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UCSD BIMM 118 - Lecture 14

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BIMM118Drugs Targeting the CNS• Hypnotics/Anxiolytics• Antidepressants• Neuroleptics• Parkinson• EpilepsyBIMM118Drugs Targeting the CNSNeurotransmitters in the CNS• Norepinephrine:– Excitory or inhibitory– Targeted by: MAO inhibitors (); tricyclic antidepressant (); amphetamines ()• Acetylcholine:– Excitory (M1; N) or inhibitory (M2)– Targeted by: M inhibitors (); Acetylcholine-esterase inhibitors ()• Glutamate:– Excitory– Targeted by: antiepileptics, ketamine, phencyclidine ()• GABA (γ-amino-butyric acid):– Inhibitory (increases gCl- and gK+, but not gNa+ => hyperpolarization (higher threshold foractivation– Targeted by: hypnotics, sedative, anti-epileptics ()• Dopamine:– Inhibitory– Targeted by: older neuroleptics (); anti-parkinson drugs, amphetamines ()• Serotonin:– Excitory or inhibitory– Targeted by: MAO inhibitors, SSRIs, Tricyclic antidepressants, hallucinogens ()BIMM118Drugs Targeting the CNSGlutamate• Excitatory amino acid:– Uniformly distributed throughout the brain– Mainly derived from glutamine or glucose– Stored in synaptic vesicles– Four distinct receptors exist -(NMDA receptor subtype most significant for drug action: needs to be“co-occupied” by glycine to become activated)– Termination mainly by re-uptake into nerve terminal and astrocytes– Astrocytes convert it to glutamine (lack activity) and return it to nerve cellsBIMM118Drugs Targeting the CNSGABA (γ-amino-butyric acid)• Inhibitory amino acid:– Only found in the brain– Mainly derived from glutamate via glutamic acid decarboxylase (GAD)– Stored in synaptic vesicles– Two distinct receptors exist - GABAA and GABAB(GABAA receptor subtype most significant for drug action: mostly post-synaptic:Cl- - influx hyperpolarizes the cell => inhibitory)– Termination mainly by deamination (GABA transaminase)BIMM118Drugs Targeting the CNSDopamine• Inhibitory amino acid:– Precursor to (nor)epinephrine– Termination mainly by reuptake (dopamine transporter - inhibited by Cocaine)and metabolism via MAOB and COMT– Two distinct receptor groups exist (coupled to heterotrimeric G proteins):D1-group (D1,D5: stimulate Adenylate cyclase: CNS, renal arteries)D2-group (D2,D3, D4: inhibit Adenylate cyclase: CNS)– Three main dopaminergic pathways:• Nigrostriatal (substantia nigra): motor control (Parkinson’s disease)• Mesolimbic/mesocortical: emotion and reward system• Tuberohypophysal: from hypothalamus to pituitary• (Medulla oblongata: Vomiting center: D2 receptors)– Schizophrenia: increased dopamine levels andD2 receptorsBIMM118Drugs Targeting the CNS5-Hydroxytryptamine (5-HT = Serotonin)• Excitatory or Inhibitory amino acid:– Generated from tryptophane– Termination mainly by reuptake and MAOB– Seven distinct receptor types exist (7-TM):5-HT1 group (CNS, blood vessels) (cAMP)5-HT2 group (CNS, blood vessels) (IP3/DAG)5-HT3 group (peripheral nervous system)5-HT4 group (enteric nervous system)– Main functions:• Intestine: increases motility• Blood vessel: constriction (large vessels) dilation (arterioles)• Nerve ending: triggers nociceptive receptors5-HT injection causes pain(5-HT found in nettle stings)• Neurons: excites some neurons, inhibits othersinhibition mostly presynaptic (inhibit transmitter release)LSD = agonist of 5-HT2A receptorBIMM118Drugs Targeting the CNSSites of drug action in the CNS:BIMM118Drugs Targeting the CNSAnxiety:Panic disorder (panic attacks) - rapid-onet attacks of extreme fear and feelings of heartpalpitations, choking and shortness of breath.Phobic anxiety is triggered by a particular object, for example; spiders,snakes, heights, or open spaces.Obsessive-compulsive disorder - uncontrollable recurring anxiety-producing thoughts anduncontrollable impulses (compulsive hand-washing, checking that doors are locked: “Monk”)Generalized anxiety disorder - extreme feeling of anxiety in the absenceof any clear causePost-traumatic stress disorder (PTSD) - recurrent recollections of atraumatic event of unusual clarity which produce intense psychological distress.BIMM118Hypnotics / AnxiolyticsBarbiturates– Derivatives of barbituric acid– Hypnotic/anxiolytic effect discovered in the early 20th century (Veronal®, 1903)– Until the 60s the largest group of hypnotics (more hypnotic than anxiolytic)– Act by both enhancing GABA responses and mimicking GABA (open Cl-channelsin the absence of GABA) => increased inhibition of the CNS (also blockglutamate receptors)– High risk of dependence (severe withdrawal symptoms)– Strong depressent activity on the CNS => anesthesia– At higher doses respiratory (inhibit hypoxic and CO2 response ofchemoreceptors) and cardiovascular depression =>very little use today as hypnotics (only for epilepsy and anesthesia)– Potent inducers of the P450 system in the liver => high risk of drug interactions(oral contraceptives)BIMM118Hypnotics / AnxiolyticsBarbituratesDifferent barbiturates vary mostly in their duration of action• Phenobarbital– Long-acting: used for anticonvulsive therapy• Thiopental– Very short acting (very lipophilic => redistributed from the brain into the fat tissue=> CNS concentration falls below effective levels: used for i.v. anesthesia• Amobarbital• Pentobarbital• SecobarbitalBIMM118Hypnotics / AnxiolyticsBenzodiazepines– Derivatives of Benzodiazepin– Valium (diazepam) in 1962– Characteristic seven-membered ring fused to aromatic ring– Selectively activates GABA receptor operatedchloride channels (bind to the benzodiazepinreceptor which is part of the GABA-receptor/chloride channel complex)– Increase the affinity of GABA for its receptor– Used to treat anxieties of all kinds (phobias,preoperative anxiety, myocardial infarction(prevent cardiac stress due to anxiety…)– Significantly fewer side effects than barbiturates=> much safer => more widespread use– Cause anterograde amnesia (usefulfor minor surgeries)BIMM118Hypnotics / AnxiolyticsBenzodiazepinesDifferent benzodiazepines vary mostly in their duration of action• Chlordiazepoxide (Librium®)– introduced in 1960, first benzodiazepine• Diazepam (Valium®), Clonazepam,– Strongly anticonvulsive => therapy of status epilepticus• Lorazepam• Flunitrazepam (Rohypnol®)– Known as “date-rape drug”, “roofie”– Color- and tasteless,– Disinhibiting effect (particularly with EtOH), amnesia !– Death


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UCSD BIMM 118 - Lecture 14

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