker. - **Imipramine:** NSRI prototype drug, NET, SERT blocker. - **Clomipramine:** NSRI agent, NET, SERT blocker. ### Dibenzocycloheptadiene TCAs - “-TRIPTYLINE” - **Nortriptyline:** SNRI agent, has N5-C12 double bond, NET blocker. - **Protriptyline:** SNRI agent, has C10-11 double bond, NET blocker. - **Amitriptyline:** NSRI agent, has a propylene moiety in the B-ring, NET, SERT blocker. - **Doxepine:** NSRI agent (E/Z isomers), E selectively inhibits NET, S selectively inhibits SERT, NET, SERT blocker. ### NON-TCA SNRIs / NSRIS - **Atomoxetine:** SNRI agent, R-enantiomer is more active. - **Duloxetine:** NSRI agent. - **Milnacipran:** NSRI agent. - **Venlafaxine:** NSRI agent. ## Antidepressants - Selective Serotonin Reuptake Inhibitors (SSRIs) ### SAR - Electronegative (-X) 4-substitution = essential for selectivity and affinity for SERT - SSRI stereochemistry significantly affects SERT selectivity: ### MOA - Inhibits SERT with high affinity and selectivity for SERT ### METABOLISM - Highly metabolized in the liver by CYP isozymes (especially CYP 2D6) - N-demethylation for N-methyl SSRIs. - MAO and Glucuronidation (Sertraline) ## Antidepressants - **Escitalopram:** S-isomer is more active, Citalopram (R-isomer). - **Fluoxetine:** R-isomer more potent, S-isomer higher affinity for SERT. - **Paroxetine:** (-)-3S,4R-isomer is more active for SERT inhibition. - **Fluvoxamine:** E-somer is essential for SERT inhibition. - **Sertraline:** 1S,4S-isomer is more active for SERT inhibition. ## Antidepressants - Monoamine Oxidase Inhibitors (MAOIs) - MAO is an enzyme responsible for the deamination of amine. 5-HT is a substrate for MAO-A, while epinephrine, NE, and DA are substrates for MAO-A and MAO-B. - MAOIs when taken with sympathomimetics or tyramine-containing food may result to hypertensive crisis (severe headache, tachycardia, diaphoresis, hyperpyrexia). ### SAR - Some has similar structure with amphetamine - Presence of electron-withdrawing groups = increases potency ### MOA - Inhibits metabolism of NE, 5-HT, and DA = increasing concentration in the brain ### METABOLISM - Oxidation and N-acetylation ## Antidepressants - **Moclobemide:** reversible inhibitor of MAO-A, antidepressant w/o hypertensive crisis. - **Tranylcypromine:** resembles amphetamine with a-methyl condensing with β-carbon. - **Phenelzine:** irreversible inhibitor of the enzyme. - **Selegiline:** (also Anti-Parkinson) selective irreversible inhibitor of MAO-B ## Antidepressants - Serotonin-2 Antagonist/Serotonin Reuptake Modulators (SARIs/SRMs) ### SAR - All agents are phenylpiperazine derivatives. ### MOA - Antagonizes 5-HT2 receptors and/or selectively inhibits SERT - **Trazodone:** antagonist at 5-HT2A receptor = blocks excitation, hypnotic effects - **Vilazodone:** partial agonist at 5-HT1A receptor = postsynaptic releases of 5-HT - **Vortioxetine:** agonist at 5-HT1A receptor and SERT inhibitor - **Aripiprazole:** antagonist at 5-HT2A receptor, and partial agonist at 5-HT1A receptor ## Antidepressants - **Trazodone:** with phenylpiperazine ring, 5-HT2A antagonist - **Vortioxetine:** 5-HT1A agonist and SERT inhibitor - **Vilazodone:** partial 5-HT1A agonist ## Antidepressants - Norepinephrine/Dopamine Reuptake Inhibitor (NDRI) - Buproprion is a unique compound acting on monoamine receptors useful in the management of depression and smoking cessation. ### MOA - Selective inhibition of DAT and NET = increasing NE - Induces release of DA and NE ### METABOLISM - CYP 2B6 alkyl hydroxylation resulting to hemiketal forms and reduction resulting to theo and erythro hydrobupropion isomers and hemiketa ## Antidepressants - Alpha-2-Noradrenrgic/Selective Serotonin Antidepressants (NaSSA) - Mirtazapine is single representative of NaSSA that has a complex mechanism of action. ### MOA - Blocks presynaptic α2-adrenergic and 5-HT receptors (may lead to orthostatic hypotension) = increasing NE and 5-HT levels. - Selectively antagonizes 5-HT2 and 5-HT3 (may lead to sedation) ### METABOLISM - CYP3A4: N-demethylation and N-oxidation. - CYP 2D6: aromatic hydroxylation. # Anti-Parkinson Drugs ## Dopamine Agonist, MAOIs, Anticholinergics, COMT Inhibitors ## Anti-Parkinsonism - Parkinson's Disease (PD) is a slowly progressive, neurodegenerative disorder of the extrapyramidal dopaminergic pathway. It is associated to basal ganglia degeneration and low levels of dopamine. ### Clinical Manifestations: - Resting tremor that improves with voluntary activity - Bradykinesia or slow initiation and paucity of voluntary movements - Rigidity of muscle and joint motility that includes postural disturbances. - Treated with agents of varying activity: L-A-B-A-S-E drugs and related substances. - **Levadopa**, **Amantadine**, **Bromocriptine**, **Anticholinergic**, **Selegiline**, and **Entacapone** ## Anti-Parkinsonism - **Normal:** Substantia nigra, Corpus striatum, Dopamine, Acetylcholine, GABA - **Parkinsonism:** Lack of dopamine, or deficiency in DA neurotransmitter results to lack of direct stimulation for thalamus modulation which is responsible for excitatory outflow to the motor cortex. - **Anti-Parkinsonism:** - **Pramipexole**, **ropinirole**, **Bromocriptine**, **pergolide**, **Dopamine receptors**. - **Selegiline**, **rasagiline**. - **Tolcapone**. - **DOPAC**, **MAO-B**, **Dopamine**, **COMT**, **3-MT**. - **DOPA decarboxylase**, **L-DOPA**, **L-amino acid transporter**. - **3-OMD**, **COMT**, **L-DOPA**, **DOPA decarboxylase**, **Dopamine**. - **Entacapone**, **tolcapone**, **Carbidopa**, **Adverse effects**. ## Anti-Parkinsonism - **Drugs and Mechanism of Action:** - **Lipophilic DA precursor:** Levadopa (dopamine precursos) - **DA agonist and Reuptake inhibitor:** Amantadine - **DA agonist:** Bromocriptine, Pergolide, Pramipexole - **Anticholinergics:** (tremor management) Benztropine, Biperiden, Trihexypeħnidyl - **MAO-B inhibitors:** (w/o HTN crisis) Selegeline and Rasagiline - **COMT Inhibitors:** Entacapone and Tolcapone