CNS Pharmacology GABA Synthesis and inactivation Isoniazid GABA Synthesis Vigabatrin GABA Degradation Sodium Valproate GABA

Degradation Tiagabine Inhibits glutamate decarboxylase – originally used for TB Inhibits GABA transaminase (GABA succinate semialdehyde) Inhibits succinate semialdehyde dehydrogenase (succinate semialdehyde succinate) GABA Reuptake Inhibits the GABA – Na cotransporter

GABAA receptor (pentameric heteromer, Cl channel – inhibitory) GABA Endogenous agonist Muscimol Agonist Bicuculline Antagonist – competitive Picrotoxin Antagonist – ion channel block Benzodiazepines Allosteric modulator – binds preferentially between and 2 subunits Barbiturates Allosteric modulator Neurosteroids Allosteric modulator – carbolines Allosteric modulator General anaesthetic Allosteric modulator GABAB receptor (GPCR - gi open K channel,block VGCC, bicuculline insens ) GABA Endogenous agonist Baclofen Agonist – anti spasmodic in spinal cord Gamma hydroxyl butyrate Agonist – date rape Phaclofen Antagonist 2-hydroxysaclofen Antagonist Anxiety and GABA Buspirone 5 HT 1A partial agonist – blockers Tricyclics and SSRI Barbiturates ? feedback inhibitory effect

Benzodiazepine

Somatic anxiety by removing peripheral effects Antidepressants ? overlap between chronic anxiety and depression Allosteric At high [ ] can open channel in absence activators of GABA. Low TI, tolerance due to GABAA hepatic enzyme induction, profound depression and dependence. Largely replaced by BZD but still used as anticonvulsant. Increase channel open time. Allosteric Safer – higher TI. Only potentiates the activators action of released GABA. Increases

Flip-flop. Nitrazepam Benzodiazepine Hypnotic – short t1/2 wears off before am. (thought to be due to 2unit) Flumazenil Antagonist at the BZD binding site on GABAA receptor.D pentamer.C. GABAA Ionotropic receptors AMPA (GluR A. Glycine (Spinal cord inhibitory [renshaw cell] pentameric receptor) Strychnine Competitive antagonist of glycine receptor. sites: glycine (+).B. muscle relaxant) Diazepam Benzodiazepine Anxiolytic – long t1/2 metabolised to chlordiazepoxide nordiazepam = hang over. Enhance agonist binding and Cl flux by increasing frequency of opening. tolerance (due to subunit change) and synergistic with alcohol and anti histamine. – carboline – carboline Inverse agonist at BZD site. ion channel (Mg). redox (SH ^freq). polyamine (+/-). anticonvulsant. nordiazepam – t1/2 = 60hr. Zn (-). hypnotic.frequency of opening and increases affinity for GABA. NOT active at glycine site on NMDA receptor. – ‘Hang over’ (effects: anxiolytic. Shows selectivity for 1 unit (shown to be involved with hypnotic effect) hence without anxiolytic effects.D.B. RNA editing. steroid (+) N methyl D aspartate Selective agonist Dizolcipine Antagonist Ketamine Antagonist (channel block) . Zaleplan Acts at BZD site short t1/2. Decreases carboxylate Allosteric frequency of opening and affinity for modulator GABA.g.). Glutamate Reuptake Dihydrokainate SITS Inhibits neuronal Na dependent uptake Inhibits glial Na dependent uptake. Some have long lived metabolites – e. Q/R RNA editing GluRB) AMPA Selective agonist Kainate (GluR5-7 KA1-2 pentamer. Neurosteroids Allosteric Includes progesterone metabolites and modulator dehydroxycorticosterone. BUT – dependence. May be able to open channel in absence of agonist. hypnotic. rapid desensitisation Kainate Selective agonist NMDA (NR1(alternative splice) + NR2A. pH (low .C.

All types INCLUDING absence (other anticonvulsants may be contraindicative of absence. see above Ethosuximide T type calcium Absence – first line treatment channel blockers Trimethadione T type calcium Absence – first line treatment channel blockers Gabapentin Calcium channel Adjunct to partials.Magnesium Phenylcyclidine Glycine Dichlorokynurenate Anticonvulsants Phenobarbitone GABAA modulator (barbiturate) Antagonist (channel block) Antagonist – angel dust! Co-agonist Antagonist at glycine site Suppress focus. Adjunctive in partials Vigabatrin GABA inactivation Inhibits GABA transaminase (GABA – SSA) Adjunctive in partials Valproate GABA inactivation Inhibits SSADH (SSA – succinate) AND Na channels. Hence increasing GABA and decreasing Na (synergistic effects). against all but absence. Useful for children. Sedation and tolerance (hepatic enzyme induction) charged not easy to cross BBB Diazepam GABAA modulator Suppress spread (less on focus) (benzodiazepine) status epilepticus. Sedation and tolerance (subunit change) Clonazepam GABAA modulator Suppress spread (less on focus) status (benzodiazepine) epilepticus and tonic/clonic. ? effect on channel blockers AMPA/Kainate Flebamate Glutamate NMDA glycine site. Tiagabine GABAA Reuptake Inhibits GAT-1 Involved in Na dependent uptake. Also no sedation so useful for children. Sedation. Role in blockers pain – can overdose Levetiracetam N type calcium Adjunct to partials. receptors . Na blockers Metabolism saturation so need to increment dose slowly and titrate plasma to monitor concentration Lamotrigine Use dependent Prevent spread. Partials and Na blockers tonic/clonic Valproate Use dependent Prevent spread. Partials and Na blockers tonic/clonic Phenytoin Use dependent Prevent spread. All except absence. All types including Na blockers absence. because can’t afford to sedate children continuously – affect learning… Carbamazepine Use dependent Prevent spread.

Partials and tonic/clonic. ACEi. amphetamine Dopamine receptors. Absence seizures Valproate Ethosuxamide.Levetiracetam Glutamate receptors AMPA and Kainate receptors.) MAO A and B inhibitors selectively at low concentration Blocks synaptic vesicle uptake of DA Promotes emptying of vesicles increasing [DA]I thus decreasing efficiency of uptake process. raising DA t1/2 in extracellular space. D1 = gs D2 = gi Dopamine D1A < D1B D2A > D2B . Alzheimers disease (B amyloid plaques and neurofibrillary tangles due to hyperphosphorylated tau. Block VG Na channel Block T type Ca channel Block VG Na channel and neuronal Ca channel N type Ca channel Contraindicated and enhance absence seizures. AChE inhibitors. Selegiline Reserpine Amphetamine Cocaine. free radical scavengers. Agonist Clorgyline. anti-inflammatory. combined AMPA/NMDA block. Block Na DA cotransporter. nomifensine. adenosine agonists. Low dose aspirin. trimethadione Lamotrigine Levetiracetam Carbamazepine. DOPAMINE Synthesis and inactivation Carbidopa and benserazide DOPA decarboxylase inhibition (note all L aromatic aa are substrates at this enzyme – trypyophan and histidine. dunazepil. in line with the ‘cholinergic hypothesis’ rivastigmine But weak effect for 12-24 months maimum. ?synergy between NMDA-R block and antiapoptotic drugs. Role of secretins in misprocessin of APP) Putative drugs for B B secretase inhibition (b secretase KO is not harmful) amyloid generation B amyloid vaccination (caused brain inflammation in trials) anti-inflammatory (ibuprofen reduces plaque in a mouse model) plaque solubilisation/inhibition of formation cholesterol lowering agents Tacrine. tiagabine. anti inflammatory Future NMDA-R block (dizolcipine – side effects) newer tolerated ones like DEXTROMETHORPHAN. (save the penumbra!!) Drugs used Statins. Zn chelators. vigabatrin Cerebrovascular accident – ischaemic damage. benztropine.

Used if typicals don’t Clozapine Sulpiride A<B=C Antagonist . constipation. Entacapone. Now aim is to delay L-DOPA use. choreiform movements. tolcopone Domperidone Block peripheral DA receptors in the ChemoTrigger Zone. Can reverse negative symptoms. transplants. constipation and blurred vision. BUT will exacerbate alzheimers symptoms – ‘pro-dementia’ Sellegeline MAO-B inhibitor – no cheese reaction. glial derived neurotrophic factor (? Neurones simply dormant not dead). Fewer motor disturbances. Dopamine agonists. decrease ACh activity. A2A decrease cortical striatal input. synergistic with L-DOPA – allowing reduced dose and prolonging onset of side effects. Benztropine Muscarinic cholinergic antagonist – dry mouth. Future Antioxidants. Shows how ‘dirty’ drugs are. 90% improve (60% on placebo) BUT side effects – motor disturbance (D2A) and tardive dyskinesia (involuntary face and trunk movements) Reduce aggression – apathy plus loss of emotion. Reduces ‘off’ time but may have more serious side effects pergolide than L-DOPA. Adenosine Reduce activity of indirect pathway. Little effect on – symptoms. glutamate antagonists. After 5-10yrs side effects – 80% dyskinesias. lisuride. Sedation (H1 block) Postural hypotension ( 1 block).Quinpirole Flupenthixol Sulpiride Clozapine Haloperidol Spiperone D2A > D2B Non selective Non selective D2 C>A=B A=C>B A=C>B Agonist Antagonist Antagonist (atypical) Antagonist (atypical) Antagonist (typical) Antagonist (typical) Parkinson’s Disease L-DOPA With carbidopa (save for brain) and Domperidone (antagonise CTZ DA receptors). May be used as an adjunct to L-DOPA. psychosis/hallucinations (^DA in mesolimbic system) Because therapeutic window decreases (supersensitivity and more neurones dying) L-DOPA holidays may help. Schizophrenia Chlorpromazine A>B=C Fluphenazine Antagonist Haloperidol Flupenthixol TYPICALS Typical. Delays requirement for L-DOPA for 1 year and may supplement it to allow a reduced dose. bromocriptine. Breast development and lactation (loss of inhibition by TI DA) and side effects of mACh block – dry mouth. blurred vision. No rapid on-off. 60% decreased efficacy of drug. no antagonist dyskinesias. rapid on/off. 1st line treatment. COMT inhibitor.

having effects at other receptors – 1. Dirty. No cheese effect since B still active. 2. irreversible.VTA) -methyl-5-HT Agonist Ketanserin Antagonist 5-HT3 (ion channel – depolarisation) Biguanides Ondansetron DEPRESSION Phenelzine MAOi tranylcypromine Agonist Antagonist (+chemo – antiemetic) Moclobemide Imipramine. therefore continuous wbc monitoring must be conducted. mACh (block – dry mouth…) . typicals are only 5-HT antagonists so the increase in VTA firing is less. Thus cheese effect. Shows how clozapine is ‘dirty’! 5-HT1A (gi Raphe – presynaptic inhibition) Buspirone Agonist (anxiolytic) partial Pindolol Antagonist 5-HT1B (gi – presynaptic inhibition) Methysergide Pindolol Agonist Antagonist 5-HT1C (gi – alters blood vessel diameter of brain) Sumatriptan Agonist (migrane therapy) Spiperone Antagonist 5-HT2A B C (gq – excitation) (c-thought to excite GABA interneurones . Note. Selective. H1 (block – sedation). amytriptiline Nomifensine MAOAi Tricyclics NA SRI Non selective. The realisation that inverse agonism had an effect to increase firing of VTA and thus has been found to increase DA in PFC and hence decreasing negative symptoms. Reversible so other drugs can be administered immediately. Also must be careful because MAO ~2-3 weeks to be resynthesised thus if give drugs requiring ^ MAO activity can lead to fatal hypertension. Inhibit NA and 5-HT uptake.Olanzapine Pimozide Clozapine. Also shown that 2 block may have and effect. [Clozapine may cause agranulocytosis in ~1% of pt. making the drug expensive and thus use is limited. Shown to reduce negative symptoms. D2 antagonist D2 antagonist and 2 block Clozapine [Typical + idazoxan] Serotonin work. olanzapine Risperidone ATYPICALS 5-HT2C inverse agonist.

Unknown mechanism. Evidence against monoamine theory – no effect on MA. Not fully understood. 2 block (? ^NA by blocking autoreceptors) H1 block (sedation) 5-HT2A 5-HT2C block. Nausea side effect (^5-HT in gut) overdose non lethal. No action on monoamine uptake. long t1/2 3 weeks to Css. Anticonvulsant Carbamezepine Anticonvulsant Lamotrigine Anticonvulsant Anti pshychotics . no sedation and may not be very efficacious Substance P antagonist – failed at phase III CRH antagonist . efficacy in ~60%. In phase III Manic phases of depression (15% suicide so must be controlled) Lithium Inhibits IMP phosphatase Valproate Inositol uptake inhibition.Citalopram fluoxetine Mianserin SSRI Iprindole FUTURE Highly specific.? implicated in stress induced depression.

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