drugs.docx

Synthesis Receptor Vesicle Txp Reuptake Txp Auto receptor Clinical Drug GABA Most common (-) nt in CNS Presyn Glutamine Glutamate GBA All INHIBIT Depolarization of POSTsyn GABAA Ionotropic Cl- Channel GABAB Metabotropic GABA binds Opening K+ channel (K+ leaves) Inhibit volt gate Ca2+ cha...

Synthesis Receptor Vesicle Txp Reuptake Txp Auto receptor Clinical Drug GABA Most common (-) nt in CNS Presyn Glutamine Glutamate GBA All INHIBIT Depolarization of POSTsyn GABAA Ionotropic Cl- Channel GABAB Metabotropic GABA binds Opening K+ channel (K+ leaves) Inhibit volt gate Ca2+ channel = HYPERPOLARIZATION of postsyn membrane & REDUCE Ca2+ influx GABAC Ionotropic Cl- Channel GABAB R’s found on PRESYN terminals of MOTOR NEURONS GABA can bind GABAB on motor neuron Inhibiting Ach release GABAA Receptor Binding Sites Benzodiazepine site (agonist, antagonist, inverse agonist) Benzos Nonbenzos Barbiturate site (agonists) Barbiturates Etomidate (Anesthetic for conscious sedation IV) Etazolate General anesthetics Propofol Steroid Halothane Ethanol GABA site VGAT GAT Presyn term & Astrocyte Presyn terminal GABA either broken down or txp into vesicle Astrocyte GABA broken down to Glutamine (GABA Glutamate Glutamine) & txp back to neuron GABAB GABA binds K+ leaves lowers depol on presyn Iinhibit volt sens Ca2+ channels b/c they don’t see enuf volt change (lowers amt on Ca2+ coming in) Reduce GABA coming in GABAA Receptor Drugs Benzodiazepines Diazepam, Lorazepam, Alprazolam, Midazolam, Triazolam, Chlordiazepoxide Bind GABAA Benzo binding sites DON’T cause GABAA to open but instead potentiate opening of Cl- channel by increasing freq of opening when bound to GABA Long term use = downregulate GABAA Greatest danger = Seizure Benzo used to managing status epilepticus (<5 min seizure) Flunitrazepam (roofies, R2, forget me pill) Nonbenzodiazepines (Z Drugs) Zolpidem, Zaleplon, Eszopiclone Sleep problem. Nonbenzo have diff structure than benzos but interact w/ same GABAA binding site Advantage = shorter ½ life than benzos (less dependence) Barbiturates Phenobarbital, Sodium thiopental Bind GABAA R Potentiate GABA action by inc length of time GABAA R is open Depress some glutamate receptors Lower glutamate release & Inhibit some volt sens Ca2+ channels Barbiturates interact w/ = GABAA + Glutamate Receptors + Some volt sens Ca2+ Channels Barbiturate = DOSE DEPENDENT Low Dose Potentiate GABA effect on receptor (it won’t open receptor on its own, needs GABA) High Dose Open GABAA receptor on its own w/o GABA General Anesthetics (Gas) Sevoflurane, Desflurane, Isoflurane Anesthetics for conscious sedation (IV) Etomidate & Propofol Given w/ Midazolam (benzo) to relax pt & potentiate amnestic effect of sedation GABAB Receptor Drugs Baclofen Used to reduce m. spams Glycine Presyn Serine Glycine GlyR Ionotropic Cl- Channel VGAT (Same as GABA) Gly-T Presyn ENHANCE Gly release Tetanus Toxin V Clostridium tetani Take up by motor presyn terminal at NMJ Retrograde to SC or BS Taken up by INTERNEURONS (RENSHAW) that use Glycine*/GABA & blocks Gly & GABA release by interfering w/ v & t-SNARES Skeletal m. Tetany S Strychnine Rodent control poison Binds GlyR blocking f(x) (Gly antagonist) M. spasm & Tetany Acetylcholine Presyn Acetyl-CoA + Choline nACHR (Iono) (Na+ influx & K+ efflux) N1 (NMJ) N2 (PNS/CNS) mACHR (Metab) M1 Depol postsyn by closing K+ channels creating EPSP M1 found on ANS ganglia w/ n2ACHR M2 Cardiac & Smooth m. Inhibit smooth m. contraction M3 Smooth m. contraction M4 OPEN K+ channels & Inhibit volt sens Ca2+ channels M5 CNS & smooth m. of peripheral organ M2 M4 = OPEN K+ channels M1 M3 M5 = Close K+ channels VAChT Acetylcholinesterase Synaptic cleft Ach Acetyl Coa + Choline Choline reuptake into presyn & astrocyte Presyn mACHR INHIBIT Ach release if Synaptic cleft [Ach] gets too high VS nACHR ENHANCE Ach release Clostridium botulinum toxin Cleaves v & t-SNARES preventing Ach release = skeletal m. paralysis FOOD & Would Poisoning Botox tx Ophthalmology for eye strabismus Sarin Gas Inhibit Acetylcholinesterase Myasthenia gravis Autoimmune Ab atk nACHR = m. weakness Alpha-neurotoxin in snake venom Binds nACHR on skeletal m. = Block f(x) (nACHR antagonist) Skeletal m. weakness or paralysis Curare From bark.stems of South American plants nACHR antagonist Skeletal m. weakness or paralysis Anticholinergic drugs Atropine Antagonist to all 5 mACHR Used to dilate pupils. Major = M3 = m. contract Scopolamine Mostly M1 R Motion sickness Neuromuscular Blocking Agents (induce skeletal m. relax during surgery by competing w/ Ach at POSTSYNAPTIC mem) Succinylcholine nACHR AGONIST in NMJ 2 MOA Prolong AChR opening Inactivates Volt sens Na+ channel (some twitching/contraction) Bind R & keeps in deactivated state preventing depolarizations DEPOLARIZING NEUROMUSCULAR BLOCKING AGENT Paralytic during deep anesthesia for surgery Rocuronium nACHR ANTAGONIST in NMJ MOA Drug binds nACHR Prevents Ach from binding R No end plate potential Paralytic during deep anesthesia for surgery NONDEPOLARIZING NEUROMUSCULAR BLOCKING AGENT Glutamate Most common (+) nt in CNS GlnN Glu GABA 4 Receptors 3 = Direct gated (IONOTROPIC GLUTAMATE R) NMDA (GluN) Needs Gly + Glu to f(x) Mg2+ PLP & Zn binding sites NMDAR = specific type of IONOTROPIC Glu & gly receptor. NMDA (N-methyl D-aspartate) = selective AGONIST binds NMDA receptors but not other glutamate R NMDAR = Control synaptic plasticity & memory f(x) Nonselective to Ca2+ Na+ & K+ Unique NMDA Receptor = Voltage dep Activation Ion channel blocked by Mg2+ SO normal membrane potential GLU DOESN’T open channel BUT if depolarized by other ionotropic R’S Glu + Gly open NMDA R (Glu + Gly MUST be present) EPSP produced by NMDA R activation inc [Ca2+] in cell (Ca2+ f(x) as 2nd messenger) Ca2+ flux thru NMDAR’s = synaptic plasticity = Learning & Memory NMDA Need = Binding of PREsynaptic Glu & POSTsynaptic depol via AMPA Kianate (GluK) Na+ K+ & Ca2+ permeable Mostly presyn membrane Thus f(x) as AUTORECEPTOR High Glu when binding Kainate = Inhibit Glu release AMPA (GluA) Na+ & K+ permeable (NOT Ca2+) Kianate + AMPA = Major excitatory action of Glutamate on motor neurons Many cells have both NMDA & non-NMDA R’s, but since Mg2+ at physiological lvls blocks NMDA most EPSP = f(x) of non-NMDA R’s BUT the more neuron is depolarized by activation of non-NMDA R’s the more current flows thru NMDA receptors 1 = 2nd messenger mGluR (metabo) EPSP & IPSP Postsyn & Presyn membranes & Astrocytes VGLUT1 & VGLUT2 Txp Glut into vesicle EAAT PRE + POST syn + ASTROCYTE Astrocyte pick up Glu via EAAT2 Converts Glu to GluN GluN transporter releases GluN from astrocyte then takes it up into Presyn terminal GluN converted to Glu in presyn VGLUT1 & VGLUT2 PUT GLU INTO VESICLE COME BACK PAGE 36 & 37 Kianate (GluK) Mostly presyn membrane Thus f(x) as AUTORECEPTOR High Glu when binding Kainate = Inhibit Glu release MOA = Unknown, maybe involve 2nd messenger that lower Ca2+ current into presyn membrane Huntington’s Autosomal DOMINANT neurodegenerative Characterized by motor disturbances, cognitive decline, & neuropsychiatric symptoms, may. Involve excess NMDA receptors Resulting too much Ca2+ into neurons = Death NMDA over-activation may play role in Alzheimer’s. Beta-Amyloid & NMDA receptors interact = Lead to deleterious effects Phencyclidine (PCP) aka angel dust Inhibits NMDA R Ketamine 1st used as anesthetic during surgery NMDA R ANTAGONIST by binding PCP sites Interacts w/ many other NT receptors. Used w/ opioids as analgesic (pain control) Analog, Esketamine, used as rapidly acting anti-depressant Ketamine can induce euphoria, possibly by inhibiting dopamine reuptake Nitrous Oxide (laughing gas) Inhibits NMDA R Stimulates dopamine, opioid, & alpha 1 & 2 receptors Ethanol Inhibits Glu release by interfering w/ glutamate receptors & potentiates GABA by interfering w/ GABA_A receptor Serotonin (5HT) (5-hydroxytryptamine) Presyn Trptophan 5HT Many 5HT receptors. ALL = METABOTROPIC EXCEPT 5HT_3 5HT_3 Na+/K+ channel When 5HT binds 5HT_3 receptor Opens Na+ influx resulting in depolarization of postsyn membrane Some of the metab receptors are (+) some are (-) VMAT2 Txp ALL monoamines into vesicles VMAT1 Found outside CNS SERT Presyn & Astrocytes After reuptake, 5HT is either: Back into vesicle via VMAT2 Degraded by MAO-A (monoamine oxidase A) = MITOCHONDRIA OUTER MEMBRANE 5HT autoreceptors INHIBIT serotonin release if [] in synaptic cleft gets too high 5HT autoreceptors play role in 5HT release & may push against effect of any drug that inhibits reuptake of 5HT 90% of 5HT in GI Tract = Gut motility Serotonin Syndrome 3,4 Methylenedioxymethamphetamine (MDMA) aka Ecstasy Inc [5HT] via 2 Mechanisms Inhibit reuptake by blocking SERT High [MDA] = Reverse SERT & cause txp of 5HT out of presyn terminal MDMA raises [5HT] in cytosol of presyn terminal by 2 means: Inhibits txp of 5HT into vesicles (VMAT2) & inhibits MOA-A activity Inhibits NET & DAT SSRI Sertraline, Fluoxetine, Citalopram, Escitalopram, Paroxetine, Fluvoxamine Inhibit SERT = Inc [serotonin] in synaptic cleft Tricyclic antidepressant (TCA) Imipramine Inhibits SERT & NET NET = Transporter for norepinephrine reuptake Thus TCA elevate BOTH 5HT & Norepinephrine Serotonin & Norepinephrine reuptake inhibitors (SNRI) Venlafaxine Like TCA, they inhibit 5HT & Norepinephrine reuptake SNRI = More specific for 5HT & Norepi than TCA (b/c TCA block reuptake of other nt’s too) Monoamine oxidase inhibitors (MAOI) Selegiline Selective for MAO-B Thus Inc Dopamine Phenelzine Non-Selective MAOI Inc monoamine release by blocking monoamines that have undergone reuptake 2 Types of MAO’s MAO-A Higher affinity for 5HT & Norepi MAO-B Higher affinity for Dopamine Some MAOI’s are nonselective for A or B Thus affect 5HT, Norepi & Dopamine MAOI not often used Pt’s on MAOI have diet restrictions Avoid food w/ tyramine Yogurt, cheese, some meats B/C MAOI breakdown tyramine This AA when elevated can cause hypertension Atypical antidepressants Bupropion Block reuptake of: 5HT via SERT Norepi via NET Dopamine via DAT Trazodone Both Agonist & Antagonist of 5HT R’s Mild inhibit 5HT reuptake Alpha 2 antagonist reduce norepi activity Norepinephrine Presyn Tyrosine Dopa Dopamine Norepi 2 Classes of Receptors (Both Metabatropic) Alpha Alpha1 (+ or -) Alpha2 (-) Can f(x) as autoreceptors b/c localized on presyn membrane Beta Beta1 (Neuron & Astro) Mostly Neuron Cardiac m. Beta2 (Neuron & Astro) Mostly Astro Smooth m. (-) Lungs Beta3 White & Brown Adipocyte Alpha 1 & 2 & Beta 1 & 2 = Thru out CNS VMAT2 NET Presyn or Astrocyte After reuptake into neuron, is either: Txp back into vesicle via VMAT2 Degraded by MAO-A = Found on MITO OUTER MEMBRANE COMT Postsyn cell Degrades Norepi Norepi degraded in astrocyte by MAO-A & COMT Alpha2 F(x) as autoreceptors b/c localized on presyn membrane Inhibit Norepi release from presyn terminal Dopamine ALL METABATROPIC (D1 & D2 Like = Opposite Effects) D1-Like = INC cAMP & may STIMULATE neuron D1 D5 D2-Like = DEC cAMP & may INHIBIT neuron D3 D4 DAT Presyn & Astrocyte NET Some areas of brain reuptake Dopamine via NET Dopamine degraded in synaptic cleft by COMT Once taken up by presynaptic terminal it’s either: Put into vesicle via VMAT2 Broken down by MAO-B D2/D3 = Autoreceptors Inhibit Dopamine release Dopamine = Important in Movement Dopamine Loss = Parkinson’s Has 2 pharmacological approaches: Supply CNS w/ exogenous dopamine Use dopamine agonist Dopamine CAN’T cross BBB L-dopa CAN cross BBB L-dopa given orally to Parkinson’s pt’s Pramipexole & Ropinirole Are dopamine D2-like agonists for Parkinsons Entacapone & Tolcapone Inhibit COMT Thus inc dopamine Selegiline Specific for MAO-B (inhibiting it) Inc dopamine Drugs mentioned above given in combo. Also given w/ a decarboxylase inhibitor (carbidopa) to prevent L-dopa from being converted to dopamine in periphery keeping plasma L-dopa [] high Dopamine too high ADHD Additive behavior Anxiety Hallucinations Schizo Dipolar Cocaine Inhibits DAT, NET, & SERT Thus inc dopamine at synapse ALSO serotonin & norepi Antipsychotics (aka neuroleptics) Block D2-Like receptors Haloperidol & Chlorpromazine Side effect = Tardive Dyskinesia (TD) w/ a year of continuous neuroleptic use = NOT reversible Atypical antipsychotics (aka Atypical neuroleptics) Newer drug Have some D2-like antagonistic activity, but are more active on 5HT_2 receptor Fewer side effects (Lower risk for TD) Olanzapine + Clozapine Lysergic acid diethylamide (LSD) D2-Like agonist & many 5HTR agonist Hallucinations Reserpine Another drug for psychiatric disorder VMAT2 inhibitor Prevent dopamine into vesicle Lowering dopamine release Affects other monoamines too Amphetamines Raise monoamine lvls by several MOA DAT, SERT & NET transport amphetamines into presynaptic terminal thus competing w/ dopamine, 5HT & norepi Also block VMAT2 so free monoamines accumulates in presynaptic terminal Very high [monoamines] in presyn terminal DAT, SERT & NET export monoamines from presynaptic terminal (REVERSE TRANSPORT) Flooding surrounding fluid w/ them Neuropeptide nt’s Synthesized in neuronal SOMA To presynaptic terminal Neuropeptide nt Examples: Oxytocin Arginine vasopressin (AVP) (AKA ADH) Endorphins (Opioid) Enkephalin (opioid) ALL Oxytocin & Vasopressin receptors are METABOTROPIC Oxytocin Anxiolytic & Antidepressant effects Vasopressin Promotes anxiety & stress response All Opioid receptors are METABOTROPIC Opioids involved in pain modulation & pleasure/euphoria Pain modulation = 5HT & Opioid Pleasure/Euphoria via opioid = inhibit GABA release on dopaminergic neurons thus disinhibition (inhibiting the inhibitor) Inc dopamine release Many Opioid receptors in CNS Major opioid receptor = mu Opiates like morphine, heroin, oxycodone, & hydrocodone, & opioids like fentanyl all interact w/ mu receptor Naloxone SHORT acting mu ANTAGONIST Heroin & other opioid overdose Naltrexone LONG-acting mu ANTAGONIST Used to reduce alcohol cravings & prevent euphoria from opioids in pt’s attempting sobriety AVP Dimorphic effects (acts on sexes differently) More important in MALES than FEMALES Oxytocin & Vasopressin Pair bonds involve dopamine & opioids Ex = Praire volves (monogamous, social pair bonding. Meadow volves = Sexually promiscuous = Distribution of oxytocin & AVP receptors is different in brain reward centers Opiate defined as any drug derived from opium poppy