Neuropharmacology Introduction Sed-Hypnotics PDF

NEUROPHARMAC OLOGY: NEUROTRANSMI TTERS & RECEPTORS Ch 7: NTs & Neuromodulators; Ganong’s Review of Medical Physiology Ch 21 & 23: Basic & Clinical Pharmacology, Katzung, 15th ed. Ch 6 & 8: Foye’s Principles of Medicinal Chemistry, 8th ed. Ch 14 & 23: Goodman & Gilman’s: Pharmacological Basis...

NEUROPHARMAC OLOGY: NEUROTRANSMI TTERS & RECEPTORS Ch 7: NTs & Neuromodulators; Ganong’s Review of Medical Physiology Ch 21 & 23: Basic & Clinical Pharmacology, Katzung, 15th ed. Ch 6 & 8: Foye’s Principles of Medicinal Chemistry, 8th ed. Ch 14 & 23: Goodman & Gilman’s: Pharmacological Basis of Therapeutics, 13th ed.  LECTURE OBJECTIVES 1. Describe neuronal cellular structure; and, where NT and neuropeptides are synthesized 2. Explain excitatory and inhibitory neuronal transmission 3. List different classes of neurotransmitters (NT), including representatives of each 4. Describe the primary effects of each NT class; including mechanism of action; i.e. related to receptor sub-types 5. Describe synthesis and metabolism of catecholamines and acetylcholine NTs 6. Describe and explain 5 steps involved in neuronal signal transmission 7. Discuss how pharmacological agents may be used to control or affect neuronal signaling  BG Katzung, AJ Trevor: Basic & Clinical Pharmacology, 13 th Ed. (www.accesspharmacy.com), copyright © McGraw-Hill Education ION CHANNELS / NEUROTRANSMITTER (NT) RECEPTORS Ion channels  Voltage-gated (A)  Ligand-gated (ionotropic) (B) Metabotropic receptor (GPCR) Alpha subunit activation of downstream effectors (C) β/γ subunit directly modulates ion channel (D)  and/or β/γ subunits activation  modulates channel (E)  ION FLUX / ION CHANNEL REGULATION OF ACTION/MEMBRANE POTENTIAL Recall ion channels/gradient control:  Membrane potentials  Action Potentials Depolarization (neuronal activation)  Influx of Na+ and/or Ca2+ Hyperpolarization (neuronal inhibition)  Influx of Cl-  Efflux of K+  Goodman & Gilman, The Pharmacological Basis of Therapeutics, 13th ed.; Figure 14-7 NT RELEASE, ACTION, INACTIVATION/ REUPTAKE AT SYNAPSE Step1: AP triggers voltage-gated Ca++ channels (axon / pre-synaptic cleft) to open Step 2: Influx of Ca++  pre-synaptic terminal, triggers… Step 3: Synaptic NT vesicles to fuse w/ plasma membrane; and, release of NTs into the synaptic cleft. Step 4: NTs diffuses throughout synapse, binding to receptors at post-synaptic membrane;  change in neuron’s membrane potential. Step 5: NTs are removed from synapse by re-uptake or by enzymatic breakdown.  ACTION POTENTIAL: EXCITATORY & INHIBITORY SIGNALS EPSP: Excitatory Post-synaptic Potential IPSP: Inhibitory Post-synaptic Potential BG Katzung, AJ Trevor: Basic & Clinical Pharmacology, Goodman & Gilman, The Pharmacological Basis of 13th Ed. (www.accesspharmacy.com), copyright © Action Potential (AP) Generation McGraw-Hill Education  Simultaneous activation excitatory synapses   depolarization sufficient to generate an AP Integration of Excitation and Inhibition  Excitatory stimulation intersecting with inhibitory input (IPSP) will prevent excitatory potential from reaching threshold and Figure 14-1 stimulating depolarization Principle features of neuron  SPECIFIC NEUROTRANSMIT TERS & THEIR RECEPTORS 7 Ganong’s Review of Medical Physiology, 26 th ed., Copyright © McGraw-Hill Education; via AccessMedicine ACETYLCHOLI Figure 7.2 Cholinergic pathways NE: in brain regions Key Points:  biosynthesis: choline + acetyl CoA  metabolism: AChE  acetate + choline  choline transporter: (re)uptake into presynapse  Receptors: GPCRs and inotropic  muscarinic receptors (GPCRs): M1 – M5  M1, M3, and M5 are excitatory  M2 and M4 are inhibitory  nicotinic, acetylcholine receptor (inotropic):  Na+ channel (excitatory)  structural details next slide … Biochemical events at cholinergic synapse  CHOLINERGIC RECEPTORS STRUCTURES Metabotropic receptors (GPCRs): Muscarinic receptors: M1 – M5  M1, M3, and M5 are excitatory  Gαq  PLC;  DAG / IP3 ;  K+ conductance  M2 and M4 are inhibitory  Gαi/o  inhibits AC;  cAMP;  K+ conductance Ligand-gated ion-channel (inotropic):  nicotinic-acetylcholine receptor: nACh- R  2-binding sites on pentameric subunits Modified from NIDA (NIH); Modified LM, Hendrickson, Front. Psychiatry (2013); https://doi.org/10.3389/fpsyt.2013.00029  Na channel (excitatory)  depolarization + Goodman & Gilman, The Pharmacological Basis of Therapeutics, 11th ed.  Ganong’s Review of Medical Physiology, 26 th ed., Copyright © McGraw-Hill Education; via AccessMedicine DOPAMINE: Key Points:  Catecholamine NT  synthesized from TYR  metabolism:  dopamine-β-hydroxylase  norepinephrine  MAO and/or COMT  inactive metabolites  DAT: reuptake into presynapse or glia  Receptors: GPCRs (i.e., D1 – D5; in brain)  D1 and D5 are excitatory  D2 – D4 are inhibitory Biochemical events at noradrenergic synapse  DOPAMINERGIC TRACTS; Goodman & Gilman; The Pharmacological Basis of Therapeutics; 13th ed; McGraw-Hill BIOSYNTHESIS AND METABOLISM Depiction of brain regions; dopaminergic pathways involved in PD Figure 10.3 Biosynthesis and catabolism of  NOREPINEPHRI Ganong’s Review of Medical Physiology, 26 th ed., Copyright © McGraw-Hill Education; via AccessMedicine NE: Key Points:  Catecholamine (adrenergic) NT  synthesized from TYR, via dopa/dopamine  metabolism (central):  inactive metabolites  via monoamine oxidase (MAO) and/or  via catechol-O-methyl transferase (COMT)  NET: reuptake into presynapse or glia  Receptors: GPCRs Biochemical events at noradrenergic synapse  alpha1 , Beta1, and Beta2 – excitatory  alpha2 – is inhibitory (presynaptic)  METABOLISM OF NOREPINEPHRINE TRACTS Biosynthesis and catabolism of norepinephrine Noradrenergic pathways in brain regions Monoamine (NE) release at synaptic junction Ganong’s Review of Medical Physiology, 26 th ed., Copyright © McGraw-Hill Education; via AccessMedicine GLUTAMATE: Key Points:  Major excitatory a.a. NT  synthesized from glutamine via glutaminase  from α-ketoglutarate via GABA-transaminase  reuptake into presynapse or glia (Na+ dep.)  glia: glu metab to glutamine (inactive) for transport  Receptors: inotropic and GPCRs Biochemical events at glutamatergic synapses  Inotropic receptors: excitatory  AMPA / kainate  NMDA  GPCRs: mGluR1-5 (mainly excitatory) Goodman & Gilman; The Pharmacological Basis of Therapeutics; 13th GLUTAMATE RECEPTOR ed; McGraw-Hill SUB-TYPES Inotropic Glutamate Receptors Permeable to Na+, K+, Ca++ ions  AMPA/kainate receptor – most prevalent type  fast depolarization of neurons  Predominantly  Na+ influx; K+ efflux  AMPA-R Antagonists: topiramate  NMDA receptor  slower neuron depolarization  Primary effect  Ca++ influx; K+ efflux  Blocked by Mg++ at more (-) membrane potential  NMDA-R Antagonists: memantine, ketamine Metabotropic Glutamate Receptors (mGluRs; GPCRs)  Group I, Gαq ( PLC)  Groups II and III, Gαi ( cAMP) Goodman & Gilman, The Pharmacological Basis of Therapeutics, 13th ed. (Figure 14-13) GLUTAMATE TOXICITY  CELL DEATH DURING ISCHEMIA  GAMMA- Ganong’s Review of Medical Physiology, 26 th ed., Copyright © McGraw-Hill Education; via AccessMedicine AMINOBUTYRIC ACID (GABA): Key Points:  Major inhibitory a.a. NT  synthesized from glutamate via glutamate decarboxylase  metabolism: via GABA-transaminase  Receptors: inotropic and GPCRs  Inotropic receptors: inhibitory GABA-glutamate turnover  GABAA – chloride (Cl-) channel (predominate)  GABAC – chloride (Cl-) channel  GPCRs: GABAB (inhibitory)  presynaptic:  Ca2+ conductance; postsynaptic: via Gαi  cAMP;  K+ conductance Figure 7-6: GABA /GABA receptors Ganong’s Review of Medical Physiology, 26 th ed., Copyright © McGraw-Hill Education; via AccessMedicine 5-HYDROXYTYRAMINE (SEROTONIN) Key Points:  Amino acid-derived NT  synthesized from tryptophan (see figure )  metabolism: via MAO  inactive metabolites  SERT: reuptake into presynapse or glia  Receptors: in brain and GI  Inotropic: 5-HT –R found in GI (Na+ channel) 3  GPCRs: activity depends upon sub-type/ location  5-HT receptors act via Gα ; opens K+ 1A i IR  5-HT receptors act via Gα / PLC 2a q  5-HT input found: amygdala & hippocampus Biochemical events at serotonergic synapse  Neuro- Norepineph acetylcholi Dopamin transmitte ne rine / Glutamate GABA e Serotonin rs Epinephrine Receptors (list all them) Receptor class (e.g., GPCR) Inhibitory, excitatory, or both Metabolism (details…) Major Physiologic al Role/ Effects Notes:  DRUG TARGETS IN NEUROLOGICAL CONDITIONS 1. Synthesis of neurotransmitters (NTs) 2. Vesicular packaging of NTs 3. Calcium entry (v-gated Ca++ channels) 4. Regulation of Pre/Post- synaptic receptor  agonist/ antagonist/ allosteric modulator 5. Neurotransmitter reuptake transport (NET/DAT/SERT) 6. Neurotransmitter metabolism 7. Neurotransmitter release 8. Modulating action potential (AP) generation   oxcarbaze pine DRUGS COVERED IN THE NEURO SECTION  primidone  gabapenti  alprazolam  phenobarbital n  chlordiazepox  pentobarbita phenytoin  lacosamid ide l  valproic e  chlorazepate*  secobarbital acid  lamotrigin  clonazepam  phenobarbi ethosuximide e  diazepam tal  carbamazep  levetiracet  butalbital ine am  flurazepam  perampanel  lorazepam  zolpidem  pregabalin  midazolam  zaleplon  retigabine  nitrazepam  eszopiclone  rufinamide  oxazepam  ramelteon  tiagabine  quazepam  tasimelteon cannabidi  topiramate ol  vigabatrin  temazepam  suvorexant  lemborexant  zonisamid  triazolam  buspirone e  Drugs Covered In The Neuro Section  benzocaine  cyclobenza  succinylchol  procaine prine  nitrous ine  tetracaine oxide  pancuroniu  baclofen  articaine  enflurane  m  tizanidine bupivicain  isoflurane e  rocuronium  lofexidine  desflurane  (approved 2018)  lidocaine  vecuronium  sevoflurane  carisoprode  mepivacai  atracurium ne  etomidate l  cistracurium  ropivacain  ketamine  methocarba e  methohexit  mivacurium mol  dibucaine al  neostigmine  metaxalone  dyclonine  thiopental  sugammade  dantrolene  pramoxine  propofol x  botulinum toxin  Drugs covered in the Neuro section  Morphine  Loperamide  Phenoxylate  apomorphi  Codeine  Dextramethorph ne  Hydrocodone  L-dopa an  Hydromorpho  carbidopa ne  Buprenorphin  entacapone  Oxycodone e  Donepezil  tolcapone  Oxymorphone  Pentazocine  Rivastigmine  Nalbuphine   selegiline  Alfentanil Galantamine  rasagiline  Fentanyl  Naltrexone  Memantine  Sufentanil  Naloxone  pramipexio  Remifentanil le  Reserpine  Meperidine  Tramadol  ropinerole  Tetrabenazin  Methadone  Tapentadol  benztropin e e  CATECHOLAMINE BIOSYNTHESIS/METABOLISM PATHWAYS Aromatic Tyrosine amine hydroxyl decarboxyl Tyrosine ase L-dopa ase Norepinephrine Dopamine β- hydroxylase Dopamine Catechol-O- Monoa methyltrans mine ferase oxidas e Norepinephrine Dopamine metabolite metabolite  LOGY: SEDATIVES, HYPNOTICS, ANXIOLYTICS & SLEEP AIDS Katzung, Basic and Clinical Pharmacology, 15th ed.; Chapter 22 Foye’s, Principles of Medicinal Chemistry, 8th ed.; Chapters 11 & 12 Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th ed.; Chapters 15 & 17  LECTURE OBJECTIVES 1. Describe GABA-A receptor and role in neurotransmission 2. Compare and contrast binding sites for different classes of drugs that act at GABA receptor 3. Explain the MOA for BDZ, Barbs, and Z-drugs 4. Explain key structural aspects of SAR for BDZs and Barbs 5. Explain how drug classes differ from each other in regulating the GABA-A receptor, metabolism, safety profile, and DDIs 6. BDZ / Barbs: know up to 3 with short / intermed / long (t1/2) 7. Describe MOA, PK, ADE for suvorexant, ramelteon, and buspirone 8. Explain the use(s) for flumazenil  DRUGS COVERED IN THIS SECTION  butalbital  midazolam  flurazepam  pentobarbi  Triazolam  nitrazepam tal  temazepa  Quazepam  phenobarb  Estazolam m ital  chlordiazepo  lorazepam  secobarbital xide  alprazolam  chlorazepate  oxazepam *  diazepam  ramelteon  zolpidem  clonazepa  tasimelteon m  zaleplon  lemborexan  eszopiclone t  CLINICAL USES  Insomnia (sleep aids)  Relief of anxiety (Generalized Anxiety Disorder = GAD)  Chronic alcoholism (withdrawal relief)  Medical / surgical procedures  Sedation and/or amnesia  Trauma-induced coma  Cancer associated sedation  Patient with epilepsy / seizures  Psychiatric treatment (Major Depressive Disorder = MDD)  GABAA RECEPTOR Ligand-gated chloride (Cl-) ion channel Activation GABAA-R  influx of Cl-  hyperpolarization of membrane potential Pentameric (5) subunits containing: 2 alpha subunits (Six different isoforms) Isoforms confer varied binding characteristics / resulting effect predominate form is α1; Binding α1 subunit associated with sedative, hypnotic, amnesic, and anti-seizure effects Binding α2 subunit is associated with anxiolytic BDZ bind to α1, α2, α3, and α5; zolpidem binds only α1  PHARMACOLOGY: GABAA RECEPTOR  Crosses BBB for CNS pharmacological effect  GABA binds between alpha (α) & beta (β) subunits  2 binding sites; outside of channel  opens Cl- ion channel  BDZ bind between alpha (α) & gamma (γ) subunits  1 binding site; (+) allosteric modulator  other drugs bind here:  Zolpidem, eszopiclone, zaleplon; and, flumazenil  Binding sites within the Cl- channel  Barbiturates; (+) allosteric modulator  Ethanol / volatile anesthetics bind at different site  OUTLINE: SEDATIVE/ HYPNOTIC AGENTS  Barbiturates  Benzodiazepines  Z-drugs  Zolpidem (Ambien)  Zaleplon (Sonata)  Eszopiclone (Lunesta)  Other sedatives & hypnotics  suvorexant (Belsomra) / lemborexant (DayVigo)  ramelteon (Rozerem) / tasimelteon (Hetlioz)  Other anxiolytic agents  Buspirone (BuSpar)  BARBITURATE S  Cyclic urides; C2-ketone tautomerizes to form acid  Aryl / alkyl substitution at C-5 confer sedative/hypnotic activity  MOA: (+) allosteric modulator of GABAA receptor  Extend duration of channel opening  Induce CNS depression in dose-related manner  At high doses  respiratory depression, coma and death  DEA Schedule II / IV drugs  BARBITURAT ES Methohexital Butalbital Pentobarbital Phenobarbital Secobarbital  BARBITURATES Ultra short-acting Barbiturates (5-15 mins duration of action) C-IV  Methohexital (discussed later in anesthesia lecture) Short-intermediate Barbiturates (~3-8 hrs duration of action) C-II  Secobarbital [Dose: 100 mg (PO) / 200-300 mg (PO) pre-op]  Rapid onset of action; 10-15 mins; DOA: 3-4 hrs;  Half-life: range: 15-40 hrs; metabolized via hepatic oxid.;  Pentobarbital [Dose: 100 mg (IV); up to 500 mg /150 mg (IM)]  Rapid onset of action; immediate (IV) / 10-15 mins (IM) C-II  DOA: 15-45 mins (IV), 1-2 hrs (IM); t : (range: 15-50 hrs) 1/2  metabolized via hepatic oxidation; Strong inducer of CYP2A6  Butalbital [Dose: 50-100 mg (PO) / 15-30 mg (PO) TID] C-III  Short-intermediate onset of action; 45 – 60 mins /DOA: 6-8 hrs;  Half-life: 35-50 hrs; metabolized by hepatic oxidation  BARBITURATES Ultra short-acting Barbiturates (5-15 mins duration of action) Short-intermediate Barbiturates (~3-8 hrs duration of action)  Secobarbital [Dose: 100 mg (PO) / 200-300 mg (PO) pre-op]  Pentobarbital [Dose: 100 mg (IV); up to 500 mg /150 mg (IM)]  Butalbital [Dose: 50-100 mg (PO) / 15-30 mg (PO) TID] C-IV Long-acting Barbiturates (longer DOA and half-life)  Phenobarbital [Dose: 30-120 mg/ 2-3 doses day (PO, IM, IV)]  Short onset of action; 5 mins (IV), 30-60 mins (Oral)  DOA: ~ 6hrs (IV), 10-12 (oral);  Half-life (t1/2) = 3-5 days; Metabolized by CYP2C19/2C9 and conjugated; strong inducer of CYP2C9, 3A4, 1A2, and 2C19  BARBITURATES Pharmacokinetics:  Metabolism via oxidation at C-5 position  Metabolized by CYP2C19 and 2C9; then glucuronidation  Strong inducer CYP2C, CYP3A4, CYP2A6, and CYP1A2  renal elimination Side effects:  Drowsiness; SOB, confusion, nausea, bradycardia, SJS Drug-Drug Interactions:  CYP2C9 substrates (e.g., NSAIDs, warfarin, statins)  NOTE 7 IMPORTANT THINGS ABOUT BARBITURATE DRUGS 1. 2. 3. 4. 5. 6. 7.  BENZODIAZEP INES  Anxiolytic, sedative effects, sleep aids  Anterograde amnesic effect; No analgesic effects  Benzodiazepine binding site between α and γ subunit; different from GABA  MOA: Allosteric modulator of GABA A Binding receptor site is outside  Enhances binding of GABA of Cl-   increase frequency of Cl- channel opening channel  increased chloride influx  inhibition of nerve signal  DEA Schedule IV drugs Why?  Slower onset & recovery compared to barbiturates  Contraindicated during pregnancy / breast feeding  ES CHEMICAL STRUCTURE  1,4-diazepine ring C7  7-membered heterocylic C7 ring containing a carboxamide group C5  Halogen or nitro group Midazolam in C-7 position Lorazepam necessary for C7 C7 sedative / hypnotic effect  C5-aryl substituent ring Flurazepam Oxazepam BENZODIAZEP INES (BDZ) Carboxamide  azepam Di/Tri-azole ring  azolam BENZODIAZEPINES: SHORT-ACTING Midazolam (Versed) Midazolam  IV onset of action: 1-5 min  Half life: 2 hr  Duration of action: 1-2 hr  Metabolized by CYP3A4/5 Triazolam (Halcion)  Half-life: 2-3 hrs  Onset of action 1 hr (oral) Temazepam (Restoril)  Uses: short-term insomnia (7-10 days)  Onset of action ~ 30 mins (oral)  Half-life: parent ~ 1 hr; metabolite (10 hrs)  Rapid phase II metabolism  INTERMEDIATE-ACTING BDZ DURATION OF ACTION ~ 10 – 24 HRS Alprazolam Alprazolam (Xanax) Lorazepam  Onset of action ~ 1-2 hrs Lorazepam (Ativan)  Onset of action ~ 1-6 hrs (oral)  IV onset of action: 5-10 min  Rapid phase II metabolism Oxazepam Oxazepam (Serax)  Onset of action ~ 2-4 hrs  Rapid Phase II metabolism Estazolam Estazolam (Prosom)  LONG-ACTING BDZ DURATION OF ACTION > 24 HRS Clonazepam (Klonopin) Clonazepam  Onset of action ~ 2 hrs; t = 12 hrs 1/2 (parent);  Metabolism via CYP 3A4 / 2C9  DOA of active metabolites ~ 17-60 hrs Diazepam (Valium) Diazepam  Half-life (t ): 40-48 hrs (parent); 1/2  Metabolism via CYP 3A4 / 2C19  DOA of active metabolites (~100 hrs) Quazepam (Doral)  Onset of action ~ 2 hrs; t = 39 hrs (parent); 1/2  Metabolism via CYP 3A4 / 2C9  DOA of active metabolites ~ 40-73 hrs Quazepam Flurazepam (Dalmane)  Onset of action: 1-2 hrs; t = 2 hrs (parent); 1/2  active metabolites ~ 47-100 hrs  BENZODIAZEPIN ES  Metabolism: mostly CYP3A4 and UGT1- glucuronidation  Exceptions: lorazepam, oxazepam, temazepam  BDZ are not inducers of CYP3A4 like barbiturates  Renal elimination  Side effects:  Drowsiness, impaired psychomotor skills  hypotension, muscle relaxation, ataxia, amnesia  High doses: SOB  Drug-drug Interactions (DDIs):  Inhibitors / inducers of CYP3A4 (amiodarone; phenytoin)  Additive PD CNS depressants PHARMACOKINETICS: BDZ AND NEWER ‘Z’ AGENTS Dose (mg) 0.25 – 0.5; TID 5-10 / 20-25; TID 7.5 – 15; BID 2 – 10; TID 1 -3; QD (bedtime) 15 – 30; QD (bedtime) 2 – 3; BID/TID 10 – 30; TID 7.5 – 30; QD (bedtime) 0.25; QD (bedtime) 10 ; QD (bedtime) 5 – 10; QD (bedtime) Katzung; Table 22-1; modified Metabolism – Major Benzodiazepines  FLUMAZENIL (ROMAZICON)  Competitive BDZ antagonist (GABAA-R)  Rescue agent for high (over-) doses of Benzos  Does not reverse effects of: EtOH, Barbs, opioids, anesthetics  Short half-life (< 2hrs); IV injection (0.2mg/2mL);  Repeated doses may be required (maximum dose = 1mg)  Adverse effects:  Confusion, agitation, dizziness and nausea  Precipitation of withdrawal with physiological dependence on benzodiazepines  Treating benzodiazepines & tricyclic anti-depressants can precipitate seizures & arrhythmias  NOTE 10 IMPORTANT THINGS ABOUT BENZODIAZEPINE DRUGS 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.  RESOURCES 1. Chapter 7 in: Barrett KE, Barman SM, Brooks HL, Yuan JJ. Eds. Ganong's Review of Medical Physiology, (2019) 26e New York, NY: McGraw-Hill; http://accessmedicine.mhmedical.com 2. Basic & Clinical Pharmacology, 15th ed. (2021) by BG Katzung and TW Vanderah. McGraw-Hill Medical (accessed via AccessPharmacy) 3. Foye’s Principles of Medicinal Chemistry, 8th ed. (2020) by Victoria F. Roche, S. William Zito, Thomas L. Lemke, and David A. Williams. Lippincott Williams & Wilkins 4. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th ed. (2018) by L.L. Brunton, J.S. Lazo, and K.L. Parker. McGraw-Hill (accessed via AccessPharmacy)