Med Phys Pharm 551 L19 Neuropharm GABA 10-23-24 Lecture Notes PDF

Lecture #19: Neuropharmacology - GABA Julia Hum, PhD Primary Course Instructor Course Meets: Monday/Wednesday/Friday: 2:00-2:50pm Office Hours: Monday/Wednesday/Friday 11:00am-12:00pm (317B or WebEx)  L19 Learning Objectives 1. Kno...

Lecture #19: Neuropharmacology - GABA Julia Hum, PhD Primary Course Instructor Course Meets: Monday/Wednesday/Friday: 2:00-2:50pm Office Hours: Monday/Wednesday/Friday 11:00am-12:00pm (317B or WebEx)  L19 Learning Objectives 1. Know the two main classes of AA NTs and their mechanisms of neurotransmission 2. Understand the main steps of GABA metabolism 3. Describe how two different pharmacological agents inhibit GABA metabolism 4. Compare and contrast the types of GABA receptors 5. Describe the main pharmacological functions, therapeutic uses, and mechanisms of GABA receptor modulators Take Home Slide: GABAA Receptor Modulators Neurotransmitters of the CNS  Neurotransmitters of the CNS Inhibitory and excitatory NTs regulate almost every behavioral process Consciousness, sleep, learning, memory, and all sensations Pathologic processes: epilepsy and disease of neurotoxicity The two most important amino acid neurotransmitters in the CNS γ-aminobutyric acid (GABA) and glutamate ht tp:/ /clinicalgate.com/wp-conten t/u ploads/ 2015/06/ B9780443103216000072_f007-003-9780443103216.jpg LO1  Gabaergic and Glutamatergic Neurotransmission GABA Two main classes of neuroactive amino acids 1. GABA - major inhibitory Glutamate 2. Glutamate - primary excitatory AA NTs elicit inhibitory or excitatory responses by changing the conductance of ion-selective channels LO1  Gabaergic and Glutamatergic Neurotransmission Inhibitory neurotransmitters GABA Net outward current, hyperpolarizing the membrane Open K+ channels or Cl− channels to induce K+ efflux or Cl− influx Either type of ion movement results in membrane hyperpolarization Loss of intracellular cations Gain of intracellular anions Moving the membrane potential further below its threshold value and reducing the ability of inward currents to depolarize the membrane LO1  Gabaergic Neurotransmission GABA Pharmacologic agents that modulate GABAergic neurotransmission: Benzodiazepines Barbiturates Gabapentin Drug classes of major clinical importance LO1  Gabaergic Neurotransmission The cell membranes of most CNS neurons and astrocytes express GABA receptors Decrease neuronal excitability through several mechanisms Drugs that modulate GABA receptors affect: Arousal, attention, memory formation, anxiety, sleep, and muscle tone Modulation of GABA signaling is also an important mechanism for treatment of neuronal hyperactivity in epilepsy LO1  GABA Metabolism The synthesis of GABA is mediated by GAD Catalyzes the decarboxylation of glutamate to GABA Amount of GABA correlates with the amount of functional GAD GABA is packaged into presynaptic vesicles by a transporter (VGAT) Elevation of intracellular Ca2+ causes GABA to be released into the synaptic cleft LO2  GABA Metabolism Termination of GABA Neurons and glia take up GABA via specific GABA transporters (GATs) GABA-transaminase (GABA-T) catalyzes the conversion of GABA to succinic semialdehyde (SSA) GABA-T then regenerates glutamate from α-ketoglutarate LO2 https://i mag e.sli de share cdn.co m/ga bam odu la to rs-16 062 405 214 9/95 /gab a-mo dul ators-9-63 8.jp g?cb =14 667 457 38  Inhibitors of GABA Metabolism: Ti∙aga∙bine “GABA reuptake inhibitor” Tiagabine increases both synaptic and extrasynaptic GABA concentrations Result is nonspecific agonism of both GABA receptors http://www.nature.com/nrd/journal/v9/n1/images/nrd2997-f1.jpg major effects being at GABAA receptors LO3  Inhibitors of GABA Metabolism: Tiagabine Tiagabine is an oral medication Rapidly absorbed with 90% bioavailability and is highly bound to serum proteins Adverse effects: high GABA activity - http://www.nature.com/nrd/journal/v9/n1/images/nrd2997-f1.jpg LO3  Inhibitors of GABA Metabolism: Vi∙gaba∙trin Vigabatrin is a “suicide inhibitor” of GABA transaminase (GABA-T) Blocks the conversion of GABA to succinic semialdehyde Resulting in high intracellular GABA concentrations Increased synaptic GABA release htt p : / www.nature.c o m/ n r d/journal/v 9/n1/images/nr d 299 7-f1j. p g LO3  Inhibitors of GABA Metabolism: Vigabatrin Vigabatrin is used in the treatment of epilepsy Investigated for treatment of drug addiction, panic disorder, and obsessive-compulsive disorder Adverse effects of vigabatrin include drowsiness, confusion, and headache htt p : / www.nature.c o m/ n r d/journal/v 9/n1/images/nr d 299 7-f1j. p g LO3  GABA Receptors GABA mediates its neurophysiologic effects by binding to GABA receptors 1. Ionotropic GABA receptors (GABAA and GABAC) Multisubunit membrane proteins that bind GABA and open an intrinsic chloride ion channel 2. Metabotropic GABA receptors (GABAB) Heterodimeric GPCR that affect neuronal ion currents through second messengers LO3  Ionotropic GABA Receptor: GABAA Most abundant GABA receptors in the CNS Members of the superfamily of fast neurotransmitter-gated ion channels Receptors containing different subunit combinations distinct distributions at the cellular and tissue levels Most synaptic GABAA receptors consist of two α, two β, and one γ subunit LO3 https://up lo ad.wi kim edi a.org/wi kip edi a/co mmon s/th umb /4/45 /GABAA-rec eptor-pro tei n-ex ampl e.pn g/27 5px-GAB AA-rec eptor-pro tei n-ex ampl e.pn g  Ionotropic GABA Receptor: GABAA GABA bind to two sites Located in extracellular portions of the receptor- channel complex at the interface between the α and β subunits GABAA receptors also contain a number of modulatory sites Presence and the impact depend on the receptor subunit composition LO4 https://up lo ad.wi kim edi a.org/wi kip edi a/co mmon s/th umb /4/45 /GABAA-rec eptor-pro tei n-ex ampl e.pn g/27 5px-GAB AA-rec eptor-pro tei n-ex ampl e.pn g  Ionotropic GABA Receptor: GABAA Fast inhibitory postsynaptic currents (IPSCs) are responses activated by very brief (high- frequency) bursts of GABA release at synapses Uptake by GAT removes GABA from the synapse in less than 1 ms Prolonged occupation of the agonist sites by GABA also leads to GABAA receptor desensitization LO4  Ionotropic GABA Receptor: GABAA Inhibitory neurotransmitters Net outward current, hyperpolarizing the GABA membrane Open K+ channels or Cl− channels to induce K+ efflux or Cl− influx Either type of ion movement results in membrane hyperpolarization Loss of intracellular cations Gain of intracellular anions Reducing the likelihood that excitatory stimuli will initiate Moving the membrane potential further below its action potentials threshold value and reducing the ability of inward currents to depolarize the membrane LO4  Pharmacologic Classes and Agents Affecting Gabaergic Neurotransmission Therapeutic agents that activate GABAA receptors are used for: Sedation Antianxiety General anesthesia Neuroprotection following stroke or head trauma Control of epilepsy LO5  GABAA Receptor Modulators Ben∙zo∙di∙az∙e∙pines and bar∙bi∙tu∙rates are modulators of GABAA receptors that act at allosteric binding sites to enhance GABAergic neurotransmission Benzodiazepines have sedative, hypnotic, muscle relaxant, amnestic, and anxiolytic effects Barbiturates for control of epilepsy, general anesthetic agents, and for control of intracranial hypertension LO5  GABAA Receptor Modulators: Benzodiazepines Benzodiazepines are widely used anxiolytic drugs Replaced barbiturates treatment of anxiety and insomnia Benzos are generally considered to be safer and more effective LO5  GABAA Receptor Modulators: Benzodiazepines Mechanism of Action: Modulate GABA effects by binding to a distinct site from the GABA-binding site Benzodiazepines increase the frequency of channel openings produced by GABA LO5  GABAA Receptor Modulators: Benzodiazepines Actions: Reduction of anxiety: reduce anxiety by selectively enhancing GABAergic signaling Sedative/hypnotic: All benzos have sedative and calming properties At higher doses some can produce artificially sleep http: //www. inspirem ali bu. com/wp-conte nt/uploads/2015/10/popular -be nz odia ze pines. jpg LO5  GABAA Receptor Modulators: Benzodiazepines Actions: http: //www. inspirem ali bu. com/wp-conte nt/uploads/2015/10/popular -be nz odia ze pines. jpg Anticonvulsant: This effect is partially mediated by α1-GABAA receptors Muscle relaxant: At high doses - relax the spasticity of skeletal muscle by increasing presynaptic inhibition in the spinal cord where the α2-GABAA receptors are largely located https://up lo ad.wi kim edi a.org/wi kip edi a/co mmon s/th umb /4/45 /GABAA-rec eptor-pro tei n-ex ampl e.pn g/27 5px-GAB AA-rec eptor-pro tei n-ex ampl e.pn g LO5  GABAA Receptor Modulators: Benzodiazepines Therapeutic Uses: Anxiety disorders: Effective for the treatment of the anxiety symptoms generalized anxiety disorder (GAD) social anxiety disorder performance anxiety posttraumatic stress disorder obsessive–compulsive disorder extreme anxiety associated with phobias Useful in treating anxiety related to depression and schizophrenia Because of their addiction potential they should only be used for short LO5 periods of time  GABAA Receptor Modulators: Benzodiazepines Therapeutic Uses: Sleep disorders: A few of the benzos are useful as hypnotic agents These agents decrease the latency to sleep onset In the treatment of insomnia important to balance the sedative effect needed at bedtime with the residual sedation (“hangover”) upon awakening LO5  GABAA Receptor Modulators: Benzodiazepines Therapeutic Uses: Sleep disorders: Commonly prescribed benzos for sleep disorders: intermediate-acting te∙maz∙e∙pam short-acting tri∙azo∙lam Long-acting flur∙az∙e∙pam is rarely used extended half-life excessive daytime sedation and accumulation of the drug especially in the elderly LO5  GABAA Receptor Modulators: Benzodiazepines Therapeutic Uses: Temazepam: useful in patients with frequent wakening Intermediate-acting Peak sedative effect occurs 1 to 3 hours after an oral dose Given 1 to 2 hours before bedtime Triazolam: useful for insomnia short-acting triazolam is effective in treating individuals who have difficulty in going to sleep Hypnotics should be given for only a limited time (less than 2 to 4 wks) LO5  GABAA Receptor Modulators: Benzodiazepines Therapeutic Uses: Amnesia The shorter-acting agents Endoscopy, dental procedures, and angioplasty Cause a form of conscious sedation Mid∙az∙o∙lam used to facilitate amnesia while causing sedation prior to anesthesia Seizures Lor∙az∙e∙pam and di∙az∙e∙pam are the drugs of choice in terminating status epilepticus LO5  GABAA Receptor Modulators: Benzodiazepines Therapeutic Uses: Muscular disorders Diazepam is useful in the treatment of skeletal muscle spasms and strain Treating spasticity from degenerative disorders Multiple sclerosis Cerebral palsy LO5  GABAA Receptor Modulators: Benzodiazepines Pharmacokinetics Absorption and distribution The benzos are lipophilic Rapidly and completely absorbed after oral administration Distribute throughout the body and penetrate into the CNS LO5  GABAA Receptor Modulators: Barbiturates Formerly mainstay of treatment to sedate patients or to induce and maintain sleep Largely replaced by the benzos Because barbiturates induce tolerance and physical dependence Very severe withdrawal symptoms All barbiturates are controlled substances LO5  GABAA Receptor Modulators: Barbiturates Mechanism of action The sedative–hypnotic action of the barbiturates is due to their interaction with GABAA receptors They enhance GABAergic transmission Binding site of barbiturates on the GABA receptor is distinct from that of the benzodiazepines Prolong the duration of the chloride channel openings LO5  GABAA Receptor Modulators: Barbiturates GABA Mechanism of action Can block excitatory glutamate receptors Glutamate Anesthetic concentrations of pentobarbital also block high-frequency sodium channels All actions lead to decreased neuronal activity LO5  GABAA Receptor Modulators: Barbiturates Barbiturates are classified according to their duration of action Ultra–short-acting thiopental acts within seconds and has a duration of action of about 30 minutes Short-acting Pentobarbital duration of hours Long-acting phenobarbital has a duration of action greater than a day LO5  GABAA Receptor Modulators: Barbiturates Therapeutic uses Anesthesia The ultra–short-acting barbiturates (thiopental) have been used intravenously to induce anesthesia Anticonvulsant Phenobarbital has specific anticonvulsant activity that is distinguished from the nonspecific CNS depression Used in long-term management of seizures Phenobarbital can depress cognitive development in children and decrease cognitive performance in adults should be used only if other therapies have failed LO5  GABAA Receptor Modulators: Barbiturates Therapeutic uses Sedative/hypnotic Used as mild sedatives to relieve anxiety, nervous tension, and insomnia Hypnotics - suppress REM sleep more than other stages No longer generally accepted given their adverse effects and potential for tolerance LO5