CNS Drugs Flashcards

Hierarchical Systems     Contraol major sensory and motor functions Excitatory NT  aspartate & glutamate Inhibitory NT  GABA & Glycine Drugs that act here have profound effect on overall excitability of CNS  Diffuse Systems    Often single cells that are distributed broadly (form synapses w/ many cells). NT  amines (norepinephrine, dopamine, serotonin) or peptides (substance P) Generally exert action metabotropic receptors. Drugs will have marked effect on attention, appetite, and emotional states.    GABA  Main NT in IPSPs in brain and also important in spinal cord. 2 types GABAA & GABAB Receptors. GABAA are inotropic receptors selectively permeable to Clo Selectively inhibited by Picrotoxin & Bicuculline  convulsions o Some anticonvulsants (gabpentin, tiagabine, vigabatrin) o Sedative-hypnotics (barbiturates, benzodiazepines, zolpidem) GABAB metabotropic receptors o Selectively activated by drug Baclofen (centrally acting muscle relaxant/antispastic) Glycine    Receptors mainly in the spinal cord. Inhibitory NT  ↑Cl- conductance. Blocked by strychnine (spinal convulsant)   Glutamate     Excitatory NT  high concentration in synaptic vesicles by vesicular glutamate transporter (VGLUT) N-methyl-D-aspartate(NMDA)  Ionotropic  Excitatory  ↑Ca2+ or cation perm. long term potentiation. Linked in learning and memory. May be responsible for cell death after neuronal injury. (phencyclidine[PCP] ketamine, & Memantine block) Act on Kainate (KA) receptors (hippocampus, cerebellum, spinal cord)  mediates fast depolarization. α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)  mediates fast depolarization Metabotropic subtypes either inhibitory presynaptically (↓Ca2+ perm. ↓cAMP) or excitatory postsynaptically (↓K+ perm. ↑IP3 & DAG) Toxicity  o o Dopamine o o o Exerts slow inhibitory actions @ synapses via G-protein copupled activation of K+ channels (postsynaptic) & inactivation of Ca++ (presynaptic). D2 receptor is main subtype in basal ganlia & also widely distributed at supraspinal level. D1 receptors inhibitory via ↑cAMP. Blocked by phenothiazines. Pathways  nigrostriatal, mesolimbic, & tuberoinfundibular tracts. Drugs  older antipsychotics, (chlorpromazine, haloperidol). ↑ dopaminergic activity (amphetamines), Antiparkinsonism drugs (levodopa)   Acetylcholine in CNS    Act on Motoneuron-Renshaw cell synapse in spinal cord, neurons in the neostriatum, medial septal nucleus, & reticular formation. Response via G-protein coupled muscarinic M1 (excitatory ↓ in K+ permeability; ↑IP3 & DAG) M2 (Inhibitory  ↑K+ permeability; ↓cAMP) nicotinic receptors (renshaw cell activation  excitatory ↑cation permeability). Drugs used in Alzheimer’s – anticholinesterases - (tacrine –list others) & Parkinson’s disease – muscarinic blocking agents – (atropine, benztropine, pirenzepine – list others).         Norepinephrine Located in brain stem & lateral tegmental area of pons  broadly spread neurons to most of CNS. Excitatory  activation α1 & β1 receptors. Inhibitory  activation of α2 & β2 receptors. Drugs  CNS stimulants (amphetamines, cocain) MAO inhibitors (phenelzine) & tricyclic antidepressants (amitriptyline). α1 (excitatory) agoinist – phenylephrine; antagonist – Prazosin α2 (inhibitory) agoinist – clonidine; antagonist - Yohimbine β1 (excitatory) agonist – dobutamine; antagonist- atenolol β2 (inhibitory) agoinst – albuterol; antagonist - atenolol       Serotonin Most originate from cell bodies in raphe or midline regions of pons & upper brain stem. Innervates most of CNS. All are meabotropic EXCEPT 5-HT3. 5-HT1A & GABAB share same K+ ch.(Inhibitory  ↑K+ perm. Partially activated by buspirone) 5-HT2A (excitatory  ↓K+ perm. ↑IP3 & DAG) bloced by clozapine, risperidone, and olanzapine. 5-HT3 (excitatory  ↑cation perm.) blocked by ondasetron 5-HT4 (excitatory  ↓K+ conductance; ↑cAMP)    Opioid Peptides    In cell bodies at all levels 3 subtypes mu, delta, kappa Inhibitory presynaptically ↓ Ca2+ perm. ↓cAMP or postsynatpically ↑K+ perm. ↓cAMP Morphine acts on many of these receptors Antagonist – Naloxone Differ in from other NT by 2 things: o Synthesized in cell body and transported to terminal. o No reuptake or enzyme degradation mechanisms. Histamine       Acts on Ventral posterior hypothalamus Regulates arousal, body temp, & vascular dynamics H1-4 H1 (excitatory) - Antagonist – Mepyramine H2 (excitatory) – Antagonist – Ranitidine H3 (inhibitory) Endocanaboids  CB1&2 receptors (inhibitory) – angagonist - rimonobant Benzodiazapines Fxn:Act on Midbrain, limbic system, Ascencding rreticular Activating system, brainstem cerebellum etc. Distributed widely in body Use: ADIAZAPEM  Alcohol withdrawl; Diagnostic & minor operative procedures, Insomnia(short term), Anticonvulsant(status epilepticus, tetanus, febrile convulsions), Preanaesthetic, Antianxiety, Muscle relaxant SE:Psychomotor dysfxn. Hangover  BZd metabolites long ½ life. Dependence. Overdosage  acute barbiturate poisoning (administer fluzenil – BZD antagoinist w/ high affinity for BZD binding site on GABAA receptor..) CI: Used cautiously in pts. w/ liver disease. Other: Anxiety relief: Diazepam, Lorazepam, alprazolam, Preoperative sedation: Diazapem, lorazepam, midazolam, triazolam. Acute Insomnia: temazepam, triazolam. Alcohol Withdrawl: Diazepam, lorazepam. Muscle Relaxant: Diazepam. Seizures: clonazepam, clorazepate, diazepam, lorazepam, midazolam. Panic Disorders & depression: alprazolam. Hypnotics Benzodiazapine Hypnotics  Diazepam  Flurazepam  Midzolam  Triazolam Nonbenzodiazepine hypnotics  Zopiclone – stimulate ω1 rreceptor – ↓REM sleep  REM sleep debt. ↓effects of anticonvulsants & muscle relaxants.  Zolpidem - stimulate ω1 receptor  doesn’t effect NREM or REM sleep while ↓latency of sleep. ↓anticonvulsant muscle relaxant effects. Reversible w/ Flumazenil.  Very habit forming  compulsive misuse of nearly all sedativehypnotics  all classified as Schedule III or IV drugs. Antianxiety     Diazepam Alprazolam  high efficacy Chlordiazepoxide  high efficacy Busiprone - - no sedation/cognitive impairment. Slow onset time (1-3weeks). 5-HT1A receptor partial agonist. Anticonvulsant     Diazepam Clonazepam Nitrazepam Phenobarbital Mimic GABA action       IV anesthetics (Alcohol; alphaxolone, etomidate, & propofol ) Volatile anesthetics (eg., halothane) Several anticonvulsants (eg, gabapentin, vigabatrin) Ivermectin (antihelmintic agent) Drugs that block the channel directly (picrotoxin) Drugs that interfere w/ GABA binding (bicucullin – anti convulsant) Stages of Anesthesia     1. Analgesia & amnesia 2. Excitement, delirium, combative behaviour 3. Unconsciousness, regular respiration, decreasing eye movements 4. Respiratory arrest, cardiac depression/arrest, no eye movements Fxn: Use: SE: CI: Other: